USP30 inhibitors and uses thereof
Inventors
Romero, Donna L. • JOHNSON, Michael Garrett • Lee, Andrew David • BEHROUZ, BAHAREH • FRITZEN, Jr., Edward Lawrence
Assignees
Elf Pharma Consulting LLC • Pharma-Vation Consulting LLC • Vincere Biosciences Inc
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Publication Number
US-11845724-B2
Publication Date
2023-12-19
Expiration Date
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of USP30, and the treatment of USP30-mediated disorders.
Core Innovation
The invention relates to compounds of formula I and formula I, or pharmaceutically acceptable salts thereof, together with compounds of any one of formulas XV-a, XV-b, XV-c, XV-d, XVII-a, XVII-b, XVII-c, XVII-d, XIX-a, XIX-b, XIX-c, XIX-d, XXI, XXIII-a, XXIII-b, XXV-a, XXV-b, XXV-c, or XXV-d. The compounds are defined by Rings A, B, and C, linker groups L1, L2, and L3, variable substituents R, R1, R2, R3, R4, R5, R6, and R7, and integer parameters m, n, and p, with optional ring-forming combinations. Ring A, Ring B, and Ring C are selected from phenyl, specified heteroaryl rings, and specified bicyclic aryl or heteroaryl ring systems with defined heteroatom counts.
L1 is a C1-3 bivalent hydrocarbon chain in which one methylene unit is replaced by one of the defined motifs, including C(O), C(O)N(R), N(R)C(O), S(O), S(O)2, S(O)N(R), S(O)2N(R), or S(O)(R)N. L2 is C(O)N(R) and L3 is C(O)N(R), with R and R being hydrogen or a C1-3 aliphatic group. The Markush framework further allows R1, R2, R6, and R7 to be selected from specified aliphatic, heterocyclic, heteroaryl, and functional group classes, with optional fused, spiro-fused, or other ring-forming constraints.
The scope is narrowed by explicit provisos excluding certain R1 choices under specified L1 and Ring A conditions, including exclusions when L1 is S(O)2N(R) and Ring A is naphthyl, and by exclusions of certain overall compounds. The provided content also states that the compounds inhibit USP30 and are useful for treating USP30-mediated disorders, diseases, or conditions, and for studying USP30/mitochondrial homeostasis. The disclosure includes specific compound examples and named structures, but the consolidated core is the same Markush-defined scaffold and its selected formula-set embodiments.
Claims Coverage
Three independent claim types are explicitly provided, covering the formula I/I scaffold, compounds selected from the named formula sets, and a selected compound from a defined set. The claim coverage centers on one Markush compound architecture with Ring A/B/C, L1/L2/L3, substituent classes, integer constraints, and provisos, plus parallel coverage of enumerated formula-set compounds and a specific selected compound, and includes method coverage for USP30 inhibition and treatment of USP30-mediated disorders.
Markush-defined compound of formula I
A compound of formula I, or a pharmaceutically acceptable salt thereof, defined by Ring A, Ring B, and Ring C selections, L1 as a C1-3 bivalent hydrocarbon chain with one methylene replaced by a defined motif, L2 as C(O)N(R), L3 as C(O)N(R), substituents R, R1, R2, R3, R4, R5, R6, and R7, and integer parameters m, n, and p with optional ring-forming combinations and explicit provisos excluding certain R1 choices and certain overall compounds.
Compounds selected from named formula sets
A compound of any one of formulas XV-a, XV-b, XV-c, XV-d, XVII-a, XVII-b, XVII-c, XVII-d, XIX-a, XIX-b, XIX-c, XIX-d, XXI, XXIII-a, XXIII-b, XXV-a, XXV-b, XXV-c, or XXV-d, or a pharmaceutically acceptable salt thereof, with the same general L1 motif, substituent classes, optional ring-forming constraints, integer limits on m, n, and p, and a proviso excluding certain R1 cases when L1 is S(O)2N(R).
Selected compound from a defined set
A compound selected from a partially shown set of compounds, or a pharmaceutically acceptable salt thereof.
USP30 inhibition by contacting a biological sample
A method for inhibiting USP30 in a biological sample by contacting the sample with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
Treating an USP30-mediated disorder
A method for treating an USP30-mediated disorder, disease, or condition in a patient by administering a pharmaceutical composition.
The inventive coverage is directed to Markush-defined compounds and selected formula-set compounds with constrained ring systems, linker motifs, substituent classes, and negative provisos, together with use coverage for USP30 inhibition and treatment of USP30-mediated disorders.
Stated Advantages
Inhibits USP30.
Treats an USP30-mediated disorder, disease, or condition in a patient.
Studying USP30/mitochondrial homeostasis.
Documented Applications
Inhibition of USP30 in a biological sample by contacting the sample with the compound or a pharmaceutically acceptable salt thereof.
Treatment of an USP30-mediated disorder, disease, or condition in a patient by administering the pharmaceutical composition.
Studying USP30/mitochondrial homeostasis.
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