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: 
         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 a sulfonimide of the formula —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 is selected from OH, SH, or NH 2 ; 
         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  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein Y is a sulfonimide of the formula —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, and wherein V is selected from OH and NH 2 . 
     
     
         4 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         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 22 NH(CO)R 21 ; 
         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 a sulfonimide of the formula —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 COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is a carboxylic acid; 
         V is selected from OH, SH, or NH 2 ; 
         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. 
       
     
     
         5 . The compound of  claim 4 , wherein:
 Y is a sulfonimide of the formula —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.   
     
     
         6 . The compound of  claim 4 , wherein:
 C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .   
     
     
         7 . The compound of  claim 5 , 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 is selected from OH and NH 2 .   
     
     
         8 . The compound of  claim 7 , wherein:
 R 5  is C(O)OR 8 ; and   R 8  is C 1-6  alkyl.   
     
     
         9 . The compound of  claim 4 , 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 is selected from OH and NH 2 .   
     
     
         10 . The compound of  claim 9 , wherein:
 R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl;   Y is COOR 9 ;   R 9  is C 1-6  alkyl;   the dashed line is a double bond; and   V is OH.   
     
     
         11 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         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 22 NH(CO)R 21 ; 
         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 a sulfonimide of the formula —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 COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is a carboxylic acid; 
         V is selected from OH, SH, or NH 2 ; 
         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. 
       
     
     
         12 . The compound of  claim 11 , wherein:
 Y is a sulfonimide of the formula —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.   
     
     
         13 . The compound of  claim 11 , wherein:
 C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .   
     
     
         14 . The compound of  claim 11 , 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 is selected from OH and NH 2 .   
     
     
         15 . The compound of  claim 14 , wherein:
 R 5  is C(O)OR 8 ; and   Y is a sulfonimide of the formula —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.   
     
     
         16 . The compound of  claim 15 , wherein:
 R 8  is C 1-6  alkyl; and   V is OH.   
     
     
         17 . The compound of  claim 14 , wherein:
 R 5  is C(O)OR 8 ; and   Y is COOR 9 , wherein R 9  is C 1-6  alkyl.   
     
     
         18 . The compound of  claim 17 , wherein:
 R 8  is C 1-6  alkyl; and   V is OH.   
     
     
         19 . A method of making a compound, comprising:
 performing an olefin metathesis ring forming reaction with a compound of formula:   
       
         
           
           
               
               
           
         
         to provide a compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein: 
         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 22 NH(CO)R 21 ; 
         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 a sulfonimide of the formula —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 COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is a carboxylic acid; 
         V is selected from OH, SH, or NH 2 ; 
         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. 
       
     
     
         20 . The compound of  claim 19 , wherein:
 Y is a sulfonimide of the formula —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.   
     
     
         21 . The compound of  claim 19 , wherein:
 C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .   
     
     
         22 . The method of  claim 19 , wherein:
 R 4 =H;   R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   Y is a sulfonimide of the formula —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.   
     
     
         23 . The method of  claim 22 , wherein:
 Y is COOR 9 , where R 9  is C 1-6  alkyl.   
     
     
         24 . The method of  claim 19 , further comprising:
 performing a coupling reaction to provide the compound of formula:   
       
         
           
           
               
               
           
         
         wherein: 
         Q is the core ring 
       
       
         
           
           
               
               
           
         
         wherein the core ring is 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; and 
         W is O, S or NH. 
       
     
     
         25 . The method of  claim 24 , wherein the coupling reaction employs:
 carbonyldimidazole and an amine,   wherein the amine has the formula   
       
         
           
           
               
               
           
         
          and is 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. 
       
     
     
         26 . The method of  claim 24  wherein the coupling reaction employs a coupling agent having the formula: 
       
         
           
           
               
               
           
         
         wherein the coupling agent is 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. 
       
     
     
         27 . The method of  claim 26 , wherein the coupling agent is substituted with a halo. 
     
     
         28 . The method of  claim 27 , wherein the halo is fluoro. 
     
     
         29 . A method of preparing a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising 
         performing an olefin metathesis ring forming reaction with the compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein: 
         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 22 NH(CO)R 21 ; 
         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 a sulfonimide of the formula —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 COOR 9 , wherein R 9  is C 1-6  alkyl; or Y is a carboxylic acid; 
         V is selected from OH, SH, or NH 2 ; 
         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. 
       
     
     
         30 . The compound of  claim 29 , wherein:
 Y is a sulfonimide of the formula —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.   
     
     
         31 . The compound of  claim 29 , wherein:
 C 1-6  alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .   
     
     
         32 . The method of  claim 29 , wherein:
 R 4 =H;   R 5  is C(O)OR 8 ;   R 8  is C 1-6  alkyl; and   Y is a sulfonimide of the formula —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.   
     
     
         33 . The method of  claim 32 , wherein:
 Y is COOR 9 , where R 9  is C 1-6  alkyl.