Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use

Inventors

Chu, Hang • Gonzalez Buenrostro, Ana Z. • Guo, Hongyan • Han, Xiaochun • Jiang, Lan • Li, Jiayao • Mitchell, Michael L. • Pyun, Hyung-Jung • Schroeder, Scott D. • Schwarzwalder, Gregg M. • Shapiro, Nathan D. • Shivakumar, Devleena M. • Wu, Qiaoyin • Yang, Hong • Zhang, Jennifer R.

Assignees

Gilead Sciences Inc

Abstract

Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, L, W1, W2, X, Y, and Z are as defined herein. Methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Core Innovation

The disclosure concerns fluorinated heterocyclic carboxamides, fluorinated methanopyrido diazonine carboxamides, and fluorinated diazonine-containing compounds that are available in multiple enantiomerically defined forms and as pharmaceutically acceptable salts. The compounds include fluorinated heterocycles and fluorinated benzyl carbamoyl groups, with examples bearing 2,4-difluorobenzyl and 2,4,6-trifluorobenzyl substituents and related hydroxy or carboxamide forms.

The disclosure describes selected compounds having structural frameworks including rings A, B, and C, with stereochemical orientations and ring variants including bridged ring, fused ring, and spirocyclic ring configurations. The structural scope is expressed across multiple formula sets, including formula I, formula II, formulas IIIa and IIIb, formula IV, formulas Va and Vb, formula VI, formulas VIIa and VIIb, formula VIII, formulas IX/IXa/IXb, formulas X/Xa/Xb, and formulas XI/XIa/XIb.

The patent content also relates to bridged tricyclic carbamoylpyridone anti-HIV compounds defined by a core scaffold formula and related variant formulas, including stereoisomers and pharmaceutically acceptable salts. It states pharmaceutical compositions and treatment or prophylaxis uses for HIV infection, and identifies integrase inhibition, reduced drug-drug interaction propensity, activity against drug-resistant HIV mutants, and suitability for less-than-daily dosing schedules.

The disclosure further includes fused methanopyrido[1,2-a][1,4]diazonine and benzo[g]pyrido[1,2-a][1,4]diazonine carboxamide derivatives, including stereochemical variants such as enantiomers and diastereomers. It describes preparation and characterization of multiple carboxamide derivatives, with stereochemical separation by preparative SFC, chiral HPLC/SFC separation, RP-HPLC, and X-ray crystallography confirmation for some compounds, together with MS and 1H NMR characterization.

Claims Coverage

The independent claims are directed to selected compounds from specified groups, or pharmaceutically acceptable salts thereof. Across the claim families, the inventive features focus on the selected compound group and dependent pharmaceutical compositions that include a therapeutically effective amount, a pharmaceutically acceptable excipient, and optionally one to four additional therapeutic agents, including anti-HIV agents in further refinements. Two independent claims are present in some excerpts, while the claim structure is repeated across multiple compound families.

The claim coverage centers on selected compounds from specified groups, or pharmaceutically acceptable salts, and extends to pharmaceutical compositions containing a therapeutically effective amount and a pharmaceutically acceptable excipient. The dependent claims further allow one to four additional therapeutic agents, with anti-HIV agents specified in further refinements.

Stated Advantages

Documented Applications