2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sgc stimulators

Abstract

Compound of Table I are described. They are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds may be useful for treating, preventing or managing various disorders that are herein disclosed.

We claim: 
     
         1 . (canceled) 
     
     
         2 . A method of treating a disease, health condition or disorder in a subject, comprising administering a therapeutically effective amount of a compound depicted in Table I, or a pharmaceutically acceptable salt thereof, to the subject in need of the treatment, wherein the disease, health condition or disorder is selected from:
 (a) a peripheral, pulmonary, hepatic, liver, cardiac or cerebral vascular/endothelial disorder/condition selected from:
 disorders related to high blood pressure and decreased coronary blood flow; resistant hypertension; diabetic hypertension; congestive heart failure; diastolic or sistolic dysfunction; coronary insufficiency; arrhythmias; 
 thromboembolic disorders and ischemias; stable or unstable angina pectoris; 
 peripheral arterial disease, peripheral occlusive arterial disease; 
 pulmonary/respiratory conditions such as pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling, 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; 
 pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, 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, other coagulation disorders, chronic thromboembolism, pulmonary embolism, connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis and compressed pulmonary vessels, arterosclerotic diseases or conditions and inflammation; 
 cardiovascular disease associated with metabolic syndrome; lipid related disorders, fatty liver disease, and hepatitis; 
 liver cirrhosis, associated with chronic liver disease, hepatic fibrosis, hepatic stellate cell activation, hepatic fibrous collagen and total collagen accumulation; liver disease of necro-inflammatory and/or of immunological origin; and urogenital system disorders, such as renal fibrosis and renal failure resulting from chronic kidney diseases or insufficiency; prostate hypertrophy; and 
   (b) sexual disorders or conditions.   
     
     
         3 . The method of  claim 2 , wherein the disorders related to high blood pressure and decreased coronary blood flow are increased acute and chronic coronary blood pressure, arterial hypertension, and vascular disorder resulting from cardiac and renal complications. 
     
     
         4 . The method of  claim 3 , wherein the cardiac and renal complications are heart disease, stroke, cerebral ischemia, and renal failure. 
     
     
         5 . The method of  claim 2 , wherein the thromboembolic disorders and ischemias are myocardial infarction, stroke, and transient ischemic attacks (TIAs). 
     
     
         6 . The method of  claim 2 , wherein the pulmonary/respiratory conditions are pulmonary hypertension, pulmonary arterial hypertension, pulmonary vascular remodeling, pulmonary hypertonia, primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, pre-capillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, and plexogenic pulmonary arteriopathy. 
     
     
         7 . The method of  claim 6 , wherein the pulmonary vascular remodeling are pulmonary vascular changes associated with localized thrombosis or right heart hypertrophy. 
     
     
         8 . The method of  claim 2 , wherein the pulmonary embolism is due to tumor, parasites or foreign material, and the compressed pulmonary vessels are due to adenopathy, tumor or fibrosing mediastinitis. 
     
     
         9 . The method of  claim 2 , wherein the arterosclerotic diseases or conditions are atherosclerosis and restenosis. 
     
     
         10 . The method of  claim 9 , wherein the atherosclerosis is associated with endothelial injury, platelet and monocyte adhesion and/or aggregation, or smooth muscle proliferation and/or migration; wherein the restenosis is developed after thrombolysis therapies, percutaneous transluminal angioplasties (PTAs), percutaneous transluminal coronary angioplasties (PTCAs) and/or bypass. 
     
     
         11 . The method of  claim 2 , wherein the metabolic syndrome is obesity, dyslipidemia, diabetes or high blood pressure, and wherein the lipid related disorders are dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and sitosterolemia. 
     
     
         12 . The method of  claim 2 , wherein the chronic kidney diseases or insufficiency is due to accumulation and/or deposition of tissue injury, progressive sclerosis, or glomerunephritis. 
     
     
         13 . The method of  claim 2 , wherein the sexual disorders or conditions are erectile dysfunction, female sexual dysfunction, vaginal atrophy and incontinence. 
     
     
         14 . The method of  claim 13 , wherein the female sexual dysfunction is female sexual arousal dysfunction. 
     
     
         15 . The method of  claim 2 , wherein the disease, health condition or disorder is
 (a) a peripheral or cardiac vascular disorder or health condition selected from: pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling, localized pulmonary thrombosis, 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 artheriopathy, plexogenic pulmonary artheriopathy; pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, 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, apnea, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, pulmonary embolism, connective tissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis or compressed pulmonary vessels;   (b) liver cirrhosis, or   (c) a urogenital system disorder selected from renal fibrosis, renal failure resulting from chronic kidney diseases or insufficiency, erectile dysfunction or female sexual dysfunction.   
     
     
         16 . The method of  claim 15 , wherein the disease, health condition or disorder is pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling, localized pulmonary thrombosis, 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 or chronic obstructive pulmonary disease, liver cirrhosis, renal fibrosis, renal failure resulting from chronic kidney diseases or insufficiency, erectile dysfunction or female sexual dysfunction. 
     
     
         17 . The method of  claim 16 , wherein the disease, health condition or disorder is hypertension, resistant hypertension, diabetic hypertension, pulmonary hypertension (PH), pulmonary arterial hypertension, PH associated with COPD, chronic airflow obstruction, asthma or pulmonary fibrosis, thrombosis, embolism, thromboembolic disorders, atherosclerosis, right heart hypertrophy, heart failure, diastolic dysfunction, systolic dysfunction, sleep apnea associated with heart failure, liver cirrhosis, renal fibrosis, renal failure resulting from chronic kidney diseases or insufficiency, metabolic disorder, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction, female sexual dysfunction, female sexual arousal dysfunction and vaginal atrophy. 
     
     
         18 . The method of  claim 2 , further comprising administering an effective amount of one or more additional therapeutic agents to the subject. 
     
     
         19 . The method of  claim 18 , wherein the one or more additional therapeutic agents are selected from edothelium-derived releasing factor, NO donors, substances that enhance cGMP concentrations, nitric oxide synthase substrates, compounds which enhance eNOS transcription, NO-independent heme-independent sGC activators, heme-dependent sGC stimulators; inhibitors of cGMP degradation, calcium channel blockers, endothelin receptor antagonists, prostacyclin derivatives or analogues, antihyperlipidemics, anticoagulants, antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers, antiarrhythmic agents, diuretics, exogenous vasodilators, bronchodilators, corticosteroids, dietary supplements, PGD2 receptor antagonists, immunosuppressants, non-steroidal antiasthmatics, non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors, anti-diabetic agents, HDL-cholesterol increasing agents, antiobesity drugs, angitensin receptor blockers, rennin inhibitors, centrally acting alpha-2-adrenoreceptors, adrenergin neuron blockers, Imidazoline I-1 receptor agonists, aldosterone antagonists, potassium channel activators, dopamine Dl agonists, 5-HT2 antagonists, vasopressin antagonists, calcium channel sensitizers, PDE-3 inhibitors, adenylate cyclase activators, positive inotropic agents, drugs for treating erectile dysfunction, anti-diabetic drugs, anti-obesity drugs, drugs for treating sleep apnea, drugs for treating hypertension, drugs for treating pulmonary hypertension, drugs for treating heart failure, drugs for treating hyperlipidemia, drugs for treating metabolic syndrome, drugs for treating female sexual dysfunction. 
     
     
         20 . (canceled)