Fused pyrazole derivatives and methods of treatment of metabolic-related disorders thereof

Abstract

The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.

1 . A compound of Formula (Ia): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, hydrate or solvate thereof, 
     wherein:
 X is N and Z is CR 7 , or X is CR 7  and Z is N; 
 R 1  and R 4  are each selected independently from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylamino, C 1-6  alkylcarboxamide, C 1-6  alkylthiocarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylthioureyl, C 1-6  alkylureyl, amino, C 1-6 -alkylamido, amino-C 1-6 -alkylsulfonyl, C 1-6 -alkylthioamido, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 1-6  dialkylcarboxamide, C 1-6  dialkylthiocarboxamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; 
 R 2  and R 3  are each selected independently from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylamino, C 1-6  alkylcarboxamide, C 1-6  alkylthiocarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylthioureyl, C 1-6  alkylureyl, amino, C 1-6 -alkylamido, amino-C 1-6 -alkylsulfonyl, C 1-6 -alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  dialkylcarboxamide, C 1-6  dialkylthiocarboxamide, C 1-6 -dialkylamido, C 1-6 -dialkylthioamido, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C 4-7  oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1  acyl, C 1-6  acyloxy, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  haloalkoxy, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, nitro, phenoxy and phenyl; or 
 R 2  and R 3  together with the carbon to which they are both bonded form a C 3-6  cycloalkyl; 
 R 5  and R 6  are each selected independently from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 7-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylamino, C 1-6  alkylcarboxamide, C 1-6  alkylthiocarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylthioureyl, C 1-6  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 1-6  dialkylcarboxamide, C 1-6  dialkylthiocarboxamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol; and 
 R 7  is carbo-C 1-6 -alkoxy, carboxy or tetrazol-5-yl. 
 
   
   
       2 . The compound according to  claim 1 , wherein:
 R 2  and R 3  are each selected independently from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylamino, C 1-6  alkylcarboxamide, C 1-6  alkylthiocarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylthioureyl, C 1-6  alkylureyl, amino, C 1-6 -alkylamido, amino-C 1-6 -alkylsulfonyl, C 1-6 -alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  dialkylcarboxamide, C 1-6  dialkylthiocarboxamide, C 1-6 -dialkylamido, C 1-6 -dialkylthioamido, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C 4-7  oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  haloalkoxy, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, nitro, phenoxy and phenyl.   
   
   
       3 . The compound according to  claim 2 , provided that R 1  and R 4  are cis to each other. 
   
   
       4 . The compound according to  claim 3 , wherein X is N; Z is CR 7 ; and R 7  is carbo-C 1-4 -alkoxy or carboxy. 
   
   
       5 . The compound according to  claim 3 , wherein X is N; Z is CR 7 ; and R 7  is carboxy. 
   
   
       6 . The compound according to  claim 3 , wherein X is N; Z is CR 7 ; and R 7  is tetrazol-5-yl. 
   
   
       7 . The compound according to  claim 3 , wherein X is CR 7 ; R 7  is carbo-C 1-6 -alkoxy or carboxy; and Z is N. 
   
   
       8 . The compound according to  claim 3 , wherein X is CR 7 ; R 7  is carboxy; and Z is N. 
   
   
       9 . The compound according to  claim 3 , wherein X is CR 7 ; R 7  is tetrazol-5-yl; and Z is N. 
   
   
       10 . The compound according to  claim 3 , wherein R 1  is H or halogen. 
   
   
       11 . The compound according to  claim 3 , wherein R 1  is H. 
   
   
       12 . The compound according to  claim 3 , wherein R 4  is H or halogen. 
   
   
       13 . The compound according to  claim 3 , wherein R 4  is H. 
   
   
       14 . The compound according to  claim 3 , wherein R 1  and R 4  are both H. 
   
   
       15 . The compound according to  claim 3 , wherein R 5  is H or halogen. 
   
   
       16 . The compound according to  claim 3 , wherein R 5  is H. 
   
   
       17 . The compound according to  claim 3 , wherein R 6  is H or halogen. 
   
   
       18 . The compound according to  claim 3 , wherein R 6  is H. 
   
   
       19 . The compound according to  claim 3 , wherein R 5  and R 6  are both H. 
   
   
       20 . The compound according to  claim 3 , wherein R 1 , R 4 , R 5  and R 6  are each H. 
   
   
       21 . The compound according to  claim 3 , wherein R 2  and R 3  are each selected independently from the group consisting of H, C 1-6  alkyl and halogen; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1-6  acyloxy, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, amino, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  haloalkoxy, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, phenoxy and phenyl. 
   
   
       22 . The compound according to  claim 3 , wherein R 2  is H or C 1-6  alkyl; and R 3  is H, C 1-6  alkyl or halogen; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1-6  acyloxy, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, amino, C 3-7  cycloalkyloxy, C 2-6  dialkylamino, C 1-6  haloalkoxy, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, phenoxy and phenyl. 
   
   
       23 . The compound according to  claim 1 , wherein R 2  is H or C 1-6  alkyl; and R 3  is H, C 2-6  alkenyl, C 1-6  alkyl, C 3-7  cycloalkyl, halogen or phenyl; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1-6  alkoxy, C 1-6  alkylthio, hydroxyl, phenoxy and phenyl; or
 R 2  and R 3  together with the carbon to which they are both bonded form a cyclopropyl, cyclopentyl or cyclohexyl group.   
   
   
       24 . The compound according to  claim 3 , wherein R 2  is H or C 1-6  alkyl; and R 3  is H, C 2-6  alkenyl, C 1-6  alkyl, halogen or phenyl; wherein said C 1-6  alkyl is optionally substituted with substituents selected from the group consisting of C 1-6  alkoxy, hydroxyl, phenoxy and phenyl. 
   
   
       25 . The compound according to  claim 3 , wherein R 2  is H or CH 3 ; and R 3  is H, CH 3  or benzyl. 
   
   
       26 . The compound according to  claim 3 , wherein R 2  is H or CH 3 ; and R 3  is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl. 
   
   
       27 . The compound according to  claim 1 , wherein R 2  is H or CH 3 ; and R 3  is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, methylsulfanylmethyl, ethoxymethyl, cyclopropyl, 1-but-2-enyl, or allyl; or
 R 2  and R 3  together with the carbon to which they are both bonded form a cyclopropyl, cyclopentyl or cyclohexyl group.   
   
   
       28 . The compound according to  claim 3 , wherein:
 X is N, Z is CR 7 , wherein R 7  is carboxyl, —CO 2 Et or tetrazol-5-yl; or   X is CR 7 , wherein R 7  is carboxyl, —CO 2 Et or tetrazolyl, and Z is N;   R 1 , R 4 , R 5  and R 6  are each H;   R 2  is H or CH 3 ; and   R 3  is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or   a pharmaceutically acceptable salt, hydrate or solvate thereof.   
   
   
       29 . The compound according to  claim 3 , wherein:
 X is N, Z is CR 7 , and R 7  is carboxyl, —CO 2 Et or tetrazol-5-yl;   R 1 , R 4 , R 5  and R 6  are each H;   R 2  is H or CH 3 ; and   R 3  is H, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl; or   a pharmaceutically acceptable salt, hydrate or solvate thereof.   
   
   
       30 . The compound according to  claim 3 , wherein:
 X is N, Z is CR 7 , and R 7  is carboxyl; or   X is CR 7 , R 7  is carboxyl or tetrazol-5-yl, and Z is N;   R 1 , R 4 , R 5  and R 6  are each H;   R 2  is H or CH 3 ; and   R 3  is H, CH 3  or benzyl; or   a pharmaceutically acceptable salt, hydrate or solvate thereof.   
   
   
       31 . The compound according to  claim 3 , having the structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
   
   
       32 . The compound according to  claim 1 , having the structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
   
   
       33 . The compound according to  claim 3 , selected from the group consisting of: 
     3b,4,4a,5-Tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid; 
     1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; and 
     4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       34 . The compound according to  claim 33 , wherein the stereochemistry for the two carbons assigned as 3b and 4a, or 1a and 5a are both R. 
   
   
       35 . The compound according to  claim 3 , selected from the group consisting of: 
     1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1,1-Dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; and 
     1-Benzyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       36 . The compound according to  claim 3 , selected from the group consisting of: 
     1-Methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Isobutyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Butyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Phenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Phenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Isopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; 
     1-Hydroxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester; and 
     1-Hydroxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       37 . The compound according to  claim 1 , selected from the group consisting of: 
     1-Methylsulfanylmethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Ethoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Cyclopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Spirocyclopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     (E)-1-Propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     (Z)-1-Propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     1-Phenoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 
     Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1′-cyclopentan]-4-carboxylic acid; 
     Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1′-cyclohexan]-4-carboxylic acid; 
     1-Allyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; and 
     4-Methyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid; 
     1-Cyclopropylmethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       38 . The compound according to  claim 3 , selected from the group consisting of: 
     1-Methyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Ethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Propyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Isobutyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Phenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Benzyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Pentyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Butyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Isopropyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Phenoxymethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     4-(2H-Tetrazol-5-yl)-1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Methoxymethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; and 
     [4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-1-yl]-methanol; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       39 . The compound according to  claim 1 , selected from the group consisting of: 
     1-Cyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     1-Spirocyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     (E)-1-Propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     (Z)-1-Propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; 
     5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1′-cyclopentan]-4-yl)-1H-tetrazole; 
     5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1′-cyclohexan]-4-yl)-1H-tetrazole; and 
     1-Allyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; or
 a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       40 . A pharmaceutical composition comprising a compound according to  claim 1 , in combination with a pharmaceutically acceptable carrier. 
   
   
       41 . A pharmaceutical composition comprising a compound according to  claim 3 , in combination with a pharmaceutically acceptable carrier. 
   
   
       42 . A pharmaceutical composition according to  claim 41  further comprising an agent selected from the group consisting of α-glucosidase inhibitor, aldose reductase inhibitor, biguanide, HMG-CoA reductase inhibitor, squalene synthesis inhibitor, fibrate, LDL catabolism enhancer, angiotensin converting enzyme inhibitor, insulin secretion enhancer, thiazolidinedione and DP receptor antagonist. 
   
   
       43 . A method of treatment of a metabolic-related disorder comprising administering to a human in need of such treatment a therapeutically-effective amount of a compound according to  claim 1 , or a pharmaceutical composition according to  claim 40 . 
   
   
       44 . A method of treatment of a metabolic-related disorder comprising administering to a human in need of such treatment a therapeutically-effective amount of a compound according to  claim 3 , or a pharmaceutical composition according to  claim 41 . 
   
   
       45 . A method of treatment of a metabolic-related disorder comprising administering to an individual in need of such treatment a therapeutically-effective amount of a compound according to  claim 1 , and a DP receptor antagonist. 
   
   
       46 . The method according to  claim 45 , wherein said DP receptor antagonist is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
   
   
       47 . A method of modulating a RUP25 receptor comprising contacting said receptor with a compound according to  claim 1 . 
   
   
       48 . A method of modulating a RUP25 receptor for the treatment of a metabolic-related disorder in an individual in need of such modulation comprising contacting said receptor with a therapeutically-effective amount of a compound according to  claim 1 . 
   
   
       49 . The method according to  claim 48 , wherein said individual is a human. 
   
   
       50 . The method according to  claim 49 , wherein said compound is an agonist. 
   
   
       51 . The method according to  claim 50 , wherein said agonist is a partial agonist. 
   
   
       52 . A method of treating atherosclerosis in a human patient in need of such treatment comprising administering to said patient a compound in accordance with  claim 1  in an amount that is effective to treat atherosclerosis. 
   
   
       53 . A method of treating dyslipidemia in a human patient in need of such treatment comprising administering to said patient a compound in accordance with  claim 1  in an amount that is effective to treat dyslipidemia. 
   
   
       54 . A method of raising HDL in a human comprising administering to said individual a therapeutically-effective amount of a compound according to  claim 1 . 
   
   
       55 . A method of treating atherosclerosis in a human patient in need of such treatment comprising administering to said patient a compound in accordance with  claim 3  in an amount that is effective to treat atherosclerosis. 
   
   
       56 . A method of treating dyslipidemia in a human patient in need of such treatment comprising administering to said patient a compound in accordance with  claim 3  in an amount that is effective to treat dyslipidemia. 
   
   
       57 . A method of raising HDL in a human comprising administering to said individual a therapeutically-effective amount of a compound according to  claim 3 . 
   
   
       58 . The method according to  claim 54 , wherein said individual is a human. 
   
   
       59 . A method of producing a pharmaceutical composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier.