Compounds and their use as inhibitors of N-myristoyl transferase
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. 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 is nitrogen;
Q is nitrogen and M is C(R 7 );
q is 0 or 1;
R 3 is hydrogen or methyl; R 4 is hydrogen or methyl;
R 5 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
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.
2. The inhibitor as claimed in claim 1 , 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—.
3. The inhibitor as claimed in claim 1 , wherein the compound has the formula (IA)
4. The inhibitor as claimed in claim 3 , 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.
5. The inhibitor as claimed in claim 4 , wherein A is selected from the group consisting of substituted pyrazolyl and thiazolyl.
6. The inhibitor as claimed in claim 5 , wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is C(O)N(R 9 ) 2 .
7. The inhibitor as claimed in claim 3 , 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 , and —C(O)-4-morpholine.
8. The inhibitor as claimed in claim 1 , wherein q is 1, R 10 is hydrogen and R 11 is hydrogen.
9. The inhibitor as claimed in claim 1 , 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.
10. The inhibitor as claimed in claim 1 , wherein Y is —CH— or —C(R 2 )—.
11. The inhibitor as claimed in claim 1 , wherein X is —O— and L is —(CH 2 ) m .
12. The inhibitor as claimed in claim 1 , wherein R 7 is hydrogen or methyl.
13. The inhibitor as claimed in claim 1 , 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.
14. The inhibitor as claimed in claim 1 , wherein the compound has the formula (IA*)
wherein 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; and
R 2** is selected from the group consisting of —H, —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.
15. The inhibitor as claimed in claim 1 , wherein s is 0, 1, 2 or 3, and, where present, each R 2 is independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, and —C 1-4 alkyl optionally substituted by up to 3 halogen or hydroxyl groups.
16. The inhibitor as claimed in claim 9 , wherein A is a 4-pyrazolyl, optionally substituted by up to 3 substituents 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; and R 9 where present is each 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.
17. The inhibitor as claimed in claim 16 , wherein the compound has the formula (IA )
and wherein R 2′ is selected from the group consisting of fluorine, chlorine, —CN and methyl; and
R 2″ is selected from the group consisting of hydrogen, fluorine, chlorine, —CN and methyl.
18. The inhibitor as claimed in claim 1 , which is selected from:
[(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl](methyl)amine;
[(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]dimethylamine;
Ethyl[(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]amine;
2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amine;
4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;
[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amine;
[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]dimethylamine;
4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;
[(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl](methyl)amine;
[(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]dimethylamine;
4-[2-(2-{3-[2-(dimethylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;
4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;
4-[2-(2-{3-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;
2-(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amine;
[2-(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amine;
2-(6-{3,4-difluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amine;
[2-(6-{3,4-difluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amine;
4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxylic acid;
{4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}methanol;
4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide;
4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,1,5-trimethyl-1H-pyrazole-3-carboxamide;
4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxylic acid;
{4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}methanol;
4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide;
4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,1,5-trimethyl-1H-pyrazole-3-carboxamide;
4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carbonitrile;
4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carbonitrile;
4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid;
4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,1,5-trimethyl-1H-pyrazole-3-carboxamide;
[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methanol;
4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide;
2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amine;
N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}acetamide;
N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}methanesulfonamide;
2-[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amine;
2-[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amine;
{[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)amine;
{[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)amine;
2-[6-(2-{2-[1,5-dimethyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amine;
4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N-(2-methoxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide;
2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethan-1-amine;
N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}-N-methylacetamide;
N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}-N-methylmethanesulfonamide;
and salts of any one thereof.
19. A pharmaceutical composition which comprises the inhibitor as claimed in claim 1 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition as claimed in claim 19 , wherein the composition
comprises a further therapeutic agent.