[go: up one dir, main page]

WO2025051180A1 - Dérivé de lactame et son utilisation - Google Patents

Dérivé de lactame et son utilisation Download PDF

Info

Publication number
WO2025051180A1
WO2025051180A1 PCT/CN2024/117039 CN2024117039W WO2025051180A1 WO 2025051180 A1 WO2025051180 A1 WO 2025051180A1 CN 2024117039 W CN2024117039 W CN 2024117039W WO 2025051180 A1 WO2025051180 A1 WO 2025051180A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
membered
atoms
alkylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/117039
Other languages
English (en)
Chinese (zh)
Inventor
赵立文
邓新山
周刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Helioson Pharmaceutical Co Ltd
Original Assignee
Shanghai Helioson Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Helioson Pharmaceutical Co Ltd filed Critical Shanghai Helioson Pharmaceutical Co Ltd
Publication of WO2025051180A1 publication Critical patent/WO2025051180A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present application relates to the field of pharmaceutical chemistry, and in particular to a molecular glue degrading agent capable of degrading GSPT1 protein.
  • protac protein degradation targeted chimera
  • Protac protein degradation targeted chimera
  • the target protein is recruited to the vicinity of the E3 ubiquitin ligase to achieve ubiquitination and proteasome degradation of the target protein.
  • protac mediates the ubiquitination and continuous degradation of the target protein, and has more effective and lasting drug activity.
  • molecular weight of protac is generally large (over 700Da), and its water solubility and permeability are poor, which affects the permeability of physiological barriers and cell membranes.
  • molecular glue can recognize and degrade new substrates (Neo-substrate) by covalently modifying the surface of E3 ligase.
  • IMDs immunomodulators
  • pomalidomide generally have relatively small molecular weights and can inhibit the growth of multiple myeloma by binding to E3 ligase CRBN and ubiquitination and degradation of transcription factors IKZF1/3 (Kronke et al. Lenalidomide causes selective degradation of IKZF1and IKZF3 in multiple myeloma cells. Science 2014; 343: 301-305).
  • eRF3 (also known as GSPT1) is an important eukaryotic peptide chain release factor involved in the termination of intracellular protein synthesis.
  • eRF3 is located in region 13 of the long arm of human chromosome 16 and is encoded by the gene that regulates the transition from G1 to S phase of the cell cycle (GSPT1).
  • GSPT1 is a small GTPase that can bind to eRF1 to terminate protein translation when the stop codon binds to the A site of the ribosome (Le Goff et al. Mouse GSPT2, but not GSPT1, can substitute for yeast eRF3 in vivo. Genes Cells 2002; 7: 1043-57).
  • GSPT1 is highly expressed in many tumors such as gastric cancer, colon cancer, lung cancer and breast cancer (Nishiguchi et al. Identification of potent, selective, and generally bioavailable small-molecule GSPT1/2 degraders from a focused library of cereblon modulators. J Med Chem 2021; 64: 7296-7311).
  • GSPT1 is a protein essential for the survival of tumor cells. The loss of GSPT1 can lead to abnormal expression of key genes related to tumor cell proliferation, thereby inhibiting tumor growth.
  • multiple GSPT1 molecular glues such as CC-885 can induce ubiquitination and degradation of GSPT1 and inhibit the growth of hematological tumors and solid tumor cells (Hansen et al.
  • CC-92480 Discovery of CRBN ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J Med Chem 2022; 63: 6648-76).
  • CC-885 can simultaneously degrade the key proteins Ikaros and Aiolos, has strong toxicity, and has not been further developed.
  • CC-90009 is optimized from CC-885.
  • the results of a phase I clinical trial in patients with relapsed or refractory acute myeloid leukemia (R/R AML) showed that CC-90009 can produce G3/4 toxicity in 51% of patients, including side effects such as hypophosphatemia, hypotension, and sepsis (Uy et al.
  • the present application provides a compound represented by formula (I), a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof:
  • Ring A is selected from 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl or C 3 -C 10 carbocyclyl;
  • Ring C is selected from
  • X is selected from CR 10 or NR 10 ;
  • Ra and Rb are independently selected from H, deuterium, halogen, cyano, SF5 , -R8 - R9 , -O-( CH2 ) 2 -O-CH3, C1-C6 alkyl , C2 - C7 alkenyl, C2 - C7 alkynyl, C1-C6 alkoxy, C1 - C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1 - C6 alkylamino, C1 - C6 aminoalkyl, C1-C6 alkylacyl, C1 - C6 alkylcarbamoyl, C1-C6 alkylthio, C1 - C6 alkylsulfone, C3 - C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1-C6 alkyl, C2 - C
  • R c is independently selected from H or deuterium
  • L is selected from a chemical bond, a 4-10 membered heterocyclic group, -CR 2 R 3 -, -O-, -S- or -NR 4 -;
  • L 1 is selected from a chemical bond, -CR 2' R 3' -, -O-, -S- or -NR 4' -;
  • R 1 is selected from a chemical bond, -CR 5 R 6 -, -OCR 5 R 6 -, -SCR 5 R 6 -, -NCR 5 R 6 -, -O-, -S- or -NR 7 -;
  • R 2 , R 3 , R 4 , R 2' , R 3' , R 4' , R 5 , R 6 , and R 7 are each independently selected from H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 alkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylacyl, C 1 -C 6 alkylcarbamoyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfone, C 3 -C 8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy,
  • R 2 and R 3 together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocyclyl;
  • R 2 and Ra or R 4 and Ra together with ring A form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocyclyl;
  • R 5 or R 6 and R 2 or R 3 together with the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocyclyl;
  • R 5 and R 4 or R 6 and R 4 together with the atoms to which they are commonly attached form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocyclyl;
  • each R 2 , R 3 , R 4 , R 2' , R 3' , R 4' , R 5 , R 6 or R 7 may be the same or different;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group or -C(O);
  • R 9 is selected from H, halogen, cyano, SF 5 , —O—(CH 2 ) 2 —O—CH 3 , C 1 -C 6 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 alkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylacyl, C 1 -C 6 alkylcarbamoyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfone, C 3 -C 8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C 1 -C 6 alkyl, C 2 -C 7 alkenyl, C 2 -
  • R 10 is selected from H, deuterium or absent
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, 2, 3 or 4;
  • p is selected from 0, 1, 2, 3 or 4;
  • q is selected from 1 or 2.
  • the ring C is selected from represents a single bond or a double bond;
  • X is selected from CR 10 or NR 10 ;
  • R 10 is selected from H, deuterium or is absent; further preferably, ring C is selected from Preferably, X is selected from CH.
  • the ring C is
  • ring B is selected from a 6-12 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms, or S atoms; preferably, ring B is selected from a 6-10 membered aryl group, or a 5-6 membered heteroaryl group containing 1-2 heteroatoms selected from N atoms, O atoms, or S atoms; more preferably, ring B is selected from a benzene ring or pyridine, for example, ring B is a benzene ring.
  • L is selected from a chemical bond, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, -CR 2 R 3 -, -O-, -S- or -NR 4 -; preferably, L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR 2 R 3 - or -NR 4 -, R 2 and R 3 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl; more preferably, L is selected from -CH 2 -, azetidinyl.
  • R 1 is selected from a chemical bond, -CR 5 R 6 -, -O-, -S- or -NR 7 -, R 5 , R 6 , R 7 are each independently selected from H, halogen or C 1 -C 6 alkyl; preferably, R 1 is selected from -O-, -S- or -NR 7 -, R 7 is selected from H or C 1 -C 5 alkyl; more preferably, R 1 is selected from -O-, -S- or -NH- (for example, R 1 is -O- or -NH-).
  • L 1 is selected from a chemical bond, -CR 2' R 3' -, or -NR 4' -, R 2' , R 3' , R 4' are each independently selected from H, halogen, C 1 -C 6 alkyl; preferably, L 1 is selected from -NR 4' -, R 4' is H or C 1 -C 6 alkyl; more preferably, L 1 is -NH-.
  • R b is independently selected from H, deuterium, halogen, cyano, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 alkylamino, C 1 -C 6 aminoalkyl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 alky
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group or -C(O);
  • R 9 is selected from -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, 3-12 membered heterocyclyl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 1 -C 6 aminoalkyl, C 3 -C 8 cycloalkyl, 3-12 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino;
  • n is selected from 0, 1, 2, 3 or 4.
  • R b is independently selected from H, deuterium, halogen, cyano, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; the C 1 -C 6 alkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group or -C(O);
  • R 9 is selected from C 1 -C 6 alkoxy, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C 1 -C 6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkylamino;
  • n is selected from 1, 2, 3 or 4.
  • R b is independently selected from H, deuterium, halogen, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, the C 1 -C 6 alkoxy being unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group
  • R 9 is selected from C 1 -C 6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C 1 -C 6 alkoxy group is unsubstituted or substituted with C 1 -C 6 alkylamino, and the 4-8 membered heterocyclic group is unsubstituted or substituted with C 1 -C 6 alkyl;
  • n is selected from 1, 2 or 3.
  • R b is independently selected from halogen, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, the C 1 -C 6 alkoxy is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group
  • R 9 is selected from C 1 -C 6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, and the C 1 -C 6 alkoxy is unsubstituted or substituted by C 1 -C 6 alkylamino;
  • n is selected from 1, 2 or 3.
  • Ra is independently selected from H, deuterium, halogen, C1 - C6 alkyl; m is selected from 0, 1, 2 or 3.
  • Ring A is R a is independently selected from H, deuterium or halogen, m is 1, 2 or 3; or Ring A is m is 0.
  • ring A is Ra is independently selected from halogen, and m is 2.
  • ring A is m is 0.
  • R c is independently selected from H or deuterium, and p is selected from 0, 1 or 2. Preferably, p is 0.
  • the compound represented by the above general formula (I) its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, the compound has the structure shown below:
  • Ring A, Ring B, Ring C, L, R 1 , Ra , R b , R c , m, n, p and X in any of the above general formulae are as defined above.
  • the compound represented by the above general formula (I) has a structure represented by formula (II):
  • Ring A is selected from * indicates the site of connection with L;
  • Ring B is selected from 6-12 membered aryl or 5-10 membered heteroaryl; preferably, ring B is selected from benzene ring or pyridine;
  • Ra , Rb , X, L, L1 , R1 , m and n are as defined above.
  • ring A When ring A is selected from When n is selected from 1, 2, 3 or 4, at least one R b is selected from C 1 -C 6 haloalkoxy or SF 5 .
  • the compound represented by the above general formula (I) has a structure represented by formula (III):
  • R b2 is selected from C 1 -C 6 haloalkoxy or SF 5 ;
  • Rb1 is selected from H, halogen, cyano, SF5 , -R8 - R9 , -O-( CH2 ) 2 -O- CH3 , C1- C6 alkyl, C2- C7 alkenyl, C2 - C7 alkynyl, C1- C6 alkoxy, C1 -C6 haloalkoxy, C1 - C6 haloalkoxyalkyl, C1-C6 alkylamino, C1 - C6 aminoalkyl, C1 - C6 alkylacyl, C1-C6 alkylcarbamoyl , C1 -C6 alkylthiol, C1 - C6 alkylsulfone, C3 -C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1 - C6 alkyl, C2- C7 alkenyl
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group or -C(O);
  • R 9 is selected from H, halogen, cyano, SF 5 , —O—(CH 2 ) 2 —O—CH 3 , C 1 -C 6 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 alkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylacyl, C 1 -C 6 alkylcarbamoyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfone, C 3 -C 8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C 1 -C 6 alkyl, C 2 -C 7 alkenyl, C 2 -
  • n 1 is selected from 0, 1 or 2;
  • Ring A, Ring B, Ring C, Ra , Rc , L, L1 , R1 , m and p are as defined above.
  • Ring A is selected from a 6-10 membered aryl group, a 5-12 membered heteroaryl group, or a 5-12 membered heterocyclic group;
  • ring A is selected from * indicates the site of connection with L;
  • ring B is selected from a 6-12-membered aryl group or a 5-10-membered heteroaryl group; preferably, ring B is selected from a 6-10-membered aryl group or a 5-6-membered heteroaryl group.
  • the compound represented by the above general formula (III), its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, ring C is selected from
  • L is selected from -CR 2 R 3 - or a 4-6 membered heterocyclic group; R 2 and R 3 are independently selected from H or C 1 -C 6 alkyl.
  • the compound represented by the above formula (I) is selected from:
  • R 11 and R 12 are each independently H, deuterium, halogen or C 1 -C 6 alkyl, or R 11 and R 12 and the carbon atom to which they are attached together form a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms;
  • L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR 2 R 3 - or -NR 4 -;
  • R 2 and R 3 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl;
  • R 4 is selected from H, C 4 -C 6 cycloalkyl, or a 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms;
  • R 1 is selected from -O-, -S- or -NR 7 -;
  • R 7 is selected from H, halogen, or C 1 -C 6 alkyl
  • R b is independently selected from H, deuterium, halogen, cyano, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; the C 1 -C 6 alkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group or -C(O);
  • R 9 is selected from C 1 -C 6 alkoxy, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C 1 -C 6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkylamino;
  • n is selected from 1, 2, 3 or 4;
  • R 1 is selected from a chemical bond, -CR 5 R 6 -, -O-, -S- or -NR 7 -;
  • R 5 , R 6 , and R 7 are each independently selected from H or C 1 -C 6 alkyl
  • R b is selected from H, deuterium, halogen, cyano, SF 5 , C 1 -C 6 alkyl; the C 1 -C 6 alkyl is unsubstituted or substituted by halogen;
  • R b is selected from H, deuterium, halogen, cyano, SF 5 , and C 1 -C 6 alkyl; the C 1 -C 6 alkyl is unsubstituted or substituted with halogen.
  • R 11 and R 12 are each independently H, or R 11 and R 12 together with the carbon atom to which they are connected form a phenyl group;
  • L is selected from -CH 2 -, azetidinyl
  • R 1 is selected from -O-, -S- or -NH- (preferably -O- or -NH-);
  • R b is independently selected from H, deuterium, halogen, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, wherein the C 1 -C 6 alkoxy is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group
  • R 9 is selected from C 1 -C 6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C 1 -C 6 alkoxy group is unsubstituted or substituted with C 1 -C 6 alkylamino, and the 4-8 membered heterocyclic group is unsubstituted or substituted with C 1 -C 6 alkyl;
  • n is selected from 1, 2 or 3.
  • R 11 and R 12 together with the carbon atom to which they are attached form a phenyl group
  • L is selected from -CH 2 -, azetidinyl
  • R1 is selected from -O-, or -NH-;
  • R b is independently selected from halogen, SF 5 , -R 8 -R 9 , -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, wherein the C 1 -C 6 alkoxy is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino;
  • R 8 is selected from a chemical bond, a C 1 -C 3 alkylene group
  • R 9 is selected from C 1 -C 6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, and the C 1 -C 6 alkoxy is unsubstituted or substituted by C 1 -C 6 alkylamino;
  • n is selected from 1, 2 or 3.
  • the compound represented by the above formula (I) is the following compound:
  • L, R 1 , R b and n are as defined above; preferably, L is selected from -CH 2 -, azetidinyl; R 1 is selected from -O-, or -NH-; R b is independently selected from fluorine, chlorine, bromine, iodine, SF 5 , (C 1 -C 6 alkyl)-NH-(C 1 -C 6 alkoxy)-(C 1 -C 3 alkylene)-(e.g. CH 3 NH(CH 2 ) 2 -O-(CH 2 ) 2 -), (C 1 -C 6 alkyl)-NH-(C 1 -C 6 alkoxy)-(e.g.
  • the 5-7 membered heterocyclic group contains 1-2 heteroatoms selected from N atoms or O atoms; n is selected from 1, 2 or 3.
  • the compound represented by the above formula (I) is the following compound:
  • R 1 , R b and n are as defined above; preferably, R 1 is selected from —O—, or —NH—; R b is independently selected from fluorine, chlorine, bromine, SF 5 , CH 3 NH(CH 2 ) 2 —O—(CH 2 ) 2 —, CH 3 NH(CH 2 ) 2 —O—, -O-(CH 2 ) 2 -O-CH 3 , C 1 -C 6 alkyl (e.g. C 1 -C 5 alkyl, C 1 -C 4 alkyl or C 1 -C 3 alkyl), C 1 -C 6 fluoroalkoxy (e.g.
  • n is selected from 1, 2 or 3.
  • R b is independently selected from fluorine, chlorine, bromine, SF 5 , CH 3 NH(CH 2 ) 2 —O—(CH 2 ) 2 —, CH 3 NH(CH 2 ) 2 —O—, -O-(CH 2 ) 2 -O-CH 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, C 1 -C 3 fluoroalkoxy; n is selected from 1, 2 or 3.
  • the compound described in any one of the general formulas (I), (II), (III), deuterated products thereof, stereoisomers thereof, tautomers thereof, pharmaceutically acceptable salts thereof, or mixtures thereof has the structure shown below:
  • R b2 is selected from C 1 -C 6 haloalkoxy or SF 5 ;
  • R b2 is selected from SF 5 ; and the other variables are as defined in any of the above items.
  • the compound described in any one of the above, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, is characterized in that the compound is selected from but not limited to the following compounds:
  • Another aspect of the present application is to provide the use of any of the above-mentioned compounds, their deuterated substances, their stereoisomers, their tautomers, their pharmaceutically acceptable salts or their mixtures in the preparation of drugs for treating and/or preventing diseases related to GSPT1; preferably diseases related to GSPT1 dysfunction.
  • the present application relates to any of the above-mentioned compounds, their deuterated substances, their stereoisomers, their tautomers, their pharmaceutically acceptable salts or their mixtures for treating and/or preventing diseases related to GSPT1.
  • the present application relates to a method for treating and/or preventing diseases related to GSPT1 in a subject in need thereof, comprising administering to the subject a preventive and/or therapeutically effective amount of any of the above-mentioned compounds, their deuterated substances, their stereoisomers, their tautomers, their pharmaceutically acceptable salts or their mixtures.
  • the preventive and/or therapeutically effective amount refers to an amount sufficient to prevent, improve, inhibit, delay, slow down the progression of diseases related to GSPT1, which can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, gender, weight, etc.
  • diseases related to GSPT1 refer to diseases that can be alleviated, improved, stopped from progressing, reduced or not alleviated by degrading GSPT1.
  • the disease associated with GSPT1 is cancer.
  • the cancer comprises a solid tumor or a hematological malignancy.
  • the cancer is selected from, but not limited to, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, upper respiratory tract cancer, cervical cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, neuroblastoma, glioblastoma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, brain stem glioma, malignant brain tumor with poor prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal
  • substituted herein refers to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds. It should be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as needed to satisfy the valence of the atom.
  • the present application refers to the number of substituents, it means that the number of substituents on the group can range from 0 to the maximum possible number of substituents.
  • C m -C n in the present application means that the number of carbon atoms is at least m and at most n, including both endpoints m and n; m and n are integers not equal to 0, wherein m ⁇ n.
  • aryl used alone or in combination in this application refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs, including dicyclic and tricyclic) group with a conjugated ⁇ electron system.
  • fused polycyclics at least one ring is an aromatic ring, and the other rings may be aromatic rings, saturated or unsaturated carbon rings, such as aryl-aryl, aryl-carbocyclic, etc.
  • at least one of the points of connection to the parent must be on a carbon atom on the ring with a conjugated ⁇ electron system.
  • specific examples of 6-12-membered aryl include, but are not limited to:
  • heteroaryl in the present application refers to a monocyclic or polycyclic group (at least one of which is a heteroaromatic ring) with aromaticity containing one to multiple heteroatoms (preferably 1-3) selected from N, O or S, and at least one of the points of connection to the parent must be on the heteroaryl, for example: aryl-heteroaryl, heteroaryl-heteroaryl, heteroaryl-carbocyclic, heteroaryl-heterocyclic, etc.
  • specific examples of 5-10 membered heteroaryl include, but are not limited to:
  • 3-12 membered heterocyclic groups include, but are not limited to: wait.
  • carrier group in the present application refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group (including fused ring, bridged ring or spirocyclic system) consisting only of carbon atoms and hydrogen atoms, which can be connected to the rest of the parent through one or more single bonds via any suitable carbon atom.
  • C3 - C10 carbocyclic groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
  • the carbocyclic groups described herein include cycloalkyl and cycloalkenyl.
  • alkyl used herein, alone or in combination, refers to a straight or branched saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms.
  • alkyl groups the following straight or branched saturated hydrocarbon groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven other isomers thereof, n-hexyl and sixteen other isomers thereof.
  • C 1 -C 6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and all isomers thereof.
  • the alkyl group may be further substituted with a halogen to form a haloalkyl group, and specific non-limiting examples include, but are not limited to, -CF 3 , -CHCF 2 , -CH 2 CH 2 F, -CH 2 CF 3 .
  • alkoxy herein refers to an "-O-alkyl” group.
  • C 1 -C 6 alkoxy refers to a saturated, straight-chain or branched hydrocarbon moiety having at least 1 and at most 6 carbon atoms bonded by an oxygen linking atom.
  • Specific exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy, etc.
  • haloalkoxy refers to a carbon atom in an alkoxy group substituted by one or more substituents independently selected from F, Cl, and Br.
  • C1 - C6 haloalkoxy include, but are not limited to: -OCF3 , -OCHF2 , -OCH2F , -OCH2CF3 , -OCH( CH3 ) CF3 , and the like .
  • alkoxyalkyl herein refers to an alkyl group in which one or more hydrogen atoms are replaced by an alkoxy group (preferably a C 1 -C 3 alkoxy group), i.e., a group having a "-WOW" structure, wherein W is an alkyl group.
  • alkoxy group preferably a C 1 -C 3 alkoxy group
  • W is an alkyl group.
  • C 1 -C 6 alkoxyalkyl groups include, but are not limited to: -CH 2 -OCH 3 , -CH 2 CH 2 -OCH 3 , -CH 2 -OCH 2 CH 3 , and the like.
  • haloalkoxyalkyl herein refers to a carbon atom in an alkoxyalkyl group substituted by one or more substituents independently selected from F, Cl, and Br.
  • substituents independently selected from F, Cl, and Br.
  • specific non-limiting examples of C 1 -C 6 haloalkoxyalkyl groups include, but are not limited to: -CH 2 -OCF 3 , -CHF-OCH 3 , -CH 2 -OCH 2 CF 3 , and the like.
  • alkylamino herein refers to a group in which the H in -NH2 is replaced by an alkyl group, i.e., -NH-alkyl or -N-(alkyl)(alkyl).
  • C1 - C6 alkylamino means that one or two hydrogens in -NH2 are replaced by a branched or straight-chain alkyl group having 1 to 6 carbon atoms.
  • Specific non-limiting examples include, but are not limited to , -NHCH3 , -NHCH2CH3 , -N( CH3 ) CH3 , and the like.
  • aminoalkyl herein refers to a group in which at least one hydrogen atom of an alkyl group is substituted by an amino group.
  • C 1 -C 6 aminoalkyl refers to a group in which at least one hydrogen atom of a straight or branched chain alkyl group having 1 to 6 carbon atoms is substituted by -NH 2.
  • Non-limiting examples include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(CH 3 )CH 2 NH 2 , and the like.
  • specific non-limiting examples of C 1 -C 6 alkylacyl include, but are not limited to, formyl, acetyl, and the like.
  • alkylcarbamoyl herein refers to a group having a "-C(O)N(C 1 -C 6 alkyl) 2 structure.
  • alkylthiol herein refers to a group having a "-S-(C 1 -C 6 alkyl)” structure.
  • alkylsulfone herein refers to a group having a "-S(O) 2 -(C 1 -C 6 alkyl)” structure.
  • amino herein refers to a -NH 2 group.
  • hydroxyl herein refers to a -OH group.
  • thiol herein refers to a -SH group.
  • alkyl, cycloalkyl/carbocyclic group, heterocyclic group, aryl and heteroaryl groups may be unsubstituted or optionally substituted by one or more substituents, for example, substituted by the following substituents: alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, halogen, hydroxyl, alkoxy, cyano, nitro, amino, aminohydroxyl groups.
  • ⁇ may be optionally substituted by groups independently selected from C 1 -C 6 alkyl, haloalkyl, C 3 -C 6 cycloalkyl, halogen, hydroxyl, hydroxyl, alkoxy, cyano, amino, aryl, heteroaryl groups, and specific examples include but are not limited to methyl, ethyl, propyl, F, Cl, trifluoromethyl, cyclopropyl, methoxy, phenyl, naphthyl, pyridyl, pyrazinyl, etc.
  • groups independently selected from C 1 -C 6 alkyl, haloalkyl, C 3 -C 6 cycloalkyl, halogen, hydroxyl, hydroxyl, alkoxy, cyano, amino, aryl, heteroaryl groups, and specific examples include but are not limited to methyl, ethyl, propyl, F, Cl, trifluoromethyl, cyclopropyl, methoxy,
  • the compounds of the present application contain one or more asymmetric centers (also called chiral centers), and the compounds and intermediates of the present application can exist in different tautomeric forms, all of which are included in the protection scope of the present application.
  • the present application includes all isomers (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)) of the structure.
  • stereoisomer refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light;
  • tautomer refers to structural isomers with different energies that can be interconverted through a low energy barrier.
  • proton tautomers include (but are not limited to) interconversions via proton migration, such as keto- Enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc.
  • the compounds of the present application may contain one or more isotopic forms, i.e., hydrogen isotopic forms of D or T, or isotopes of any atoms, such as all isotopic forms of C and N. All isotopic forms of any C, N or H in the compounds of the optional structures of the present application are included in the protection scope of the present application.
  • the solution mentioned in the reaction of the present application is an aqueous solution.
  • room temperature in the present application refers to a temperature between 10°C and 25°C.
  • the filter cake was washed with a saturated aqueous solution of sodium bicarbonate and water in sequence, filtered, and dried to remove most of the water to obtain a light yellow solid.
  • the solid was dissolved in ethanol (50 mL) and water (60 mL), stirred at room temperature, and a 1.5 M aqueous solution of sodium hydroxide (33 mL) was slowly added.
  • the reaction temperature was raised to 90°C, refluxed and stirred for 3 hours, and the mixture was stirred at room temperature.
  • Step 3 3-(4-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1-5)
  • Step 4 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-4-carboxylic acid (1-6)
  • Step 5 3-(4-(Hydroxymethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1-7)
  • Step 6 (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-chloro-4-methylphenyl)carbamate
  • Step 6 (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (Example 2)
  • the target compound was prepared by a synthetic method similar to that of Example 2 to obtain a yellow product (30.0 mg, HPLC purity: 99.6%, yield 42%).
  • the target compound was prepared by a synthetic method similar to that of Example 2 to obtain a yellow solid product (1.47 mg, HPLC purity: 96.28%, yield 6.9%).
  • the target compound was prepared by a synthetic method similar to that of Example 2 to obtain a yellow solid product (6.0 mg, HPLC purity: 92.8%, yield 79%).
  • the target compound was prepared by a synthetic method similar to that of Example 2 to obtain a yellow solid product (6.80 mg, HPLC purity: 99.5%, yield 72%).
  • Step 2 (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindol-5-yl)methyl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • Step 3 (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • Step 4 (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • a white solid target product (126 mg, HPLC purity: 98.1%, yield 69.6%) was obtained by a preparation method similar to Example 7.
  • MS: m/z [M+1] + 520.1; 1 H NMR (400 MHz, DMSO) ⁇ 11.01 (s, 1H), 10.35 (s, 1H), 7.85–7.82 (m, 3H), 7.71-7.64 (m, 4H), 5.31 (s, 2H), 5.15-5.11 (m, 1H), 4,50-4.32 (m, 2H), 2.97–2.86 (m, 1H), 2.68–2.59 (m, 1H), 2.43-2.38 (m, 1H), 2.04-1.98 (m, 1H).
  • a yellow solid target product (55 mg, HPLC purity: 99.9%, yield 72%) was obtained by a preparation method similar to Example 1.
  • 1 H NMR 500 MHz, DMSO
  • the target compound (20 mg, HPLC purity: 96.4%, yield 47%) was prepared as a yellow solid by a synthetic method similar to Example 2.
  • the target compound (36 mg, HPLC purity: 91.3%, yield 44%) was prepared as a yellow solid using a synthetic method similar to Example 2.
  • MS: m/z[M+1] + 530.0; 1 H NMR (400MHz, DMSO) ⁇ 11.15(s,1H),10.21(s,1H),8.30(s,1H),8.17(s,1H),7.
  • Example 14 1-(1-(4-(2,6-dioxol-3-yl)-3,5-difluorophenyl)azetidin-3-yl)-3-(4-(pentafluoro- ⁇ 6 -thio)phenyl)urea
  • the target compound (37 mg, HPLC purity: 96.0%, yield: 17.01%) was prepared as a white solid using a synthetic method similar to Example 2.
  • Example 16 1-(4-(2,6-dioxopiperazine-3-yl)-3,5-difluorophenyl)azetidin-3-yl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • a white solid target compound (20 mg, HPLC purity: 90.7%, yield 52%) was prepared by a synthetic method similar to Example 2.
  • Example 17 1-(4-(2,6-dioxopiperazine-3-yl)-3,5-difluorophenyl)azetidin-3-yl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • the target compound (11 mg, HPLC purity: 90.4%, yield 45%) was prepared as a white solid by a method similar to that of Example 2.
  • Example 18 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(3-(pentafluoro- ⁇ 6 -thio)phenyl)carbamate
  • a yellow solid target compound (10.01 mg, HPLC purity: 92.8%, yield 7.4%) was prepared by a synthetic method similar to Example 2.
  • the yellow solid target compound (27.34 mg, HPLC purity: 97.16%, yield) was prepared by a method similar to that of Example 2. 23.3%).
  • a yellow solid target compound (14.2 mg, HPLC purity: 95.54%, yield: 18.8%) was prepared by a synthetic method similar to Example 2.
  • Example 21 1-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)azetidin-3-yl)urea
  • a yellow solid target compound (21.48 mg, HPLC purity: 94.7%, yield 16.03%) was prepared by a synthetic method similar to Example 2.
  • a yellow solid target compound (37 mg, HPLC purity: 97.0%, yield 19.08%) was prepared by a synthetic method similar to Example 2.
  • Example 23 1-(1-(4-(2,6-dioxopiperazine-3-yl)-3,5-difluorophenyl)azetidin-3-yl)-3-(3-(pentafluoro- ⁇ 6 -thio)phenyl)urea
  • a white solid target compound (135 mg, HPLC purity: 96.0%, yield 20.05%) was prepared by a synthetic method similar to Example 2.
  • the target compound as a white solid was prepared by a method similar to that in Example 2 (39 mg, HPLC purity: 92.0%, yield 15.03%).
  • Example 25 1-((3-(2,6-dioxol-3-yl)benzofuran-6-yl)methyl)-3-(4-(pentafluoro- ⁇ 6 -thio)phenyl)urea
  • the target compound (45 mg, HPLC purity: 91.0%, yield: 16.07%) was prepared as a white solid by a synthetic method similar to Example 2.
  • the target compound (30 mg, HPLC purity: 94.3%, yield: 16.51%) was prepared as a yellow solid using a synthetic method similar to Example 2.
  • ESI-MS: m/z [M+H] + 631.0; 1 H NMR (400MHz, DMSO) ⁇ 11.15(s,1H),10.16(s,1H),8.30(s,1H),8.17(s,1H),7.
  • a yellow solid target compound (52.25 mg, HPLC purity: 96.67%, yield: 27.5%) was prepared by a synthetic method similar to Example 2.
  • the target compound as a yellow solid was prepared by a method similar to that in Example 2 (47.74 mg, HPLC purity: 98.28%, yield 67.9%).
  • the target compound (53 mg, HPLC purity: 98.98%, yield: 82.8%) was prepared as a yellow solid by a method similar to that of Example 2.
  • the target compound (3.60 mg, HPLC purity: 98.49%, yield: 4.63%) was prepared as a yellow solid using a synthetic method similar to Example 2.
  • Test Example 1 Cell experiment (NCI-H1155 cell proliferation inhibition experiment)
  • NCI-H1155 cells were placed in McCoys-5A (Gibco) medium (containing 10% fetal bovine serum; ExCell bio), and 1% penicillin and streptomycin were added, and cultured in a cell culture incubator at 37°C, 5% CO 2 and saturated humidity. After the cells were full, the cells were subcultured to 96-well plates (5000 cells/well). After overnight culture, compounds at concentrations of 0.04nM, 0.15nM, 0.61nM, 2.44nM, 9.77nM, 39.1nM, 156.3nM, 625nM, 2500nM and 10000nM were added to the cells, and 0.1% DMSO and culture medium were set as solvents and negative controls, respectively.
  • Each sample had 2 replicates, and the compounds were mixed and cultured in a 37°C, 5% CO 2 incubator for 72h. After treatment, the 96-well plate was placed at room temperature for 30 min, and 50 ⁇ L (Promega), and placed on an orbital shaker for 2 minutes, and then placed at room temperature in the dark for 10 minutes. The 96-well plate was placed in a SpectraMax Paradigm (Molecular Devices) to test the luminance signal.
  • SpectraMax Paradigm Molecular Devices
  • Cell activity inhibition rate (%) 100-(RLU compound -RLU blank )/(RLU control -RLU blank )*100%, Control is the 0.1% DMSO treatment group, blank is the culture medium treatment group, and the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0 was used to calculate the compound IC50 and draw the dose-effect curve.
  • PBMCs were purchased from Miaoshun Biotechnology Co., Ltd. PBMCs were resuspended in RPMI-1640 (Solarbio, 11965) cell culture medium (containing 10% FBS: Solarbio, S903), and the cells were cultured overnight in an incubator at 37°C and 5% CO 2. The cells were stained with AOPI and counted using a cell counter. The proportion of live cells must be above 80%. The cells after overnight culture were inoculated into a 96-well plate, and each well was stained with 1% ...
  • 20,000 cells were added to the cell suspension at concentrations of 10,000 nM, 2,500 nM, 625 nM, 156.25 nM, 39 nM, 9.8 nM, 2.4 nM, 0.6 nM, and 0.15 nM.
  • the final DMSO concentration was 0.2%.
  • the 96-well plate was placed in a 37°C, 5% CO 2 incubator for 72 h, and 50 ⁇ L of (Promega, G7573) and mixed well. After incubation in the dark for 10 min, the luminance signal value was read on SpectraMax Paradigm (Molecular Devices).
  • Phase I metabolic stability test uses an in vitro incubation system of liver microsomes to simulate the physiological conditions of liver microsomes and add redox coenzymes (NADPH) for related reactions.
  • NADPH redox coenzymes
  • test compound or control compound (testosterone, diclofenac and propafenone) at a concentration of 100 ⁇ M was added.
  • 50 ⁇ L of potassium phosphate buffer was added to each well of the NCF60 incubation plate to start the reaction, and a T0 stop 96-well plate was prepared.
  • stop solution acetonitrile solution containing 200 ng/mL tolbutamide and 200 ng/mL labetalol
  • NADPH regeneration system working solution NADPH powder was dissolved in 10 mM MgCl 2 solution to prepare a 10 mM NADPH solution
  • 54 ⁇ L of sample was taken from the T60 incubation plate to the T0 stop plate (T0 sample generation).
  • the final reaction concentration of the compound, testosterone, diclofenac and propafenone is 1 ⁇ M
  • the concentration of liver microsomes is 0.5 mg/mL
  • the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v/v) and 0.99% (v/v), respectively.
  • NCI-H1155 cells were seeded into 6-well plates at a seeding number of 3 ⁇ 10 5 cells/well. Drugs were administered 24 hours after seeding, with a final drug concentration of 10 nM. Cells and drugs were co-incubated in an incubator at 37°C and 5% CO 2. After 24 hours, 100 ⁇ L of trypsin working solution (0.25%) was added to each well for digestion. The cells were collected and washed once with PBS. The centrifugation conditions were 4°C, 1000 rpm, and 5 min. The cells were collected by shaking at 4°C and 13000 rpm for 10 s.
  • the PVDF membrane after transfer is blocked for 1h (5% milk powder), incubated with primary antibody overnight, washed with TBST for 30min, incubated with secondary antibody for 1h, and finally washed with TBST for 30min.
  • Prepare ECL luminescent solution incubate the strips with the luminescent solution at room temperature for about 5min, drain the excess luminescent solution, and expose. Analyze the strips with Image J.
  • the compounds in the examples of the present application showed strong protein degradation capabilities for GSPT1 and MYC in NCI-H1155 cells.
  • the clear solution of the compound of the embodiment of the present application was injected into ICR mice via the tail vein (overnight fasting), or administered to ICR mice by gavage (fed).
  • the intravenous and gavage dosages were 0.5 mg/kg and 1 mg/kg, respectively, and the administration solvent was 5% DMSO + 10% Solutol + 85% Saline.
  • 50 ⁇ L of blood was collected from cheek puncture at 0h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24h after intravenous injection or gavage, and placed in a sodium heparin anticoagulant tube. After blood sample collection, it was placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6000g, 3min, 2-8°C).
  • the plasma drug concentration was determined by the LC-MS/MS internal standard method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using Phoenix WinNonlin8.2.0 pharma
  • the NOD/SCID mice used in this experiment were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., female, 6-8 weeks old, weighing 18-22 grams. After the animals arrived, they were isolated and quarantined in the experimental environment for 7 days before the experiment began. NCI-H1155 cells in the logarithmic growth phase (with matrix gel, Corning, BD356230, volume ratio of 1:1) were subcutaneously inoculated on the right back of the mice, and group administration began when the average tumor volume reached about 150-200mm 3. Oral QD was administered continuously for 21 days, and the tumor was measured and weighed 3 times a week.
  • TGI (%) [(1-(average tumor volume of a treatment group at the end of drug administration-average tumor volume of the treatment group at the beginning of drug administration)/(average tumor volume of the solvent control group at the end of treatment-average tumor volume of the solvent control group at the beginning of treatment)] ⁇ 100%.
  • the compounds of the examples of the present application all exhibited tumor-suppressing effects in the NCI-H1155 mouse subcutaneous transplant tumor model.

Landscapes

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

Abstract

L'invention concerne un composé représenté par la formule (I), un composé deutéré de celui-ci, un stéréoisomère de celui-ci, un tautomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci ou un mélange de ceux-ci, qui est un agent de dégradation de type colle moléculaire pour dégrader une protéine GSPT1. Le composé peut être utilisé pour préparer un médicament destiné au traitement et/ou à la prévention de maladies associées à GSPT1.
PCT/CN2024/117039 2023-09-06 2024-09-05 Dérivé de lactame et son utilisation Pending WO2025051180A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202311142120 2023-09-06
CN202311142120.0 2023-09-06
CN202311158338.5 2023-09-08
CN202311158338 2023-09-08
CN202311409162 2023-10-27
CN202311409162.6 2023-10-27

Publications (1)

Publication Number Publication Date
WO2025051180A1 true WO2025051180A1 (fr) 2025-03-13

Family

ID=94922926

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/117039 Pending WO2025051180A1 (fr) 2023-09-06 2024-09-05 Dérivé de lactame et son utilisation

Country Status (1)

Country Link
WO (1) WO2025051180A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120441535A (zh) * 2025-07-08 2025-08-08 苏州国匡医药科技有限公司 一种含炔基的gspt1降解剂及其应用

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021069705A1 (fr) * 2019-10-09 2021-04-15 Monte Rosa Therapeutics Composés d'iso-indolinone
WO2022152822A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Traitement de cancers entraînés par myc avec des agents de dégradation gspt1
WO2022152821A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Composés d'isoindolinone
WO2022200857A1 (fr) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Compositions pharmaceutiques destinées à être utilisées pour prévenir ou traiter une maladie ou un trouble provoqué par ou associé à un ou plusieurs codons de terminaison prématurés
WO2022219407A1 (fr) * 2021-04-14 2022-10-20 Monte Rosa Therapeutics Ag Composés d'iso-indolinone
WO2022256623A1 (fr) * 2021-06-04 2022-12-08 Monte Rosa Therapeutics, Inc. Protéines de fusion e3 ligase pour la détection de proximité
WO2023001028A1 (fr) * 2021-07-19 2023-01-26 南京明德新药研发有限公司 Composé hétéroaryle-3-pipéridinedione et son utilisation
WO2023061478A1 (fr) * 2021-10-15 2023-04-20 先声再明医药有限公司 Composé tricyclique
WO2023069731A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés assurant la médiation de la dégradation de protéines et leurs procédés d'utilisation
WO2023069708A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés qui assurent la médiation de la dégradation de protéines et leurs utilisations
WO2023091567A1 (fr) * 2021-11-17 2023-05-25 Monte Rosa Therapeutics, Inc. Identification de dégron et de néosubstrat
WO2024015855A1 (fr) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. Polythérapie comprenant des agents de dégradation de colle moléculaire ciblant le gspt1 et des inhibiteurs de la voie pi3k/akt/mtor
WO2024015565A1 (fr) * 2022-07-14 2024-01-18 Monte Rosa Therapeutics, Inc. Procédés de préparation d'un dérivé d'isoindolinone et formes cristallines de celui-ci
CN118184639A (zh) * 2022-12-13 2024-06-14 南京圣和药业股份有限公司 Gspt1降解剂及其应用
WO2024187121A1 (fr) * 2023-03-08 2024-09-12 Red Queen Therapeutics, Inc. Polythérapies comprenant des peptides sars-cov-2 stabilisés
CN118852145A (zh) * 2023-04-28 2024-10-29 南京圣和药业股份有限公司 Gspt1降解剂及其应用

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021069705A1 (fr) * 2019-10-09 2021-04-15 Monte Rosa Therapeutics Composés d'iso-indolinone
WO2022152822A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Traitement de cancers entraînés par myc avec des agents de dégradation gspt1
WO2022152821A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Composés d'isoindolinone
WO2022200857A1 (fr) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Compositions pharmaceutiques destinées à être utilisées pour prévenir ou traiter une maladie ou un trouble provoqué par ou associé à un ou plusieurs codons de terminaison prématurés
WO2022219407A1 (fr) * 2021-04-14 2022-10-20 Monte Rosa Therapeutics Ag Composés d'iso-indolinone
WO2022256623A1 (fr) * 2021-06-04 2022-12-08 Monte Rosa Therapeutics, Inc. Protéines de fusion e3 ligase pour la détection de proximité
WO2023001028A1 (fr) * 2021-07-19 2023-01-26 南京明德新药研发有限公司 Composé hétéroaryle-3-pipéridinedione et son utilisation
WO2023061478A1 (fr) * 2021-10-15 2023-04-20 先声再明医药有限公司 Composé tricyclique
WO2023069731A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés assurant la médiation de la dégradation de protéines et leurs procédés d'utilisation
WO2023069708A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés qui assurent la médiation de la dégradation de protéines et leurs utilisations
WO2023091567A1 (fr) * 2021-11-17 2023-05-25 Monte Rosa Therapeutics, Inc. Identification de dégron et de néosubstrat
WO2024015855A1 (fr) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. Polythérapie comprenant des agents de dégradation de colle moléculaire ciblant le gspt1 et des inhibiteurs de la voie pi3k/akt/mtor
WO2024015565A1 (fr) * 2022-07-14 2024-01-18 Monte Rosa Therapeutics, Inc. Procédés de préparation d'un dérivé d'isoindolinone et formes cristallines de celui-ci
CN118184639A (zh) * 2022-12-13 2024-06-14 南京圣和药业股份有限公司 Gspt1降解剂及其应用
WO2024187121A1 (fr) * 2023-03-08 2024-09-12 Red Queen Therapeutics, Inc. Polythérapies comprenant des peptides sars-cov-2 stabilisés
CN118852145A (zh) * 2023-04-28 2024-10-29 南京圣和药业股份有限公司 Gspt1降解剂及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 7 March 2022 (2022-03-07), XP093286673, Database accession no. 2761392-80-5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120441535A (zh) * 2025-07-08 2025-08-08 苏州国匡医药科技有限公司 一种含炔基的gspt1降解剂及其应用

Similar Documents

Publication Publication Date Title
CN111423416B (zh) Ret的抑制剂
TW202144340A (zh) 稠合咪唑類衍生物、其製備方法及其在醫藥上的應用
CN110612285B (zh) 作为Nav1.7及Nav1.8阻断剂的酰胺衍生物
JP2021506966A (ja) Ｎｌｒｐ３インフラマソーム調節剤としてのスルホニル尿素誘導体
CN112566900B (zh) 免疫调节剂及其组合物和制备方法
ES2426482T3 (es) Inhibidor de IGF-1R
CN115785068A (zh) Kif18a抑制剂
CN112457296B (zh) 嘧啶类化合物及其制备方法
WO2022258040A1 (fr) Composé hétérocyclique pour inhibiteur de tead
WO2023041055A1 (fr) Inhibiteur de kif18a
WO2022007659A1 (fr) Immunomodulateur hétérocyclique
CN116789647A (zh) 作为parp7抑制剂的化合物
WO2022083616A9 (fr) Composé quinazoline et composition pharmaceutique associée
CN118772176A (zh) 一种嘧啶并芳环化合物及其制备方法和用途
WO2025051180A1 (fr) Dérivé de lactame et son utilisation
WO2024012496A1 (fr) Composé récepteur cannabinoïde et son utilisation
WO2023116812A1 (fr) Composé de sulfonylurée
WO2022166983A1 (fr) Dérivé d'hétéroaryloxypipéridine, composition pharmaceutique de celui-ci et son utilisation
CN112513041A (zh) 三环化合物
WO2021047406A1 (fr) Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée
CN113666863B (zh) 可用作RORγ调节剂的联芳基类化合物
CN113773251B (zh) 可用作RORγ调节剂的苯胺类化合物
WO2024012570A1 (fr) Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci
WO2022222911A1 (fr) Composé pyrimidone et son utilisation
CN117479934A (zh) 用于治疗肾纤维化的噁二唑基二氢吡喃并[2,3-b]吡啶的HIPK2抑制剂

Legal Events

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

Ref document number: 24862020

Country of ref document: EP

Kind code of ref document: A1