Inhibitors of APOL1 and methods of using same
Inventors
DAKIN, Leslie A. • Brodney, Michael A. • Daniel, Kevin B. • DOLGIKH, Elena • GARCIA BARRANTES, Pedro M. • Medek, Ales • OLSEN, Jessica H. • Senter, Timothy J. • Shimizu, Akira J. • STONE, Steven D. • TSAY, Charlene
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12612379-B2
Publication Date
2026-04-28
Expiration Date
Abstract
The disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).
Core Innovation
The disclosure describes Formula I APOL1-inhibitor compounds, including tautomers, deuterated derivatives, and pharmaceutically acceptable salts. These substituted aryl and heteroaryl piperidine compounds, encompassing substituted 2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ols, define selections for Ring A, Ring B, and associated substituents. The disclosure further identifies specific compounds listed in Tables 1–4, Compound 16, silicon-, boron-, and phosphorus-substituted derivatives, and pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier.
The subject matter identifies crystalline Compound 16 Form A, characterized by an orthorhombic P212121 crystal structure, XRPD, TGA, DSC, solid-state NMR, and single-crystal X-ray diffraction. Targeting APOL1, including APOL1 G1 and G2 risk alleles, provides therapeutic intervention for APOL1-mediated diseases. Synthetic routes for substituted piperidinone and hydroxypiperidine analogs, including stereodefined variants and Compound 16, are described. [procedural detail omitted for safety]
Documented therapeutic indications comprise the treatment of focal segmental glomerulosclerosis, non-diabetic kidney disease, and APOL1-mediated cancers such as pancreatic cancer. Pharmaceutical compositions and combination therapies provide APOL1 inhibition using the disclosed compounds. Because the supplied patent content omits certain introductory sections, the chemical disclosure is primarily defined through structural formulas, characterized solid forms, and enumerated compound examples.
Claims Coverage
The relevant independent claims are claims 1, 29, 30, 31, 33, 35, and 37–40, which encompass ten inventive features relating to APOL1-inhibitor compounds, specific forms, pharmaceutical compositions, and therapeutic methods.
Formula I compounds with ring A and ring B selections
Claim 1 covers a compound represented by the recited formula, or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein Ring A is selected from C6 aryl and 5- and 6-membered heteroaryl groups, and Ring B and substituents are defined by recited selections and substitution patterns.
Compounds selected from Tables 1–4
Claim 29 covers compounds chosen from Table 1, Table 2, Table 3, and Table 4, including tautomers, deuterated derivatives, and pharmaceutically acceptable salts.
Formula compounds with specified R1 and ring B selections
Claim 30 covers a compound represented by the recited formula, or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, specifying selections for R1a, R1b, R1c, R2, Ring B, and associated substituents.
Formula compounds with specified R1 groups
Claim 31 covers a compound represented by the recited formula, or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R1a and R1b are independently chosen from halogen, H, C1–C4 alkyl, and C1–C4 haloalkyl groups, and R1c is chosen from halogen, H, CH3, —OH, and CH2OH.
Compound 16 Form A
Claim 33 covers crystalline Compound 16 Form A as the claimed subject matter.
Pharmaceutical composition comprising Compound 16 Form A
Claim 35 covers a pharmaceutical composition comprising Compound 16 Form A and a pharmaceutically acceptable carrier.
Treatment of focal segmental glomerulosclerosis or non-diabetic kidney disease
Claim 37 covers a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease by administering Compound 16, Compound 16 Form A, or a pharmaceutical composition comprising either form and a pharmaceutically acceptable carrier to a patient in need thereof.
Compound 16 and specified forms
Claim 38 covers Compound 16, a tautomer thereof, a deuterated derivative of the compound or tautomer, and pharmaceutically acceptable salts of these forms.
Compound 16 or pharmaceutically acceptable salts
Claim 39 covers Compound 16 or a pharmaceutically acceptable salt thereof.
Compound 16
Claim 40 covers Compound 16 as the claimed compound.
The independent claims collectively cover formula-defined compound genera, compounds listed in Tables 1–4, Compound 16 and its crystalline Form A, associated pharmaceutical compositions, and methods of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Inhibition of APOL1 and treatment of APOL1-mediated diseases.
Treatment of focal segmental glomerulosclerosis and/or non-diabetic kidney disease by administering a claimed compound, Compound 16, Compound 16 Form A, or a pharmaceutical composition thereof to a patient in need.
Treatment of APOL1-mediated cancer, including pancreatic cancer.
Pharmaceutical compositions comprising at least one claimed compound, Compound 16 Form A, or a specified form thereof and a pharmaceutically acceptable carrier, as well as combination therapies.
Interested in licensing this patent?