BCKDK inhibitors and/or degraders
Described herein are compounds of Formula I, wherein the variables are defined herein, their use as branched-chain alpha keto acid dehydrogenase kinase inhibitors and/or degraders, pharmaceutical compositions containing such compounds and their use to treat, for example, diabetes, kidney disease, NASH and heart failure.
1. A compound of Formula I
wherein
Z is S;
A is
X 1 is CR 11 ;
each of R 1 , R 3 and R 4 are independently selected from H;
R 2 is fluoro;
each of R 5 , R 6 , R 7 , R 8 , R 9 and R 11 are independently selected from H, halo, hydroxyl, amino, cyano, (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) fluoroalkyl, (C 3 -C 6 ) fluorocycloalkyl, (C 1 -C 4 ) fluoroalkoxy, or (C 1 -C 4 ) alkyl-(C 1 -C 4 ) alkoxy; and
R 10 is H, fluoro, chloro, cyano, or (C 1 -C 4 ) alkyl;
wherein at least one R 5 , R 6 , R 7 , R 10 and R 11 is other than H;
or a pharmaceutically acceptable salt of said compound.
2. The compound as recited in claim 1 , wherein R 5 is fluoro, chloro, cyano or (C 1 -C 4 ) alkyl and R 10 is H, fluoro or chloro; and wherein R 6 and R 7 are each independently selected from H, fluoro, chloro, cyano, (C 1 -C 4 ) alkyl, and (C 1 -C 4 ) alkoxy; or a pharmaceutically acceptable salt thereof.
3. The compound as recited in claim 2 , wherein R 11 is H, fluoro, chloro, cyano, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkoxy; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is:
6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;
6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;
3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid;
3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2;
3-(3-chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid;
3-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; or
ammonium 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylate;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is:
6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; or
3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2;
or a pharmaceutically acceptable salt thereof.
6. A method of treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis or hepatocellular carcinoma comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
7. A method of treating or reducing the risk of hospitalization for heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with midrange ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with Type II diabetes mellitus, coronary heart disease, unstable angina, peripheral arterial disease peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndromes or modification of cardiovascular risk comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
8. A method of treating Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, skin or connective tissue disorders, foot ulcerations or ulcerative colitis, endothelial dysfunction or impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease at risk of progression, or maple syrup urine disease comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
9. A method of treating hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, lung adenocarcinoma comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
11. A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the compound is crystalline, and has an X-ray powder diffractogram comprising diffraction peaks at 7.6±0.2, 14.6±0.2, and 27.9±0.2, as determined on a diffractometer using Cu-Kα radiation with a wavelength of 1.54056 Å.
13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the compound has an amorphous form.
14. A compound, wherein the compound is
15. A compound, wherein the compound is:
or a mixture thereof;
or a pharmaceutically acceptable salt of said compound or mixture of compounds.
16. A compound, wherein the compound is
or a mixture thereof.