Metalloenzyme inhibitor compounds

A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound is:

• 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (2);
• 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (3);
• 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (4);
• 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (6);
• 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (7);
• N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8);
• ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (9);
• 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (10);
• 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (12);
• 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (13);
• 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (14);
• 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (15);
• N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16);
• 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (18);
• 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (19);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (21);
• 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22);
• 1-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (23);
• 1-cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (24);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine (25);
• 1-cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole (27);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (28);
• 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (29);
• N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (31);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (32);
• 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (33);
• 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (34);
• 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (35);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (42);
• 2-(6-cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (43);
• 1-cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (44);
• 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45);
• 1-cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (46);
• 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (47);
• 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (49);
• 1-cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole (50);
• 1-cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (51);
• N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl) ethanesulfonamide (52);
• 1-cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole (53);
• 3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (54);
• 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (55);
• 1-cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (57);
• 1-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (59);
• 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60);
• 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (61);
• 1-cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (62);
• 1-cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5, 6-difluoro-1H-benzo[d]imidazole (63);
• 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (64);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (66);
• 1-cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5, 6-difluoro-1H-benzo[d]imidazole (70);
• 1-cyclopropyl-5, 6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (71);
• 5-chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (73);
• 1-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (75);
• 3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (76);
• N-((5-(1-cyclopropyl-5, 6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)methane sulfonamide (77);
• N-((5-(1-cyclopropyl-5, 6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2-sulfonamide (79);
• 1-cyclopropyl-5,6-difluoro-2-(6-(methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazole (80);
• 1-cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (81);
• 1-cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazole (82);
• 1-cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (83);
• 5-chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84);
• 1-cyclopropyl-5, 6-difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (85);
• 1-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86);
• 3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (87);
• 3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (89);
• 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (90);
• N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl) methanesulfonamide (91);
• 1-cyclopropyl-5,6-difluoro-2-(6-(fluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (92);
• 1-cyclopropyl-2-(5,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (93);
• (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (94);
• 5-chloro-3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (95);
• N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl) ethanesulfonamide (96);
• 2-(6-butylpyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (97);
• 1-cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (98);
• 1-cyclopropyl-2-(3,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (100);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6,7-difluoro-1H-benzo[d]imidazole (101);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-thiol (102);
• 4-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5,6,7,8-tetrahydrocinnoline (106);
• 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-5-carbonitrile (107);
• 1-cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (108);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-ol (109);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (110);
• 1-cyclopropyl-7-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (111);
• 5-chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (112);
• 4-chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (113);
• 1-cyclopropyl-5,6-difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (114);
• methyl 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (115);
• 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (116);
• 1-cyclopropyl-2-(6-(cyclopropylmethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (117);
• 1-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (118);
• 6-chloro-1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole (119);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole-6-carbonitrile (120);
• 4-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridazine (121);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (122);
• 1-cyclopropyl-5,6-difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (123);
• 1-cyclopropyl-5,6-difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (124);
• 1-cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (125);
• 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-ol (126);
• 1-cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (127);
• 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-ol (128);
• 1-cyclopropyl-5,6-difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (129);
• 1-cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazole (130);
• 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (131);
• 1-cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (133);
• or
• 1-cyclopropyl-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (136).

A method of inhibiting aldosterone synthase (CYP11B2) activity in a subject comprising contacting the subject with a compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein
• A is N;
• W is N or CR6;
• X is N or CR6;
• Y is N or CR6;
• Z is N or CR6;
• provided that no more than two of W, X, Y, and Z are N;
• R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, —NRaRb, —NHSO2Rc, —CH2NRaRb, —CReRfNHSO2Rd, —ORf, —SRf, —CO2Re, —CORf, —S(O)Rd, —S(O)2Rd, —CH2ORf, or —CReRfOH, wherein any R1 can be optionally substituted with 1-3 independent substituents R7;
• R2 is hydrogen, halogen, cyano, alkyl, or haloalkyl;
• or R1 and R2 together with the atoms to which they are attached form an aryl, or cycloalkyl ring;
• R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, —NRaRb, —NHSO2Rc, —CH2NRaRb, —CH2NHSO2Rd, —CO2Re, —CORf, —CH2ORf, or —CReRfOH;
• R4 is cycloalkyl;
• each occurrence of R6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, ORf, or carboxyl;
• each occurrence of R7 is, independently, halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with 1-3 independent halogen, —(CH2)nC(O)NRgRh, —S(O)2Ri, —CO2Rj, or —NRgRh,
• each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each occurrence of Ra, Rb, Rc, Rd, Re, and Rf is, independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —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;
• and
• each occurrence of Rg, Rh, Ri, and Rj is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)OC1-6 alkyl, —C(O)C1-6 alkyl, or Rg and Rh together with the atoms to which they are attached form a heterocycloalkyl ring.

A method of alleviating or abating a disorder or disease or ameliorating a symptom thereof, comprising administering to a subject an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein
• A is N;
• W is N or CR6;
• X is N or CR6;
• Y is N or CR6;
• Z is N or CR6;
• provided that no more than two of W, X, Y, and Z are N;
• R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, —NRaRb, —NHSO2Rc, —CH2NRaRb, —CReRfNHSO2Rd, —ORf, —SRf, —CO2Re, —CORf, —S(O)Rd, —S(O)2Rd, —CH2ORf, or —CReRfOH, wherein any R1 can be optionally substituted with 1-3 independent substituents R7;
• R2 is hydrogen, halogen, cyano, alkyl, or haloalkyl;
• or R1 and R2 together with the atoms to which they are attached form an aryl, or cycloalkyl ring;
• R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, —NRaRb, —NHSO2Rc, —CH2NRaRb, —CH2NHSO2Rd, —CO2Re, —CORf, —CH2ORf, or —CReRfOH;
• R4 is cycloalkyl;
• each occurrence of R6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, ORf, or carboxyl;
• each occurrence of R7 is, independently, halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with 1-3 independent halogen, —(CH2)nC(O)NRgRh, —S(O)2Ri, —CO2Rj, or —NRgRh,
• each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• each occurrence of Ra, Rb, Rc, Rd, Re, and Rf is, independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —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;
• and
• each occurrence of Rg, Rh, Ri, and Rj is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)OC1-6 alkyl, —C(O)C1-6 alkyl, or Rg and Rh together with the atoms to which they are attached form a heterocycloalkyl ring,
• wherein the disorder or disease is hypertension, resistant hypertension, primary or secondary hyperaldosteronism, 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, atherosclerosis, 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.