WO2023215449A1 - Tetrahydroisoquinoline heterobifunctional bcl-xl degraders - Google Patents

Tetrahydroisoquinoline heterobifunctional bcl-xl degraders Download PDF

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WO2023215449A1
WO2023215449A1 PCT/US2023/020956 US2023020956W WO2023215449A1 WO 2023215449 A1 WO2023215449 A1 WO 2023215449A1 US 2023020956 W US2023020956 W US 2023020956W WO 2023215449 A1 WO2023215449 A1 WO 2023215449A1
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Prior art keywords
compound
cancer
group
alkyl
inhibitor
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English (en)
French (fr)
Inventor
Evan J. Horn
Joshua D. Hansen
Matthew D. Alexander
Fei Huang
Mark A. Nagy
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Treeline Biosciences, Inc
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Treeline Biosciences, Inc
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Priority to CA3252016A priority Critical patent/CA3252016A1/en
Priority to US18/858,971 priority patent/US20250288683A1/en
Priority to EP23727754.6A priority patent/EP4519272A1/en
Priority to JP2024565274A priority patent/JP2025516359A/ja
Priority to AU2023264537A priority patent/AU2023264537A1/en
Publication of WO2023215449A1 publication Critical patent/WO2023215449A1/en
Priority to MX2024013312A priority patent/MX2024013312A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the BCL-2 family of proteins is involved in the regulation of cell apoptosis and includes proteins that are pro-apoptosis, pro-survival, and BH3-only. At a high level, the balance of binding of BH3-only proteins to the pro-apoptosis and pro-survival members of the BCL-2 family can determine whether a cell will undergo apoptosis.
  • the protein BCL-X L encoded by the BCL2L1 gene, is a pro-survival member of the BCL-2 family.
  • VHL von Hippel- Lindau
  • a degradation approach for a target protein can have potential advantages compared to, e.g., small molecule inhibition of the target protein.
  • One potential advantage is that the duration of effect of a heterobifunctional compound is generally based on the resynthesis rate of the target protein.
  • Another potential advantage is that many heterobifunctional compounds are believed to be released from the ubiquitinated target protein-E3 ligase complex and made available for formation of further ternary complexes; this is sometimes referred to as “catalytic” turnover of the heterobifunctional compound.
  • VBM is and L is selected from the group consisting of: , , wherein bb represents the point of attachment to VBM.
  • the compounds are selected from the group consisting of the compounds in Table C1, or pharmaceutically acceptable salts thereof
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • degradation typically increases over time, though the appearance of degradation (e.g., as expressed by the percentage degradation compared to a control, or the parameters Ymin, DC 50 , and/or Dmax) is affected by the resynthesis rate of the protein. It is common in the art to examine degradation after a specified period of time, such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or more. For example, degradation can be expressed as the percent degradation after 24 hours. Exemplary assays for validating the degradation-inducing mechanism of a compound as provided herein are known in the art and are described, for example, in International Publication No. WO 2019/144117 and Wu, et al.
  • EC 50 refers to the concentration of the compound of Formula (I) or (II) that results in a 50% decrease in the concentration of a protein (e.g., BCL-X L protein) relative to the trough concentration of the protein in a cell, when compared to the concentration of the protein before the cell is contacted with the compound of Formula (I) or (II), or compared to the concentration of the protein in a cell not contacted with the compound of Formula (I) or (II).
  • a compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent compound relative to a compound with a higher EC 50 value.
  • Ymin refers to the ratio of trough concentration of a protein (e.g., BCL-X L protein) in a cell compared to the concentration of the protein before the cell is contacted with the compound of Formula (I) or (II), or compared to the concentration of the protein in a cell not contacted with the compound of Formula (I) or (II), expressed as a percentage.
  • Dmax is 1-Ymin.
  • Ymin can be measured by a HiBiT assay as described in Example B1. A compound with a lower Y min value, as determined under substantially similar conditions, is a more potent inducer of degradation relative to a compound with a higher Ymin value.
  • a 3D cell proliferation assay can include growing cells in a 3D medium, contacting the cells with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from an experiment with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof).
  • an appropriate reagent e.g., CELLTITERGLO® 3D
  • cells expressing BCL-X L protein can be incubated with various concentrations of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, then exposed to a detection reagent (e.g., a CELLTITER-GLO® Cell Viability Assay kit) to determine cell viability.
  • a detection reagent e.g., a CELLTITER-GLO® Cell Viability Assay kit
  • An exemplary assay for evaluating the affinity of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof includes using a competition assay with recombinant BCL-X L protein.
  • a PDX model can be run in immunodeficient mice (e.g., athymic nude, outbred homozygous (e.g., Crl:NU(NCr)-Foxn1 nu ) or Fox Chase SCID (CB17/Icr- Prkdc scid /IcrIcoCrl), mice).
  • the mice can be female, 6-12 weeks old at tumor implantation and have access to food and water ad libitum.
  • Approximately 70 mg of a tumor can be implanted subcutaneously in the right flank of each mouse. Following implantation, tumors can be measured weekly and once the tumor volumes reach 150-300 mm 3 , the mice can be randomized into treatment and control groups.
  • IV intravenous
  • PO oral gavage
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof can be formulated in solution for the IV route and solution or suspension for the PO route.
  • the AUC for a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, dosed PO in rats at 10 mg/kg is about 10 ⁇ M•h to about 150 ⁇ M•h (e.g., about 10 ⁇ M•h to about 100 ⁇ M•h, about 10 ⁇ M•h to about 50 ⁇ M•h, or about 30 ⁇ M•h to about 80 ⁇ M•h).
  • Heterobifunctional degraders can, in some cases, induce the degradation of off-target proteins. For heterobifunctional degraders that utilize VHL, a common off-target proteins that can be degraded is CDO1.
  • a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof shows between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject and has a Ymin value of less than about 50%.
  • a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof shows between about 30% and 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability) when administered to a subject and has a Y min value of about 0% to about 50%.
  • therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof shows at least about 50% platelet viability (e.g., at least about 80% platelet viability) when administered to a subject and has a Ymin value of about 50% to about 70%.
  • a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof shows at least about 50% platelet viability (e.g., at least about 80% platelet viability) when administered to a subject and has a Y min value of less than about 50%.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof when tested at a concentration of about 0.25 ⁇ M to about 3 ⁇ M in the assay in Example B6, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability).
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof when tested at a concentration of about 0.25 ⁇ M to about 3 ⁇ M in the assay in Example B6, shows about 30% to about 100% platelet viability (e.g., about 50% to about 100% platelet viability, or about 80% to about 100% platelet viability).
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof when tested at a concentration of about 0.25 ⁇ M to about 3 ⁇ M in the assay in Example B6, shows at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) and has a Ymin value of less than about 50% in the assay described in Example B1.
  • the subject has previously been treated with another anticancer agent, a chemotherapeutic agent, radiation, surgery, a multi-kinase inhibitor, or a combination thereof.
  • another anticancer agent e.g., a chemotherapeutic agent, radiation, surgery, a multi-kinase inhibitor, or a combination thereof.
  • a method of treating an ocular disease or condition in a subject in need of such treatment comprising administering (e.g., intravitreally or topically) to the subject a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a method for modulating (e.g., decreasing) BCL-X L protein activity in a cell comprising contacting the cell with an effective compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, to a subject.
  • the cell is a cancer cell.
  • the cell is a mammalian cell.
  • the cell is a mammalian cancer cell.
  • the BCL-2 inhibitor is lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or a phosphate prodrug thereof), UBX-1967 (or a phosphate prodrug thereof), ZN- d5, or a combination thereof.
  • the cancer is a BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), encorafenib (e.g., BRAFTOVITM, LGX818), or vemurafenib (e.g., ZELBORAF®, RO5185426), and binimetinib, cobimetinib (e.g., cobimetinib fumarate), selumetinib (e.g., selumetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide).
  • dabrafenib e.g., dabrafenib mesylate, GSK2118436
  • encorafenib e.g., BRAFTO
  • the anti-EGFR antibody or anti-EGFR antibody- drug conjugate is amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL- 140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof),
  • the HER2 inhibitor is afatinib (e.g., afatinib dimaleate), dacomitinib (e.g., dacomitinib monohydrate), lapatinib (e.g., lapatinib ditosylate monohydrate), mobocertinib (e.g., mobocertinib succinate), neratinib (e.g., neratinib maleate), poziotinib, pyrotinib (e.g., pyrotinib maleate), sunvozertinib, tesevatinib, tucatinib, varlitinib, an anti-HER2 antibody or anti-HER2 antibody-drug conjugate, or a combination thereof.
  • afatinib e.g., afatinib dimaleate
  • dacomitinib e.g., dacomitinib monohydrate
  • the cancer is a HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab (e.g., HERCEPTIN® (trastuzumab), or a biosimilar thereof (e.g., FACEPTOR® (trastuzumab), HERTICAD® (trastuzumab), TUZNUE® (trastuzumab), ZERCEPAC® (trastuzumab), trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-qyyp, EG-12014, or TX- 05)).
  • trastuzumab e.g., HERCEPTIN® (trastuzumab)
  • a biosimilar thereof e.g., FACEPTOR® (trastuzum
  • a KRas mutation (e.g., a KRas G12C mutation or a KRas G12D mutation) can be detected in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a G12C mutation or a G12D mutation in KRas protein and/or detecting a KRas protein having a G12C mutation or a G12D mutation).
  • the subject was determined (e.g., prior to administration of a compound of Formula (I) or (II)) to have a cancer having a KRas G12C mutation.
  • the cancer is a KRas mutant lung cancer (e.g., a KRas mutant NSCLC (e.g., a KRas G12C mutant NSCLC)), a KRas mutant CRC (e.g., a KRas G12C mutant CRC), or a KRas mutant pancreatic cancer (e.g., a KRas G12C mutant pancreatic cancer), and the additional therapy or therapeutic agent is adagrasib.
  • a KRas mutant lung cancer e.g., a KRas mutant NSCLC (e.g., a KRas G12C mutant NSCLC)
  • a KRas mutant CRC e.g., a KRas G12C mutant CRC
  • pancreatic cancer e.g., a KRas G12C mutant pancreatic cancer
  • the additional therapy or therapeutic agent is adagrasib.
  • the subject was determined (e.g., prior to administration of a compound of Formula (I) or (II)) to have a cancer having a BRCA2 mutation.
  • the cancer is ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer, HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), or LGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).
  • the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).
  • the cancer is LGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC), and the additional therapy or therapeutic agent is a MEK inhibitor (e.g., binimetinib, cobimetinib, selumetinib, or trametinib).
  • the PARP inhibitor is a PARP1 inhibitor.
  • the PARP1 inhibitor is saruparib (AZD5305), NMS-03305293, or a combination thereof.
  • the cancer is BRCA1 mutant breast cancer or BRCA2 mutant breast cancer, and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293).
  • a PARP inhibitor e.g., fuzuloparib (fluzoparib),
  • the antibody-drug conjugate including the microtubule inhibitor is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof).
  • the antibody-drug conjugate including the microtubule inhibitor is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof).
  • the antibody-drug conjugate including the microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof).
  • the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is carboplatin and etoposide. In some embodiments, the cancer is a lung cancer (e.g., SCLC), and the additional therapy or therapeutic agent is cisplatin and etoposide.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • the mixture was stirred at 25 °C for 3 hours.
  • the reaction mixture was quenched by addition water (4 mL).
  • the reaction mixture was filtered and the filter cake was washed with water (10 mL). After washing, the filter cake was diluted in DCM (20 mL).
  • Step E Procedure for preparation of 3-[4-[[3-[6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4- dihydro-1H-isoquinolin-2-yl]-2-tert-butoxycarbonyl-3-pyridyl]-2-methyl- phenoxy]methyl]phenyl]propanoic acid
  • Step G Procedure for preparation of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro- 1H-isoquinolin-2-yl]-3-[3-[4-[4-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1R)-2,2,2-trifluoro-1-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl- propyl]amino]-4-oxo-butyl]phenoxy]-2-methyl-phenyl]pyridine-2-carboxylic acid A solution of tert-butyl 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-iso

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PCT/US2023/020956 2022-05-06 2023-05-04 Tetrahydroisoquinoline heterobifunctional bcl-xl degraders Ceased WO2023215449A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA3252016A CA3252016A1 (en) 2022-05-06 2023-05-04 HETEROBORCTIONAL TETROHYDROISOQUINOLINE-BASED BCL-XL DEGRADING AGENTS
US18/858,971 US20250288683A1 (en) 2022-05-06 2023-05-04 Tetrahydroisoquinoline heterobifunctional bcl-xl degraders
EP23727754.6A EP4519272A1 (en) 2022-05-06 2023-05-04 Tetrahydroisoquinoline heterobifunctional bcl-xl degraders
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WO2025036119A1 (zh) * 2023-08-11 2025-02-20 北京三秀生物医药科技有限公司 靶向Bcl-xL蛋白的PROTAC及其应用

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