N-cyano-7-azanorbornane derivatives and uses thereof
Inventors
Butler, John R. • Erlanson, Daniel • Graceffa, Russell • IWIG, Jeffrey • Jeong, Joon Won • White, Ryan D. • Wu, Yongwei • Yi, Shuyan • Zheng, Xiao Mei • McFarland, Jesse M. • Banerjee, Abhisek
Assignees
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Publication Number
US-11572374-B2
Publication Date
2023-02-07
Expiration Date
Abstract
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.
Core Innovation
The invention relates to compounds or salts thereof according to Formula (I), defined by an azanorbornane scaffold linked through L as a —C(O)N(RB) group attached to the azanorbornane by the right most atom. The structure includes variable groups D, r, R1–R7, R8, A, and B, with D defined as (CR1R2), r as 1 or 2, and broad independently selected substituent sets including hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy. The azanorbornane-linked framework is presented as a highly variable chemical space while preserving the same core scaffold.
Within Formula (I), A is a divalent moiety selected from alkenylene, phenylene, naphthylene, heteroarylene, or saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocycle or heterocycle options with specified ring heteroatom constraints and optional substitution. B is defined as hydrogen or a broad range of substituents including halogen, hydroxy, amino, alkyl, cyanoalkyl, alkoxy, cycloalkyl, C(O)-containing groups, and aryl, heteroaryl, or heterocycle options with optional substitution. The disclosed family also includes stereochemical and structural representations such as Formula Ia and Formula II-a or II-b, and an endo orientation refinement for the azanorbornane moiety.
The provided content describes representative substituted bicyclic azanorbornane-containing carboxamide or amide-like compounds, including 7-cyano-7-azabicyclo[2.2.1]heptane cores and variants with heteroaryl, aryl, benzamide, pyridinyl, indazole, pyrazolyl, thiazole, and related substituent patterns. The examples and family descriptions repeatedly preserve the azanorbornane-linked carboxamide scaffold while varying the attached aromatic or heterocyclic substituents and optional halogen, cyano, alkyl, alkoxy, and related substituents.
Claims Coverage
The independent claim coverage centers on one broad compound or salt defined by Formula (I), with dependent claims refining the structure by specific formula representations, azanorbornane orientation, and pharmaceutical salt/composition context. The combined coverage is based on the core Formula (I) architecture and extensive variable groups D, r, R1–R8, L, A, and B.
Formula (I) azanorbornane-linked compound or salt
A compound or salt thereof according to Formula (I), wherein D is (CR1R2), r is 1 or 2, each of R1–R7 is independently selected from hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkoxy, R8 is independently selected from hydrogen or C1-C4 alkyl, L is —C(O)N(RB) attached to the azanorbornane by the right most atom, RB is hydrogen or C1-C4 alkyl, A is a divalent moiety selected from the listed alkenylene/phenylene/naphthylene/heteroarylene/carbocycle/heterocycle options with optional substitution, and B is selected from the listed substituent classes with optional substitution.
Formula Ia structural representation
The compound according to Formula (I) is represented by Formula Ia.
Formula II-a or II-b structural representation
The compound according to Formula (I) is provided in a form represented by Formula II-a or Formula II-b.
Endo orientation of the azanorbornane moiety
The compound according to Formula (I) has the azanorbornane moiety in an endo orientation.
Pharmaceutically acceptable salt form
The compound according to Formula (I) is provided as a pharmaceutically acceptable salt.
Pharmaceutical composition with excipient, carrier, or adjuvant
A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier, or adjuvant together with at least one compound according to Formula (I).
Overall, the claims cover a broad Formula (I) azanorbornane-linked compound or salt with variable substitution across D, r, R1–R8, L, A, and B. The claim set is further defined by Formula Ia and Formula II-a/II-b representations, an endo azanorbornane orientation, and additional coverage for pharmaceutically acceptable salts and pharmaceutical compositions containing excipients, carriers, or adjuvants.
Stated Advantages
Modulates USP30 protein activity.
Inhibits USP30 protein activity.
Selective USP30 deubiquitinating enzyme inhibition versus other cysteine proteases and deubiquitinating enzymes, with reported selectivity ranges of at least 10-fold and up to 20/50/100-fold.
Provides treatment and prevention of disorders mediated by USP30 activity and mitochondrial dysfunction.
Therapeutic utility for diseases mediated by mitochondrial dysfunction/USP30 activity, including neurodegenerative/CNS disorders, cancer, and mitochondrial disorders.
Documented Applications
Treatment and prevention of disorders mediated by USP30 activity and mitochondrial dysfunction, including neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.
Treatment and prevention of cancer.
Treatment and prevention of metabolic, cardiovascular, and psychiatric diseases.
Treatment and prevention of osteoarthritis.
Treatment and prevention of diseases mediated by mitochondrial dysfunction/USP30 activity, including neurodegenerative/CNS disorders, cancer, and mitochondrial disorders, by administering a therapeutically effective amount of the compounds or pharmaceutical compositions.
Use in pharmaceutical compositions comprising at least one compound according to Formula (I) together with a pharmaceutically acceptable excipient, carrier, or adjuvant.
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