Substituted cyclohexyl compounds as NOP inhibiiors
Inventors
Thompson, Jillian Basinger • Bookser, Brett C. • Burley, Scott • Garcia-Reynaga, Pablo • Hudson, Andrew • Peters, Marco • Pratt, Benjamin • Thompson, Aaron • TRAN, Joe • Valdez, Lino
Assignees
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Publication Number
US-11365191-B2
Publication Date
2022-06-21
Expiration Date
Abstract
Substituted cyclohexyl chemical entities of Formula (I): wherein Ra, G, and Rb have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive therapies; modulating and treating disorders mediated by nociceptin activity or dopamine signaling; treating neurological disorders, neurodegenerative diseases, depression, and schizophrenia; enhancing the efficiency of cognitive and motor training; and treating peripheral disorders, including renal, respiratory, gastrointestinal, liver, genitourinary, metabolic, and inflammatory disorders.
Core Innovation
The invention concerns compounds of Formula (I), or pharmaceutically acceptable salts thereof, in which G, Ra, and Rb define constrained structural groups and ring systems. G is selected from C(=O), C(=N—OH), CH2, CHR1B, or C(R1B)2; Ra is a 6- or 10-membered aryl or heteroaryl optionally substituted with 1 to 4 R1A; and Rb is a C3-7 cycloalkyl or 5-10-membered heterocycloalkyl optionally substituted with 1 to 7 R1B. The substituent sets for R1A and R1B define the permitted chemical space for the scaffold.
The disclosure also presents explicitly listed stereochemical variants and selected compounds within the scaffold, including cis and trans members and compounds with ring cores such as tetrahydro-2H-pyran, oxane, cyclopentane, cyclohexane, piperidinone, and pyrrolidinone. The named exemplars include substituted cyclohexyl-linked amino, amide, and oxane/tetrahydro-2H-pyran derivatives with aromatic substituents such as chloro, fluoro, difluoro, trifluoromethyl, methyl, methoxymethyl, and 3-chloro-5-fluoropyridin-2-yl groups.
The compounds are presented in the context of NOP receptor inhibition and receptor binding selectivity. The document also describes pharmacological evaluation context, behavioral pharmacology, additional functional assays, pharmaceutical compositions, and therapeutic use for neurological disorders, including post-stroke neurological deficits during rehabilitation and post-traumatic brain injury neurological deficits during post-TBI rehabilitation.
Claims Coverage
The claims cover three main inventive feature groups: a broad Formula (I) scaffold with enumerated substituent sets, an enumerated set of stereochemically defined compounds, and a narrower enumerated subset of oxane/tetrahydro-2H-pyran carboxamides. The partial claim content also includes a pharmaceutical composition and a method for treating a neurological disorder by administering an effective amount of a specified compound.
Constrained Formula (I) scaffold
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein G is C(=O), C(=N—OH), CH2, CHR1B, or C(R1B)2; Ra is a 6 or 10-membered aryl or 6 or 10-membered heteroaryl optionally substituted with 1 to 4 R1A; and Rb is a C3-7 cycloalkyl or 5-10-membered heterocycloalkyl optionally substituted with 1 to 7 R1B, with R1A and R1B independently selected from broad enumerated sets.
Enumerated stereochemically defined compound selection
A compound, or pharmaceutically acceptable salt thereof, selected from a group of specifically listed structures, including cis and trans variants and related compounds with tetrahydro-2H-pyran, oxane, cyclopentane, cyclohexane, piperidinone, and pyrrolidinone ring cores, together with specified aromatic substitution patterns.
Narrower enumerated oxane and tetrahydro-2H-pyran carboxamides
A compound, or pharmaceutically acceptable salt thereof, selected from a narrower group including N-Methyl-4-({2-[(cis)-4-[4-fluoro-2-(trifluoromethyl)phenyl]cyclohexyl]ethyl}amino)oxane-4-carboxamide, the corresponding trans compound, 4-((2-((cis)-4-(4-fluoro-2-methylphenyl)cyclohexyl)ethyl)amino)tetrahydro-2H-pyran-4-carboxamide, and cis/trans 4-({2-[(2-Chloro-4-fluorophenyl)cyclohexyl]ethyl}amino)oxane-4-carboxamide variants.
Pharmaceutical composition including a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Method for treating a neurological disorder
A method for treating a neurological disorder by administering an effective amount of a specified compound, or pharmaceutically acceptable salt thereof, to a subject in need.
The claims are directed to a broad chemical scaffold defined by Formula (I) with constrained variable selections, together with separately claimed stereochemically defined compound sets and a narrower subset of oxane/tetrahydro-2H-pyran carboxamides. The claim coverage also includes a pharmaceutical composition and a neurological disorder treatment method.
Stated Advantages
Provides compounds intended as NOP receptor inhibitors.
Provides therapeutic methods for neurological and peripheral disorders via administration of an effective amount of the compound.
Provides pharmaceutical compositions and dosage forms comprising the compound with a pharmaceutically acceptable carrier.
Documented Applications
NOP antagonism assay reporting pIC50 values using a cell-based cAMP assay.
Receptor binding selectivity using scintillation proximity assay for NOP, MOP, KOP, and DOP receptors.
In vivo behavioral pharmacology indicating effects on memory and behavior in rats.
Ex vivo vas deferens contractility assay reporting estimated EC50 values.
Treatment of neurological disorder by administering an effective amount of a specified compound.
Therapeutic use for post-stroke neurological deficits during rehabilitation, including motor deficit and cognitive deficit, during acute and post-stroke stages.
Therapeutic use for post-traumatic brain injury neurological deficits during post-TBI rehabilitation.
Combining NOP inhibition with task-based training while reducing training dose in rehabilitation contexts for post-stroke and post-TBI neurological deficits.
Peripheral disorders with altered nociceptin/NOP and cases involving reduced dopaminergic signaling.
Pharmaceutical composition including the compound or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
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