Substituted pyridine and pyrazine compounds as PDE4 inhibitors

Inventors

Bollu, Venkataiah • Breitenbucher, James • Kaplan, Alan • Lemus, Robert • Lindstrom, Andrew • VICKERS, Troy • Wilson, Mark • Zapf, James

Assignees

Dart Neuroscience LLC

Abstract

The invention provides a chemical entity of Formula (I) wherein R1, R2, R3, R4, Y and Z 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, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.

Core Innovation

The disclosure concerns chemical entities of Formula (I), including pharmaceutically acceptable salts, where Z is N, R1 is H, and Y is CH2. The core structure allows R2 to be a phenyl substituted with one or two Rd members, a six-membered monocyclic heteroaromatic ring, a five-membered monocyclic heteroaromatic ring, or an oxazole optionally substituted with one or two Rb members, while R3 is phenyl substituted with Cl, OC1-3 alkyl, or OC1-3 haloalkyl and R4 is C1-3 alkyl.

The disclosure also includes specific enumerated chemical entities within the same small-molecule family, including pyrimidine-, pyrazine-, pyridine-, and pyridazine-related structures bearing difluoromethoxy, chlorophenyl, methoxy, ethoxy, and heterocycle moieties such as triazole, imidazole, pyrazole, tetrazole, thiazole, and oxazole-related substituents. The examples provide characterization data for multiple numbered compounds, including 1H NMR and [M+H] mass values, and identify some compounds as TFA salts.

The document frames the chemical entities in connection with PDE4 enzymatic activity and includes a pharmaceutical composition comprising an effective amount of at least one chemical entity of Formula (I) together with a pharmaceutically acceptable excipient. It also refers to treatment of diseases or medical conditions mediated by PDE4 enzymatic activity and links the compounds to neurological, cognitive, psychiatric, inflammatory, respiratory, peripheral inflammatory, renal, and other medical conditions.

Claims Coverage

The independent claim coverage centers on a defined Formula (I) chemical entity family, an independent pharmaceutical composition claim, and an independent claim to a selected group of specific small-molecule structures. Across these claims, the main inventive features are the Formula (I) structural definition with constrained R2, R3, R4, and Rb selections, the composition format, and the enumerated chemical entity selection, all including pharmaceutically acceptable salts.

Overall, the claims cover a structurally defined Formula (I) chemical entity family with explicit substitution constraints, a pharmaceutical composition using those entities, and an additional independent set of enumerated chemical structures, each with pharmaceutically acceptable salt coverage.

Stated Advantages

Documented Applications