Compounds and their use as BACE1 inhibitors

Inventors

CHERUKURY, Madhu • LIN, Hsiao-Wen • YU, Shu Chieh • PHANG, Riping • RAJAN, Yesudoss Christu • TANG-LIU, Diane Dan-Shya • White, Andrew D. • Malone, Thomas • Beresis, Richard

Assignees

Allgenesis Biotherapeutics Inc

Abstract

The present invention relates to compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X, Y, Z, Q, W, m, u, ring (A), R2, R3, R4, R5 and R6, are as defined in the specification and claims. The present invention provides a pharmaceutical composition containing the compounds of Formula (I) and a therapeutic method of treating and/or preventing Downs syndrome, 3-amyloid angiopathy, disorders associated with cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative diseases, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, Alzheimer's disease and/or Down syndrome, age-related macular degeneration (AMD), glaucoma, olfactory function impairment, traumatic brain injury, progressive muscle diseases, Type II diabetes mellitus and cardiovascular diseases (stroke).

Core Innovation

The patent describes compounds according to Formula (VI), with X selected from C(O) and S(O)2, Y selected as (CR7R8)n or CH2, Z absent, and W absent or present with alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR9, O, NR9R10, NR9, C(O)R9, C(O)NR9, NR9C(O), C(O)OR9, OC(O)R9, and heterocycloalkyl options. The framework further defines Q as selected from O, S, NR1, (CR14R15)t, or C(O), together with Gi and Gii selections and a single bond between Gi and Gii.

The structural definition also specifies extensive substituent coverage for Ri, Rii, Riii, Riv, Rv, Rvi, Rvii, and Rviii, including hydrogen, halogen, cyano group, amino group, amido group, alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, with optional mono-, di-, or tri-substitution and optional fusion. The disclosure includes stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, solvates, and solvate of a salt thereof.

The patent presents preferred and enumerated examples within the tetrahydropyrimidin-4(1H)-one, imino, and thiomorpholine 1,1-dioxide scaffold space, including dibenzo[b,d]thiophene and related fused heteroaryl motifs, alkynyl substituents, fluorinated substituents, and stereochemically defined compounds. It also identifies named stereoisomeric forms and prodrug-like substituents such as benzoate, palmitamide, and related ester or amide derivatives, and ties the compounds to BACE1 inhibitors and to treatment of Alzheimer’s disease.

Claims Coverage

The consolidated claim coverage centers on compound claims according to Formula (VI), with independent claims defining different selections and constraints for X, Y, Z, W, Q, Gi, Gii, and the Ri through Rviii substituent set. In total, three independent claim patterns are represented, with one pattern using broader X options and two patterns narrowing X to C(O) and S(O)2, including one with Y fixed as CH2. All independent claims retain coverage of stereoisomers, tautomers, prodrugs, and pharmaceutically acceptable salts/solvates.

The claim coverage is centered on a Formula (VI) compound family defined by constrained selections for X, Y, Z, W, Q, Gi, Gii, and multiple R variables, with one independent claim fixing Y as CH2 and others retaining broader Y definitions. The claims also expressly cover stereoisomers, tautomers, prodrugs, and pharmaceutically acceptable salts and solvates, while dependent claim content extends to pharmaceutical composition and Alzheimer’s disease treatment contexts.

Stated Advantages

Documented Applications