Metalloenzyme inhibitor compounds
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
1. A method of reducing one or more symptoms of an aldosterone related disease or disorder in a subject suffering from said disease or disorder, comprising administering to said subject in need thereof, an effective amount of a compound of the formula
or a pharmaceutically acceptable salt thereof; wherein
A is N;
W is CR6;
X is CR6;
Y is CR6;
Z is CR6;
R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHSO2Rc, (CH2)nNRaRb, (CH2)nNHSO2Rd, (CH2)nNHCO2Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH;
R2 is hydrogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NHSO2Rc, CH2NRaRb, CH2NHSO2Rd, CO2Re, CORf, CH2ORf, or CReRfOH;
R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHSO2Rc, (CH2)nNRaRb, (CH2)nNHSO2Rd, CO2Re, CORf, (CH2)nORf, or CReRfOH;
each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl;
each occurrence of R6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl; and
each occurrence of Ra, Rb, Rc, Rd, Re, and Rf are, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC1-6 alkyl, C(O)C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or Ra and Rb together with the atoms to which they are attached form a heterocycloalkyl ring; or Re and Rf together with the atoms to which they are attached form a cycloalkyl ring.
2. The method of claim 1 , wherein the aldosterone related disorder or disease is mediated by aldosterone synthase (CYP11B2) or 11-beta-hydroxylase (CYP11B1).
3. The method of claim 1 , wherein the aldosterone related disorder or disease is cardiovascular disease, endocrinologic disease, inflammatory disease, gynecologic disease, urologic disease, or gastrointestinal disease.
4. The method of claim 1 , wherein the aldosterone related disorder or disease is hypertension, resistant hypertension, morbidities associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction, coronary heart disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling following hypertension, fibrosis and matrix remodeling following endothelial cell dysfunction, cardiovascular diseases, atrial fibrillation, renal dysfunction, liver diseases, non-alcoholic steatohepatitis, vascular diseases, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, fibrinoid necrosis of the arteries, kidney diseases, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephritic syndrome, polycystic kidney disease, diabetes mellitus, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, liver cirrhosis, non-alcoholic fatty liver disease, renal disorders, diabetic renal disorders, or stroke.