Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto

Abstract

The present invention relates to amide derivatives of Formula (XIIIa) 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); idiopathic PAH; familial PAH; PAH associated with a collagen vascular disease, a congenital heart disease, portal hypertension, HIV infection, ingestion of a drug or toxin, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH); PAH with significant venous or capillary involvement; 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 is: 
     
       1. A method for modulating a prostacyclin (PGI2) receptor in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a prostacyclin receptor modulator a compound selected from compounds of Formula (XIIIa) (Xa) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloakoalkyl and halogen; 
 X is O or NR 3 ; 
 R 3  is selected from H and C 1 -C 6  alkyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H, 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino, carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino 
 R 10  is H; and 
 R 11  is selected from: H and C 1 -C 6  alkyl; and 
 performing radio-imaging to localize and quantitate the PGI2 receptor in tissues in the individual; 
 wherein the individual has a disorder that is diabetic neuropathy, diabetic peripheral neuropathy, diabetic retinopathy, glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, acne, type 1 diabetes, or type 2 diabetes; 
 wherein the compound of Formula (Xa) is radio-labeled with  18 F,  125 I,  123 I,  124 I,  131 I,  75 Br,  76 Br or  77 Br. 
 
       
     
     
       2. The method according to  claim 1 , wherein R 1  and R 2  are each independently selected from: H, diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, methyl, phenyl, n-propyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl. 
     
     
       3. The method according to  claim 1 , wherein R 1  is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; and R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl. 
     
     
       4. The method according to  claim 1 , wherein X is O; and Q is OH. 
     
     
       5. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIc) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl and halogen; 
 X is O or NR 3 ; 
 R 3  is selected from H and C 1 -C 6  alkyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H, 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamine, 3-carboxy-1-carboxylatopropylamino, carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino. 
 
       
     
     
       6. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIc) and pharmaceutically acceptable salts, solvate and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; 
 X is O or NR 3 ; 
 R 3  is selected from H and methyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino. 
 
       
     
     
       7. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; 
 
         wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6  haloalkoxy, C 1 -C 6 haloalkyl and halogen;
 X is O or NR 3 ; and 
 R 3  is selected from H and C 1 -C 6  alkyl. 
 
       
     
     
       8. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; 
 
         wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6 haloalkoxy; C 1 -C 6 haloalkyl and halogen;
 X is O or NR 3 ; and 
 R 3  is selected from H and C 1 -C 6  alkyl. 
 
       
     
     
       9. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ic) and pharmaceutically acceptable salt, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; 
 X is O or NR 3 ; and 
 R 3  is selected from H and methyl. 
 
       
     
     
       10. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6 haloalkoxy; C 1 -C 6 haloalkyl and halogen. 
 
       
     
     
       11. The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl. 
 
       
     
     
       12. The method according to  claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:
 2-(((1r,4r)-4-((3-benzhydrylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((1-methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-m-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-di p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-di m-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-(3-trifluoromethyl)phenyl)ureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((3-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((2-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,4-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(2,3-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3,5-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((2,3-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-(2-fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3,4-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,4-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(5-methylthiophenyl-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(4-trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((6-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((benzhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((2-fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(5-(trifluoromethyl)pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((benzhydryl(propyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid; and   2-(((1r,4r)-4-(((5-methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid.   
     
     
       13. The method according to  claim 1 , wherein the compound is selected from the following pharmaceutically acceptable salts of compounds of Formula XIIIa and solvates and hydrates thereof:
 sodium 2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate;   sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;   sodium 2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;   sodium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;   magnesium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;   potassium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate; and   calcium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate.   
     
     
       14. The method according to  claim 1 , wherein the compound is selected from the following solvates and hydrates:
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate hydrate;   sodium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate hydrate;   
       magnesium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate isopropanol solvate; 
       potassium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate isopropanol solvate; and 
       calcium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate isopropanol solvate. 
     
     
       15. The method according to  claim 1  wherein the compound is selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof:
 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
       16. The method according to  claim 1  wherein the compound is selected from the following pharmaceutically acceptable salt and solvates and hydrates thereof:
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate. 
 
     
     
       17. The method according to  claim 1  wherein the compound is:
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate hydrate. 
 
     
     
       18. The method according to  claim 1 , wherein the individual has a disorder comprising platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, diabetic neuropathy, diabetic peripheral neuropathy, diabetic retinopathy, vasoconstriction, platelet aggregation in a diabetic patient, glaucoma, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, ischemia-reperfusion injury, restenosis, acne, type 1 diabetes, type 2 diabetes, sepsis, or chronic obstructive pulmonary disease. 
     
     
       19. The method according to  claim 1 , wherein the individual has pulmonary arterial hypertension (PAH). 
     
     
       20. The method according to  claim 19 , wherein the 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 venoocclusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH).   
     
     
       21. A method for modulating a prostacyclin (PGI2) receptor in an individual comprising administering to the individual in need thereof, a therapeutically effective amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, or hydrate thereof. 
     
     
       22. The method according to  claim 21 , wherein the individual has a disorder comprising platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, atherosclerosis, atherothrombosis, asthma, diabetic neuropathy, diabetic peripheral neuropathy, diabetic retinopathy, vasoconstriction, platelet aggregation in a diabetic patient, glaucoma, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, ischemia-reperfusion injury, restenosis, acne, type 1 diabetes, type 2 diabetes, sepsis, or chronic obstructive pulmonary disease. 
     
     
       23. The method of  claim 21 , wherein the individual has pulmonary arterial hypertension (PAH). 
     
     
       24. The method according to  claim 23 , wherein the 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 venooclusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH).   
     
     
       25. A method for inhibiting platelet aggregation in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound of Formula (XIIIa), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently selected from: H, C 1 -C 6  alkyl, aryl and heteroaryl; 
 
         wherein C 1 -C 6  alkyl, aryl and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6  alkyl, aryl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl and halogen;
 X is O or NR 3 ; 
 R 3  is selected from H and C 1 -C 6  alkyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H, 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino, carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino. 
 
       
     
     
       26. The method according to  claim 25 , wherein the compound has the structure of Formula (Ik), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from: diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl, 4-trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and pyridin-3-yl; and 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl. 
 
       
     
     
       27. The method according to  claim 26 , wherein the compound is:
 2-(((1r,4r)-4-((3-benzhydrylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(1-methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-m-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-di p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3,3-di m-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(4-methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-phenyl-3-(3-trifluoromethyl)phenyl)ureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((3-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((2-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1s,4s)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,4-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(2,3-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3,5-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3-chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((2,3-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-(4-chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-(2-fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-(3,4-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,4-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3,5-dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(5-methylthiophenyl-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((3-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(4-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((6-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((benzhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((3-benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((4-ethoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((2-fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((phenyl(5-(trifluoromethyl)pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-(((5-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   2-(((1r,4r)-4-((benzhydryl(propyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid; or   2-(((1r,4r)-4-(((5-methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;   or a pharmaceutically acceptable salt, solvate, or hydrate thereof, of any one of the preceding compounds.   
     
     
       28. The method of  claim 25 , wherein the individual has pulmonary arterial hypertension (PAH). 
     
     
       29. The method according to  claim 28 , wherein the 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 hemorrhage telangiectasia;   PAH associated with splenectomy;   PAH associated with significant venous or capillary involvement;   PAH associated with pulmonary venooclusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH).   
     
     
       30. A method for inhibiting platelet aggregation in an individual comprising administering to the individual in need thereof, a therapeutically effective amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
       31. The method of  claim 30 , wherein the individual has pulmonary arterial hypertension (PAH). 
     
     
       32. The method according to  claim 31 , wherein the PAH is selected from:
 idiopathic PAH;   familial PAH;   PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematous (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 venoocclusive disease (PVOD); and   PAH associated with pulmonary capillary hemangiomatosis (PCH).   
     
     
       33. The method of  claim 1 , wherein the individual has type 1 diabetes or type 2 diabetes.  
     
     
       34. The method of  claim 1 , wherein R 11  is H.  
     
     
       35. A process for the preparation of a compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a salt form thereof, 
         wherein: 
         R 1  is selected from C 1 -C 6  alkyl, aryl and heteroaryl; 
         R 2  is selected from: H, C 1 -C 6  alkyl and aryl; and 
         R 5  is C 1 -C 6  alkyl; 
       
       comprising reacting a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a salt from thereof; with a compound of Formula (V): 
       
         
           
           
               
               
           
         
         wherein R 6  is selected from: C 1 -C 6  alkylarylsulfonate, C 1 -C 6  alkylsulfonate, arylsulfonate, C 1 -C 6  haloalkylsulfonate and halogen; 
       
       in the presence of a base to form a compound of Formula (III) or a salt form thereof.