US2007093535A1PendingUtilityA1
Vinyl phenyl derivatives as GLK activators

Assignee: ASTRAZENECA ABPriority: Jun 26, 2001Filed: Oct 10, 2006Published: Apr 26, 2007
Est. expiryJun 26, 2021(expired)· nominal 20-yr term from priority
Inventors:Barry Hayter Gordon Stuart Currie Rodney B. Hargreaves Peter William Rodney Caulkett Roger James
C07D 277/56C07D 213/80C07D 413/04C07D 213/78C07D 307/68C07D 413/12C07D 405/12C07D 239/28C07D 213/82A61P 3/04A61P 43/00A61P 3/10C07D 417/12
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Claims
Abstract

The invention related to novel compounds of Formula (I) or a salt, solvate or prodrug thereof, wherein A, R 1 , R 2 , R 3 , n and m are as described in the specification, useful in the treatment of a disease or condition mediated through glucokinase (GLK), such as type 2 diabetes. The invention also relates to methods for preparing compounds of Formula (I) and their use as medicaments in the treatment of diseases mediated by glucokinase.
Claims

exact text as granted — not AI-modified
1 - 18 . (canceled)  
   
   
       19 . A method for the treatment or prevention of a disease or medical condition mediated through GLK, comprising administering to an animal in need thereof, a compound of Formula (I) or a salt, solvate or prodrug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 A is heteroaryl;  
 m is 0, 1 or 2;  
 n is 0, 1, 2, 3 or 4;  
 and n+m&gt;0;  
 each R 1  is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , —OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN, formyl, phenyl and heterocyclyl optionally substituted with C 1-6 alkyl;  
 each R 2  is the group Y—X—;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 1-4 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 CH 3-a F a  and —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted with up to 3 R 4  groups;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —;  
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, —SO 2 C 1-6 alkyl, and —(CH 2 ) 0-3 OH;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each a is independently 1, 2 or 3;  
 p is 0, 1 or 2;  
 q is 0, 1 or 2;  
 and p+q&lt;4.  
 
   
   
       20 . A method of  claim 19 , wherein the compound or salt, solvate or prodrug thereof is administered together with a pharmaceutically acceptable diluent or carrier.  
   
   
       21 . A compound of Formula (Ib) or a salt, solvate or prodrug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 A is heteroaryl;  
 m is 0, 1 or 2;  
 n is 0, 1, 2, 3 or 4;  
 and n+m&gt;0;  
 each R 1  is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , —OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN, formyl, phenyl and heterocyclyl optionally substituted with C 1-6 alkyl;  
 each R 2  is the group Y—X—;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 1-4 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 CH 3-a F a  and —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted with up to 3 R 4  groups;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —; 
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, SO 2 C 1-6 alkyl, and (CH 2 ) 0-3 OH;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each a is independently 1, 2 or 3;  
 p is 0, 1 or 2;  
 q is 0, 1 or 2;  
 and p+q&lt;4;  
 with the proviso that:  
 (i) when m is 1 or 2 and n is 0, R 3  is OH or —O—C 1-6 alkyl, then R 1  is other than OH, CN, halo, methyl, amino or nitro;  
 (ii) when m is 0, n is 1, X is —O—, —O—C(O)—, —S—, —S(O)—, —S(O 2 )—, —N(CH 3 )—, —N(CH 3 )—CH 2 — or —C(O)—NH—, R 3  is OH or —O—C 1-6 alkyl, then Y cannot be C 1-6 alkyl or C 1-6 alkyl substituted with C 1-6 alkyl;  
 (iii) when m is 0 or 1 and R 1  is NO 2 , R 3  is OH or —O—C 1-6 alkyl, then when n is 2, (R 2 ), cannot be di-C 1-6 alkyl-O— or C 1-6 alkyl-O—C 1-6 alkenyl-O— and when n is 3, (R 2 ), cannot be tri-C 1-6 alkyl-O—;  
 (iv) when A is pyridyl, m is 0 or 1 and R 1  is halo, n is 1 and R 2  is phenyl, phenyl-CH 2 —O— or pyridyl-NH—, then R 3  cannot be OH or —O—C 1-6 alkyl; and  
 (v) when A is pyridyl, R 3  is OH, m is 0, n is 2 and one of the R 2  groups is phenyl-CH 2 —O—, then the other R 2  group must be other than CH 3 —S— or CH 3 —SO 2 —.  
 
   
   
       22 . A compound according to  claim 21  or a salt, solvate or prodrug thereof, wherein m is 0 or 1 and n is 1 or 2.  
   
   
       23 . A compound according to  claim 22  or a salt, solvate or prodrug thereof, wherein n+m is 2 and the R 1  and/or R 2  groups are substitutents at the 2- and 5-positions.  
   
   
       24 . A compound according to  claim 21  or a salt, solvate or prodrug thereof, wherein each R 1  is independently selected from OH, CH 3-a F a , OCH 3-a F a , halo, C 1-6 alkyl, NO 2  and heterocyclyl optionally substituted with C 1-6 alkyl.  
   
   
       25 . A compound according to  claim 21  or a salt, solvate or prodrug thereof, wherein 
 each R 2  is the group Y—X—;    each X is independently selected from —O-Z-, —C(O)O-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )SO 2 , Z-SO 2 NH-Z-, —(CH 2 ) 1  4-, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z- and a direct bond; and    each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7  cycloalkyl-Z 1 -, C 1-6  alkyl, C 2-6 alkenyl and —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted with R 4 .    
   
   
       26 . A compound according to  claim 21  or a salt, solvate or prodrug thereof, wherein each R 4  is independently selected from halo, —CH 3-a F a , —OCH 3-a F a , CN, NO 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —(CH 2 ) 1-3 COOH, —(CH 2 ) 0-3 COOH, —C(O)phenyl, —C(O)NH 2 , —C(O)NH-phenyl, —SO 2 NH 2 , —SO 2 C 1-6 alkyl, and phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl.  
   
   
       27 . A compound of Formula (II) or a salt, solvate or prodrug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 A is heteroaryl, except A is not pyridyl;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 1-4 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, SO 2 C 1-6 alkyl, and (CH 2 ) 0-3 OH;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —; 
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 
 each a is independently 1, 2 or 3;  
 p is 0, 1 or 2;  
 q is 0, 1 or 2;  
 and p+q&lt;4.  
 
   
   
       28 . A compound of Formula (IIa) or a salt, solvate or prodrug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 Het is a monocyclic heterocyclyl, optionally substituted with between 1 and 3 groups selected from R 4 ;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —; 
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 
 A is heteroaryl;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 14 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, SO 2 C 1-6 alkyl, and (CH 2 ) 0-3 OH;  
 each a is independently 1, 2 or 3;  
 p is 0, 1 or 2;  
 q is 0, 1 or 2;  
 and p+q&lt;4.  
 
   
   
       29 . A compound of Formula (IIf) or a salt, solvate or pro-drug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 Het is a monocyclic heterocyclyl; wherein the Het and C 1-6 alkyl groups are independently optionally substituted with between 1 and 3 groups selected from R 4 , and wherein the C 1-6 alkyl group optionally contains a double bond;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —;  
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 A is heteroaryl;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 1-4 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, SO 2 C 1-6 alkyl, and (CH 2 ) 0-3 OH;  
 each a is independently 1, 2 or 3;  
 p is an integer between 0 and 2;  
 q is an integer between 0 and 2;  
 and p+q&lt;4.  
 
   
   
       30 . A compound according to  claim 27 , or a salt, solvate or prodrug thereof, wherein 
 X is independently selected from —O-Z-, SO 2 N(R 7 )-Z- and —N(R 7 )-Z-;    Z is independently selected from a direct bond and —CH 2 —; and    Z 1  is independently selected from a direct bond, —CH 2 —, —(CH 2 ) 2 — and                          
   
   
       31 . A compound according to  claim 21  or a salt, solvate or prodrug thereof, wherein A is selected from pyridyl, pyrimidinyl, pyrazinyl, furanyl and thiazolyl.  
   
   
       32 . A process for the preparation of a compound of Formula (I), or a salt, solvate or prodrug thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 A is heteroaryl;  
 m is 0, 1 or 2;  
 n is 0, 1, 2, 3 or 4;  
 and n+m&gt;0;  
 each R 1  is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , —OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN, formyl, phenyl and heterocyclyl optionally substituted with C 1-6 alkyl;  
 each R 2  is the group Y—X—;  
 each X and X 1  is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 14 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —C(O)N(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- and a direct bond;  
 each Z is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —;  
 each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 CH 3-a F a  and —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted with up to 3 R 4  groups;  
 each R 4  is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH, phenyl optionally substituted with C 1-6 alkyl or —C(O)OC 1-6 alkyl, and R 5 —X 1 —; 
 R 5  is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl and C 3-7 cycloalkyl; wherein R 5  is optionally substituted with halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, and wherein each phenyl, naphthyl or heterocyclyl ring in R 5  is optionally substituted with halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH;  
 
 each Z 1  is independently selected from a direct bond, C 2-6 alkenylene and a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —;  
 R 3  is selected from OH, —OC 1-6 alkyl and NHR 6 ;  
 R 6  is selected from hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, —SO 2 C 1-6 alkyl, and —(CH 2 ) 0-3 OH;  
 each R 7  is independently selected from hydrogen, C 1-6 alkyl and —C 2-4 alkyl-O—C 1-4 alkyl;  
 each a is independently 1, 2 or 3;  
 p is 0, 1 or 2;  
 q is 0, 1 or 2;  
 and p+q&lt;4;  
 which comprises  
 (a) reacting a compound of Formula (IIIa) with a compound of Formula (IIIb),  
                     
 (b) for compounds of Formula (I) wherein R 3  is hydrogen, de-protecting a compound of Formula (IIIc),  
                     wherein P 1  is a protecting group;    
 (c) reacting a compound of Formula (IIId) with a compound of Formula (IIIe),  
                     wherein X′ and X″ comprise groups which when reacted together form the group X;    
 (d) for a compound of Formula (I) wherein X or X 1  is —SO-Z- or —SO 2 -Z-, oxidizing the corresponding compound of Formula (I) wherein X or X 1  respectively is —S-Z-; or  
 (e) for a compound of Formula (I) wherein R 3  is NHR 6 , reacting a compound of Formula (IIIf) with a compound of Formula (IIIg),  
                     and optionally:    i) converting a compound of Formula (I) into another compound of Formula (I);    ii) removing any protecting groups; and/or    iii) forming a salt, pro-drug or solvate thereof.    
 
   
   
       33 . A method for the combined treatment or prevention of diabetes and obesity comprising administering a GLK activator.  
   
   
       34 . A method for the combined treatment or prevention of diabetes and obesity comprising administering a GLK activator selected from a compound of Formula Ib, II, IIa or IIf, according to any one of  claims 21  to  31 , or a salt, solvate or prodrug thereof.  
   
   
       35 . A pharmaceutical composition comprising a compound of Formula Ib, II, IIa or IIf, according to any one of  claims 21  to  31 , or a salt, solvate or prodrug thereof with a pharmaceutically acceptable diluent or carrier.
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