Novel compounds and their use in therapy

Abstract

This invention provides compounds of formula (I) and salts thereof, which have activity as inhibitors of N-myristoyl transferase (NMT). The invention also relates to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect, including protozoan infections (such as malaria and leishmaniasis), viral infections (such as human rhinovirus and HIV), and hyperproliferative disorders (such as B-cell lymphoma).

1 - 69 . (canceled) 
     
     
         70 . An inhibitor of N-myristoyl transferase (NMT) which is a compound of formula (I) or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Y is selected from the group consisting of —CH—, —C(R 2 )— and —N—; 
         R 1  is a group of formula —X-L-A; 
         X is selected from the group consisting of —O—, —N(H)— and —S—, or is absent; 
         L is selected from the group consisting of —(CHR 12 ) m — and —(CHR 12 ) m O—, or is absent; 
         m is 1, 2 or 3; 
         A is a 6-10-membered aromatic carbocycle or a 5-10-membered aromatic heterocycle, said aromatic carbocycle or heterocycle being optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, —C 1-6 alkyl optionally substituted by up to 3 halogen, hydroxyl, or —OC 1-4 alkyl groups, —S(O)C 1-4  alkyl, —S(O) 2 C 1-4 alkyl, —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , —NHS(O) 2 C 1-4 alkyl, CH 2 N(R 13 ) 2 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, —CH 2 S(O) 2 C 1-4 alkyl, and CO 2 H 
         s is 0, 1, 2, or 3; 
         each R 2  is independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, —C 1-4 alkyl optionally substituted by up to 3 halogen or hydroxyl groups, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , and —NHS(O) 2 C 1-4 alkyl; 
         E, J and G are each C(R 7 ); 
         K, Q and M are each nitrogen; 
         q is 0 or 1; 
         R 3  is hydrogen or methyl; R 4  is hydrogen or methyl; 
         R 6  is hydrogen or C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3  or —CN groups; R 6  is hydrogen or C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3  or —CN groups; or the R 5  and R 6  groups and the N they are bonded to form a 4 to 7 membered non-aromatic heterocycle, the heterocycle optionally comprising 1 or 2 further heteroatoms selected from N, O and S, optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3  or —CN groups; 
         when present R 10  is hydrogen or methyl; 
         when present R 11  is hydrogen or methyl; 
         or the R 3  group and the R 5  group and the intervening atoms form a 3 to 7 membered non-aromatic heterocycle composed of the intervening atoms and bond, or the intervening atoms and —(CHR a ) r —; or the R 10  group and the R 5  group and the intervening atoms form a 3 to 7 membered non-aromatic heterocycle composed of the intervening atoms and —(CHR a ) r —; 
         r is 1, 2, 3, 4 or 5; R a  is hydrogen or methyl; 
         each R 7  is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkoxy, and C 1-4 alkyl optionally substituted with 1, 2 or 3 halogens; and 
         R 7  is selected from the group selected from hydrogen and C 1-4 alkyl; 
         each R 9  is independently selected from the group consisting of hydrogen and C 1-4 alkyl, or two R 9  groups and the N they are bonded to form a 4 to 7 membered non-aromatic heterocycle, the heterocycle optionally comprising 1 or 2 further heteroatoms selected from N, O and S; and 
         each R 12  is independently selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3  or —CN groups, C 1-6 alkenyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3  or —CN groups, and C 1-6 alkynyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3  or —CN groups; and each R 13  is independently selected from the group consisting of hydrogen and C 1-4 alkyl. 
       
     
     
         71 . The inhibitor of NMT as claimed in  claim 70 , wherein X is selected from the group consisting of —O—, —N(H)— and —S—; and/or L is selected from the group consisting of —(CHR 12 ) m — and —(CHR 12 ) m O—. 
     
     
         72 . The inhibitor of NMT as claimed in  claim 70 , wherein the compound has the formula (IA) 
       
         
           
           
               
               
           
         
       
     
     
         73 . The inhibitor of NMT as claimed in  claim 72 , wherein
 Y is —CH—;   X is —O—;   L is —(CH 2 ) m ;   m is 1 or 2;   A is an aromatic carbocycle or heterocycle selected from the group consisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, or CO 2 H;   q is 1;   R 7  is hydrogen or methyl; and   R 10  is hydrogen and R 11  is hydrogen.   
     
     
         74 . The inhibitor of NMT as claimed in  claim 73 , wherein A is selected from the group consisting of substituted pyrazolyl and thiazolyl. 
     
     
         75 . The inhibitor of NMT as claimed in  claim 74 , wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is C(O)N(R 9 ) 2 . 
     
     
         76 . The inhibitor of NMT as claimed in  claim 72 , wherein q is 1, R 10  is hydrogen, R 11  is hydrogen, and A is 4-pyrazolyl, substituted by up to 3 groups independently selected from the group consisting of —C 1-4 alkyl; —CH 2 OC 1-4 alkyl, CF 2 H, CF 3 , C(O)N(Me) 2 , —C(O)-1-pyrazole; and —C(O)-4-morpholine. 
     
     
         77 . The inhibitor of NMT as claimed in  claim 70 , wherein q is 1, R 10  is hydrogen and R 11  is hydrogen. 
     
     
         78 . The inhibitor of NMT as claimed in  claim 70 , wherein A is an aromatic carbocycle or heterocycle selected from the group consisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, said aromatic carbocycle or heterocycle being optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —C 1-4 alkyl, wherein each —C 1-4 alkyl is optionally substituted by up to 3 halogen, hydroxyl or —OC 1-4 alkyl groups; —C(O)N(R 9 ) 2 ; —CH 2 C(O)N(R 9 ) 2 ; —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl; —CH 2 N(R 13 ) 2  and CH 2 N(R 13 )S(O) 2 C 1-4 alkyl. 
     
     
         79 . The inhibitor of NMT as claimed in  claim 70 , wherein Y is —CH— or —C(R 2 )—. 
     
     
         80 . The inhibitor of NMT as claimed in  claim 70 , wherein X is —O— and L is —(CH 2 ) m . 
     
     
         81 . The inhibitor of NMT as claimed in  claim 70 , wherein R 7  is hydrogen or methyl, and/or R 7  is hydrogen or methyl. 
     
     
         82 . The inhibitor of NMT as claimed in  claim 70  wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH— 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, or CO 2 H. 
     
     
         83 . The inhibitor of NMT as claimed in  claim 78 , wherein A is an optionally substituted 5-thiazolyl. 
     
     
         84 . The inhibitor of NMT as claimed in  claim 83 , wherein the compound has the formula (IA″) 
       
         
           
           
               
               
           
         
         and wherein: 
         said 5-thiazolyl is optionally substituted with 1 or 2 methyl groups; 
         X is —O—; L is —(CH 2 ) m —; m is 1, 2 or 3; 
         R 2′  is hydrogen, chlorine or fluorine; and 
         R 3  and R 4  are each independently hydrogen or methyl; R 5  and R 6  are each independently hydrogen or methyl. 
       
     
     
         85 . The inhibitor of NMT as claimed in  claim 78 , wherein the compound has the formula (IA′″) 
       
         
           
           
               
               
           
         
         and wherein: 
         X is —O— or absent; L is —(CH 2 ) m —; m is 2 or 3; 
         R 2′  is hydrogen or fluorine; R 2  is hydrogen or —OCH 3 ; 
         R 3  and R 4  are each hydrogen; R 5  and R 6  are each methyl. 
       
     
     
         86 . The inhibitor of NMT as claimed in  claim 70 , wherein:
 X is —O—; L is —(CH 2 ) m —; m is 1 or 2;   A is selected from the group consisting of optionally substituted 3-pyridinyl, 4-pyridinyl and 1-imidazolyl;   s is 0;   R 3  and R 4  are each hydrogen; and   R 5  and R 6  are each methyl.   
     
     
         87 . The inhibitor of NMT as claimed in  claim 70 , which is selected from:
 (6-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine;   (6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine;   1-(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;   1-(6-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-methylmethanamine;   1-(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-methylmethanamine;   1-(6-(4-chloro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine   1-(6-(4-chloro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;   1-(6-(4-fluoro-2-(2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;   1-(6-(4-fluoro-2-(2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;   4-(2-{2-[3-(azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,3,5-trimethyl-1H-pyrazole;   4-[2-(5-fluoro-2-{3-[(methylamino)methyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;   {[6-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;   {[6-(2-{2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;   4-(2-{2-[3-(azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;   4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;   4-(2-{5-fluoro-2-[3-(pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]phenoxy}ethyl)-1,3,5-trimethyl-1H-pyrazole;   [2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl](methyl)amine;   N-methyl[(6-{3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]amine;   {[6-(2-{2-[1,5-dimethyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;   {[6-(2-{2-[1,5-dimethyl-3-(pyrrolidine-1-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;   [(6-{5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl](methyl)amine;   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt of any one thereof. 
       
     
     
         88 . A pharmaceutical composition which comprises the inhibitor of NMT as claimed in  claim 70  and a pharmaceutically acceptable carrier. 
     
     
         89 . A method of treating or preventing a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect in a mammal, which comprises administering to the mammal a therapeutically effective amount of the inhibitor of NMT as claimed in  claim 70 .