US2015126527A1PendingUtilityA1
Modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto

Assignee: TRAN THUY-ANHPriority: Mar 18, 2008Filed: Oct 9, 2014Published: May 7, 2015
Est. expiryMar 18, 2028(~1.6 yrs left)· nominal 20-yr term from priority
Inventors:Thuy-Anh Tran Weichao George Chen Bryan A. Kramer Abu J.M. Sadeque Anna Shifrina Young-Jun Shin Pureza Vallar Ning Zou
A61P 9/10A61P 9/00A61P 9/12A61P 11/06A61P 11/16A61P 11/00C07C 309/15C07B 2200/13A61K 31/4406A61K 31/4402C07C 275/28A61K 31/44C07C 271/28C07D 333/36C07C 2601/14C07C 275/30C07C 275/34A61K 31/4965A61K 31/381A61K 31/426C07D 241/20C07B 53/00C07C 275/24C07C 271/12C07B 2200/07A61K 31/195C07D 213/75C07D 277/48A61K 31/325A61K 31/27A61P 1/00A61P 19/02A61P 27/02A61P 3/10A61P 37/00A61P 7/06A61P 29/00A61P 7/00A61P 31/18
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Claims
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).
Claims

exact text as granted — not AI-modified
1 . 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 selected from compounds of Formula (XIIIa) 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-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. 
 
     
     
         2 . The method according to  claim 1 , 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: methoxy, ethoxy, methyl, phenyl, trifluoromethyl, trifluoromethoxy, fluoro and chloro. 
     
     
         3 . The method according to  claim 1 , wherein R 1  and R 2  are each independently selected from: H, methyl, phenyl, pyrazinyl, pyridinyl and thiazolyl; wherein methyl, phenyl, pyrazinyl, pyridinyl and thiazolyl are each optionally substituted with one or two substituents selected from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl, trifluoromethoxy, fluoro and chloro. 
     
     
         4 . 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, 5-methylpyridin-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. 
     
     
         5 . The method according to  claim 1 , 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; and 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. 
     
     
         6 . The method according to  claim 5 , wherein R 1  is selected from: C 1 -C 6  alkyl, aryl and heteroaryl; each optionally substituted with one or two substituents selected from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl, trifluoromethoxy, fluoro and chloro; and 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: methyl and fluoro. 
     
     
         7 . The method according to  claim 6 , 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. 
     
     
         8 . The method according to  claim 1 , wherein X is O. 
     
     
         9 . The method according to  claim 1 , wherein X is NR 3 . 
     
     
         10 . The method according to  claim 9 , wherein R 3  is H. 
     
     
         11 . The method according to  claim 9 , wherein R 3  is C 1 -C 6  alkyl. 
     
     
         12 . The method according to  claim 9 , wherein R 3  is methyl. 
     
     
         13 . The method according to  claim 1 , wherein Q is OH. 
     
     
         14 . The method according to  claim 1 , wherein Q is —NHCH 2 CH 2 SO 3 H. 
     
     
         15 . The method according to  claim 1 , wherein Q is selected from: 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. 
     
     
         16 . The method according to  claim 1 , wherein Q is selected from: (S)-1-carboxyethylamino, (S)-1-carboxy-4-guanidinobutylamino, (S)-3-amino-1-carboxy-3-oxopropylamino, (S)-1,2-dicarboxyethylamino, (S)-1-carboxy-2-mercaptoethylamino, (S)-4-amino-1-carboxy-4-oxobutylamino, (S)-3-carboxy-1-carboxylatopropylamino, carboxymethylamino, (S)-1-carboxy-2-(1H-imidazol-4-yl)ethylamino, (1S,2S)-1-carboxy-2-methylbutylamino, (S)-1-carboxy-3-methylbutylamino, (S)-5-amino-1-carboxypentylamino, (S)-1-carboxy-3-(methylthio)propylamino, (S)-1-carboxy-2-phenylethylamino, (S)-2-carboxypyrrolidin-1-yl, (S)-1-carboxy-2-hydroxyethylamino, (1S,2R)-1-carboxy-2-hydroxypropylamino, (S)-1-carboxy-2-(1H-indol-3-yl)ethylamino, (S)-1-carboxy-2-(4-hydroxyphenyl)ethylamino and (S)-1-carboxy-2-methylpropylamino. 
     
     
         17 . The method according to  claim 1 , wherein Q is carboxymethylamino. 
     
     
         18 . 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-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. 
 
     
     
         19 . The compound 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  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. 
 
     
     
         20 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIe) 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-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. 
 
     
     
         21 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIe) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         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. 
       
     
     
         22 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIg) 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; and 
 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. 
 
     
     
         23 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIg) 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; 
 R 3  is selected from H and methyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino. 
 
     
     
         24 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIi) 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; 
 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. 
 
     
     
         25 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIi) 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; 
 R 3  is selected from H and methyl; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino. 
 
     
     
         26 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIk) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         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; 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. 
       
     
     
         27 . The compound method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIk) 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; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino. 
 
     
     
         28 . The compound method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIm) 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; 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. 
 
     
     
         29 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (XIIIm) 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; and 
 Q is selected from: OH, —NHCH 2 CH 2 SO 3 H and carboxymethylamino. 
 
     
     
         30 . 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. 
 
     
     
         31 . 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. 
 
     
     
         32 . The compound 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  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. 
 
     
     
         33 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ie) 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. 
 
     
     
         34 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ie) 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; 
 X is O or NR 3 ; and 
 R 3  is selected from H and methyl. 
 
     
     
         35 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ig) 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; and 
 R 3  is selected from H and C 1 -C 6  alkyl. 
 
     
     
         36 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ig) 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; and 
 R 3  is selected from H and methyl. 
 
     
     
         37 . The compound method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ii) 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; and 
 R 3  is selected from H and C 1 -C 6  alkyl. 
 
     
     
         38 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Ii) 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; and 
 R 3  is selected from H and methyl. 
 
     
     
         39 . 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. 
 
     
     
         40 . 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; and 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl. 
 
     
     
         41 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Im) 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. 
 
     
     
         42 . The method according to  claim 1 , wherein the compound is selected from compounds of Formula (Im) 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; and 
 R 2  is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl. 
 
     
     
         43 . A 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-methylthiophen-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)pyridin-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. 
 
     
     
         44 . A 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-((3-(3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         45 . A 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. 
 
     
     
         46 . A 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-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         47 . A 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-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         48 . A 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-chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         49 . A 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-(((3,5-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         50 . A 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-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         51 . A 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-(((5-chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         52 . A 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-(((5-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid. 
 
     
     
         53 . A method according to  claim 1  wherein the compound is selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof:
 2-(2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonic acid 
 
     
     
         54 . A method according to  claim 1  wherein the compound is selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof:
 2-(2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)acetic acid. 
 
     
     
         55 . A method according to  claim 1  wherein the compound is selected from the following salts of compounds of Formula XIIIa and pharmaceutically acceptable 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. 
 
     
     
         56 . A method according to  claim 1  wherein the compound is selected from the following salt of a compound of Formula XIIIa and pharmaceutically acceptable solvates and hydrates thereof:
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate. 
 
     
     
         57 . A method according to  claim 1  wherein the compound is selected from the following salt of a compound of Formula XIIIa and pharmaceutically acceptable solvates and hydrates thereof:
 sodium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate. 
 
     
     
         58 . A 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. 
 
     
     
         59 . A method according to  claim 1  wherein the compound is:
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate hydrate. 
 
     
     
         60 . A method according to  claim 1  wherein the compound is:
 sodium 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate hydrate. 
 
     
     
         61 . A method according to claim wherein the compound is a crystalline form of
 sodium 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate.   
     
     
         62 . The method according to  claim 61  having an X-ray powder diffraction pattern substantially as shown in  FIG. 9 . 
     
     
         63 . The method according to  claim 61  having a dynamic vapor sorption profile substantially as shown in  FIG. 10 . 
     
     
         64 . The method according to  claim 61  having a differential scanning calorimetry thermogram substantially as shown in  FIG. 11 . 
     
     
         65 - 85 . (canceled)
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