Tricyclic compounds and their use as phosphodiesterase inhibitors
Inventors
Chappie, Thomas Allen • Patel, Nandini Chaturbhai • Verhoest, Patrick Robert • Helal, Christopher John • Sciabola, Simone • LaChapelle, Erik Alphie • Wager, Travis T. • Chandrasekaran, Ramalakshmi Yegna
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11472805-B2
Publication Date
2022-10-18
Expiration Date
Abstract
The present invention is directed to compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein the substituents A, R1, R2, R3a, R3b, R4a, R4b and n are as defined herein. The inventions also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds and methods of preparing the compounds.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, in which Ring A is a fused (5- to 6-membered) nitrogen-containing heteroaryl ring optionally substituted with one R8. The substituent selections for R1, R2, R3a, R3b, R4a, R4b, R5, R6, R7, R8, and R9 define a broad set of compounds, including optional substitution patterns and a conditional single or double bond relationship controlled by n.
The invention further includes compound subsets in which Ring A is restricted to specific fused heteroaryl rings such as pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, and selected compounds from a listed group of specific structures or pharmaceutically acceptable salts thereof. The disclosure also includes specific compound embodiments and crystallographic, NMR, LCMS, and structural characterization for example compounds.
The described subject matter also relates to the treatment of PDE4B-isoform-mediated disease or condition by administering a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt thereof. The documented conditions include schizophrenia, depression, anxiety, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cerebral vascular disease, allergic conjunctivitis, psychosis, psoriatic arthritis, autoimmune and inflammatory diseases, traumatic brain injury, and behavioral disorders due to drug dependence and abuse.
Claims Coverage
The document provides independent claim coverage for Formula I compounds with detailed Ring A and substituent constraints, a selected-compound claim directed to listed specific structures, and a therapeutic-use claim for PDE4B-isoform-mediated disease or condition. Across these claims, the inventive features center on the Formula I scaffold, restricted Ring A embodiments, specific compound selection, and the treatment use.
Formula I compound with fused nitrogen-containing heteroaryl Ring A and substituent constraints
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring A is a fused (5- to 6-membered) nitrogen-containing heteroaryl ring optionally substituted with one R8; R1 and R2 are selected from their defined groups with optional substitution by R9; R3a is hydrogen or (C1-C6)alkyl, and R2 and R3a together form a (4- to 6-membered) heterocycloalkyl ring; R3b, R4a, and R4b are hydrogen where present; R5 and R6 are each independently hydrogen or (C1-C6)alkyl; R7 is (C1-C6)alkyl; R8 is fluoro, chloro, or (C1-C6)alkyl when present; R9 is independently selected from the defined substituent list; and n controls the single or double bond condition.
Ring A selected from pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, each optionally substituted with one R8; R8 is fluoro when present; and the remaining substituent and bond constraints follow the defined Formula I limitations.
Selected compound from a defined group or pharmaceutically acceptable salt thereof
A compound selected from the group consisting of the listed compounds, or a pharmaceutically acceptable salt thereof.
Therapeutic method for PDE4B-isoform-mediated disease or condition
A method treating a PDE4B-isoform-mediated disease or condition by administering to a patient a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt thereof.
The claims coverage centers on Formula I compounds defined by fused nitrogen-containing heteroaryl Ring A, detailed substituent-selection rules, optional fluoro or chloro substitution at R8, the conditional bond feature governed by n, and specific listed compound selection. The independent claim set also includes a therapeutic-use claim for PDE4B-isoform-mediated disease or condition.
Stated Advantages
Documented Applications
Treating a PDE4B-isoform-mediated disease or condition by administering to a patient a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt thereof. Conditions explicitly listed include schizophrenia, depression, anxiety, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, inflammation, stroke, asthma, cerebral vascular disease, allergic conjunctivitis, psychosis, psoriatic arthritis, autoimmune and inflammatory diseases, traumatic brain injury, and behavioral disorders due to drug dependence and abuse.
Interested in licensing this patent?