NMT inhibitor treatment of a senescence-associated disease or disorder of the liver
The present invention provides a method of prophylaxis or treatment of a senescence-associated disease or disorder by administering to a subject in need thereof, a therapeutically effective amount of a NMT inhibitor.
1 . A method of treatment of a senescence-associated disease or disorder by administering to a subject in need thereof, a therapeutically effective amount of a NMT inhibitor, wherein the senescence-associated disease or disorder is a liver-related disease or disorder, wherein the senescence-associated disease or disorder is not cancer.
2 . The method according to claim 1 , wherein the liver-related disease or disorder is selected from non-alcoholic steatohepatitis, liver fibrosis, non-alcoholic fatty liver disease, hepatic steatosis, and liver cirrhosis.
3 . The method according to claim 2 , wherein the liver-related disease or disorder is selected from non-alcoholic steatohepatitis, liver fibrosis, non-alcoholic fatty liver disease, and hepatic steatosis.
4 . The method according to claim 1 , wherein the NMT inhibitor is a compound of formula (I):
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 represents —O—;
L represents —(CH 2 ) m —;
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;
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 -4alkoxy, and C 1-4 alkyl optionally substituted with 1, 2 or 3 halogens; and
R 8 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;
each R 13 is independently selected from the group consisting of hydrogen and C 1-4 alkyl; and wherein
i) E, J and G are each C(R 7 ), K is carbon, Q is N(R 8 ), and M is nitrogen;
ii) E, J and G are each C(R 7 ), and K, Q and M are each nitrogen; or
iii) E, J, G and M are each C(R 7 ), and K and Q are each nitrogen;
or a pharmaceutically acceptable salt and/or solvate thereof.
5 . The method according to claim 1 , wherein the NMT inhibitor is a compound of formula (II):
wherein:
R 1 is H or —CH 3 ; and
R 2 is H or F;
or a pharmaceutically acceptable salt and/or solvate thereof.
6 . The method according to claim 5 , wherein the NMT inhibitor is 4-(2-{2-[3-(2-aminoethyl) imidazo[1,2-a]pyridin-6-yl]-5-chlorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide:
or a pharmaceutically acceptable salt and/or solvate thereof.
7 . A method of treatment of a senescence-associated disease or disorder by administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising a NMT inhibitor or a pharmaceutically acceptable salt and/or solvate thereof, wherein the senescence-associated disease or disorder is a liver-related disease or disorder, wherein the senescence-associated disease or disorder is not cancer.
8 . The method according to claim 7 , wherein the pharmaceutical composition comprises one or more therapeutic agents and/or one or more pharmaceutically acceptable excipients.
9 . The method according to claim 7 , wherein the liver-related disease or disorder is selected from non-alcoholic steatohepatitis, liver fibrosis, non-alcoholic fatty liver disease, hepatic steatosis, and liver cirrhosis.
10 . The method according to claim 9 , wherein the liver-related disease or disorder is selected from non-alcoholic steatohepatitis, liver fibrosis, non-alcoholic fatty liver disease, and hepatic steatosis.
11 . The method according to claim 7 , wherein the NMT inhibitor is a compound of formula (I):
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 represents —O—;
L represents —(CH 2 ) m —;
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;
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 Re 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 8 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;
each R 13 is independently selected from the group consisting of hydrogen and C 1-4 alkyl; and wherein
i) E, J and G are each C(R 7 ), K is carbon, Q is N(R 8 ), and M is nitrogen;
ii) E, J and G are each C(R 7 ), and K, Q and M are each nitrogen; or
iii) E, J, G and M are each C(R 7 ), and K and Q are each nitrogen;
or a pharmaceutically acceptable salt and/or solvate thereof.
12 . The method according to claim 7 , wherein the NMT inhibitor is a compound of formula (II):
wherein:
R 1 is H or —CH 3 ; and
R 2 is H or F;
or a pharmaceutically acceptable salt and/or solvate thereof.
13 . The method according to claim 12 , wherein the NMT inhibitor is 4-(2-{2-[3-(2-aminoethyl) imidazo[1,2-a]pyridin-6-yl]-5-chlorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide:
or a pharmaceutically acceptable salt and/or solvate thereof.