Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators

Abstract

Cyclohexane derivatives of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the PGI2 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pulmonary arterial hypertension (PAH) and related disorders; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clot formation in an angioplasty or coronary bypass surgery individual or in an individual suffering from atrial fibrillation; atherosclerosis; atherothrombosis; asthma or a symptom thereof; a diabetic-related disorder such as diabetic peripheral neuropathy, diabetic nephropathy or diabetic retinopathy; glaucoma or other disease of the eye with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn's disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; ischemia-reperfusion injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructive pulmonary disorder (COPD).

What is claimed: 
     
         1 . A compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from: H and C 1 -C 8  alkyl; 
         R 2  and R 3  are each independently selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; and X is selected from: N and CH. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is H. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is C 1 -C 6  alkyl. 
     
     
         4 . The compound according to any one of  claims 1  to  3 , wherein R 2  and R 3  are each independently selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio, phenyl and trifluoromethyl. 
     
     
         5 . The compound according to any one of  claims 1  to  3 , wherein R 2  and R 3  are each independently selected from: H, 1H-pyrazol-4-yl, methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl; wherein said methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each optionally substituted with one or more substituents each independently selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio, phenyl and trifluoromethyl. 
     
     
         6 . The compound according to any one of  claims 1  to  3 , wherein R 2  and R 3  are each independently selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-chloropyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl. 
     
     
         7 . The compound according to any one of  claims 1  to  3 , wherein R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen. 
     
     
         8 . The compound according to any one of  claims 1  to  3 , wherein R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio, phenyl and trifluoromethyl. 
     
     
         9 . The compound according to any one of  claims 1  to  3 , wherein R 2  is selected from: methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl; wherein said methyl, phenyl, pyridinyl, thiophen-2-yl and thiophen-3-yl are each optionally substituted with one or more substituents each independently selected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl, methylthio, phenyl and trifluoromethyl. 
     
     
         10 . The compound according to any one of  claims 1  to  3 , wherein R 2  is selected from: 2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl. 
     
     
         11 . The compound according to any one of  claims 1  to  3 , wherein R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
     
     
         12 . The compound according to any one of  claims 1  to  3 , wherein R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: chloro, fluoro, methoxy and methyl. 
     
     
         13 . The compound according to any one of  claims 1  to  3 , wherein R 3  is selected from: H, 1H-pyrazol-4-yl, phenyl, pyridinyl and thiophen-2-yl; wherein said phenyl, pyridinyl and thiophen-2-yl are each optionally substituted with one or more substituents each independently selected from: chloro, fluoro, methoxy and methyl. 
     
     
         14 . The compound according to any one of  claims 1  to  3 , wherein R 3  is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl. 
     
     
         15 . The compound according to any one of  claims 1  to  14 , wherein X is N. 
     
     
         16 . The compound according to any one of  claims 1  to  14 , wherein X is CH. 
     
     
         17 . The compound according to  claim 1 , selected from compounds of Formula Ic and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; and 
         R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
       
     
     
         18 . The compound according to  claim 1 , selected from compounds of Formula Ic and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: 2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and 
         R 3  is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl. 
       
     
     
         19 . The compound according to  claim 1 , selected from compounds of Formula Ie and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; and 
         R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
       
     
     
         20 . The compound according to  claim 1 , selected from compounds of Formula Ie and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: 2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and 
         R 3  is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl. 
       
     
     
         21 . The compound according to  claim 1 , selected from compounds of Formula Ig and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; and 
         R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
       
     
     
         22 . The compound according to  claim 1 , selected from compounds of Formula Ig and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: 2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; 
         and 
         R 3  is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl. 
       
     
     
         23 . The compound according to  claim 1 , selected from compounds of Formula Ii and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; and 
         R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
       
     
     
         24 . The compound according to  claim 1 , selected from compounds of Formula Ii and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: 2,3-difluorophenyl, 2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and 
         R 3  is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl. 
       
     
     
         25 . A compound according to  claim 1  selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:
 2-(((1r,4r)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-benzhydryl-6-oxopyridazin-1(6H)yl)-methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((3-benzhydryl-6-oxopyridazin-(6H)yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl)methyl) cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-3-phenyl-4-m-tolylpyridazin-1(6H)yl)methyl)cyclohexyl)methoxy) acetic acid; 
 2-(((1s,4s)-4-((6-oxo-3-phenyl-4-p-tolylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(4-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(4-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-fluoro-3-methoxyphenyl)-6-oxo-3-phenylpyridazin-(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-p-tolylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(2-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(2-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(3-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(3-fluoro-5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(2,3-difluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(3-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(5-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-chloro-4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3,5-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3,4-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-ethylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl) pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(3-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-isopropylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-(methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-5,6-di-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(pyridin-3-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(5-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(1H-pyrazol-4-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((5,6-bis(4-fluorophenyl)-3-oxo-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(4-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-chloro-2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(4-chloro-3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(6-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(2-fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(5-methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(5-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-(4-fluorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-(6-chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((4-(5-chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-(4-methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((5-(3-methoxyphenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((6-(4-chlorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-5-(pyridin-4-yl)-6-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1s,4s)-4-((3-oxo-5-n-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)yl)methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3)yl) methyl)cyclohexyl)methoxy)acetic acid; 
 2-(((1r,4r)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid; and 
 2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)yl) methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         26 . A pro-drug of compound according to anyone of  claims 1  to  25  selected from compounds of Formula Ha and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  and R 3  are each independently selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen; 
         R 5  is selected from: H and carboxyl; and 
         R 6  is selected from: H and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with 4-hydroxyphenyl, amino, carboxamide, carboxyl, guanidine, hydroxyl, imidazolyl, indolyl, methylthio, phenyl, pyrrolidinyl, sulfo and thiol. 
       
     
     
         27 . A pro-drug of compound according to any one of  claims 1  to  25  selected from compounds of Formula Ha and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from: C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkylthio, aryl, C 1 -C 8  haloalkyl and halogen. 
         R 3  is selected from: H, C 1 -C 8  alkyl, aryl and heteroaryl; wherein said C 1 -C 8  alkyl, aryl and heteroaryl are each optionally substituted with one or more substituents each independently selected from: C 1 -C 8  alkyl, C 1 -C 8  alkoxy and halogen. 
         R 5  is H or carboxyl; and 
         R 6  is H or —CH 2 SO 3 H. 
       
     
     
         28 . A pro-drug according  claim 26 , selected from 2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)acetic acid and pharmaceutically acceptable salts, solvates and hydrates thereof. 
     
     
         29 . A pro-drug according  claim 26 , selected from: 2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamide)ethanesulfonic acid and pharmaceutically acceptable salts, solvates and hydrates thereof. 
     
     
         30 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  25 , or a pro-drug according to any one of  claims 26  to  29 , and a pharmaceutically acceptable carrier. 
     
     
         31 . A method of modulating the activity of a PGI2 receptor by contacting the receptor with a compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 . 
     
     
         32 . A method of agonizing a PGI2 receptor by contacting the receptor with a compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 . 
     
     
         33 . A method for the treatment of a PGI2 receptor mediated disorder in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 . 
     
     
         34 . A method for the treatment of PAH in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 . 
     
     
         35 . The method according to  claim 34 , wherein said PAH is selected from:
 idiopathic PAH;   familial PAH;   PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis;   PAH associated with a congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in an individual;   PAH associated with portal hypertension;   PAH associated with HIV infection;   PAH associated with ingestion of a drug or toxin;   PAH associated with hereditary hemorrhagic telangiectasia;   PAH associated with splenectomy;   PAH associated with significant venous or capillary involvement;   PAH associated with pulmonary veno-occlusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH) in an individual.   
     
     
         36 . A method for the treatment of a disorder selected from: platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, a symptom of asthma, a diabetic-related disorder, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or other disease of the eye with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonary disorder (COPD) in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 . 
     
     
         37 . Use of a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , in the manufacture of a medicament for modulating the activity of a PGI2 receptor. 
     
     
         38 . Use of a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , in the manufacture of a medicament for agonizing a PGI2 receptor. 
     
     
         39 . Use of a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , in the manufacture of a medicament for the treatment of a PGI2 receptor mediated disorder. 
     
     
         40 . Use of a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , in the manufacture of a medicament for the treatment of PAH. 
     
     
         41 . The use according to  claim 40 , wherein said PAH is selected from:
 idiopathic PAH;   familial PAH;   PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis;   PAH associated with a congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in an individual;   PAH associated with portal hypertension;   PAH associated with HIV infection;   PAH associated with ingestion of a drug or toxin;   PAH associated with hereditary hemorrhagic telangiectasia;   PAH associated with splenectomy;   PAH associated with significant venous or capillary involvement;   PAH associated with pulmonary vena-occlusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH) in an individual.   
     
     
         42 . Use of a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , in the manufacture of a medicament for the treatment of a disorder selected from: platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, a symptom of asthma, a diabetic-related disorder, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or other disease of the eye with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonary disorder (COPD). 
     
     
         43 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of treatment of the human or animal body by therapy. 
     
     
         44 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of modulating the activity of a PGI2 receptor. 
     
     
         45 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of agonizing a PGI2 receptor. 
     
     
         46 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of treatment of a PGI2 receptor mediated disorder. 
     
     
         47 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of treatment of PAH. 
     
     
         48 . A compound according to  claim 47 , wherein said PAH is selected from:
 idiopathic PAH;   familial PAH;   PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis;   PAH associated with a congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in an individual;   PAH associated with portal hypertension;   PAH associated with HIV infection;   PAH associated with ingestion of a drug or toxin;   PAH associated with hereditary hemorrhagic telangiectasia;   PAH associated with splenectomy;   PAH associated with significant venous or capillary involvement;   PAH associated with pulmonary vena-occlusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH).   
     
     
         49 . A compound according to any one of  claims 1  to  25 , a pro-drug according to any one of  claims 26  to  29 , or a pharmaceutical composition according to  claim 30 , for use in a method of treatment of a disorder selected from: platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, a symptom of asthma, a diabetic-related disorder, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glaucoma or other disease of the eye with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonary disorder (COPD). 
     
     
         50 . A process for preparing a composition comprising admixing a compound according to any one of  claims 1  to  25  or a pro-drug according to any one of  claims 26  to  29 , and a pharmaceutically acceptable carrier.