sGC STIMULATORS

Abstract

Compounds of Formulae I′ and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

1 - 140 . (canceled) 
     
     
         141 . A compound represented by Formula XIa or Formula XIb: 
       
         
           
           
               
               
           
         
         wherein J B  is halogen; 
         R 1  is hydrogen or C 1-6  alkyl; 
         R 2  is a C 1-6  alkyl group optionally and independently substituted by up to three instances of R 5a ; 
         each R 5a  is independently selected from halogen, —CN, C 1-6  alkyl, —(C 1-6  alkyl)R 6a , —OR 6a , —SR 6a , —COR 6a , —OC(O)R 6a , —C(O)OR 6a , —C(O)N(R 6a )SO 2 R 6a , —N(R 6a )C(O)R 6a , —N(R 6a )C(O)OR 6a , —N(R 6a )C(O)N(R 6a ) 2 , —N(R 6a ) 2 , —SO 2 R 6a , —SO 2 OH, —SO 2 NHOH, —SO 2 N(R 6a ) 2 , —SO 2 N(R 6a )COOR 6a , —SO 2 N(R 6a )C(O)R 6a , —N(R 6a )SO 2 R 6a , —(C═O)NHOR 6a , a C 3-8  cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a bicyclic group: wherein each 5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein each of said C 1-6  alkyl, C 1-6  alkyl portion of the —(C 1-6  alkyl)R 6a  moiety, C 3-8  cycloalkyl ring, 4 to 7-membered heterocyclic ring, 5 or 6-membered heteroaryl ring, benzyl or phenyl group is optionally and independently substituted with up to 3 instances of halogen, C 1-4  alkyl, C 1-4  haloalkyl, —OH, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CN, —COOH, —CONH 2 , —COO(C 1-4  alkyl), —O(C 1-4  alkyl), —O(C 1-4  haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two in a fused or bridged relationship, said ring one is a 4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted by up to six instances of halogen, C 1-4  alkyl, —OH, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CN, —COOH, —CONH 2 , —COO(C 1-4  alkyl), —O(C 1-4  alkyl), —O(C 1-4  haloalkyl) or oxo; and 
         each R 6a  is independently selected from hydrogen, a C 1-6  alkyl, phenyl, benzyl, a C 3-8  cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each of said C 1-6  alkyl, each of said phenyl, each of said benzyl, each of said C 3-8  cycloalkyl group, each of said 4 to 7-membered heterocyclic ring and each of said 5 or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 instances of halogen, C 1-4  alkyl, —OH, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CN, —COOH, —C(O)NH 2 , —C(O)N(C 1-6  alkyl) 2 , —C(O)NH(C 1-6  alkyl), —C(O)N(C 1-6  haloalkyl) 2 , —C(O)NH(C 1-6  haloalkyl), C(O)N(C 1-6  alkyl)(C 1-6  haloalkyl), —COO(C 1-6  alkyl), —COO(C 1-6  haloalkyl), —O(C 1-4  alkyl), —O(C 1-4  haloalkyl) or oxo, wherein each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S. 
       
     
     
         142 . The compound of  claim 141 , or a pharmaceutically acceptable salt thereof, wherein R 2  is a C 1-3  alkyl group optionally and independently substituted by up to three instances of R 5a ; wherein each instance of R 5a  is independently selected from hydroxyl and C 1-2  haloalkyl. 
     
     
         143 . (canceled) 
     
     
         144 . A pharmaceutical composition comprising a compound of  claim 141 , or a pharmaceutically acceptable salt thereof, and one or more excipients. 
     
     
         145 . A method of treating a disease, health condition or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of the compound of  claim 141 , or a pharmaceutically acceptable salt thereof, to the subject in need of treatment, wherein the disease, health condition or disorder is selected from:
 (1) a peripheral, pulmonary, hepatic, kidney, cardiac or cerebral vascular/endothelial disorders/conditions or diseases otherwise related to circulation selected from:
 disorders related to high blood pressure and decreased coronary blood flow; increased acute and chronic coronary blood pressure; arterial hypertension; vascular disorder resulting from cardiac and renal complications, heart disease, stroke, cerebral ischemia or renal failure; resistant hypertension; diabetic hypertension; congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; reduction of ventricular preload; cardiac hypertrophy; heart failure/cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; 
 thromboembolic disorders and ischemias; myocardial infarction; stroke; transient ischemic attacks (TIAs); obstructive thromboanginitis; stable or unstable angina pectoris; coronary spasms; variant angina; Prinzmetal's angina; restenosis resulting from thrombolysis therapies; thrombogenic disorders; 
 Alzheimer's disease; Parkinson's disease; dementia; vascular cognitive impairment; cerebral vasospasm; traumatic brain injury; 
 peripheral arterial disease; peripheral occlusive arterial disease; peripheral vascular disease; hypertonias; Raynaud's syndrome or phenomenon; critical limb ischemia; vasculitis; peripheral embolism; intermittent claudication; vaso-occlusive crisis; Duchene's muscular dystrophy; Becker muscular dystrophy; microcirculation abnormalities; vascular leakage or permeability issues; 
 shock; sepsis; cardiogenic shock; control of leukocyte activation; inhibition or modulation of platelet aggregation; 
 pulmonary/respiratory conditions; pulmonary hypertension; pulmonary arterial hypertension and associated pulmonary vascular remodeling; localized thrombosis and right heart hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic pulmonary hypertension, pre-capillary pulmonary hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy; plexogenic pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; lung fibrosis; lung transplant; 
 pulmonary hypertension associated with or related to left ventricular dysfunction, hypoxemia, WHO groups I, II, III, IV and V hypertensions, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous drainage, pulmonary venooclusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease; coagulation disorders; chronic thromboembolism, pulmonary embolism due to tumor, parasites or foreign material, connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis and compressed pulmonary vessels due to adenopathy, tumor or fibrosing mediastinitis; 
 arterosclerotic diseases or conditions; atherosclerosis; atherosclerosis associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation and migration; restenosis; restenosis developed after thrombolysis therapies, percutaneous transluminal angioplasties (PTAs), percutaneous transluminal coronary angioplasties (PTCAs) and bypass; inflammation; 
 cardiovascular disease associated with metabolic syndrome, obesity, dyslipidemia, diabetes, high blood pressure; lipid related disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclamsia; polycystic kidney disease progression; subcutaneous fat accumulation; 
 liver cirrhosis; liver cirrhosis associated with chronic liver disease; hepatic fibrosis, hepatic stellate cell activation, hepatic fibrous collagen; total collagen accumulation; liver disease of necro-inflammatory and/or of immunological origin; 
 urogenital system disorders; renal fibrosis; renal failure resulting from chronic kidney diseases or insufficiency; renal failure due to accumulation/deposition and tissue injury, progressive sclerosis and glomerulonephritis; prostatic hypertrophy; 
 systemic sclerosis; 
 cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; 
   (2) ischemia, reperfussion damage; ischemia/reperfussion associated with organ transplant, lung transplant, pulmonary transplant or cardiac transplant; conserving blood substituents in trauma patients;   (3) a sexual, gynecologicaland urological disorders selected from erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction; hypoactive sexual arousal disorder; vaginal atrophy; dyspaneuria; atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement; bladder outlet obstruction; bladder pain syndrome (BPS); interstitial cystitis (IC); overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy;   (4) ocular diseases or disorders selected from glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, Sjögren's Syndrome;   (5) hearing diseases or disorders selected from hearing impairment; partial or total hearing loss; partial or total deafness; tinnitus; noise-induced hearing loss;   (6) topical or skin disorders or conditions selected from dermal fibrosis, scleroderma, skin fibrosis;   (7) wound healing; wound healing in diabetics; microvascular perfusion improvement; microvascular perfusion improvement following injury, to counteract the inflammatory response in perioperative care; anal fissures; diabetic ulcers; and   (8) other diseases or conditions selected from cancer metastasis; osteoporosis, gastroparesis; functional dyspepsia; diabetic complications; diseases associated with endothelial dysfunction; and neurologic disorders associated with decreased nitric oxide production.   
     
     
         146 - 169 . (canceled) 
     
     
         170 . The method of  claim 145 , wherein the compound is used in combination with one or more additional therapeutic agents. 
     
     
         171 . The method of  claim 145 , wherein the disease, health condition or disorder is myocardial infarction, stable or unstable angina pectoris; coronary spasms; variant angina; or Prinzmetal's angina. 
     
     
         172 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from arterial hypertension, pulmonary hypertension, pulmonary arterial hypertension, resistant hypertension, diabetic hypertension, and portal hypertension. 
     
     
         173 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from renal fibrosis, renal failure resulting from chronic kidney diseases or insufficiency, chronic kidney disease, renal failure due to accumulation/deposition and tissue injury, progressive sclerosis, glomerulonephritis, and polycystic kidney disease progression. 
     
     
         174 . The method of  claim 145 , wherein the disease, health condition or disorder is diabetic nephropathy. 
     
     
         175 . The method of  claim 145 , wherein the disease, health condition or disorder is retinopathy or diabetic retinopathy. 
     
     
         176 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from heart failure, congestive heart failure, right heart hypertrophy, diastolic dysfunction, systolic dysfunction, heart failure/cardiorenal syndrome, coronary insufficiency, arrhythmias, reduction of ventricular preload and cardiac hypertrophy. 
     
     
         177 . The method of  claim 145 , wherein the disease, health condition or disorder is heart failure, diastolic dysfunction, cardiorenal syndrome, or cardiac hypertrophy. 
     
     
         178 . The method of  claim 145 , wherein the disease, health condition or disorder is renal fibrosis. 
     
     
         179 . The method of  claim 145 , wherein the disease, health condition or disorder is renal failure due to accumulation/deposition and tissue injury, progressive sclerosis, glomerulonephritis, and polycystic kidney disease progression. 
     
     
         180 . The method of  claim 145 , wherein the disease, health condition or disorder is vaso-occlusive crisis. 
     
     
         181 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from pulmonary/respiratory conditions; pulmonary hypertension; pulmonary arterial hypertension and associated pulmonary vascular remodeling; localized thrombosis and right heart hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic pulmonary hypertension, pre-capillary pulmonary hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy; plexogenic pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; or lung fibrosis; and lung transplant. 
     
     
         182 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from pulmonary hypertension associated with or related to left ventricular dysfunction, hypoxemia, WHO groups I, II, III, IV and V hypertensions, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous drainage, pulmonary venooclusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease; coagulation disorders; chronic thromboembolism, pulmonary embolism due to tumor, parasites or foreign material, connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, and lymphangiomatosis and compressed pulmonary vessels due to adenopathy, tumor or fibrosing mediastinitis. 
     
     
         183 . The method of  claim 145 , wherein the disease, health condition or disorder is cardiovascular disease associated with metabolic syndrome, obesity, dyslipidemia, diabetes, high blood pressure; lipid related disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclamsia; or subcutaneous fat accumulation. 
     
     
         184 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from liver cirrhosis; liver cirrhosis associated with chronic liver disease; hepatic fibrosis, hepatic stellate cell activation, and hepatic fibrous collagen. 
     
     
         185 . The method of  claim 145 , wherein the disease, health condition or disorder is selected from cardiac interstitial fibrosis, cardiac remodeling and fibrosis.