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WO2024141052A1 - Modulateur du récepteur des œstrogènes et son utilisation - Google Patents

Modulateur du récepteur des œstrogènes et son utilisation Download PDF

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Publication number
WO2024141052A1
WO2024141052A1 PCT/CN2023/143411 CN2023143411W WO2024141052A1 WO 2024141052 A1 WO2024141052 A1 WO 2024141052A1 CN 2023143411 W CN2023143411 W CN 2023143411W WO 2024141052 A1 WO2024141052 A1 WO 2024141052A1
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alkyl
membered
alkoxy
halogenated
hydroxy
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Chinese (zh)
Inventor
吴勇
龚彦春
刘永强
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Jiangsu Vcare Pharmatech Co Ltd
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Jiangsu Vcare Pharmatech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • X1 is N or CR b1 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • the condition is that when Cy3 is hour, Not for
  • q is 0 or 1
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 , -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are each independently any integer from 0 to 6;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • X1 is N or CR b1 ;
  • X3 is N or CR b3 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group, wherein the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • q is 0 or 1
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 , -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are each independently any integer from 0 to 6;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X3 is N or CR b3 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • CR b1 , CR b2 , CR b3 , CR b4 and CR b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl , aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl ;
  • Cy5 is selected from 6-13 membered bicyclic fused cyclic groups and 8-21 membered polycyclic fused cyclic groups, wherein the 6-13 membered bicyclic fused cyclic groups and the 8-21 membered polycyclic fused cyclic groups are unsubstituted or optionally substituted with 1-3 R a5 ;
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, halogen, hydroxy, amino , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl;
  • q is 0 or 1
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl is unsubstituted or optionally substituted with one or more substituted or substituted radicals selected from
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X5 is N or CR b5 ;
  • Another embodiment of the present invention relates to a compound represented by formula (ii), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, methoxy, methyl, and ethyl;
  • L2 is selected from a bond, -NH-;
  • L4 is selected from -CH 2 -, -NH-CH 2 -, -C(O)-;
  • Cy4 is selected from
  • L5 is selected from a bond
  • L6 is selected from a bond, -O-;
  • Cy5 is selected from Said unsubstituted or optionally substituted with 1-3 Ra5 ;
  • Each R a5 is independently selected from hydroxyl, methyl, methoxy, phenyl,
  • the phenyl group is unsubstituted or substituted with one or more fluorine, methoxy, trifluoromethyl, replace.
  • Cy3 is selected from Said are unsubstituted or are each independently substituted with 1 to 3 Ra3 .
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by general formula (iii):
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl , C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl , ( C1-6 alkyl) 2aminocarbonyl ;
  • L1, L2, L3, L4, L5 and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 , -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl and C 2-8 alkynyl;
  • q is 0 or 1
  • n and m are each independently any integer from 0 to 6;
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl
  • X1 is N or CR b1 ;
  • X4 is N or CR b4 ;
  • CR b1 , CR b2 , CR b3 , CR b4 and CR b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl , aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl ;
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy;
  • L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;
  • q is 0 or 1
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 or 4-6 membered heterocyclyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy4 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 6-13 membered bicyclic spiroalkyl, 6-13 membered bicyclic spiroheterocyclyl, 4-6 membered cycloalkyl substituted by 1-3 R a4 , 4-6 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiroalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiroheterocyclyl substituted by 1-3 R a4 , and the heteroatom of the 4-6 membered heterocyclyl or 6-13 membered bicyclic spiroheterocyclyl is selected from O, N or S;
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, amino, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, 4-6 membered cycloalkyl or 4-6 membered heterocyclyl, wherein said C1-6 alkyl , halogenated C1-6 alkyl, C1-6 alkoxy, 4-6 membered cycloalkyl or 4-6 membered heterocyclyl is unsubstituted or optionally substituted with one or more groups selected from hydroxy, amino, halogen, C1-6 alkyl, C1-6 alkoxy, 4-6 membered cycloalkyl or 4-6 membered heterocyclyl;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • CR b1 , CR b2 , CR b3 , CR b4 and CR b5 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
  • Each R a5 is independently selected from hydroxy, amino, carboxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkoxy or aryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkoxy or aryl is unsubstituted or optionally substituted with one or more groups independently selected from hydroxy, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy or halo-substituted C 1-6 alkyl.
  • Step 1 Synthesis of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenol
  • A is CO2
  • B is IPA
  • Step 3 Preparation of (S)-3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (R)-3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-6 or I-7)
  • Step 1 Synthesis of tert-butyl 4-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)phenyl)piperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl)piperidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)piperidine-1-carboxylate
  • Example 8 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound II-2)
  • Step 2 Synthesis of 3-(1-oxo-5-(4-(piperazin-1-yl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride
  • Step 1 Synthesis of 3-(5-(4-(((1R,2R)-2-((9-(4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Step 1 Synthesis of 3-(5-(4-(((1S,2S)-2-((9-(4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Step 1 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)azetidin-3-yl)piperazin-1-yl)methyl)cyclohexane)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Example 25 Synthesis of 3-(4-((((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound I-23)
  • Step 1 Synthesis of 3-(5-(4-(4-(((1S,2S)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Example 27 Synthesis of 3-(5-(4-(4-(((1R,2R)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound I-25)
  • Step 1 Synthesis of 3-(5-(4-(4-(((1R,2R)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Example 28 Synthesis of 3-(5-(4-((1R, 2R)-2-((3-(4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-1-methyl)azetidin-1-alkyl)methyl)cyclohexyl)methyl)piperazine-1-phenyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (Compound I-26)
  • Tetraisopropyl titanate (0.5 mL) was added and the reaction was carried out at room temperature for 16 h.
  • Sodium cyanoborohydride (70 mg, 1.06 mmol) was added and the reaction was terminated for 1 h.
  • the mixture was quenched with water, filtered, concentrated, and purified by thick preparative plate (MeOH/DCM system) to obtain 147.8 mg of an off-white solid with a yield of 31.7%.
  • Example 29 Synthesis of 3-(5-(4-((1S, 2S)-2-((4-(4-)((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-1-methyl)cyclohexyl)methyl)piperazine-1-alkyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (Compound I-27)
  • Step 1 Synthesis of 3-(5-(4-((1S,2S)-2-((4-(4-)((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-1-methyl)cyclohexyl)methyl)piperazin-1-alkyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione
  • Tetraisopropyl titanate (0.6 mL) was added and reacted at room temperature for 16 h.
  • Sodium cyanoborohydride 60 mg, 0.82 mmol was added and the reaction was terminated for 1 h.
  • the mixture was quenched with water, filtered, concentrated, and purified by thick preparative plate (MeOH/DCM system) to obtain 5.8 mg of an off-white solid with a yield of 1.7 %.
  • Step 1 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(1-(4-((1R,2S)-6-hydroxy-)2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)isoindoline-1,3-dione
  • Step 1 Synthesis of 3-(5-(4-(((1S,2S)-2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)amino)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Example 33 Synthesis of 3-(5-(4-(((1R,2R)-2-(((S)-4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)-3-methylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound I-31)
  • Step 1 Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate
  • Step 1 Synthesis of 3-((4-(4-(((1R,2R)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione
  • Step 1 Synthesis of (1R,2R)-2-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)cyclohexane-1-carboxylic acid
  • the filtrate was filtered, water and ethyl acetate were added, the filtrate was separated, washed with water, dried, spin-dried and sanded, and column chromatography (MeOH/DCM system) was performed to obtain 0.30 g of a white solid with a yield of 81%.
  • Example 40 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)azetidin-3-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound I-38)
  • Step 6 Synthesis of 6-(4-methoxyphenyl)-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol
  • Step 7 (1R,2R)-2-((4-(6-hydroxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-ylmethyl)cyclohexane-1-carbaldehyde
  • Step 8 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(6-hydroxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-ylmethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione
  • Example 46 Synthesis of 3-(5-1-(1R,2R)-2-(4-(4-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-phenyl)piperazine-1-methyl)cyclohexylmethyl)piperidin-4-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (Compound I-44)
  • Step 1 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl(methyl)cyclohexyl)methyl)piperidin-4-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione
  • reaction was carried out under nitrogen protection at room temperature for 24 h, and NaBH(OAc) 3 (0.076 g, 0.36 mmol) was added.
  • the reaction was terminated under nitrogen protection at room temperature for 1 h.
  • the reaction solution was quenched, filtered, rinsed, combined, concentrated and purified by column chromatography (MeOH/DCM system) to obtain 3 mg of a white solid with a yield of 3.0%.
  • Step 2 Synthesis of tert-butyl 4-(4-(6-(benzyloxy)-2-(4-(trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(4-(6-hydroxy-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate
  • Step 4 5-(4-(piperazin-1-yl)phenyl)-6-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-hydroxy
  • Example 48 Synthesis of 1-(4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-2-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound I-46)
  • Step 2 Synthesis of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)-3-methoxyphenyl)piperazine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamido)-3-methoxyphenyl)piperazine-1-carboxylate
  • the mixture was quenched with water, extracted three times with 20 mL of DCM, and the organic phases were combined, spin-dried, and passed through a column with petroleum ether and ethyl acetate to obtain 280 mg of a light yellow solid.
  • Example 50 Synthesis of 1-(4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound I-48)
  • tert-butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate (10.0 g, 36 mmol) was added to a single-mouth bottle in sequence, and dissolved with DMF (100 mL), potassium carbonate (7.5 g, 54 mmol) and ethyl 3-bromopropionate (13.0 g, 72 mmol) were added, and reacted at 80 ° C for 19 h. Water was added to quench, and 40 mL DCM was extracted three times. The organic phases were combined, concentrated and purified by column chromatography (PE/EA system) to obtain 4.2 g of yellow oily product.
  • PE/EA system column chromatography
  • tert-butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamido)phenyl)piperidine-1-carboxylate (3.2 g, 11.1 mmol) was added to a single-mouth bottle in sequence and dissolved in toluene (60 mL), acetaldehyde oxime (1.85 g, 33.3 mmol) and indium chloride (4.8 g, 33.3 mmol) were added, and the mixture was reacted at 100°C for 1 h. The mixture was dried by rotation, concentrated and purified by column chromatography (PE/EA system) to obtain 1.2 g of a yellow oil.
  • PE/EA system column chromatography
  • Example 52 Synthesis of 1-(4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-2-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound I-50)
  • Step 2 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-[1,4'-bipiperidinyl]-1'-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • tert-butyl 4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-2-fluorophenyl)piperazine-1-carboxylate (4 g, 7.73 mmol) was added to a single-mouth bottle in sequence and dissolved in dioxane/water (60 mL/15 mL), and then phenylboric acid (1.13 g, 9.3 mmol), sodium carbonate (1.6 g, 15.4 mmol), Pd(dppf)Cl 2 (560 mg, 0.77 mmol) were added, and the reaction was terminated at 100°C for 2 h. The mixture was spin-dried and passed through a PE/EA column to obtain 3.5 g of a yellow oil.
  • Step 5 tert-Butyl 4-(2-fluoro-4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate
  • Step 7 (1R,2R)-2-(4-(2-fluoro-4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde
  • Step 8 3-(5-(4-(1R,2R)-2-(4-(2-fluoro-4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  • Step 1 1-(4-(1S,2S)-2-(4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 57 Synthesis of 1-(2-ethyl-4-(4-(1R,2R)-2-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound I-56)
  • tert-butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)-3-ethylphenyl)piperazine-1-carboxylate (6.1 g, 15 mmol) to a single-mouth bottle and dissolve it in toluene (50 mL), add sodium bicarbonate (2.5 g, 30 mmol) and cyanogen bromide (3.2 g, 30 mmol), and react at room temperature for 5 h. Filter, spin-dry the filtrate, and pass the PE/EA system through a column to obtain 4.7 g of a yellow oil.
  • tert-butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamido)-3-ethylphenyl)piperazine-1-carboxylate (4.7 g, 10.93 mmol) was added to a single-mouth bottle in sequence and dissolved in toluene (60 mL), and then acetaldehyde oxime (1.93 g, 32.79 mmol) and indium chloride (5.05 g, 32.79 mmol) were added, and the reaction was terminated at 100°C for 1 h. The mixture was directly spin-dried and passed through a PE/EA system column to obtain 2.5 g of a yellow oil.
  • Step 5 tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-ethylphenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-ethylphenyl)piperazine-1-carboxylate 500 mg, 1.24 mmol was added to a single-mouth bottle and dissolved in DCM (10 mL), and then 4.0 N hydrochloric acid dioxane solution (5 mL) was added, and the reaction was terminated at room temperature for 2 h. The mixture was spin-dried to obtain 450 mg of an off-white solid.
  • Step 7 1-(2-ethyl-4-(4-(1R,2R)-2-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • the reaction was carried out at room temperature for 19 h, and NaBH(OAc) 3 (120 mg, 0.58 mmol) was added. The reaction was terminated at room temperature for 2 h. Ice water was added to quench the reaction, and the mixture was filtered. The filtrate was spin-dried and purified by DCM/MeOH system to obtain 40 mg of a white solid.
  • tert-butyl 4-(4-nitronaphthalene-1-yl)piperazine-1-carboxylate (18.3 g, 51.2 mmol) was added to a single-mouth bottle in sequence and dissolved with MeOH/H 2 O (150 mL/50 mL), and then iron powder (14.3 g, 256 mmol) and ammonium chloride (13.7 g, 256 mmol) were added, and the reaction was terminated at 80°C for 2 h.
  • the filtrate was filtered, and the filtrate was dried by rotary evaporation. 13.0 g of brown solid was obtained by column chromatography with PE/EA system.
  • tert-butyl 4-(4-aminonaphthalene-1-yl)piperazine-1-carboxylate 13 g, 39.7 mmol was added to a single-mouth bottle and dissolved in DMF (100 mL), cesium carbonate (26 g, 79.4 mmol), ethyl 3-bromopropionate (14.4 g, 79.4 mmol) were added, and the mixture was reacted at 110°C for 3 h. The mixture was quenched with ice water, extracted with DCM three times, the organic phases were combined, washed with water twice, spin-dried, and passed through a PE/EA system column to obtain 8.7 g of brown oil.
  • Step 5 Synthesis of tert-butyl 4-(5-formylpyrimidin-2-yl)piperazine-1-carboxylate
  • Step 7 Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)bbbpiperazine-1-carboxylate
  • Step 8 Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride
  • tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (1.39 g, 7.80 mmol) was added and stirred at room temperature for 4 h. The mixture was concentrated to obtain 960 mg of a pale yellow solid crude product with a yield of 99%. The product was directly used for the next step without purification.
  • indole-3-acetone (18.85 g, 108.82 mmol), R(+)-alpha-methylbenzylamine (1.12 g, 3.12 mmol), and DCM (500 mL) were added to a single-mouth bottle in sequence.
  • the mixture was protected by nitrogen and reacted at room temperature for 1 h.
  • the temperature was lowered to 0-5 °C, and sodium triacetoxyborohydride (75.40 g, 355.76 mmol) was slowly added.
  • the mixture was kept warm for 1 h and then heated to room temperature for 12 h. After the reaction of the raw materials by TLC was completed, saturated NaHCO 3 (100 mL) was added and stirred for 15 min.

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Abstract

La présente invention appartient au domaine technique des médicaments, et concerne un modulateur du récepteur des œstrogènes et son utilisation. Plus particulièrement, la présente invention concerne un composé tel que représenté par la formule générale (i), un isomère ou un sel pharmaceutiquement acceptable de celui-ci et son utilisation, et en particulier l'utilisation en tant qu'agent de dégradation du récepteur des œstrogènes, l'utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies ou d'états médiés ou dépendants du récepteur des œstrogènes et l'utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention d'une maladie ou d'un état par dégradation d'une protéine cible.
PCT/CN2023/143411 2022-12-30 2023-12-29 Modulateur du récepteur des œstrogènes et son utilisation Ceased WO2024141052A1 (fr)

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WO2025119380A1 (fr) * 2023-12-08 2025-06-12 江苏威凯尔医药科技股份有限公司 Modulateur du récepteur des œstrogènes et son utilisation

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