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  • 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
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  • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • 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
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  • 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
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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  • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
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  • 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
  • C07D513/02—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 two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • C—CHEMISTRY; METALLURGY
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  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• R 1 is hydrogen or optionally substituted Ci-Ce alkyl
• each R 2 and each R 3 are independently hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl
• Z 1 is (C(R 9 )2). In some embodiments, Z 1 is absent. In some embodiments, Z 1 is O.
• the group is a group of the following structure
• L 1 is some embodiments, R L1 is hydrogen. In some embodiments, L 1 is
• a 2 is a bond to L 2 .
• a 2 is a bond to L 2 .
• L 1 is N
• n is 1 . In some embodiments, n is 2. In some embodiments, n is 3.
• n 0.
• R 1 is hydrogen
• the compound is selected from the group consisting of compounds 1-523 and pharmaceutically acceptable salts thereof.
• the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 7. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 10. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 15. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 20. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 25. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 30.
• the BAF complex-related disorder is cancer.
• the invention features a method of inhibiting BRM, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
• the cell is a cancer cell.
• the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.
• the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein- Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvitus K*, CMV, varicella-zoster virus), Papill
• the effective amount of the compound that reduces the level and/or activity of BRG1 by at least 90% e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
• the effective amount of the compound reduces the level and/or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).
• 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%
• halo means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
• BRG1 loss of function disorder refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least 1 % reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).
• determining the level” of a protein or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly.
• Directly determining means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
• Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
• reference standard or level is meant a value or number derived from a reference sample.
• a “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”).
• a subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker.
• the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
• animal e.g., mammals such as mice, rats, rabbits, non-human primates, and humans.
• a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
• FIG. 8C is a graph illustrating body weight change of mice engrafted with uveal melanoma cell lines and dosed with a BRG1/BRM inhibitor (Compound C).
• each R X1 is independently deuterium, optionally substituted Ci-Ce alkyl, or halo, or two geminal R X1 groups, together with the atom to which they are attached, combine to form a carbonyl;
• An aspect of the present invention relates to methods of treating disorders related to BRG1 loss of function mutations such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, nonmelanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof.
• cancer e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, nonmelanoma skin cancer, endometrial cancer, or penile cancer
• T reating cancer can result in a reduction in size or volume of a tumor.
• tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
• Size of a tumor may be measured by any reproducible means of measurement.
• the size of a tumor may be measured as a diameter of the tumor.
• the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab/Yervoy or tremelimumab).
• the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/Opdivo®; pembrolizumab/Keytruda®; pidilizumab/CT- 011).
• the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
• the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.
• Step 1 Preparation of tert-butyl ((2-(3-(difluoromethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl) carbamate
• Step 2 Preparation of 3-fluoro-4-hydroxy-5-sulfanyl-benzoic acid.
• 3-chlorosulfonyl-5-fluoro-4-hydroxy-benzoic acid 15 g, 58.91 mmol
• PPti3 54.08 g, 206.19 mmol
• Step 5 Preparation of methyl 9-fluoro-5-oxo-3,4-dihydro-2H-1 ,5 4-benzoxathiepine-7-carboxylat e.
• tert-butyl ((4-((6-(difluoromethoxy) pyridin-2-yl) ethynyl) pyridin-2-yl) methyl) carbamate (116 mg, 289.24 umol, 64.79% yield) as a yellow oil.
• Step 5 Preparation of (R)-9-chloro-N-((2-(6-((2S, 6R)-2, 6-dimethylmorpholino)pyridin-2-yl)-1, 6- naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide
• Step 6 Preparation of methyl (trans)-4,9-difluoro-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxylate 5,5-dioxide and methyl (cis)-4,9-difluoro-2-methyl-3,4- dihydro-2H-benzo[b][1 , 4]oxathiepine-7-carboxylate 5, 5-dioxide
• the eluent was concentrated under vacuum.
• the residue was purified by reverse phase flash (0.1 % FA condition).
• the eluent was concentrated in vacuum to remove MeCN andextracted with EA (50 mL*3).
• the organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuum.
• Step 7 Preparation of (cis)-4,9-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxylic acid 5,5-dioxide
• Step 2 Preparation of tert-butyl ((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)carbamate
• Step 3 Preparation of (2-(6-((2S, 6R)-2, 6-dimethylmorpholino)pyridin-2-yl)-1, 6-naphthyridin-7- yl)methanamine
• Step 4 Preparation of tert-butyl 8-bromo-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate
• a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[f][1 ,4]thiazepine (945 mg, 3.87 mmol) in THF (10 mL) was added (Boc)20 (1.69 g, 7.74 mmol) and DMAP (47.29 mg, 387.06 umol) and TEA (1.17 g, 11 .61 mmol). The mixture was stirred at 25 °C for 4 hrs.
• Step 9 Preparation of methyl 2-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine-8- carboxylate 1, 1 -dioxide
• Step 1 Preparation of N'-(3-(benzyloxy)cyclobutylidene)-4-methylbenzenesulfonohydrazide.
• 3-benzyloxycyclobutanone 10 g, 56.75 mmol
• MeOH 100 mL
• 4-methylbenzenesulfonohydrazide 10.57 g, 56.75 mmol
• Step 10 Preparation of Intermediate 4, 2-[(2-chloro-1 ,6-naphthyridin-7-yl)methyl]isoindoline-1 ,3- dione
• the reaction was diluted with water (10 mL), extract with EA (5 mL * 3). The combined organic layers were dried over Na2SC , filtered and concentrated to get the residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 47%-77%, 10min). The fraction was concentrated to remove MeCN. The liquid was extract with DCM (5 mL * 3).
• the assay reaction mixture (10 pL) contains 30 nM of BRM or BRG-1 , 20 nM salmon sperm DNA (from Invitrogen, UltraPureTM Salmon Sperm DNA Solution, cat# 15632011), and 400 pM of ATP in the ATPase assay buffer, which comprises of 20 mM Tris, pH 8, 20 mM MgCh, 50 mM NaCI, 0.1 % Tween-20, and 1 mM fresh DTT (PierceTM DTT (Dithiothreitol), cat# 20290).
• BRG1 and BRM dependent transcription were study by testing the activity of against the BRG1 mutant lung cancer cell line A549 and a MDA cell line with BRM removed by CRISPR. Both cell lines were genetically engineered with a BRG1 or BRM-dependent mouse mammary tumor virus luciferase reporter. Luciferase transcription was induced by dexamethasone in the presence of compound at different concentrations and luminescence was measured using a plate reader s hours after stimulation. IC50 data from the assay described herein are shown in Table 11 below.
• BRG1/BRM Inhibitor compound A has the structure:
• Example 9 Effects of BRG1/BRM ATPase inhibition on the growth of cancer cell lines.
• a pooled cell viability assay was performed using PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) as previously described (“High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines”, Yu et al, Nature Biotechnology 34, 419-423, 2016), with the following modifications.
• Cell lines were obtained from the Cancer Cell Line Encyclopedia (CCLE) collection and adapted to RPMI-1640 medium without phenol red, supplemented with 10% heat-inactivated fetal bovine serum (FBS), in order to apply a unique infection and pooling protocol to such a big compendium of cell lines.
• CCLE Cancer Cell Line Encyclopedia
• FBS heat-inactivated fetal bovine serum
• Cells were treated with either DMSO or compound in a 8-point 3-fold dose response in triplicate, starting from a top concentration of 10 pM.
• As control for assay robustness cells were treated in parallel with two previously validated compounds, the pan-Raf inhibitor AZ-628, and the proteasome inhibitor bortezomib, using a top concentration of 2.5 pM and 0.039 pM, respectively.
• Example 10 Effects of BRG1/BRM ATPase inhibitors on the growth of uveal melanoma cell lines.
• Uveal melanoma cell lines (92-1 , MP41 , MP38, MP46) and Non-small cell lung cancer cells (NCIH1299) were plated into 96 well plates with growth media (see Table 9).
• BRG1/BRM ATPase inhibitor, compound 67 was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37 °C for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer).
• Example 11 Comparison of BRG1/BRM Inhibitors to clinical PKC and MEK inhibitors in uveal melanoma cell lines
• MP41 uveal melanoma cells were made resistant to the PKC inhibitor (LXS196; MedChemExpress), by long-term culture in growth media (see Table 9) containing increasing concentrations of the compound, up to 1 micromolar. After 3 months, sensitivity of the parental MP41 cells and the PKC inhibitor (PKCi)-resistant cells to the PKC inhibitor (LXS196) or the BRG1/BRM ATPase inhibitor (Compound B) was tested in a 7-day growth inhibition assay as described above in Example 6.
• PKC inhibitor LXS196; MedChemExpress

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