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WO2022194269A1 - Nouvel agent de dégradation de l'egfr - Google Patents

Nouvel agent de dégradation de l'egfr Download PDF

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Publication number
WO2022194269A1
WO2022194269A1 PCT/CN2022/081618 CN2022081618W WO2022194269A1 WO 2022194269 A1 WO2022194269 A1 WO 2022194269A1 CN 2022081618 W CN2022081618 W CN 2022081618W WO 2022194269 A1 WO2022194269 A1 WO 2022194269A1
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WO
WIPO (PCT)
Prior art keywords
amino
methyl
bifunctional compound
phenyl
mmol
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PCT/CN2022/081618
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English (en)
Chinese (zh)
Inventor
潘建峰
孙大庆
Original Assignee
上海齐鲁制药研究中心有限公司
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Priority to CN202280013925.2A priority Critical patent/CN116888108B/zh
Publication of WO2022194269A1 publication Critical patent/WO2022194269A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • 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
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a novel bifunctional compound capable of degrading EGFR, a pharmaceutical composition containing the compound, a preparation method thereof, and a method for treating EGFR-mediated cancer using the compound of the present invention.
  • PROTAC 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 (linker), and E3 ligase ligand (degron).
  • target protein ligand Linker
  • E3 ligase ligand degron
  • the protein of interest (POI) 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 A complex in which the E3 ligase mediates the ubiquitination of POIs by the ubiquitin-conjugating enzyme E2.
  • the ubiquitin-tagged POI is recognized and degraded by the proteasome.
  • PROTAC is an event-driven pharmacological mode of action. This process does not require the target protein ligand to occupy the binding site for a long time.
  • the ubiquitination of the target protein can be instantaneously completed only by the short-term formation of the ternary complex. Therefore, compared with traditional small molecule inhibitors and macromolecular antibodies, PROTAC has obvious advantages, and it is expected to target those proteins that are difficult to make medicines, and may have the advantages of small dosage, low toxicity, and no drug resistance. It relies on the advantages of affinity, high selectivity, and overcoming drug resistance caused by target protein mutation/overexpression.
  • EGFR epidermal growth factor receptor
  • epidermal growth factor receptor epidermal growth factor receptor
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation.
  • EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, EGFR has always been one of the most popular targets in pharmaceutical industry research.
  • the first generation is reversible targeted drugs, such as gefitinib, erlotinib, and icotinib.
  • the second generation is irreversible targeted drugs, such as afatinib and dacomitinib.
  • the first and second-generation targeted drugs are effective, most patients will develop drug resistance within 1-2 years of use.
  • 50% of the resistance is related to the T790M mutation.
  • the third-generation EGFR-targeted drug osimertinib can bind to the T790M mutation site of EGFR-sensitive mutation to inhibit tumor resistance caused by T790M mutation. Its advent has brought good survival benefits to more lung cancer patients .
  • resistance to third-generation EGFR inhibitors is inevitable due to the C797S mutation.
  • the present invention aims to develop a bifunctional small molecule that can specifically degrade EGFR protein. triplet compound.
  • the present invention provides a novel bifunctional compound that can be used to degrade EGFR, a pharmaceutical composition containing the compound, its preparation method and its use in the treatment of EGFR-mediated cancer.
  • the compound according to the present invention is a triplet compound comprising a targeting ligand, a linker and a degron, as shown in formula (X),
  • 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 the linking group between the targeting ligand and the degron , one end is covalently bound to the targeting ligand, and the other end is covalently bound to the degron;
  • the degron can bind ubiquitin ligases, such as E3 ubiquitin ligase, to covalently bind to the linker.
  • the present invention provides a bifunctional compound represented by formula (I) and stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopes thereof labelled derivatives,
  • Formula (TL) is a targeting ligand, which is covalently bound to the linker through the R 1 group, wherein,
  • R 1 is selected from or A optionally substituted with one or more R groups
  • A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7-membered heterocycloalkyl)-, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered heterocyclyl;
  • R 2 is selected from C 6-10 aryl, 5-12 membered heteroaryl, 5-6 membered heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 membered heteroaryl, 5-6 membered
  • the heterocycloalkenyl groups are each independently optionally substituted with one or more R 10 groups;
  • R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;
  • M is selected from N or CR 11 ;
  • R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;
  • R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl, halogen, C 3-6 cycloalkyl;
  • R 6 , R 7 and the atoms to which they are attached are cyclized to C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;
  • R 7 , R 8 and the atoms to which they are attached are cyclized together to form C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;
  • Each R 9 is independently selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ;
  • Each R 10 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl;
  • R 11 is selected from H, halogen, C 1-4 alkyl
  • R a is selected from H, C 1-4 alkyl
  • R b , R c , and R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;
  • the linker is the group covalently bound to the R1 group and the degron in the targeting ligand;
  • a degron is a group capable of binding to ubiquitin ligases.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization things of which,
  • R 1 is selected from or A optionally substituted with one or more R groups
  • A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7 membered heterocycloalkyl)-, 6-14 membered spiro heterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 membered heterocyclyl;
  • R 2 is selected from C 6-10 aryl, 5-12 membered heteroaryl, 5-6 membered heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 membered heteroaryl, 5-6 membered
  • the heterocycloalkenyl groups are each independently optionally substituted with one or more R 10 groups;
  • R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;
  • M is selected from N or CR 11 ;
  • R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;
  • R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl
  • R 6 , R 7 and the atoms to which they are attached are cyclized together to form C 4-6 cycloalkyl, 5-7 membered heteroaryl;
  • R 7 , R 8 and the atoms to which they are attached are cyclized together to form C 4-6 cycloalkyl, 5-7 membered heteroaryl;
  • Each R 9 is independently selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ;
  • Each R 10 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl;
  • R 11 is selected from H, halogen, C 1-4 alkyl
  • R a is selected from H, C 1-4 alkyl
  • R b , R c , and R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;
  • the linker is the group covalently bound to the R1 group and the degron in the targeting ligand;
  • a degron is a group capable of binding to ubiquitin ligases.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization things of which,
  • R 1 is selected from or A optionally substituted with one or more R groups
  • A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7 membered heterocycloalkyl)-, 6-14
  • R 2 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups are optionally substituted with one or more R 10 groups;
  • R 3 is selected from C 1-4 alkoxy
  • M is selected from CR 11 ;
  • R 4 is selected from H, halogen, C 1-4 alkyl
  • R 6 , R 7 and R 8 are each independently selected from H, C 1-4 alkyl
  • R 6 , R 7 and the atoms to which they are attached are cyclized together to form a 5-7 membered heteroaryl
  • each R 9 is independently selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl;
  • Each R 10 is independently selected from H, C 1-4 alkyl
  • R 11 is selected from H, halogen
  • R a is selected from H, C 1-4 alkyl
  • R b and R c are each independently selected from H, C 1-4 alkyl
  • the linker is the group covalently bound to the R1 group and the degron in the targeting ligand;
  • a degron is a group capable of binding to ubiquitin ligases.
  • A is selected from the group consisting of 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl-O-, 5-6 membered heterocycloalkyl-NR a- , -(5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-, 7-11 membered spiroheterocyclyl, 8-10 membered heterocyclyl.
  • A is selected from the group consisting of 5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl-O-, 5-6 membered azacycloalkyl-NR a- , -( 5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-, 7-11 membered spiroheterocyclyl, 8-10 membered azanocyclyl.
  • A is selected from 5-6 membered azacycloalkyl.
  • A is selected from 11-membered azaspirocyclyl.
  • A is selected from 8-membered azacyclocyclyl.
  • M is selected from CH.
  • M is selected from CF.
  • a above is selected from Ra is as defined above.
  • a above is selected from
  • a above is selected from
  • R 1 is selected from Ra is as defined above.
  • R 1 is selected from
  • R 1 is selected from
  • a above is selected from
  • R 1 is selected from
  • the above R 10 is selected from H, methyl, ethyl or difluoromethyl.
  • R 2 is selected from
  • R 2 is selected from
  • the above R3 is selected from methoxy.
  • R3 is selected from H, methyl, F.
  • the above R4 is selected from F, Cl, Br or methyl.
  • R4 is selected from Br.
  • R4 above is selected from H.
  • the above R4 is selected from trifluoromethyl.
  • R 5 is selected from
  • R 5 is selected from
  • R 6 , R 7 , R 8 are selected from H.
  • R 6 , R 7 , and R 8 are each independently selected from CH 3 , cyclopropyl, and fluorine.
  • R 6 and R 7 are selected from CH 3 .
  • R 6 is selected from H
  • R 7 is selected from CH 3 , cyclopropyl, and fluorine.
  • R6, R7 above, and the atoms to which they are attached are cyclized together to form a pyrazine ring.
  • R6, R7 above, and the atoms to which they are attached are cyclized together to form a pyridine ring.
  • the targeting ligand formula (TL) is selected from:
  • the targeting ligand is Covalently binds to the linker.
  • the targeting ligand formula (TL) is selected from:
  • the targeting ligand formula (TL) is selected from:
  • the targeting ligand formula (TL) is selected from:
  • the targeting ligand formula (TL) is selected from:
  • the above linker has the formula LA:
  • p 1 is selected from an integer of 0-6;
  • p 2 is selected from an integer of 0-6;
  • p 3 is selected from an integer of 0-6;
  • each Q is independently selected from a bond, CH2 , O, S, NH or NR12 ;
  • R 12 is selected from C 1-4 alkyl
  • the linker is covalently bound to R 1 in the targeting ligand (formula TL) through the U group, and the W group is covalently bound to the degron.
  • TL-LA is selected from:
  • TL represents targeting ligand, which does not belong to linker LA, but only represents the connection relationship between linker LA and targeting ligand; and formula TL has the above-mentioned definition.
  • TL-LA is selected from:
  • TL-LA is selected from:
  • the above linker has the formula LB:
  • p 1 is selected from an integer of 0-6;
  • p 2 is selected from an integer of 0-6;
  • p 3 is selected from an integer of 0-6,
  • p 4 is selected from an integer of 0-6;
  • p 5 is selected from an integer of 0-6 integer;
  • each Q is independently selected from a bond, CH2 , O, S, NH or NR13 ;
  • R 13 is selected from C 1-4 alkyl
  • Each Z 1 is independently selected from absent, phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, C 3- 6 -membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl are each independently optionally substituted with one or more R 14 groups; each R 14 is independently selected from halogen, C 1 -4 alkyl, hydroxyl;
  • each Z 1 is independently selected from a 7-11 membered azaspirocycle, wherein the 7-11 membered azaspirocycle is optionally substituted with one or more R 14 groups; each R 14 is independently selected from halogen, C 1-4 alkyl, hydroxyl;
  • the linker is covalently bound to R 1 in the targeting ligand through the U group, and the W group is covalently bound to the degron.
  • the above-mentioned linker LB is selected from:
  • p 1 , p 2 , p 3 , p 4 , U, W, and Z 1 are as defined above.
  • TL-LB is selected from:
  • TL represents a targeting ligand, which does not belong to the linker LB, but only represents the connection relationship between the linker LB and the targeting ligand; and the formula TL has the above-mentioned formula Definition.
  • TL-LB is selected from:
  • TL-LB is selected from:
  • TL-LB is selected from:
  • p 1 , p 3 , p 4 , and Z 1 are defined as described above.
  • TL-LB is selected from: Among them, p 1 , p 2 , and Z 1 are defined as above.
  • TL-LB is selected from:
  • TL-LB is selected from:
  • TL-LB is selected from
  • TL-LB is selected from
  • TL-LB is selected from
  • the degron is of formula D1
  • each R 15 is independently selected from C 1-4 alkyl
  • R 16 is selected from H, deuterium
  • each R 17 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy;
  • Y is a bond, O or NH; it is connected to the linker by a covalent bond;
  • n is selected from an integer from 0 to 3;
  • n is selected from an integer of 0-4.
  • Y in the degron D1 is selected from bond or NH.
  • Y in the degron D1 is selected from O.
  • the degron D1 is selected from:
  • the degron D1 is selected from:
  • the degron D1 is selected from:
  • the degron D1 is selected from:
  • the degron is of formula D2,
  • each R 15 is arbitrarily independently selected from C 1-4 alkyl
  • R 16 selected from H, deuterium
  • each R 17, optionally independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy;
  • Y' is a bond, O or NH, which is connected to the linker by a covalent bond
  • n is selected from an integer from 0 to 3;
  • n is selected from an integer of 0-4.
  • the degron D2 is selected from:
  • the degron is of formula D3,
  • R 18 is selected from H, C 1-4 alkyl
  • each R 19 is arbitrarily independently selected from C 1-4 alkyl
  • R 20 is selected from H, C 1-4 alkyl
  • q is an integer selected from 0-4;
  • R 18 in said degron D3 is selected from methyl.
  • R 20 in said degron D3 is selected from methyl.
  • the degron D3 is selected from:
  • the degron has the formula D3 ' ,
  • R 18a is selected from H, C 1-4 alkyl
  • Each R 19a is arbitrarily independently selected from C 1-4 alkyl, C 1-4 alkoxy;
  • R 20a and R 20b are independently selected from H, C 1-4 alkyl
  • R 20a is connected with R 20b , and cyclized to form C 3-6 cycloalkyl;
  • R 19a and R 20a or R 19a and R 20b are connected, and cyclized to form a 3-6 membered heterocycloalkyl
  • r is an integer selected from 0-4;
  • R 18a in said degron D3' is selected from methyl.
  • R 20a , R 20b in the degron D3' and the atoms to which they are attached are cyclized together to form a cyclopropyl group.
  • R 19a in the degron D3' is cyclized with R 20a and the atom to which it is attached, or R 19a is cyclized with R 20b and the atom to which it is attached to form tetrahydropyridine pyran ring.
  • the degron has formula D3', selected from:
  • the degron is of formula D4,
  • Y is a bond, or NH, which is covalently attached to the linker.
  • the degron D4 is selected from:
  • the degron is of formula D5,
  • M is selected from NH, O or S
  • V is a bond, NH or O, which is covalently attached to the linker
  • Each R is independently selected from halogen
  • S is selected from 0, 1, 2 or 3.
  • the degron D5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the degron D5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the degron D5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the degron D5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the degron D5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the degron is selected from
  • the degron is selected from
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization is selected from the following structures:
  • A, M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , Y, R 15 , n, linker, degron are as defined above.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization object selected from the following structures:
  • R 6 , R 7 , R 15 , Y, n, linker and degron are as defined above.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization substance selected from formula (Ic):
  • linker and degron are as defined above.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization thing selected from formula (Id):
  • linker and degron are as defined above.
  • the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization object selected from the following structures:
  • linker R 20 , Y, R 15 , and n are as defined above.
  • bifunctional compounds provided by the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates and isotopically labeled derivatives are selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned bifunctional compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, Isotopically labeled derivatives and pharmaceutically acceptable carriers.
  • compositions according to the present invention can be formulated for various conventional or specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like.
  • Dosage forms for oral administration such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, sprays dry dispersions), syrups and emulsions; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions ); nasal administration, for example to the nasal mucosa, by inhalation spray; topical administration, for example in the form of creams or ointments; rectal administration, for example in the form of suppositories.
  • the compounds according to the present invention may be administered alone, but will generally be administered with a pharmaceutical carrier selected
  • “Pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients depending on the mode of administration and the nature of the dosage form Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricants agent and dispersant.
  • excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricants agent and dispersant.
  • a pharmaceutically acceptable carrier can be selected and formulated in combination with a number of factors within the purview of one of ordinary skill in the art. It includes, but is not limited to: the type and nature of the active agent formulated, the subjects to whom the composition containing the agent is to be administered, the intended route of administration of the composition and the target therapeutic indication, and the like.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers may include many different ingredients and additives, and it is well known to those of ordinary skill in the art to include additional ingredients in formulations for a variety of reasons (eg, stabilizing the active agent, binders, etc.).
  • Dosage regimens for compounds of the present invention may, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient. , nature and extent of symptoms, types of coexisting treatments, frequency of treatments, route of administration, renal and hepatic function of the patient, and desired effects.
  • the therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the subject, the condition or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.
  • the present invention also provides the above-mentioned bifunctional compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the preparation of the above-mentioned pharmaceutical compositions Application in the treatment of cancer drugs.
  • Epidermal growth factor receptor EGFR epidermal growth factor receptor
  • EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation.
  • EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%.
  • the present invention also provides a method of treating cancer, comprising administering to a patient a therapeutically effective amount of the compound described above, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvent thereof compounds, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions.
  • the above cancers include lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, stomach cancer, uterus Endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple Myeloma, melanoma.
  • the present invention also provides the above-mentioned compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions in the preparation of treatment Applications in EGFR-related cancer drugs.
  • the above cancers include lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, stomach cancer, uterus Endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple Myeloma, melanoma.
  • the above cancer is lung cancer.
  • bifunctional compounds provided by the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions are used
  • cancers including lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia , gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, Mesothelioma, Multiple Myeloma, Melanoma.
  • cancers including lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer,
  • the above cancer is lung cancer.
  • the linker and the targeting ligand can be linked by chemical reaction first, and then the degron is added to prepare the triplet compound of the present invention; or as shown in the general scheme 2, the linker is first combined with The degrons are connected by chemical reaction, and then the targeting ligand is added to prepare the triplet compound of the present invention;
  • the two parts in the triplet compound when the two parts in the triplet compound are connected, the two parts may be prepared separately and then connected, or they may be connected first, and then the synthesis of each part is completed.
  • the targeting ligand is connected with the linker part. It can be that the prepared targeting ligand is connected to the linker, or a part of the targeting ligand is first connected to the linker, and after the connection is completed, the The preparation of the targeting ligand itself 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 nucleophilic substitution, condensation or coupling reactions.
  • triplet compound in the present invention can be prepared in the following manner:
  • the targeting ligand is connected to the linker, it is then connected to the degron to obtain:
  • targeting ligand, linker, degron are as defined above.
  • step 1 the carboxylic acid in the linker and the amino group in the degron undergo condensation reaction under the action of a condensation reagent to form an amide bond.
  • condensation reagents include but are not limited to 4-(4,6-dimethoxytriazine)- 4-Methylmorpholine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), etc.
  • DTMM dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide
  • step 2 the amino group in the targeting ligand attacks the LG group of the degron, and the LG leaves and undergoes a nucleophilic substitution reaction to prepare a triplet compound; wherein, LG represents a common leaving group, such as trifluoromethanesulfonic acid group, Methanesulfonic acid group, p-toluenesulfonic acid group, and halogen atoms such as fluorine, bromine, iodine, and chlorine.
  • LG represents a common leaving group, such as trifluoromethanesulfonic acid group, Methanesulfonic acid group, p-toluenesulfonic acid group, and halogen atoms such as fluorine, bromine, iodine, and chlorine.
  • base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate and the like.
  • Step 1 the amino group in the targeting ligand attacks the LG group in the linker, and the LG leaves to undergo a nucleophilic substitution reaction;
  • LG represents a common leaving group, such as trifluoromethanesulfonate, methanesulfonate, p-toluene Sulfonate and halogen atoms such as fluorine, bromine, iodine, chlorine;
  • PG in the linker represents a commonly used amino protecting group, including but not limited to tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, watmethoxycarbonyl, p- Methoxybenzyl, benzyl, trityl, etc.
  • step 2 the amino protecting group is generally removed under the action of acid, and commonly used acids include but are not limited to hydrochloric acid, formic acid, trifluoroacetic acid, hydrobromic acid and the like.
  • step 3 the amino group in the targeting ligand-linker attacks the LG group in the degron, and the LG leaves to undergo a nucleophilic substitution reaction to prepare a triplet compound.
  • LG represents a common leaving group such as triflate, methanesulfonate, p-toluenesulfonate, and halogen atoms such as fluorine, bromine, iodine, chlorine, and the like.
  • Steps 1 and 3 are usually carried out under the catalysis of bases, and commonly used base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate and the like.
  • step 1 under the action of a catalyst, the linker and the degron undergo a coupling reaction, and the commonly used catalyst is bis(triphenylphosphine) palladium(II), tetrakis(triphenylphosphine) palladium or [1, 1'-bis (diphenylphosphino) ferrocene] palladium dichloride and cuprous iodide, etc.
  • the commonly used catalyst is bis(triphenylphosphine) palladium(II), tetrakis(triphenylphosphine) palladium or [1, 1'-bis (diphenylphosphino) ferrocene] palladium dichloride and cuprous iodide, etc.
  • step 2 the hydroxyl group in step 2 is converted into an easily leaving group LG, and undergoes a nucleophilic substitution reaction with the amino group in the targeting ligand to generate a triplet compound.
  • targeting ligand used in the present invention, reference may be made to the targeting ligand in the preparation method of related compounds in CN112538072A, and the relevant content is incorporated into this application by reference.
  • the compound of the present invention has a good inhibitory effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR triple mutant cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line.
  • the compounds of the present invention can significantly induce the degradation of EGFR protein.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions or other problems or complications, with a reasonable benefit/risk ratio those compounds, materials, compositions and/or dosage forms.
  • salts refers to derivatives of compounds of the present invention prepared with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, purification of the compound, or the free form of the purified compound alone can be reacted with a suitable acid or base.
  • the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including alkali metal and alkaline earth metal based cations and non-toxic ammonium, quaternary ammonium and amine cations, Also contemplated are salts of amino acids and the like. When 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 compounds provided by the present invention also include the form of prodrugs, which represent compounds that are rapidly transformed in vivo to obtain the parent compound of the above formula, which can be converted into the compounds of the present invention by chemical or biochemical methods in an in vivo or in vitro environment, such as by means of blood of hydrolysis.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent in pharmaceutical effect to the unsolvated forms and are also encompassed within the scope of the present invention.
  • tautomers refers to a type of functional group isomer which has a different point of attachment by displacement of one or more double bonds, eg, a ketone and its enol form is a keto-enol tautomer.
  • the compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which belong to the present invention within the range.
  • tautomers refers to a type of functional group isomer which has a different point of attachment by displacement of one or more double bonds, eg, a ketone and its enol form is a keto-enol tautomer.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • cis-trans isomer refers to a configuration in which a double bond or a single bond of a ring-forming carbon atom cannot rotate freely and exists in a molecule.
  • Stereoisomers of the compounds of the present invention can be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • an enantiomer of a certain compound of the present invention can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology.
  • compounds with a single stereoconfiguration can be obtained from a mixture by chiral resolution techniques.
  • it can be prepared directly from chiral starting materials. Separation of optically pure compounds in the present invention is usually accomplished by preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.
  • optically pure or “enantiomerically enriched” means that the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95% or greater, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8 or greater %, or greater than or equal to 99.9%.
  • the absolute stereo configuration of a compound can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction method can also confirm the absolute configuration of the compound by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis.
  • the present invention also includes isotopically labeled derivatives. Including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, respectively , 35 S, 18 F and 36 Cl. Compounds of the present invention containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • prodrug, hydrate, solvate isotopically labeled derivative thereof suitable for use in A sufficient amount of the compound to treat the disorder with a reasonable effect/risk ratio for any medical treatment and/or prevention.
  • compounds represented by formula I of the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives and compositions The total daily dosage must be determined by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and Similar factors well known in the medical field. For example, it is the practice in the art to start with a dose of the compound below that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • the dosage of the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof for mammals, especially humans can range from 0.001 to 1000 mg/kg body weight/day, for example, from 0.01 to 100 mg/kg body weight/day. day, for example between 0.01-10 mg/kg body weight/day.
  • optionally substituted means that the term “optionally substituted” may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization, for example, the term “optionally substituted”"Optionally substituted with one or more R 0 " means that it may be substituted with one or more R 0 or not .
  • any variable eg, R 12
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two R 12 , with independent options for R 12 in each case.
  • n 0 indicates that the linking group is a single bond, ie -OCH 3 .
  • substituent R 12 can be substituted at any position on the benzene ring.
  • substituents When the listed substituents do not indicate through which atom they are attached to the general chemical structure, such substituents may be bonded through any of their atoms.
  • pyrazole as a substituent means that any carbon atom on the pyrazole ring is attached to the substituted group; when the structure appears or , indicating that the atom is a bonding atom, for example and Both indicate that the N atom on the morpholine ring is a bonding atom.
  • ring refers to saturated, partially saturated or unsaturated monocycles as well as polycycles, “polycycles” including spiro, paracyclic 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, the heteroatoms generally selected from N, O, S, the oxidized forms generally including NO, SO, S(O) 2 , the nitrogen atom may be is substituted, that is, NR (R is H or other substituents as defined in the text); the number of atoms on the ring is usually defined as the number of ring members, for example, "3-6 membered heterocycloalkyl” refers to 3-6 A ring of atoms arranged around each other, each ring optionally contains 1 to 3 heteroatoms, namely N, O, S, NO, SO, S(O) 2 or NR, and each ring is optionally surrounded by R group is substituted, and R is any substituent as defined in the present invention.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon group. Cycloalkyl is preferably 3-8 membered monocycloalkyl, more preferably 3-6 membered monocycloalkyl, examples of these monocycloalkyl include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl.
  • heterocycloalkyl refers to a monoheterocycloalkyl group containing a number of heteroatoms or heteroatomic groups in the ring, generally selected from N, O, S, NO, SO, S (O) 2 and NR.
  • Heterocycloalkyl is preferably 3-8 membered monoheterocycloalkyl, more preferably 3-6 membered monoheterocycloalkyl, examples of these monoheterocycloalkyl include, but are not limited to, oxiranyl, tetrahydropyrrolyl , piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.
  • spirocyclyl refers to a polycyclic system in which a single carbon atom (called a spiro atom) is shared between the single rings, and each single ring may contain a certain number of double bonds, and the spirocyclyl is preferably 5- 13 membered spirocyclyl, 6-12 membered spirocyclyl, or 7-11 membered spirocyclyl.
  • spirocyclyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl , spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro[5.5]tenyl Monoalkyl, spiro[5.6]dodecyl, spiro[6.6]tridecyl, spiro[6.7]tetradecyl.
  • “Spiroheterocyclyl” refers to a spirocyclyl in which one or more carbon atoms in the spirocyclic skeleton structure are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO , S(O) 2 , etc.
  • the spiroheterocyclic group is preferably a 5-13 membered spiroheterocyclic group, a 6-12 membered spiroheterocyclic group, a 7-11 membered spiroheterocyclic group and a 7-11 membered azaspirocyclic group.
  • spiroheterocyclyl groups include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl , 2-oxa-6-azaspiro[3.3]heptane-6-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 1,4,9-triaza Spiro[5.5]undecan-9-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2,6-diazaspiro[3.3]heptane-2-yl , 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-diazaspiro[5.3]nonyl, 3,9-diazaspiro[5.5]undecan-3- base, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa
  • bridged cyclyl refers to a polycyclic ring system that shares two non-directly linked carbon atoms, which system may contain a certain number of double bonds.
  • the bridged ring group is preferably a 4-13-membered bridged ring group, a 5-12-membered bridged ring group, a 6-12-membered bridged ring group, a 6-11-membered bridged ring group, and a 7-11-membered bridged ring group. Examples of bridged ring groups include, but are not limited to Wait.
  • Bridged heterocyclyl refers to a bridged ring radical in which one or more carbon atoms constituting the bridged ring skeleton are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO, S(O) 2 etc.
  • the bridged heterocyclic group is preferably a 4-13-membered bridged heterocyclic group, a 5-12-membered bridged heterocyclic group, a 6-12-membered bridged heterocyclic group, a 6-11-membered bridged heterocyclic group, and a 7-11-membered bridged heterocyclic group.
  • Examples of bridged heterocyclyl groups include, but are not limited to Wait.
  • paracyclic refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein each ring may contain a certain number of double bonds.
  • Said bacyl is preferably a 5-14 membered bacyl group, more preferably a 7-12 membered bacyl group, more preferably an 8-10 membered bacyl group, and examples of the bacyl group include but are not limited to Wait.
  • Parenterocycle refers to a para-cyclic group in which one or more carbon atoms constituting the para-ring skeleton are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO, S (O) 2 and so on.
  • Preferred are 5-14-membered no-heterocyclyl, more preferably 7-12-membered no-heterocyclyl, more preferably 8-10-membered no-heterocyclyl, more preferably 8-10-membered aza-heterocyclyl, examples of no-heterocyclyl including but not limited to Wait.
  • Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can all be condensed with a benzene ring to form a corresponding polycyclic structure.
  • structure in, “R 7 and R 8 can be cyclized to C 4-6 cycloalkyl” means that the structure can be Examples of “R 7 and R 8 can be cyclized into 4-6 membered heterocycloalkyl” include but are not limited to Examples of “R 7 and R 8 can be cyclized into a 5-7 membered heteroaryl group” include but are not limited to
  • aryl refers to a polyunsaturated, aromatic hydrocarbon group, which may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl. naphthyl.
  • heteroaryl means a stable monocyclic or polycyclic aryl containing at least one heteroatom or heteroatom group (N, O, S, NO, SO, S(O) 2 or NR) family group.
  • N O, S, NO, SO, S(O) 2 or NR
  • heteroatom or heteroatom group N, O, S, NO, SO, S(O) 2 or NR
  • 5-12 membered heteroaryl more preferably 5, 6, 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic heteroaryl; preferably containing carbon atoms and 1, 2, 3 or 4 independently Ring heteroatom selected from N, O and S.
  • heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, Pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolinyl, quinoxalinyl, quinolinyl.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group.
  • a C 1-6 alkyl group more preferably a C 1-3 alkyl group
  • examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl , isopentyl, neopentyl, n-hexyl, etc.
  • halogen refers to 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 groups are preferred, examples of haloalkyl groups include but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl base, 2,2,2 trichloroethyl, etc.
  • alkoxy refers to an alkyl group attached through an oxygen bridge, ie, a group obtained by substituting an alkyl group for a hydrogen atom in a hydroxyl group.
  • a C 1-6 alkoxy group is preferable, and a C 1-3 alkoxy group is more preferable.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentyloxy base, n-hexyloxy, etc.
  • cycloalkyloxy refers to a cycloalkyl group attached through an oxygen bridge, ie, a group resulting from the substitution of a cycloalkyl group for a hydrogen atom in a hydroxy group.
  • the cycloalkyloxy group is preferably a 3-7 membered, 4-7 membered, or 5-7 membered cycloalkoxy group.
  • Examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, and the like.
  • cycloalkenyl refers to a stable monocyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds in the ring.
  • examples of such cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and the like.
  • heterocycloalkenyl refers to a cycloalkenyl group containing 1-3 heteroatoms or groups of heteroatoms in the ring.
  • the nomenclature of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by synthesizing relevant information and reaction routes; if it cannot be confirmed by other methods, the given compound structural formula shall prevail.
  • the preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the charging ratio of the reactants, the reaction solvent, and the reaction temperature can be appropriately adjusted according to the different reactants.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured with a Bruker Avance III 400M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • LC-MS The determination of LC-MS was performed with a Shimadzu LCMS-2020 mass spectrometer (the ion source was electrospray ionization). The determination of HPLC used Shimadzu LCMS-20 high performance liquid chromatography.
  • Preparative high performance liquid chromatography used Waters 2767-2489 (Xbridge, C18, 10 ⁇ m, OBD 250 cm ⁇ 19 cm) or Waters 2767-2489 (Sunfire Prep, C18, 10 ⁇ m, OBD 250 cm ⁇ 19 cm).
  • the thin layer chromatography silica gel plate uses GF254 silica gel plate of Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate of Rushan Shangbang New Materials Co., Ltd.
  • the 200-300 mesh silica gel used in Cheng Chemical Industry Co., Ltd. is used as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 1 Dissolve quinoxalin-6-amine (5.0 g, 34.5 mmol) in acetic acid (150 mL) at room temperature, slowly add a solution of iodine chloride (6.1 g, 37.6 mmol) in acetic acid (55 mL) dropwise, under argon Stir at 20°C for 2 hours under atmosphere until the reaction is complete.
  • Step 2 5-Iodoquinoxalin-6-amine (6.0 g, 22.1 mmol), dimethylphosphine oxide (2.6 g, 33.2 mmol) and potassium phosphate (7.0 g, 33.2 mmol) were dissolved in N' at room temperature To N-dimethylformamide (100 mL) and water (20 mL), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.2 g, 2.2 mmol) and palladium acetate (494 mg) were added , 2.2 mmol). The reaction solution was heated to 120°C under an argon atmosphere and stirred for 24 hours until the reaction was complete. Cool to room temperature and concentrate under reduced pressure.
  • Step 3 Dissolve (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (1.0 g, 4.5 mmol) in ethanol (20 mL) at room temperature, add 5-bromo-2,4-dichloropyridine (2.0 g, 9.0 mmol) and N,N-diisopropylethylamine (3.5 g, 27.1 mmol). The reaction solution was heated to 120°C under argon protection and stirred for 72 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 4 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (5.0 g, 20.1 mmol) and tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol) were dissolved in To N'N-dimethylformamide (60 mL), potassium carbonate (8.3 g, 60.0 mmol) was added, and the temperature was raised to 60° C. and stirred overnight. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL ⁇ 3 times). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 5 4-(2-Bromo-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (3.0 g, 7.2 mmol) and 1-methyl-4 -1H-Pyrazole borate pinacol ester (2.25g, 10.8mmol) was dissolved in dioxane (60mL) and water (6mL), sodium carbonate (2.3g, 21.6mmol) and ferrocene dichloride were added Palladium (587.5 mg, 0.72 mmol). The reaction solution was heated to 105°C under an argon atmosphere and stirred overnight.
  • Step 6 To tert-butyl 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine-1-carboxylate ( To a solution of 1.9 g, 4.6 mmol) in methanol (2 mL) was added a solution of hydrochloric acid in dioxane (12 mL, 4 M). After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure to obtain 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride ( 1.4g, crude).
  • Step 7 Add 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride (1.0 g, crude , about 2.8 mmol) and methyl 6-bromohexanoate (0.6 mL, 3.8 mmol) in N'N-dimethylformamide (41 mL) was added cesium carbonate (3.5 g, 10.8 mmol). The reaction solution was stirred at room temperature for 18 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (150 mL ⁇ 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure.
  • Step 8 Addition of 6-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl) at room temperature
  • methyl hexanoate 927 mg, 2.1 mmol
  • methanol 20 mL
  • 10% palladium-carbon catalyst Pd/C 223 mg
  • Step 9 Addition of 6-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexyl at room temperature acid methyl ester (204 mg, 0.49 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (203 mg, 0.49 mmol) To a solution of isopropanol (8 mL) was added trifluoroacetic acid (0.36 mL, 4.9 mmol). The reaction solution was heated to 100°C and stirred for 36 hours.
  • Step 10 Addition of 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino at room temperature )-methyl 5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexanoate (200 mg, 0.25 mmol) in tetrahydrofuran (2 mL) Lithium hydroxide (32 mg, 0.75 mmol) was added to the mixed solution with water (1 mL).
  • reaction solution was stirred at room temperature for 2 hours, and the pH value of the reaction solution was adjusted to 5 with dilute hydrochloric acid, and the obtained mixture was directly purified by reverse-phase column chromatography to obtain 6-(4-(4-((5-bromo-4- ((5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piperazin-1-yl)hexanoic acid (111 mg, 57% yield).
  • Step 11 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexanoic acid (60 mg, 0.077 mmol), HATU (44 mg, 0.10 mmol) ) and triethylamine (23 mg, 0.11 mmol) were dissolved in N'N-dimethylformamide (4 mL), stirred at room temperature for 0.1 hour, and then added (2S,4R)-1-((S)-2-amino -3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide hydrochloride (34 mg, 0.077 mmol).
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 2 2,2,2-Trifluoro-1-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)piperazin-1-yl)ethan-1-one (2.0 g, 4.8 mmol) and 10% palladium on carbon (500 mg) were added to ethanol (30 mL), and the reaction was stirred at 55 °C under a hydrogen balloon atmosphere. 2 hours.
  • Step 3 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (1.0 g, 2.6 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl) Dimethylphosphine oxide (859 mg, 2.1 mmol) and trifluoroacetic acid (2.96 g, 26.0 mmol) were successively added to isopropanol (30 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours.
  • Step 4 1-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (2.5 g, 3.3 mmol) and potassium hydroxide (1.85 g, 33.0 mmol) were added to methanol (100 mL) and water (10 mL), and the temperature was raised to 60° C. and stirred for 5 hours.
  • reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated.
  • the organic phase was first washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain ((6-((5-bromo-2-((2-methoxy-5-( 1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyloxide Phosphine (1.5 g, 69% yield).
  • Step 5 5-Chloropentanoic acid (62 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, followed by HATU (172 mg, 0.45 mmol) and DIEA (135 mg, 1.05 mmol) After stirring for 30 minutes, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methyl) was added dropwise Thiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (150 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) and stirring was continued at room temperature for 3 hours.
  • Step 6 (2S,4R)-1-((S)-2-(5-chloropentamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4- (4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (125 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by sodium iodide (51 mg) , 0.34 mmol), DIEA (88 mg, 0.76 mmol) and ((6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)) -4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (151 mg, 0.23 mmol), the reaction was heated to 90 °C and stirred for 4 hours.
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Step 1 ((6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) and (2-(2-(2-(2-bromo) Ethoxy)ethoxy)ethoxy)ethyl)carbamate (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL) and DIEA (39 mg, 0.30 mmol) was added and catalytic amount of sodium iodide, the reaction system was heated to 85 ° C and stirred for 5 hours.
  • Step 2 To (2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethoxy)ethyl
  • 2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethoxy)ethyl To a solution of tert-butyl oxy)ethoxy)ethyl)carbamate (90 mg, ca. 0.096 mmol) in dichloromethane (2
  • Step 3 (6-((2-((4-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazine at room temperature -1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxaline- 5-yl) dimethylphosphine oxide hydrochloride (60 mg, about 0.072 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (20 mg, 0.72 mmol) was dissolved in DMSO (5 mL), DIEA (47 mg, 0.36 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 110 °C and stirred for 12 hours.
  • DMSO 5 mL
  • DIEA 47 mg, 0.36
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Step 1 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (400 mg, 1.04 mmol), (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide ( 331 mg, 0.92 mmol) and trifluoroacetic acid (296 mg, 2.6 mmol) were successively added to isopropanol (20 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 2 1-(4-(4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl at room temperature
  • Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluorothiophen-1-one (510 mg, 0.72 mmol ) and potassium hydroxide (403 mg, 7.2 mmol) were added to methanol (15 mL) and water (6 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours.
  • the reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • the LCMS monitoring reaction was basically completed, the reaction solution was filtered, and the filtrate was purified by high performance preparative liquid chromatography to obtain the final product 4-((15 -(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxopendecyl)amino)- 2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (42 mg, 16% yield).
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-hydroxypropoxy)ethyl)amino)isoindoline-1,
  • the 3-diketone 100 mg, 0.27 mmol
  • dichloromethane 5 mL
  • triethylamine 40 mg, 0.40 mmol
  • the temperature was lowered to 0°C
  • methanesulfonyl chloride 46 mg, 0.40 mmol
  • Step 2 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (48 mg, 0.073 mmol) and 3-(2-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propyl mesylate (50 mg, 0.11 mmol) was dissolved in N,N- To dimethylformamide (5 mL), DIEA (28.7 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 80°C and stirred overnight.
  • N,N- To dimethylformamide 5 mL
  • DIEA 28.7 mg, 0.22
  • Step 1 Combine 2-(piperidin-4-yl)ethyl acetate hydrochloride (500 mg, 2.4 mmol), 1-Boc-3-iodoazetidine (1.05 g, 3.6 mmol) and sodium iodide (36 mg, 0.24 mmol) was dissolved in acetonitrile (100 mL), potassium carbonate (1.0 g, 7.2 mmol) was added, and the reaction system was heated to 80° C. and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water (200 mL).
  • Step 2 Dissolve tert-butyl 3-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl)azetidine-1-carboxylate (240 mg, 0.74 mmol) In a solution of hydrogen chloride in dioxane (3M, 5 mL), it was stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain 190 mg of ethyl 2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl acetate hydrochloride.
  • Step 3 Combine 2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl acetate hydrochloride (250 mg, 0.95 mmol) and 2-(2,6-dioxo Piperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (263 mg, 0.95 mmol) was dissolved in acetonitrile (100 mL), N,N-diisopropylethylamine (245 mg) was added , 1.90 mmol), the reaction system was heated to 85 °C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water (200 mL).
  • Step 4 Convert 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclic Ethyl butan-3-yl)piperidin-4-yl)acetate (140 mg, 0.29 mmol) was dissolved in water (5 mL), cooled to 0°C, and concentrated sulfuric acid (1 mL) was slowly added dropwise. The reaction system was heated to 100°C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete.
  • Step 5 Convert 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclic Butan-3-yl)piperidin-4-yl)acetic acid (27.7 mg, 0.06 mmol) was dissolved in DMF (3 mL), followed by (6-((5-bromo-2-((2-methoxy -5-(1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) Dimethylphosphine oxide (33 mg, 0.05 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol) were stirred at room temperature for 2 hours.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)amino)isoindoline-1,3-dione (65mg, 0.18 mmol, prepared, see Journal of Medicinal Chemistry, 2020, 192, 112186) was dissolved in dichloromethane (10 mL) and triethylamine (27 mg, 0.27 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (31 mg, 0.27 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour.
  • Step 2 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (98 mg, 0.15 mmol) and 5-((2-(2,6-dioxo) Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (65 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL) and DIEA (48 mg, 0.15 mmol) was added.
  • Step 1 Dissolve 7-bromoheptanoic acid (210 mg, 1.0 mmol) in DMF (3 mL), add HATU (1.1 g, 3.0 mmol) and DIEA (387 mg, 3.0 mmol), stir at room temperature for 30 minutes, then dropwise Add (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methyl) Thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (444 mg, 1.0 mmol) in DMF (2 mL), and the reaction was stirred at room temperature for 1 hour.
  • Step 2 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (105 mg, 0.16 mmol) and (2S,4R)-1-((S)-2 -(7-Bromoheptanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) )ethyl)pyrrolidine-2-carboxamide (100 mg, 0.16 mmol) was dissolved in DMF (5 mL), DIEA (62 mg, 0.48 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80 °C and stirred overnight.
  • DMF
  • Step 1 9-Aminononan-1-ol (95 mg, 0.60 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-isoindoline-1,3-
  • the diketone 110 mg, 0.40 mmol
  • NMP 3 mL
  • N,N-diisopropylethylamine 0.1 mL
  • TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (10 mL).
  • Step 2 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl)amino)isoindoline-1,3-dione (80 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.04 mL) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (31 mg, 0.27 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete, and the reaction solution was poured into water (10 mL).
  • Step 3 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (52 mg, 0.08 mmol) and 9-((2-(2,6-dioxo) Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonylmethanesulfonate (55 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (0.04 mL) was added ) and a catalytic amount of sodium iodide, the reaction was heated to 80°C and stirred for 16 hours.
  • Step 1 Combine 9-bromo-1-nonanol (222 mg, 1.0 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-isoindoline-1,3-
  • the diketone (274 mg, 1.0 mmol) was dissolved in DMF (10 mL), sodium bicarbonate (168 mg, 2.0 mmol) was added, and the reaction system was warmed to 70° C. and stirred for 12 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (100 mL).
  • Example 24 gave the final product 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)nonyl)oxo)-2-( 2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg).
  • Step 1 3-(4-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.16 mmol), bis(triphenylphosphine)dichloride Palladium(II) (43 mg, 0.06 mmol) and cuprous iodide (17 mg, 0.09 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, then DIEA (216 mg, 1.7 mmol) and dec-9-yne were added -1-ol (213 mg, 1.4 mmol), the reaction system was warmed to 65°C and stirred for 16 hours.
  • Step 1 2-Aminoethan-1-ol (166 mg, 2.7 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-
  • the diketone 500 mg, 1.8 mmol
  • NMP 10 mL
  • N,N-diisopropylethylamine 351 mg, 2.7 mmol
  • TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (50 mL).
  • Step 1 (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (500 mg, 0.76 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (705 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (312 mg, 2.3 mmol) was added, and the reaction system was heated to 100° C. and stirred for 36 hours.
  • Step 2 Addition of 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) at room temperature -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate tert-butyl ester (460 mg, 0.54 mmol) A solution of hydrochloric acid in dioxane (10 mL, 4M) was added to a solution of dichloromethane (5 mL).
  • Step 3 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) pyridin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (68 mg, about 0.08 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (60 mg, 0.14 mmol) in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 85 °C and stirred for 12 hours.
  • Step 1 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine- 4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, 0.13 mmol) and 3-iodo Azetidine-1-carboxylate tert-butyl ester (209 mg, 0.74 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (102 mg, 0.74 mmol) was added, and the reaction system was heated to 100 °C and stirred for 5 days.
  • Step 2 3-(4-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1- tert-Butyl carboxylate (90 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes.
  • Step 3 (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)-2 -Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Phosphorus oxide trifluoroacetate (25mg, 0.03mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (25mg, 0.09 mmol) was dissolved in DMSO (5 mL), DIEA (12 mg, 0.09 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60°C and stirred overnight.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-
  • the diketone 100 mg, 0.27 mmol, see WO2018140809A1 for preparation
  • dichloromethane 5 mL
  • triethylamine 81.5 mg, 0.81 mmol
  • the temperature was lowered to 0°C
  • methanesulfonyl chloride 34 mg, 0.30 mmol was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete.
  • reaction solution was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL ⁇ 2 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) Perid-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (86 mg, about 0.10 mmol) and (1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methylmethanesulfonate (52 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL), DIEA (45 mg, 0.35 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 85°C and stirred for 12 hours.
  • acetonitrile 5 mL
  • Step 1 Addition of 9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[ 5.5] To a solution of tert-butyl undecane-3-carboxylate (346 mg, 0.71 mmol, see CN112538072A for preparation) in dichloromethane (2 mL) was added a solution of hydrochloric acid in dioxane (12 mL, 4 M).
  • Step 2 3-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[ 5.5]
  • Undecane hydrochloride (458mg, crude product) and DMAP (342mg, 2.8mmol) were added to dichloromethane (10mL), stirred for 5 minutes, then added trifluoroacetic anhydride (588mg, 2.8mmol), stirred at room temperature React for 2 hours.
  • Step 3 2,2,2-Trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one (382 mg, crude) and 10% palladium on carbon (50 mg) were added to methanol (15 mL), hydrogen After three replacements, the reaction was stirred at room temperature for 2 hours.
  • Step 4 1-(9-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazepine Spiro[5.5]undecan-3-yl)-2,2,2-trifluoroethane-1-one (371 mg, crude), (6-((5-bromo-2-chloropyrimidin-4-yl ) Amino)quinoxalin-5-yl)dimethylphosphine oxide (310mg, 0.75mmol) and trifluoroacetic acid (857mg, 7.5mmol) were added to isopropanol (10mL) successively, and the temperature was raised to 100 under argon protection.
  • Step 5 1-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 , 2,2-Trifluoroethyl-1-one (237 mg, 0.29 mmol) and potassium hydroxide (160 mg, 2.9 mmol) were added to methanol (10 mL) and water (4 mL), the temperature was raised to 60 °C and the reaction was stirred for 4 hours .
  • reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated.
  • the organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1 -Methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline Oxalin-5-yl)dimethylphosphine oxide (174 mg, 83% yield).
  • Step 6 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(3,9- Diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (54 mg, 0.074 mmol) and (1 -(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methylmethanesulfonate (50mg , 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (29 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 85 °C and stirred overnight.
  • acetonitrile 5 mL
  • DIEA 29
  • Step 1 Combine 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (250 mg, 1.0 mmol) and tert-hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid Butyl ester (233 mg, 1.1 mmol) was dissolved in N'N-dimethylformamide (10 mL), potassium carbonate (414 mg, 3.0 mmol) was added, and the temperature was raised to 60°C and stirred overnight. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3 times).
  • Step 2 5-(2-Bromo-5-methoxy-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (280mg , 0.63 mmol) and 1-methyl-4-1H-pyrazole boronate pinacol ester (197 mg, 0.95 mmol) were dissolved in dioxane (10 mL) and water (2 mL), potassium phosphate (267 mg, 1.26 mL) was added mmol) and ferrocene palladium dichloride (46 mg, 0.06 mmol). The reaction solution was heated to 110°C under an argon atmosphere and stirred for 12 hours.
  • reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by slurrying with ethyl acetate to give 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3, 4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (170 mg, 60% yield).
  • Step 3 Addition of 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c] at room temperature
  • a solution of tert-butyl pyrrole-2(1H)-carboxylate (170 mg, 0.38 mmol) in dichloromethane (2 mL) was added a solution of hydrochloric acid in dioxane (8 mL, 4 M).
  • Step 4 2-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)octahydropyrrole[3,4-c] Pyrrole hydrochloride (20 mg, about 0.046 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine Perid-4-yl)methylmethanesulfonate (36 mg, 0.08 mmol) was dissolved in acetonitrile (10 mL), DIEA (16 mg, 0.12 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 85° C.
  • Step 5 2-(2,6-dioxopiperidin-3-yl)-5-(4-((5-(5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 , 3-dione (21 mg, 0.03 mmol) and 10% palladium on carbon (10 mg) were added to tetrahydrofuran (6 mL), and the reaction was stirred at room temperature for 2 hours after hydrogen replacement for three times.
  • Step 6 5-(4-((5-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydropyrrole[ 3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dione (18 mg, 0.027 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (12 mg, 0.029 mmol) and trifluoroacetic acid (34 mg, 0.3 mmol) were successively added to isopropanol (4 mL), and the temperature was raised to 95° C.
  • Step 1 4-(Piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (2.0 g, 7.4 mmol), 1-bromo-2-fluoro-4-methoxy-5- Nitrobenzene (1.9 g, 7.4 mmol) was dissolved in DMF (50 mL) and potassium carbonate (2.1 g, 15.0 mmol) was added. The reaction was heated to 60°C and stirred overnight. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (250 mL), and extracted with ethyl acetate (200 mL ⁇ 2).
  • Step 2 4-(1-(2-Bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1.9 g, 3.8mmol) and 1-methyl-4-1H-pyrazole boronate pinacol ester (0.95g, 4.6mmol) were dissolved in dioxane (50mL) and water (10mL), potassium phosphate (1.6g, 7.6 mmol) and ferrocene palladium dichloride (0.28 g, 0.38 mmol), the reaction solution was heated to 110 °C under nitrogen atmosphere and stirred overnight.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)oxo)isoindoline-1,3-dione (16mg , 0.044 mmol, see CN112552293A for preparation) was dissolved in dichloromethane (10 mL), and DIEA (17 mg, 0.13 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (6 mg, 0.05 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 19 hours. TLC monitoring showed that the reaction was complete.
  • reaction solution was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL ⁇ 2 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) Peridin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (17 mg, about 0.02 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxo)pentylmethanesulfonate (10 mg, 0.023 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (10 mg, 0.072 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 90°C and stirred for 16 hours.
  • Step 1 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.5 g, 6.0 mmol), 2,6-dihydropyrrolo[3,4-c]pyrazole at room temperature tert-Butyl-5(4H)-carboxylate (1.3 g, 6.0 mmol) was dissolved in DMF (50 mL) and potassium carbonate (1.7 g, 12.0 mmol) was added. The reaction system was heated to 85°C and stirred for 18 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step 2 2-(2-Bromo-5-methoxy-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- tert-Butyl carboxylate (1.6 g, 3.6 mmol) and 1-methyl-4-1H-pyrazole boronic acid pinacol ester (0.76 g, 3.7 mmol) were dissolved in 1,4-dioxane (100 mL) and In water (20 mL), cesium carbonate (3.6 g, 10.9 mmol) and ferrocene palladium dichloride (0.27 g, 0.36 mmol) were added, and the reaction solution was heated to 110° C. under nitrogen atmosphere and stirred for 18 hours.
  • cesium carbonate 3.6 g, 10.9 mmol
  • ferrocene palladium dichloride 0.27 g, 0.36 mmol
  • Step 3 Addition of 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dihydropyrrolo[
  • tert-butyl 3,4-c]pyrazole-5(4H)-carboxylate 1. g, 3.1 mmol
  • dichloromethane 100 mL
  • trifluoroacetic acid 25 mL
  • Step 4 2-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,4,5,6-tetra Hydropyrrolo[3,4-c]pyrazole trifluoroacetate (1.1 g, crude) and DMAP (789 mg, 6.5 mmol) were added to dichloromethane (50 mL) and stirred for 5 min, followed by trifluoroethyl Acid anhydride (1.4 g, 6.5 mmol) was stirred at room temperature for 2 hours. It was quenched by adding water (100 mL) and extracted with dichloromethane (100 mL ⁇ 3 times).
  • Step 5 2,2,2-Trifluoro-1-(2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethan-1-one (1.1 g, 2.5 mmol) and 10% wet palladium on carbon (110 mg) It was added to a mixed solution of dichloromethane (25 mL) and methanol (25 mL), replaced by a hydrogen balloon three times, and stirred at room temperature for 2 hours.
  • Step 6 1-(2-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrole at room temperature [3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (960 mg, 2.4 mmol), (6-((5-bromo-2 -Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (975 mg, 2.4 mmol) and trifluoroacetic acid (2.7 g, 23.6 mmol) were added sequentially to n-butanol (25 mL) , the temperature was raised to 110 °C under argon protection and the reaction was stirred for 16 hours.
  • Step 7 1-(2-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H )-yl)-2,2,2-trifluoroethane-1-one (540 mg, 0.69 mmol) and potassium hydroxide (77 mg, 1.4 mmol) were added to methanol (10 mL) and water (5 mL), and the temperature was raised to The reaction was stirred at 60°C for 2 hours.
  • reaction solution was cooled to room temperature, most methanol was removed by rotary evaporation, and extracted with ethyl acetate (50 mL ⁇ 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((4-(5,6-dihydropyrrolo[3,4-c]pyridine) oxazol-2(4H)-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline- 5-yl)dimethylphosphine oxide (480 mg, crude).
  • Step 8 (6-((5-Bromo-2-((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (140 mg, about 0.20 mmol) and 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octylmethanesulfonate (98 mg, 0.20 mmol, see patent WO201889736A1 for preparation) was dissolved in acetonitrile (25 mL), DIEA (77 mg, 0.60 mmol) and a catalytic amount of sodium iodide were added, the reaction system was heated to 80° C.
  • Step 1 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (0.5 g, 1.3 mmol), (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide ( 375 mg, 1.2 mmol) and trifluoroacetic acid (1.35 g, 11.8 mmol) were successively added to isopropanol (20 mL), and the temperature was raised to 100 °C under argon protection, and the reaction was stirred for 16 hours.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by beating with ethyl acetate to obtain 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2, 2-Trifluoroethyl-1-one (480 mg, 60% yield).
  • Step 2 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl at room temperature
  • Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (430 mg, 0.65 mmol ) and potassium hydroxide (363 mg, 6.5 mmol) were added to methanol (10 mL) and water (4 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours.
  • the reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated.
  • the next step is (2-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 32 to obtain the final product 4-((5-(4-(4-(4-(4-(5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 , 3-diketone (20.2 mg).
  • Step 1 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (714 mg, 1.9 mmol), (2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, 1.7 mmol) and trifluoroacetic acid (1.94 g, 17.0 mmol) were successively added to isopropanol (50 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours.
  • Step 2 1-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (500 mg, 0.78 mmol) and potassium hydroxide (437 mg, 7.8 mmol) were added to methanol (50 mL) and water (20 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (50 mL), and separated.
  • Step 3 (2-((2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)benzene yl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (50 mg, 0.092 mmol) and 5-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (60 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and DIEA (35 mg, 0.27 mmol) were added.
  • acetonitrile 5 mL
  • DIEA 35 mg, 0.27 mmol
  • DIEA 35 mg, 0.27 mmol

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Abstract

L'invention concerne un nouveau composé bifonctionnel (I) capable de dégrader un EGFR, une composition pharmaceutique contenant le composé, un procédé de préparation et une méthode de traitement d'une maladie proliférative cellulaire, telle qu'un cancer, à l'aide du composé.
PCT/CN2022/081618 2021-03-19 2022-03-18 Nouvel agent de dégradation de l'egfr WO2022194269A1 (fr)

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WO2024083184A1 (fr) * 2022-10-20 2024-04-25 西藏海思科制药有限公司 Composition pharmaceutique comprenant un inhibiteur d'egfr
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2024235289A1 (fr) * 2023-05-17 2024-11-21 浙江同源康医药股份有限公司 Composé utilisé pour la dégradation de la protéine egfr et son utilisation
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EP4212522A4 (fr) * 2020-09-11 2024-12-04 J2H Biotech Inc. Composés destinés à éliminer le cancer mutant de l'egfr et leur utilisation pharmaceutique
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
CN116135852A (zh) * 2021-11-17 2023-05-19 浙江同源康医药股份有限公司 用于egfr蛋白降解的化合物及其用途
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WO2024083184A1 (fr) * 2022-10-20 2024-04-25 西藏海思科制药有限公司 Composition pharmaceutique comprenant un inhibiteur d'egfr
WO2024235289A1 (fr) * 2023-05-17 2024-11-21 浙江同源康医药股份有限公司 Composé utilisé pour la dégradation de la protéine egfr et son utilisation

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