Macrocyclic compounds as inhibitors of viral replication

Abstract

The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q is a core ring selected from: 
       
       
         
           
           
               
               
           
         
         wherein the core ring can be unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, substituted C 1-6  alkyl, substituted C 1-6  alkoxy, C 6 or 10  aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, 
         or Q is R 1 -R 2 , wherein R 1  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; and R 2  is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
         R 4  is H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
         R 5  is C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ; 
         R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 6  and R 7  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; or R 8  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 8  is C 1-6  alkyl optionally substituted with up to 5 fluoro groups; or R 8  is a tetrahydrofuran ring linked through the C 3  or C 4  position of the tetrahydrofuran ring; or R 8  is a tetrahydropyran ring linked through the C 4  position of the tetrahydropyran ring; 
         Y is COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is —C(O)NHS(O) 2 R 9 , where R 9  is C 1-3  alkyl, C 3-7  cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3  alkyl, C 3-7  cycloalkyl, or C 1-3  alkoxy; or Y is a carboxylic acid; 
         V and W are each individually selected from O, S, or NH; 
         the dashed line represents an optional double bond; 
         R 21  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 21  is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and 
         R 22  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, or phenyl. 
       
     
     
         2 . The compound of  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q is a core ring selected from: 
       
       
         
           
           
               
               
           
         
         wherein the core ring can be unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxyl-C 1-6  alkyl, substituted C 1-6  alkyl, substituted C 1-6  alkoxy, or C 6 or 10  aryl; 
         R 4  is H; 
         R 5  is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ; 
         R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
         R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; and 
         V and W are each individually selected from O or NH. 
       
     
     
         3 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q is the core ring: 
       
       
         
           
           
               
               
           
         
         wherein the core ring can be unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxyl-C 1-6  alkyl, substituted C 1-6  alkyl, substituted C 1-6  alkoxy, C 6 or 10  aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl; 
         R 4  is H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
         R 5  is C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ; 
         R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 6  and R 7  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; or R 8  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 8  is C 1-6  alkyl optionally substituted with up to 5 fluoro groups; or R 8  is a tetrahydrofuran ring linked through the C 3  or C 4  position of the tetrahydrofuran ring; or R 8  is a tetrahydropyran ring linked through the C 4  position of the tetrahydropyran ring; 
         Y is COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is —C(O)NHS(O) 2 R 9 , where R 9  is C 1-3  alkyl, C 3-7  cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3  alkyl, C 3-7  cycloalkyl, or C 1-3  alkoxy; or Y is a carboxylic acid; 
         V and W are each individually selected from O, S, or NH; 
         R 21  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 21  is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and 
         R 22  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, or phenyl. 
       
     
     
         4 . The compound of  claim 3 , wherein:
 the core ring is unsubstituted or substituted with halo;   R 4  is H;   R 5  is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;   Y is COOR 9 ;   R 9  is C 1-6  alkyl; and   V and W are each individually selected from O or NH.   
     
     
         5 . The compound of  claim 4 , wherein:
 the core ring is unsubstituted; and   V and W are each O.   
     
     
         6 . The compound of  claim 3 , wherein:
 R 4  is H;   R 5  is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;   Y is —C(O)NHS(O) 2 R 9 ; and   R 9  is C 1-3  alkyl, or C 3-7  cycloalkyl.   
     
     
         7 . The compound of  claim 6 , wherein:
 the core ring is substituted with halo; and   R 9  is C 3-7  cycloalkyl.   
     
     
         8 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q is the core ring: 
       
       
         
           
           
               
               
           
         
         wherein the core ring can be unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxyl-C 1-6  alkyl, substituted C 1-6  alkyl, substituted C 1-6  alkoxy, C 6 or 10  aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl; 
         R 4  is H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
         R 5  is C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or —(CO)CHR 21 NH(CO)R 22 ; 
         R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 6  and R 7  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; 
         R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; or R 8  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 8  is C 1-6  alkyl optionally substituted with up to 5 fluoro groups; or R 8  is a tetrahydrofuran ring linked through the C 3  or C 4  position of the tetrahydrofuran ring; or R 8  is a tetrahydropyran ring linked through the C 4  position of the tetrahydropyran ring; 
         Y is COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is —C(O)NHS(O) 2 R 9 , wherein R 9  is C 1-3  alkyl, C 3-7  cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3  alkyl, C 3-7  cycloalkyl, or C 1-3  alkoxy; or Y is a carboxylic acid; 
         V and W are each individually selected from O, S, or NH; 
         R 21  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, C 1-6  alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 21  is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and 
         R 22  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, phenyl, or C 1-6  alkyl optionally substituted with up to 5 fluoro. 
       
     
     
         9 . The compound of  claim 8 , wherein:
 R 4  is H;   R 5  is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ; and   V and W are each individually selected from O or NH.   
     
     
         10 . The compound of  claim 9 , wherein:
 the core ring is substituted with halo;   Y is COOR 9 ; and   R 9  is C 1-6  alkyl.   
     
     
         11 . The compound of  claim 10 , wherein:
 the halo is fluoro;   R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   V and W are each O.   
     
     
         12 . The compound of  claim 9 , wherein:
 the core ring is substituted with halo;   Y is —C(O)NHS(O) 2 R 9 ; and   R 9  is C 1-3  alkyl, or C 3-7  cycloalkyl.   
     
     
         13 . The compound of  claim 12 , wherein:
 the halo is fluoro; and   R 9  is C 3-7  cycloalkyl.   
     
     
         14 . The compound of  claim 13 , wherein:
 R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   V and W are each O.   
     
     
         15 . The compound of  claim 1 , wherein:
 Q is R 1 -R 2 , wherein R 1  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; and R 2  is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro;   R 4  is H;   R 5  is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;   R 6  and R 7  are each independently H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, hydroxyl-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 6  and R 7  are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;   R 8  is C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6  alkoxy, or phenyl; or R 8  is C 6 or 10  aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  alkylcycloalkyl, C 2-6  alkenyl, C 1-6  alkoxy, hydroxy-C 1-6  alkyl, C 1-6  alkyl optionally substituted with up to 5 fluoro, or C 1-6  alkoxy optionally substituted with up to 5 fluoro; or R 8  is C 1-6  alkyl optionally substituted with up to 5 fluoro groups; or R 8  is a tetrahydrofuran ring linked through the C 3  or C 4  position of the tetrahydrofuran ring; or R 8  is a tetrahydropyran ring linked through the C 4  position of the tetrahydropyran ring;   Y is COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is —C(O)NHS(O) 2 R 9 , wherein R 9  is C 1-3  alkyl, C 3-7  cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3  alkyl, C 3-7  cycloalkyl, or C 1-3  alkoxy; or Y is a carboxylic acid; and   V and W are each individually selected from O or NH.   
     
     
         16 . The compound of  claim 15 , wherein:
 R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   Y is COOR 9 , wherein R 9  is C 1-6  alkyl.   
     
     
         17 . The compound of  claim 15 , wherein:
 R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   Y is —C(O)NHS(O) 2 R 9 , wherein R 9  is C 1-3  alkyl or C 3-7  cycloalkyl.   
     
     
         18 . A method of making a compound, comprising:
 performing an olefin metathesis ring forming reaction with the compound of formula:   
       
         
           
           
               
               
           
         
       
       to provide a compound of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Q, V, W, R 4 , R 5  and Y are defined as in  claim 8 . 
       
     
     
         19 . The method of  claim 18 , wherein:
 R 4 ═H;   R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   Y is —C(O)NHS(O) 2 R 9  where R 9  is C 1-3  alkyl or C 3-7  cycloalkyl; or Y is COOR 9 , where R 9  is C 1-6  alkyl.   
     
     
         20 . The method of  claim 19 , wherein:
 the core ring is substituted with a halo; and   Y is COOR 9 , where R 9  is C 1-6  alkyl.   
     
     
         21 . The method of  claims 20 , wherein the halo is fluoro. 
     
     
         22 . A method of preparing a compound of formula: 
       
         
           
           
               
               
           
         
         comprising, cyclizing a compound having the formula: 
       
       
         
           
           
               
               
           
         
         wherein Q, V, W, R 4 , R 5  and Y are defined as in  claim 8 . 
       
     
     
         23 . The method of  claim 22 , wherein:
 the core ring is substituted with halo;   R 4  is H;   R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl;   Y is COOR 9 , wherein R 9  is C 1-6  alkyl; and   V and W are each O.