5-(thiophen-2-yl)-1 H-tetrazole derivative as BCKDK inhibitors useful for treating various diseases
Inventors
Bhattacharya, Samit Kumar • BUTLER, Christopher Ryan • Filipski, Kevin James • Kormos, Bethany Lyn • Martinez-Alsina, Luis Angel • Miller, Russell Alan • Omoto, Kiyoyuki • Raymer, Brian • Reese, Matthew Richard • Roth Flach, Rachel Jane • Zhang, Yuan
Assignees
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Publication Number
US-12715863-B2
Publication Date
2026-08-25
Expiration Date
Abstract
Described herein are compounds of Formula I, wherein R1, R2, and R3 are defined herein, their use as branched-chain alpha keto acid dehydrogenase kinase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, diabetes, NASH and heart failure.
Core Innovation
The disclosed invention comprises substituted thiophenyl-1H-tetrazoles of Formula I and pharmaceutically acceptable salts thereof, including pharmaceutical formulations and crystalline forms. These compounds act as BCKDK inhibitors that promote BCKDH activity and branched-chain amino-acid catabolism. The claimed subject matter encompasses defined substituent alternatives for R1, R2, and R3, eight specified individual thiophenyl-tetrazoles, and crystals comprising recited chemical structures.
The disclosure also includes crystalline Forms 1 of Examples 6 and 10 characterized by powder X-ray diffraction peaks. In vivo evaluation indicates that Example 1 reduces fasting glucose and glucose-tolerance-test area under the curve to 72% of vehicle in high-fat-diet mice. Documented applications comprise the treatment of metabolic disorders, fatty liver diseases such as NASH and NAFLD, cardiovascular conditions, and cancers.
Claims Coverage
The patent claims define six inventive features across independent claims 1, 10, 12, 14, 30, and 32, covering Formula I compounds, specified thiophenyl-1H-tetrazoles, and crystalline forms.
Formula I compounds and salts
Claim 1 covers a compound of Formula I with specified alternatives for R1, R2, and R3, or a pharmaceutically acceptable salt thereof, encompassing halogens, amino, cyano, ethynyl, alkyl, cycloalkyl, alkoxy, fluoroalkyl, and fluoroalkoxy groups, subject to the stated condition when R2 and R3 are H.
Specified substituted thiophenyl-1H-tetrazoles
Claim 10 covers a group of eight specified substituted thiophenyl-1H-tetrazole compounds or pharmaceutically acceptable salts thereof: 5-(5-chloro-4-fluoro-3-methylthiophen-2-yl)-1H-tetrazole; 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazole; 5-(5-fluoro-3-methylthiophen-2-yl)-1H-tetrazole; 5-(5-chloro-3-methylthiophen-2-yl)-1H-tetrazole; 5-(3,5-dichlorothiophen-2-yl)-1H-tetrazole; 5-(4-bromo-3-methylthiophen-2-yl)-1H-tetrazole; 5-(4-bromo-3-ethylthiophen-2-yl)-1H-tetrazole; and 5-(4-chloro-3-ethylthiophen-2-yl)-1H-tetrazole.
5-(5-chloro-4-fluoro-3-methylthiophen-2-yl)-1H-tetrazole
Claim 12 covers 5-(5-chloro-4-fluoro-3-methylthiophen-2-yl)-1H-tetrazole or a pharmaceutically acceptable salt thereof.
5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazole
Claim 14 covers 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazole or a pharmaceutically acceptable salt thereof.
First crystal comprising a recited compound
Claim 30 covers a crystal comprising a compound having the structure recited in that claim, or a pharmaceutically acceptable salt thereof, with dependent claim 31 further characterizing the crystal by powder X-ray diffraction peaks at 2-theta values of 10.6, 15.9, 23.5, and 32.1 degrees (each ±0.2 degrees).
Second crystal comprising a recited compound
Claim 32 covers a crystal comprising a compound having the structure recited in that claim, or a pharmaceutically acceptable salt thereof, with dependent claim 33 further characterizing the crystal by powder X-ray diffraction peaks at 2-theta values of 24.5, 26.8, 33.9, and 39.1 degrees (each ±0.2 degrees).
The independent claims cover a broad Formula I genus, eight specified substituted thiophenyl-tetrazoles, two individually designated compounds, and two crystal forms defined by recited chemical structures, along with pharmaceutically acceptable salts thereof.
Stated Advantages
The compounds act as BCKDK inhibitors that promote BCKDH activity and branched-chain amino-acid catabolism, with reported BCKDK assay IC50 values across several examples.
Treatment with Example 1 reduces fasting glucose and glucose-tolerance-test area under the curve to 72% of vehicle in high-fat-diet mice.
Documented Applications
Treatment of fatty liver disease, including nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).
Treatment of diabetes and related metabolic disorders.
Treatment of cardiovascular diseases and conditions, including heart failure, congestive heart failure, coronary heart disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndromes, and modification of cardiovascular risk.
Treatment of cancer conditions.
Pharmaceutical compositions and combination compositions containing a claimed compound or salt and a pharmaceutically acceptable carrier, vehicle, or diluent.
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