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 verso-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).

1 .- 72 . (canceled) 
     
     
         73 . 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; 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; 
         R 2  is selected from: H, C 1 -C 6  alkyl and aryl; wherein said aryl is optionally substituted with one or two substituents selected from: C 1 -C 6  alkyl and halogen; and 
         R 5  is C 1 -C 6  alkyl, wherein the alkyl is optionally substituted; 
         or —OR 5  is R 9 ; 
         R 9  is a radical derived from any natural or unnatural amino acid, upon the loss of a hydrogen atom from the α-amino group of said natural or unnatural amino acid; or R 9  is —NHCH 2 CH 2 SO 2 H; or R 9  is —NH—CH(R 10 )(R 11 ); 
         R 10  is selected from: H and carboxyl; and 
         R 11  is selected from: H and C 1 -C 6  alkyl; wherein C 1 -C 6  alkyl is optionally substituted with one or two substituents such as 4-hydroxyphenyl, amino, carboxamide, carboxyl, guanidino, hydroxyl, imidazolyl, indolyl, methylthio, phenyl, pyrrolidinyl, sulfo and thiol; 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. 
       
     
     
         74 . The process of  claim 73 , wherein the R 1  is aryl, 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. 
     
     
         75 . The process of  claim 73 , wherein the R 2  is aryl optionally substituted with one or two substituents selected from: C 1 -C 6  alkyl and halogen. 
     
     
         76 . The process of  claim 73 , wherein the R 5  is tert-butyl. 
     
     
         77 . The process of  claim 73 , wherein the R 6  is halogen. 
     
     
         78 . The process of  claim 73 , wherein R 1  is aryl 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;
 R 2  is aryl is optionally substituted with one or two substituents selected from: C 1 -C 6 alkyl and halogen; and   R 5  is C 1 -C 6  alkyl.   
     
     
         79 . The process of  claim 73 , wherein the compound of Formula (IV) is prepared by a process comprising reacting a compound of Formula (VI): 
       
         
           
           
               
               
           
         
         or a salt form thereof; 
         wherein R 7  is a first leaving group; 
         with a compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         to form a compound of Formula (IV) or a salt form thereof. 
       
     
     
         80 . The process of  claim 79 , wherein the compound of Formula (VI) is prepared by a process comprising reacting a compound of Formula (VIII): 
       
         
           
           
               
               
           
         
         or a salt form thereof; 
         with a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein R 8  is a second leaving group; 
         to form a compound of Formula (VI) or a salt form thereof.