Metalloenzyme inhibitor compounds
Inventors
Sparks, Steven • Yates, Christopher M. • Shaver, Sammy R.
Assignees
Corxel Pharmaceuticals Hong Kong Ltd • Mycovia Pharmaceuticals Inc
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Publication Number
US-11919883-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The disclosure relates to a compound of Formula I, including pharmaceutically acceptable salts, with a constrained ring-atom selection at A, W, X, Y, and Z. A is N or CR5, each of W, X, Y, and Z is N or CR6, and no more than two of W, X, Y, and Z are N. The substituent framework includes R1 through R6 and variable indices n with broad definitions across the scaffold.
The document describes pyrimidine-containing Formula I compounds, benzimidazole-pyrimidine compounds, and other substituted bicyclic or heteroaryl compounds consistent with the Formula I scaffold. Example compounds are reported with analytical characterization such as HPLC, LC-MS, 1H NMR, purity, retention time, and [M+H] or [M−H] values. The disclosure also includes example substituted compounds and related synthetic exemplification.
The invention identifies aldosterone synthase (CYP11B2) as a target in order to avoid CYP11B1 inhibition, and it evaluates pyrimidine-containing compounds for CYP11B2 inhibition, CYP11B1/CYP11B2 selectivity, and metabolic stability. The overall core innovation is the selection of the defined Formula I scaffold and related substitutions to achieve the stated target profile and compound properties.
Claims Coverage
The claim coverage centers on a Formula I compound, or pharmaceutically acceptable salt thereof, defined by a constrained heteroatom pattern at A/W/X/Y/Z and broad substituent options for R1-R6 with index n. Across the provided material, the main inventive coverage includes the Formula I scaffold, the no more than two N-atoms constraint among W, X, Y, and Z, fixed cyclopropyl at R4, and dependent narrowing of substituent choices. A pharmaceutical composition with a pharmaceutically acceptable carrier is also recited.
Formula I compound with constrained heteroatom pattern
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is N or CR5; W, X, Y, and Z are each N or CR6; and no more than two of W, X, Y, and Z are N.
Broad substituent definitions for R1-R3 and ring-index variability
R1, R2, and R3 are defined by broad substituent lists including hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and nitrogen- or oxygen-containing forms; each n is independently 1 to 10.
Cyclopropyl substitution and defined R5/R6 variability
R4 is cyclopropyl; R5 is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; and each occurrence of R6 is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition containing a compound, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claim coverage focuses on the Formula I scaffold with the W/X/Y/Z heteroatom constraint, cyclopropyl at R4, and broad but enumerated substitution sets for R1-R3 and R5-R6. The provided claims also include a pharmaceutical composition claim using a pharmaceutically acceptable carrier.
Stated Advantages
Potent CYP11B2 activity.
Improved selectivity versus CYP11B1.
Greater metabolic stability in cynomolgus and rat liver microsomes.
Avoiding CYP11B1 inhibition while targeting aldosterone synthase (CYP11B2).
Inhibiting or modulating metalloenzyme activity for treating metalloenzyme- or metalloenzyme-mediated disorders, including hypertension and primary hyperaldosteronism.
Documented Applications
CYP11B2 inhibition and CYP11B1/CYP11B2 selectivity evaluation.
Metabolic stability assessment in cynomolgus liver microsomes and rat liver microsomes.
Analytical characterization of example compounds using HPLC/LCMS, 1H NMR, purity, retention time, and mass values.
Treating metalloenzyme- or metalloenzyme-mediated disorders, including hypertension and primary hyperaldosteronism.
Therapeutic methods for modulating metalloenzyme activity using the described Formula I compounds and salts.
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