1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives and related compounds as LRRK2, NUAK1 and/or TYK2 kinase modulators for the treatment of e.g. autoimmune disease
Inventors
Koestler, Roland • Tassel, Jean • Thormann, Michael • Yehia, Nasser • Treml, Andreas • Almstetter, Michael
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12384788-B2
Publication Date
2025-08-12
Expiration Date
Abstract
The present invention relates to compounds of formula (I) that are capable of modulating, e.g., inhibiting or activating, one or more kinases, especially LRRK2 and/or NUAK1 and/or TYK2 or mutants thereof. The compounds are useful for treating diseases, such as autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 40 to 146; examples 1 to 63; compounds 1 to 248; tables 1 to 3). Preferred compounds are e.g. 1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives and related compounds. An exemplary compound is e.g. 5-(2,6-difluorophenyl)-8-methoxy-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (example 49). (Formula (II):
Core Innovation
The invention relates to compounds of formula (I), including a tautomer thereof or a pharmaceutically acceptable salt thereof. R1 is aryl or heteroaryl, optionally substituted, and A is aryl or a 5- or 6-membered heteroaryl. R2 is limited to defined substituent types including H, halo, OH, CN, CF3, and carbon-based and ring-based groups, while additional positions permit a broad set of optionally substituted moieties.
The disclosure further defines additional substituent positions, including R3 through R6 and the groups R, R3, and R33, each independently selected from specified substituent classes. In some embodiments, R and R3 or R3 and R33 together with the nitrogen to which they are attached form C2-8 heterocycloalkyl, and alternative scaffold representations are provided as compounds of formula (II) and formula (III).
The patent identifies preferred compound classes including 1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine derivatives, with an example compound identified as 5-(2,6-difluorophenyl)-8-methoxy-1,4-dihydrobenzo[d]pyrazolo[3,4-f][1,3]diazepine (example 49). It states that the compounds are associated with protein kinases including LRRK2, NUAK1, and TYK2, and describes therapeutic and diagnostic contexts including autoimmune and inflammatory diseases, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, and radiolabeled derivatives for PET use.
Claims Coverage
The consolidated claim coverage identifies one independent structural genus for compounds of formula (I), including tautomer and pharmaceutically acceptable salt forms, together with dependent refinements to formula (II) and formula (III). The inventive features focus on the aryl/heteroaryl scaffold, the restricted substituent definitions for R1, R2, and A, broad optionally substituted group definitions, and ring-formation constraints for R, R3, and R33 or for R3 through R6.
Compound of formula (I) scaffold with restricted aryl/heteroaryl definitions
A compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl or heteroaryl optionally substituted, A is aryl or 5- or 6-membered heteroaryl, and R2 is selected from H, halo, OH, CN, CF3, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 thioalkyl, C3-8 cycloalkyl, C2-8 heterocycloalkyl, aryl, or heteroaryl.
Optionally substituted substituent framework
The C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 thioalkyl, C3-8 cycloalkyl, C2-8 heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more moieties selected from halo, OH, CN, CF3, NH2, NO2, alkyl, haloalkyl, thioalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, aralkyl, heteroaralkyl, aryl, heteroaryl, and carbonyl, alkoxy, amino, and sulfoxide-like variants.
Substituent interdependency enabling heterocycloalkyl ring formation
Each of R, R3, and R33 independently is H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkyl, C2-8 heterocycloalkyl, aryl, or heteroaryl, with the condition that R and R3 or R3 and R33 together with the nitrogen to which they are attached form C2-8 heterocycloalkyl.
Formula (II) embodiment with constrained ring-atom assignment pattern
A compound of formula (II) with R1 and R2 and ring-atom options U, V, W, and X satisfying the structural and substituent definitions.
Formula (III) embodiment with additional ring-forming option
A compound of formula (III) with R1 as aryl or heteroaryl optionally substituted, R2 selected from H, halo, OH, CN and carbon-based substituents, and R3 through R6 independently selected from H and functional or cyclic/heterocyclic groups, with an additional option that R4 and R5 form a 5-10 member ring.
Hydrogen-count constraint on R3 through R6
At least three of R3 through R6 are H.
Fixed-position hydrogen pattern with constrained R4 and R5 substitution
R3 and R6 are H, while R4 and R5 are independently selected from halo, functional, cyclic/heterocyclic, aryl/heteroaryl, and carbonyl/alkoxy/amino substituent groups.
Overall, the claim coverage is anchored by the independent genus of compounds of formula (I), with tautomer and pharmaceutically acceptable salt forms, broad but defined substituent sets, and dependent claims that narrow the scope through alternative formula representations, hydrogen-count limitations, fixed-position hydrogen patterns, and ring-forming or fluorinated/halogenated substitution options.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic/disease areas explicitly described include autoimmune diseases, inflammatory diseases, and neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease.
Diagnostic positron emission tomography (PET) use is explicitly described with radiolabeled derivatives.
Interested in licensing this patent?