Purine derivatives

Abstract

The present invention relates to compounds of the formula and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds as adenosine A2a receptor agonists.

1 - 24 . (canceled)  
     
     
         25 . A method of agonising an A2a receptor in a mammal, said method comprising administering to said mammal in need of such treatment an effective amount of a compound of formula (I),  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 1  is hydrogen or C 1 -C 6  alkyl optionally and independently substituted with 1 to 2 phenyl or naphthyl, said phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano;  
 R 2  is H or C 1 -C 6  alkyl;  
 A is C 1 -C 6  alkylene;  
 R 3  is (i) hydrogen, C 1 -C 6  alkyl, —COOR 4 , —CN, —CONR 4 R 4 , C 3 -C 8  cycloalkyl, phenyl or naphthyl, said C 3 -C 8  cycloalkyl, phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4  cyano, COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 ,  
 or (ii) when A is C 2 -C 6  alkylene, R 3  is —NR 4 R 4 , —OR 4 , —OCOR 5 , —SO 2 R 5 , —SO 2 NR 4 R 4  or —NR 4 COR 5 ,  
 or (iii) a C-linked, 4- to 11-membered ring, mono- or bicyclic, heterocycle comprising 1 to 4 ring nitrogen atoms, or 1 to 2 nitrogen and 1 oxygen or 1 sulfur ring atoms, said heterocycle optionally and independently C-substituted with oxo, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, fluoro(C 2 -C 5 )alkanoyl, halo, cyano, —OR 6 , R 7 , —COR 6 , —NR 6 R 6 , —COOR 6 , —S(O) m R 7 , —SO 2 NR 6 R 6 , —CONR 6 R 6 , —NR 6 SO 2 R 7  or —NR 6 COR 7 , and said heterocycle optionally and independently N-substituted with C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 2 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 2 -C 5 )alkanoyl, R 7 , —COR 6 , —COOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 6  or —CONR 6 R 6 ,  
 or (iv) when A is C 2 -C 6  alkylene, R 3  is an N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said R 3  is optionally and independently C-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4 , cyano, —COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 , and where said R 3  is piperazinyl and homopiperazinyl, R 3  is optionally and independently N-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 2 -C 6 )alkyl, R 4 R 4 N(C 2 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl C 2 -C 5  alkanoyl, —COOR 5 , C 3 -C 8  cycloalkyl, —SO 2 R 5 , —SO 2 NR 4 R 4  or —CONR 4 R 4 ;  
 R 4  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 5  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 6  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 R 7  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 m is 0, 1 or 2; and  
 “het” is a C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoguinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, where said het is optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cyano or halo.  
 
     
     
         26 . A method of treating an inflammatory disease or a respiratory disease in a mammal, said method comprising administerinq to said mammal in need of such treatment an effective amount of a compound of formula (I),  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 1  is hydrogen or C 1 -C 6  alkyl optionally and independently substituted with 1 to 2 phenyl or naphthyl, said phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano;  
 R 2  is H or C 1 -C 6  alkyl;  
 A is C 1 -C 6  alkylene;  
 R 3  is (i) hydrogen, C 1 -C 6  alkyl, —COOR 4 , —CN, —CONR 4 R 4 , C 3 -C 8  cycloalkyl, phenyl or naphthyl, said C 3 -C 8  cycloalkyl, phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4  cyano, COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 ,  
 or (ii) when A is C 2 -C 6  alkylene, R 3  is —NR 4 R 4 , —OR 4 , —OCOR 5 , —SO 2 R 5 , —SO 2 NR 4 R 4  or —NR 4 COR 5 ,  
 or (iii) a C-linked, 4- to 11-membered ring, mono- or bicyclic, heterocycle comprising 1 to 4 ring nitrogen atoms, or 1 to 2 nitrogen and 1 oxygen or 1 sulfur ring atoms, said heterocycle optionally and independently C-substituted with oxo, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, fluoro(C 2 -C 5 )alkanoyl, halo, cyano, —OR 6 , R 7 , —COR 6 , —NR 6 R 6 , —COOR 6 , —S(O) m R 7 , —SO 2 NR 6 R 6 , —CONR 6 R 6 , —NR 6 SO 2 R 7  or —NR 6 COR 7 , and said heterocycle optionally and independently N-substituted with C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 2 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 2 -C 5 )alkanoyl, R 7 , —COR 6 , —COOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 6  or —CONR 6 R 6 ,  
 or (iv) when A is C 2 -C 6  alkylene, R 3  is an N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said R 3  is optionally and independently C-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4 , cyano, —COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 , and where said R 3  is piperazinyl and homopiperazinyl, R 3  is optionally and independently N-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 2 -C 6 )alkyl, R 4 R 4 N(C 2 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, C 2 -C 5  alkanoyl, —COOR 5 , C 3 -C 8  cycloalkyl, —SO 2 R 5 , —SO 2 NR 4 R 4  or —CONR 4 R 4 ;  
 R 4  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 5  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 6  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 R 7  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 m is 0, 1 or 2; and  
 “het” is a C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoguinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, where said het is optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cyano or halo.  
 
     
     
         27 . (canceled)  
     
     
         28 . The method of  claim 26  where the disease is adult respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis or rhinitis.  
     
     
         29 . (canceled)  
     
     
         30 . (canceled)  
     
     
         31 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein X is a leaving group; or  
       
         
           
           
               
               
           
         
       
       wherein R 8  and R 9  are taken separately and are each independently a protecting group, or R 8  and R 9  are taken together to form a protecting group; or  
       
         
           
           
               
               
           
         
       
       wherein R 8 , R 9  are taken separately and are each independently a protecting group, or R 8  and R 9  are taken together to form a protecting group and R 10  is a protecting group; or  
       
         
           
           
               
               
           
         
       
       wherein R 8 , R 9  and R 10  are taken separately and are each independently a protecting group, or R 8  and R 9  are taken together to form a protecting group, and R 10  is a protecting group; or  
       
         
           
           
               
               
           
         
       
       wherein R 11 , R 12  and R 13  are taken separately and are each independently a protecting group, or R 11  is a protecting group and R 12  and R 13  are taken together to form a protecting group; or  
       
         
           
           
               
               
           
         
       
       wherein R 14  is a protecting group; or  
       
         
           
           
               
               
           
         
       
       wherein R 14  is a protecting group;  
       or a pharmaceutically acceptable salt thereof: 
 wherein R 1  is hydrogen or C 1 -C 6  alkyl optionally and independently substituted with 1 to 2 phenyl or naphthyl, said phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano;  
 R 2  is H or C 1 -C 6  alkyl;  
 A is C 1 -C 6  alkylene;  
 R 3  is (i) hydrogen, C 1 -C 6  alkyl, —COOR 4 , —CN, —CONR 4 R 4 , C 3 -C 8  cycloalkyl, phenyl or naphthyl, said C 3 -C 8  cycloalkyl, phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4  cyano, COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 ,  
 or (ii) when A is C 2 -C 6  alkylene, R 3  is —NR 4 R 4 , —OR 4 , —OCOR 5 , —SO 2 R 5 , —SO 2 NR 4 R 4  or —NR 4 COR 5 ,  
 or (iii) a C-linked, 4- to 11-membered ring, mono- or bicyclic, heterocycle comprising 1 to 4 ring nitrogen atoms, or 1 to 2 nitrogen and 1 oxygen or 1 sulfur ring atoms, said heterocycle optionally and independently C-substituted with oxo, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, fluoro(C 2 -C 5 )alkanoyl, halo, cyano, —OR 6 , R 7 , —COR 6 , —NR 6 R 6 , —COOR 6 , —S(O) m R 7 , —SO 2 NR 6 R 6 , —CONR 6 R 6 , —NR 6 SO 2 R 7  or —NR 6 COR 7 , and said heterocycle optionally and independently N-substituted with C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 2 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 2 -C 5 )alkanoyl, R 7 , —COR 6 , —COOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 6  or —CONR 6 R 6 ,  
 or (iv) when A is C 2 -C 6  alkylene, R 3  is an N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said R 3  is optionally and independently C-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4 , cyano, —COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 , and where said R 3  is piperazinyl and homopiperazinyl, R 3  is optionally and independently N-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 2 -C 6 )alkyl, R 4 R 4 N(C 2 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, C 2 -C 5  alkanoyl, —COOR 5 , C 3 -C 8  cycloalkyl, —SO 2 R 5 , —SO 2 NR 4 R 4  or —CONR 4 R 4 ;  
 R 4  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 5  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 6  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 R 7  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 m is 0, 1 or 2; and  
 “het” is a C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoguinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, where said het is optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cyano or halo.  
 
     
     
         32 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein R 17  is H or an ester-forming group; or  
       
         
           
           
               
               
           
         
       
       wherein R 11 , R 12  and R 13  are taken separately and are each independently a protecting group, or R 11  is a protecting group and R 12  and R 13  are taken together to form a protecting group, and R 17  is an ester-forming group; or  
       
         
           
           
               
               
           
         
       
       wherein R 17  is an ester-forming group; or  
       
         
           
           
               
               
           
         
       
       wherein R 4  is a protecting group and R 15  is C 1 -C 6  alkyl;  
       or a pharmaceutically acceptable salt thereof: 
 wherein R 1  is C 1 -C 6  alkyl optionally and independently substituted with 1 to 2 phenyl or naphthyl, said phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano.  
 
     
     
         33 . A compound of  claim 31  wherein R 1  is 2,2-diphenylethyl, R 2  is H and -A-R 3  is 2-(1-piperidinyl)ethyl.  
     
     
         34 . A compound of  claim 31  of formula (II) wherein X is iodo.  
     
     
         35 . A compound of  claim 31  of formula (VI), (IX) or (X) wherein R 8  and R 9  are taken separately and are each independently acetyl or benzoyl or are taken together and are 1,1-dimethylmethylene.  
     
     
         36 . A compound of  claim 31  of formula (IX) or (X) wherein R 10 is a silyl protecting group.  
     
     
         37 . A compound of  claim 31  of formula (XII) wherein R 11 , R 12  and R 13  are taken separately and are each independently acetyl or benzoyl, or R 12  and R 13  are taken together and are 1,1-dimethylmethylene.  
     
     
         38 . A compound of  claim 31  of formula (XXI) or (XXII) wherein R 14  is tetrahydro-2H-pyran-2-yl.  
     
     
         39 . A compound of  claim 32  of formula (XXV), (XXVI) or (XXVII) wherein R 17  is C 1 -C 4  alkyl.  
     
     
         40 . A compound of  claim 32  of formula (XXVI) wherein R 11 , R 12  and R 13  are taken separately and are each independently acetyl or benzoyl, or R 12  and R 13  are taken together and are 1,1-dimethylmethylene.  
     
     
         41 . A compound of  claim 32  wherein R 1  is 2,2-diphenylethyl.  
     
     
         42 . A compound of  claim 32  of formula (XX) wherein R 14  is tetrahydro-2H-pyran-2-yl.  
     
     
         43 . A method of inhibiting neutrophil function in a mammal, said method comprising administering to said mammal in need of such treatment an effective amount of a compound of formula (I),  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 1  is hydrogen or C 1 -C 6  alkyl optionally and independently substituted with 1 to 2 phenyl or naphthyl, said phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano;  
 R 2  is H or C 1 -C 6  alkyl;  
 A is C 1 -C 6  alkylene;  
 R 3  is (i) hydrogen, C 1 -C 6  alkyl, —COOR 4 , —CN, —CONR 4 R 4 , C 3 -C 8  cycloalkyl, phenyl or naphthyl, said C 3 -C 8  cycloalkyl, phenyl and naphthyl optionally and independently substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4  cyano, COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 ,  
 or (ii) when A is C 2 -C 6  alkylene, R 3  is —NR 4 R 4 , —OR 4 , —OCOR 5 , —SO 2 R 5 , —SO 2 NR 4 R 4  or —NR 4 COR 5 ,  
 or (iii) a C-linked, 4- to 11-membered ring, mono- or bicyclic, heterocycle comprising 1 to 4 ring nitrogen atoms, or 1 to 2 nitrogen and 1 oxygen or 1 sulfur ring atoms, said heterocycle optionally and independently C-substituted with oxo, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, fluoro(C 2 -C 5 )alkanoyl, halo, cyano, —OR 6 , R 7 , —COR 6 , —NR 6 R 6 , —COOR 6 , —S(O) m R 7 , —SO 2 NR 6 R 6 , —CONR 6 R 6 , —NR 6 SO 2 R 7  or —NR 6 COR 7 , and said heterocycle optionally and independently N-substituted with C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 6 R 6 N(C 2 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 2 -C 5 )alkanoyl, R 7 , —COR 6 , —COOR 7 , —SO 2 R 7 , —SO 2 NR 6 R 6  or —CONR 6 R 6 ,  
 or (iv) when A is C 2 -C 6  alkylene, R 3  is an N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said R 3  is optionally and independently C-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, R 4 R 4 N(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, C 2 -C 5  alkanoyl, halo, —OR 4 , cyano, —COOR 4 , C 3 -C 8  cycloalkyl, —S(O) m R 5 , —NR 4 R 4 , —SO 2 NR 4 R 4 , —CONR 4 R 4 , —NR 4 COR 5  or —NR 4 SO 2 R 5 , and where said R 3  is piperazinyl and homopiperazinyl, R 3  is optionally and independently N-substituted with C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy(C 2 -C 6 )alkyl, R 4 R 4 N(C 2 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, C 2 -C 5  alkanoyl, —COOR 5 , C 3 -C 8  cycloalkyl, —SO 2 R 5 , —SO 2 NR 4 R 4  or —CONR 4 R 4 ;  
 R 4  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 5  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
 R 6  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 R 7  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, naphthyl or het;  
 m is 0, 1 or 2; and  
 “het” is a C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoguinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, where said het is optionally and independently substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cyano or halo.  
 
     
     
         44 . The compound of  claim 31  of formula (II), with the proviso that when X is bromo or iodo, R 1  is not H.  
     
     
         45 . The compound of  claim 44  of formula (IX), with the proviso that when R 1  is H, R 8 , R 9  and R 10 are not each t-butyldimethylsilyl or acetyl.