Anti-infective agents

Abstract

The present invention relates to a novel class of chromene-2-carboxamide compounds inhibitors of general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and X are as defined herein, to their use in medicine, and their use as anti-infective agents in particular, to compositions containing them, to processes for their preparation and to intermediates used in such processes.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is H or OH; 
         wherein R 2  is H, OH, CN, halogen, a —(C 1 -C 3 ) alkyl group, an —O—(C 1 -C 3 ) alkoxy group, a —C(O)(C 1 -C 3 ) group, a C(O)NR 8 R 9  group, a C(NH)NH methylcyclohexyl group,
 wherein said —(C 1 -C 3 ) alkyl (R 2 ) or —O—(C 1 -C 3 ) alkoxy (R 2 ) groups may be optionally substituted by one or more substituents independently selected from: OH; halogen; or CN; 
 
         wherein R 3  is H, OH, CN, halogen, a —(C 1 -C 3 ) alkyl group, wherein said —(C 1 -C 3 ) alkyl (R 3 ) group may be optionally substituted by one or more substituents independently selected from: OH; halogen; or CN; 
         wherein R 4  is H, OH, CN, halogen, a —(C 1 -C 3 ) alkyl group, an —O—(C 1 -C 3 ) alkoxy group, a —C(O)R 10  group, —NR 8 R 9 , an —SO 2 NR 8 R 9  group, an —N(R 10 )SO 2 R 10  group, or a C-linked heterocyclic group containing from one to three O or N heteroatoms
 wherein said —(C 1 -C 3 ) alkyl (R 4 ) groups may be optionally substituted by one or more substituents independently selected from: OH; halogen; or CN, 
 wherein said or —O—(C 1 -C 3 ) alkoxy (R 4 ) groups may be optionally substituted by one or more substituents independently selected from: NR 11 R 12 ; or a C-linked 6-membered heterocyclic group which may be optionally independently substituted with one or more halogens, methyl, ethyl or OH groups; 
 
         wherein R 5  and R 6  are each independently H, or a —(C 1 -C 3 ) alkyl group; 
         wherein R 7  represents an —X—R x  group,
 wherein X is a bond or a —(C 1 -C 3 ) alkyl group, or is represented by a —(CH 2 ) n — group, wherein n is 0, 1, 2 or 3, or a —[(CH 2 ) m —CH(CH 3 )] p — group wherein m and p are each independently 0, or 1, 
 wherein R x  is: 
 
         (i) a C-linked saturated or unsaturated 4, 5, 6, or 7-membered cycloalkyl ring, wherein said cycloalkyl (R x ) ring is optionally substituted by one or more substituents independently selected from: OH; halogen; or —(CH 2 ) q —Y wherein q is 0, 1 or 2 and wherein Y is H, NR 13 R 14 , or CO 2 R 15 ; 
         (ii) a C- or N-linked 4, 5 or 6-membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N or S, wherein said heterocyclic (R x ) ring is optionally substituted by one or more substituents independently selected from: a —(C 1 -C 3 ) alkyl group; an —O(C 1 -C 3 ) alkoxy group; a —(C 3 -C 5 ) cycloalkyl ring; a —C(O)R 10  group; an —SO 2 R 16  group; and wherein said optionally substituted heterocyclic (R x ) ring is optionally fused to a 5- or 6-membered saturated or unsaturated ring optionally containing one or two O atoms; 
         (iii) an aryl or a heteroaryl group, wherein said aryl or heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen; a —SO 2 NR 17 R 18  group; a —(CH 2 ) q —Y group wherein q is 0, 1 or 2 and wherein Y is H, NR 13 R 14 , or CO 2 R 15 ; a —C(O)R 10  group; or a —C(O)NR 17 R 18  group; and wherein said optionally substituted aryl or heteroaryl (R x ) groups are optionally fused to a 5- or 6-membered saturated or unsaturated heterocyclic ring containing one or two O and/or N atoms; 
         (iv) a —(C 1 -C 4 ) alkyl group optionally substituted by one or more substituents independently selected from: halogen; 
         (v) an —SO 2 R 16  group; 
         wherein R 8 , R 9 , R 10 , R 17  and R 18  are each independently selected from: H; or —(C 1 -C 3 ) alkyl; 
         wherein R 13  and R 14  are independently from one another selected from H, CO 2 R 19 , and COR 19  or optionally R 13 , R 14  and the nitrogen of the —NR 13 R 14  group together define a saturated or unsaturated 4, 5, 6 or 7-membered heterocyclic ring, which is optionally substituted by one or more substituents independently selected from: OH, halogen or linear or branched chain C1 to C6 alkyl; 
         wherein R 19  is selected from linear or branched chain C 1  to C 6  alkyl; 
         wherein R 15  is selected from H and linear or branched chain C 1  to C 6  alkyl; 
         wherein R 11  and R 12  are independently selected from: H; or a —(C 1 -C 3 ) alkyl group, or where together with the —N atom of the —NR 11 R 12  amine group, the N, R 11  and/or R 12  groups form an —N-linked 4-, 5- or 6-membered saturated or unsaturated ring heterocyclic group; 
         wherein R 16  is H, a —(C 1 -C 3 ) alkyl group, or NH 2 ; with the proviso that when R 1 =R 2 =R 3 =R 4 =R 5 =R 6 =H, R 7  is not —(CH 2 )-cyclohexyl; 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         2 . A compound of formula C-I according to  claim 1   
       
         
           
           
               
               
           
         
         wherein the compounds of formula C-I are compounds of formula I wherein n is 0, 1, 2 or 3; wherein X is a bond, an —O-link, or an —S-link, and R p  is H or CH 3  and when R p  is CH 3  n is 1. 
       
     
     
         3 . A compound of formula C-II according to  claim 1   
       
         
           
           
               
               
           
         
         wherein the compounds of formula C-II are compounds of formula I wherein R 1 , R 5  and R 6  are all H; 
         wherein n is 1; X is a bond; R p  is H; 
         wherein R 2  is H, OH, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —CN; 
         wherein R 3  is H, F, or Cl; 
         wherein R 4  is H, F, OH, —CH 2 OH, —C(O)OH, —NH 2 , —NHSO 2 CH 3 , or a 1H-tetrazol-5-yl group; 
         wherein R x  is a C-linked 6-membered saturated cycloalkyl group, which is optionally substituted with one or more groups independently selected from: OH, or F; 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         4 . A compound of formula C-III according to  claim 1   
       
         
           
           
               
               
           
         
         wherein the compounds of formula C-III are compounds of formula I wherein R 1  is H; 
         wherein n is 1 or 2; 
         wherein X is a bond; 
         wherein R x  is a cyclohexyl, cyclopentyl, cyclobutyl, tetrahydropyranyl, or a benzoxazole group, wherein each of said R x  groups may be optionally substituted by one or more groups independently selected from: OH, CH 3 , or F; 
         wherein R p  is H or CH 3  and wherein when R p  is H, n is 1 or 2, and wherein when R p  is CH 3 , n is 1; 
         wherein R 2  is H, OH, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —CN; 
         wherein R 3  is H, OH, F, Cl, or —O(CH 2 ) 2 NH 2 ; 
         wherein R 4  is H, F, Br, OH, —OCH 3 , —C(O)NH 2 , —CH 2 OH, —C(O)OH, —NH 2 , —NHSO 2 CH 3 , —SO 2 NH 2 , or a 1H-tetrazol-5-yl group; 
         wherein R 5  and R 6  are each independently selected from H or CH 3 ; 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         5 . A compound of formula A-I according to  claim 1   
       
         
           
           
               
               
           
         
         wherein the compounds of formula A-I are compounds of formula I wherein R 1 , R 3 , R 5  and R 6  are all H; 
         wherein n, R 2  and R 4  and R x  are as defined in accordance with formula (I), 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         6 . A compound of formula A-II according to  claim 1   
       
         
           
           
               
               
           
         
         wherein the compounds of formula A-II are compounds of formula I wherein R 1 , R 3 , R 4 , R 5  and R 6  are all H; 
         wherein n, R 2  and R x  are as defined in accordance with formula I, hereinbefore, 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         7 . A compound of formula S-I 
       
         
           
           
               
               
           
         
         wherein the compounds of formula S-I are compounds of formula I wherein R 4  is an —N(R 10 )SO 2 R 10  group; wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7  and R 10  are as defined in  claim 1 , or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         8 . A compound of formula S-II 
       
         
           
           
               
               
           
         
         wherein the compounds of formula S-II are compounds of formula I wherein R 1 , R 3 , R 5  and R 6  are all H and R 4  is an —N(R 10 )SO 2 R 10  group; 
         wherein R 2 , R 7  and R 10  are as defined in accordance with formula (I) in  claim 1 , or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         9 . A compound of formula S-III 
       
         
           
           
               
               
           
         
         wherein the compounds of formula S-III are compounds of formula I wherein R 1 , R 3 , R 5  and R 6  are all H, R 4  is an —N(R 10 )SO 2 R 10  group, and R 7  is a cyclohexylmethyl group; 
         wherein said cyclohexylmethyl (R 7 ) group may be optionally substituted by one or more groups independently selected from: OH, CH 3 , or F; 
         wherein R 2  and R 10  are as defined in accordance with formula (I) in  claim 1 , 
         or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. 
       
     
     
         10 . A compound according to  claim 1 , having a pEC 50  for Pf 3D7 of 5 or more, preferably 5.5 or more, more preferably 6 or more, especially 6.5 or 7 or more. 
     
     
         11 . A compound according to  claim 1 , having a pIC 50  for Pf KRS1 of 6 or more, preferably 6.3 or more, more preferably 6.5 or more, especially 7 or more. 
     
     
         12 . A compound according to  claim 1 , having a pEC 50  for  Crytosporidium parvum  of 5 or more, preferably 5.5 or more, more preferably 6 or more, especially 6.5 or 7 or more. 
     
     
         13 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, according to  claim 1 , together with one or more pharmaceutically acceptable, carriers, diluents or excipients. 
     
     
         14 . A pharmaceutical composition according to  claim 13  including one or more additional therapeutic agents. 
     
     
         15 . A compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof according to  claim 1 . 
     
     
         16 . A compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof according to  claim 1 . 
     
     
         17 . A compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof according to  claim 1 . 
     
     
         18 . A compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof according to  claim 1 . 
     
     
         19 . A compound of formula (I) or a pharmaceutically acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof according to  claim 1 .