Substituted aminopropionic derivatives as neprilysin inhibitors

Abstract

The present invention provides a compound of formula I′; or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 5 , B 1 , X and n are defined herein. The invention also relates a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

What is claimed is: 
     
         1 - 19 . (canceled) 
     
     
         20 . A compound according to Formula VII or VIIA: 
       
         
           
           
               
               
           
         
         wherein R 1  is H; 
         R 2  is independently halo, C 1-7 alkoxy, hydroxy, C 1-7 alkyl or halo-C 1-7 alkyl; 
         n is 0, 1 or 2; 
         X is independently OH or —O—C 1-7 alkyl, 
         A 2  is a bond or CH 2  or CH 2 —CH 2 ; 
         R4 is a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-7 alkyl, C 1-7 alkoxy, halo, halo-C 1-7 alkyl or benzyl. 
       
     
     
         21 . The compound of  claim 20  wherein R 2  is meta-chloro or meta-fluoro and the other optional R 2  group is halo, C 1-7 alkyl, halo-C 1-7 alkyl, hydroxy and C 1-7 alkoxy, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound according to  claim 20  wherein R 4  is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, pyranone, pyridinone, pyrimidinone; or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The compound according to  claim 21  wherein R 4  is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, pyranone, pyridinone, pyrimidinone; or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The compound according to  claim 20  wherein R 4  is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene, imidazole and thiadiazole; or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound according to  claim 21  wherein R 4  is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene, imidazole and thiadiazole; or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound according to  claim 20  wherein R 4  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The compound according to  claim 21  wherein R 4  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 20  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         29 . A combination comprising: a compound according to  claim 20 , or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker, angiotensin converting enzyme Inhibitor, a calcium channel blocker, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors, a CETP inhibitor and a phosphodiesterase of type 5 (PDE5) inhibitor. 
     
     
         30 . A method of inhibiting neutral endopeptidase EC. 3.4. 24.11. activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound according to  claim 20 , or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method according to  claim 30 , wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, polycystic kidney disease (PKD), pulmonary arterial hypertension, renal failure, cyclical oedema, Menières disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.