Benzamide glucokinase activators

Abstract

The present invention relates to N-heteroaryl-benzamides of the formula (I), pharmaceutical compositions comprising the same, and methods of using the same. The N-heteroaryl-benzamides are useful as glucokinase activators.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1, or 2; 
 n is 0, 1, 2, 3 or 4; 
 n+m>0; 
 Each R 1  is independently selected from the group consisting of 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 , Cl, F, Br, I, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, amino, C 1-4 -alkyl-amino, C 1-4 -dialkyl-amino, cyano, formyl, phenyl, and 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t  optionally substituted with C 1-6 -alkyl; 
 Each R 2  is a group Y—X— 
 wherein each X is independently —O—Z—, —O—Z—O—Z—, —C(O)O—Z—, —OC(O)—Z—, —S—Z—, —S(O)—Z—, —S(O) 2 —Z‘ 3 , —N(R 6 )—Z—, —N(R 6 )S(O) 2 —Z, —S(O) 2 N(R 6 )—Z, —(CH 2 ) 1-4 , —CH═CH—Z, —C≡C—Z, —N(R 6 )C(O)—Z, —C(O)N(R 6 )—Z, —C(O)N(R 6 )S(O) 2 —Z, —S(O) 2 —N(R 6 )C(O)—Z, —C(O)—Z, —Z, —C(O)—Z—O—Z, —N(R 6 )—C(O)—Z—O—Z, —O—Z—N(R 6 )—Z, —O—C(O)—Z—O—Z or a direct bond, 
 wherein X is attached to the phenyl ring by the first-mentioned atom; 
 Each Z is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —; 
 Each Y is independently aryl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t ; 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 , or —CH(OH)CH 3-a F a , wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 ; 
 Z 1  is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q ; 
 At each occurrence, p is independently selected from 0, 1, 2, or 3; 
 At each occurrence, q is independently selected from 0, 1, 2, or 3; 
 R 4  is independently R 5 —X 1 —, Cl, F, Br, I, CH 3-a F a , —CN, NH 2 , C 1-6 -alkyl, —C(O)OH, —CC(O)OR 7 , OH, or phenyl optionally substituted by R 7 ; 
 or two R 4  attached to adjacent atoms may form a —O—(CH 2 ) 1-2 -O— bridge; 
 or 
 R 4  is —C(O)NR 26 R 27 , —S(O) 2 NR 26 R 27 , —S(O) t R 26  or HET-2; 
 X 1  is independently defined as X above: 
 R 5  is H, CH 2 F, CHF 2 , CF 3 , phenyl, naphthyl, a 5-10 membered heterocyclyl consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t , or C 3 - 7 cycloalkyl, wherein each R 5  is optionally substituted by one or more substituents independently selected from R 25 ; 
 R 25  is independently Cl, F, Br, I, CH 3-a F a , —CN, OH, NH 2 , C(O)OH, or —C(O)OC 1-6 alkyl; 
 R 6  is independently hydrogen, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 -alkyl; 
 R 7  is independently C 1-6 -alkyl or —C(O)OC 1-6 -alkyl; 
 B is 
 
       
         
           
           
               
               
           
         
         R 8  is S(O) r (CH 2 ) s —R 9 ; 
         r is 0, 1 or 2; 
         s is 1, 2, 3, or 4; 
         R 9  is independently carboxy, or —C(O)O—C 1-6 -alkyl; 
         R 10  is independently H, Cl, F, Br, I, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 alkyl; 
         R 18  is hydrogen or C 1-6 -alkyl; 
         R 26  is hydrogen, C 1-4 -alkyl optionally substituted with one or two substituents independently selected from the group consisting of HET-2, —OR 27 , —S(O) 2 R 27 , C 3-6 -cycloalkyl, and —C(O)NR 27 R 27 , C 3-6 -cycloalkyl, or HET-2; 
         R 27  is hydrogen or C 1-4 -alkyl; 
         or R 26  and R 27  together with the nitrogen atom to which they are attached form a heterocyclyl ring as defined in HET-3; 
         HET-2 is morpholino, furyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxo-piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, or 2-oxo-imidazolidinyl, each of which is optionally substituted with one or two substituents independently selected from R 29 ; 
         HET-3 is a 4-, 5-, or 6-membered N-linked saturated or partially unsaturated heterocyclyl ring optionally containing 1 or 2 further heteroatoms (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group, and wherein a sulphur atom in the ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is an N-linked, 7-membered saturated or partially unsaturated heterocyclyl ring optionally containing one further heteroatom (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is a 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring optionally containing one further nitrogen atom (in addition to the linking nitrogen atom), wherein a —CH 2 — group can optionally be replaced by a —C(O)—, which ring is optionally substituted on an available carbon or nitrogen atom by one substituent independently selected from R 30 ; 
         R 29  is independently —OR 27 , C 1-4 -alkyl, —C(O)—C 1-4 -alkyl, —C(O)NR 26 R 27 , C 1-4 -alkylamino, di(C 1-4 -alkyl)amino, HET-3 (wherein said ring is unsubstituted), C 1-4 -alkoxyC 1-4 -alkyl, hydroxyC 1-4 -alkyl, or —S(O) t R 26 ; 
         R 30  is independently hydroxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy or cyano; 
         t is independently 0, 1, or 2; 
         a is independently 1, 2, or 3; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A pharmaceutical composition according to  claim 1  wherein R 1  is independently —CH 2 F, —CHF 2 , —CF 3 , Cl, F, or C 1-6 -alkyl. 
     
     
         3 . A pharmaceutical composition according to  claim 1  wherein X is independently —O—Z— or —O—Z—O—Z—. 
     
     
         4 . A pharmaceutical composition according to  claim 1  wherein Z is a direct bond or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —. 
     
     
         5 . A pharmaceutical composition according to  claim 1  wherein HET-3 is morpholino, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl, each of which is optionally substituted with one or two substituents independently selected from R 29 . 
     
     
         6 . A pharmaceutical composition according to  claim 1  wherein R 30  is independently halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, or methoxy. 
     
     
         7 . A pharmaceutical composition according to  claim 1  wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition according to  claim 1  wherein R 8  is —S(O) 2 (CH 2 ) 1-2 —R 9 . 
     
     
         9 . A pharmaceutical composition according to  claim 1  wherein R 8  is —S(CH 2 ) 1-2 —R 9 . 
     
     
         10 . A method of treating type II diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1, or 2; 
 n is 0, 1, 2, 3 or 4; 
 n+m>0; 
 Each R 1  is independently selected from the group consisting of 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 , Cl, F, Br, I, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, amino, C 1-4 -alkyl-amino, C 1-4 -dialkyl-amino, cyano, formyl, phenyl, and 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t  optionally substituted with C 1-6 -alkyl; 
 Each R 2  is a group Y—X— 
 wherein each X is independently —O—Z—, —O—Z—O—Z—, —C(O)O—Z—, —OC(O)—Z—, —S—Z—, —S(O)—Z—, —S(O) 2 —Z—, —N(R 6 )—Z—, —N(R 6 )S(O) 2 —Z, —S(O) 2 N(R 6 )—Z, —(CH 2 ) 1-4 , —CH═CH—Z, C≡C—Z, —N(R 6 )C(O)—Z, —C(O)N(R 6 )—Z, —C(O)N(R 6 )S(O) 2 —Z, —S(O) 2 —N(R 6 )C(O)—Z, —C(O)—Z, —Z, —C(O)—Z—O—Z, —N(R 6 )—C(O)—Z—O—Z, —O—Z—N(R 6 )—Z, —O—C(O)—Z—O—Z or a direct bond, 
 wherein X is attached to the phenyl ring by the first-mentioned atom; 
 Each Z is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —; 
 Each Y is independently aryl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t ; 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 , or —CH(OH)CH 3-a F a , wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 ; 
 Z 1  is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —; 
 At each occurrence, p is independently selected from 0, 1, 2, or 3; 
 At each occurrence, q is independently selected from 0, 1, 2, or 3; 
 R 4  is independently R 5 —X 1 —, Cl, F, Br, I, CH 3-a F a , —CN, NH 2 , C 1-6 -alkyl, —C(O)OH, —C(O)OR 7 , OH, or phenyl optionally substituted by R 7 ; 
 or two R 4  attached to adjacent atoms may form a —O—(CH 2 ) 1-2 —O— bridge; 
 or 
 R 4  is —C(O)NR 26 R 27 , —S(O) 2 NR 26 R 27 , —S(O) t R 26  or HET-2; 
 X 1  is independently defined as X above: 
 R 5  is H, CH 2 F, CHF 2 , CF 3 , phenyl, naphthyl, a 5-10 membered heterocyclyl consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t , or C 3 - 7 cycloalkyl, wherein each R 5  is optionally substituted by one or more substituents independently selected from R 25 ; 
 R 25  is independently Cl, F, Br, I, CH 3-a F a , —CN, OH, NH 2 , C(O)OH, or —C(O)OC 1-6 alkyl; 
 R 6  is independently hydrogen, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 -alkyl; 
 R 7  is independently C 1-6 -alkyl or —C(O)OC 1-6 -alkyl; 
 B is 
 
       
         
           
           
               
               
           
         
         R 8  is S(O) r (CH 2 ) s —R 9 ; 
         r is 0, 1 or 2; 
         s is 1, 2, 3, or 4; 
         R 9  is independently carboxy, or —C(O)O—C 1-6 -alkyl; 
         R 10  is independently H, Cl, F, Br, I, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 alkyl; 
         R 18  is hydrogen or C 1-6 -alkyl; 
         R 26  is hydrogen, C 1-4 -alkyl optionally substituted with one or two substituents independently selected from the group consisting of HET-2,—OR 27 , —S(O) 2 R 27 , C 3-6 -cycloalkyl, and —C(O)NR 27 R 27 , C 3-6 -cycloalkyl, or HET-2; 
         R 27  is hydrogen or C 1-4 -alkyl; 
         or R 26  and R 27  together with the nitrogen atom to which they are attached form a heterocyclyl ring as defined in HET-3; 
         HET-2 is morpholino, furyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxo-piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, or 2-oxo-imidazolidinyl, each of which is optionally substituted with one or two substituents independently selected from R 29 ; 
         HET-3 is a 4-, 5-, or 6-membered N-linked saturated or partially unsaturated heterocyclyl ring optionally containing 1 or 2 further heteroatoms (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group, and wherein a sulphur atom in the ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is an N-linked, 7-membered saturated or partially unsaturated heterocyclyl ring optionally containing one further heteroatom (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is a 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring optionally containing one further nitrogen atom (in addition to the linking nitrogen atom), wherein a —CH 2 — group can optionally be replaced by a —C(O)—, which ring is optionally substituted on an available carbon or nitrogen atom by one substituent independently selected from R 30 ; 
         R 29  is independently —OR 27 , C 1-4 -alkyl, —C(O)—C 1-4 -alkyl, —C(O)NR 26 R 27,  C 1-4 -alkylamino, di(C 1-4 -alkyl)amino, HET-3 (wherein said ring is unsubstituted), C 1-4 -alkoxyC 1-4 -alkyl, hydroxyC 1-4 -alkyl, or —S(O) t R 26 ; 
         R 30  is independently hydroxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy or cyano; 
         t is independently 0, 1, or 2; 
         a is independently 1, 2, or 3; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . A method according to  claim 10  wherein R 1  is independently —CH 2 F, —CHF 2 , —CF 3 , Cl, F, or C 1-6 -alkyl. 
     
     
         12 . A method according to  claim 10  wherein X is independently —O—Z— or —O—Z—O—Z—. 
     
     
         13 . A method according to  claim 10  wherein Z is a direct bond or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —. 
     
     
         14 . A method according to  claim 10  wherein HET-3 is morpholino, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl, each of which is optionally substituted with one or two substituents independently selected from R 29 . 
     
     
         15 . A method according to  claim 10  wherein R 30  is independently halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, or methoxy. 
     
     
         16 . A method according to  claim 10  wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         17 . A method according to  claim 10  wherein R 8  is —S(O) 2 (CH 2 ) 1-2 —R 9 . 
     
     
         18 . A method according to  claim 10  wherein R 8  is —S(CH 2 ) 1-2 —R 9 . 
     
     
         19 . A method of blood glucose lowering comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1, or 2; 
 n is 0, 1, 2, 3 or 4; 
 n+m>0; 
 Each R 1  is independently selected from the group consisting of 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 , Cl, F, Br, I, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, amino, C 1-4 -alkyl-amino, C 1-4 -dialkyl-amino, cyano, formyl, phenyl, and 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t  optionally substituted with C 1-6 -alkyl; 
 Each R 2  is a group Y—X— 
 wherein each X is independently —O—Z—, —O—Z—O—Z—, —C(O)O—Z—, —OC(O)—Z—, —S—Z—, —S(O)—Z—, —S(O) 2 —Z—, —N(R 6 )—Z—, —N(R 6 )S(O) 2 —Z, —S(O) 2 N(R 6 )—Z, —(CH 2 ) 1-4 , —CH═CH—Z, —C≡C—Z, —N(R 6 )C(O)—Z, —C(O)N(R 6 )—Z, —C(O)N(R 6 )S(O) 2 —Z, —S(O) 2 —N(R 6 )C(O)—Z, —C(O)—Z, —Z, —C(O)—Z—O—Z, —N(R 6 )—C(O)—Z—O—Z, —O—Z—N(R 6 )—Z, —O—C(O)—Z—O—Z or a direct bond, 
 wherein X is attached to the phenyl ring by the first-mentioned atom; 
 Each Z is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —; 
 Each Y is independently aryl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from the group consisting of ), N, and S(O) t ; 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 , or —CH(OH)CH 3-a F a , wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 ; 
 Z 1  is independently a direct bond, C 2-6 -alkenylene, or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —; 
 At each occurrence, p is independently selected from 0, 1, 2, or 3; 
 At each occurrence, q is independently selected from 0, 1, 2, or 3; 
 R 4  is independently R 5 —X 1 —, Cl, F, Br, I, CH 3-a F a , —CN, NH 2 , C 1-6 -alkyl, —C(O)OH,  13  C(O)OR 7 , OH, or phenyl optionally substituted by R 7 ; 
 or two R 4  attached to adjacent atoms may form a —O—(CH 2 ) 1-2 —O— bridge; 
 or 
 R 4  is —C(O)NR 26 R 27 , —S(O) 2 NR 26 R 27 , —S(O) t R 26  or HET-2; 
 X 1  is independently defined as X above: 
 R 5  is H, CH 2 F, CHF 2 , CF 3 , phenyl, naphthyl, a 5-10 membered heterocyclyl consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of O, N, and S(O) t , or C 3 - 7 cycloalkyl, wherein each R 5  is optionally substituted by one or more substituents independently selected from R 25    
 R 25  is independently Cl, F, Br, I, CH 3-a F a , —CN, OH, NH 2 , C(O)OH, or —C(O)OC 1-6 alkyl; 
 R 6  is independently hydrogen, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 -alkyl; 
 R 7  is independently C 1-6 -alkyl or —C(O)OC 1-6 -alkyl; 
 B is 
 
       
         
           
           
               
               
           
         
         R 8  is S(O) r (CH 2 ) s —R 9 ; 
         r is 0, 1 or 2; 
         s is 1, 2, 3, or 4; 
         R 9  is independently carboxy, or —C(O)O—C 1-6 -alkyl; 
         R 10  is independently H, Cl, F, Br, I, C 1-6 -alkyl, or —C 2-4 -alkyl-O—C 1-4 alkyl; 
         R 18  is hydrogen or C 1-6 -alkyl; 
         R 26  is hydrogen, C 1-4 -alkyl optionally substituted with one or two substituents independently selected from the group consisting of HET-2,—OR 27 , —S(O) 2 R 27 , C 3-6 -cycloalkyl, and —C(O)NR 27 R 27 , C 3-6 -cycloalkyl, or HET-2; 
         R 27  is hydrogen or C 1-4 -alkyl; 
         or R 26  and R 27  together with the nitrogen atom to which they are attached form a heterocyclyl ring as defined in HET-3; 
         HET-2 is morpholino, furyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinyl, 3-oxo-piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydropyranyl, 1,1-dioxotetrahydrothienyl, or 2-oxo-imidazolidinyl, each of which is optionally substituted with one or two substituents independently selected from R 29 ; 
         HET-3 is a 4-, 5-, or 6-membered N-linked saturated or partially unsaturated heterocyclyl ring optionally containing 1 or 2 further heteroatoms (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group, and wherein a sulphur atom in the ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is an N-linked, 7-membered saturated or partially unsaturated heterocyclyl ring optionally containing one further heteroatom (in addition to the linking nitrogen atom) independently selected from the group consisting of O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidized to an S(O) or S(O) 2  group, which ring is optionally substituted on an available carbon or nitrogen atom by one or two substituents independently selected from R 29 ; or 
         HET-3 is a 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring optionally containing one further nitrogen atom (in addition to the linking nitrogen atom), wherein a —CH 2 — group can optionally be replaced by a —C(O)—, which ring is optionally substituted on an available carbon or nitrogen atom by one substituent independently selected from R 30 ; 
         R 29  is independently —OR 27 , C 1-4 -alkyl, —C(O)—C 1-4 -alkyl, —C(O)NR 26 R 27 , C 1-4 -alkylamino, di(C 1-4 -alkyl)amino, HET-3 (wherein said ring is unsubstituted), C 1-4 -alkoxyC 1-4 -alkyl, hydroxyC 1-4 -alkyl, or —S(O) t R 26 ; 
         R 30  is independently hydroxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy or cyano; 
         t is independently 0, 1, or 2; 
         a is independently 1, 2, or 3; 
         or a pharmaceutically acceptable salt thereof.