Pharmaceutical compound
Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises formula (I) wherein X 1 , and X 2 may be the same or different and each is independently selected from C, N, O and S; X 3 , X 4 , X 5 , and X 6 may be the same or different and each is independently selected from C and N; each bond represented by a dotted line may be present or absent, provided that at least one such bond is present; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 groups present is such that the respective valencies of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are maintained; and wherein at least one of R 5 and R 6 comprises a group Y, wherein Y is a group having a formula selected from (II), (III), (IV), (V), (VI), (VII) wherein L may be present or absent, and may be a substituted or unsubstituted organic linking group; R 31 and R 32 may be the same or different and are selected from H and a substituted or unsubstituted organic group; each R 34 may be the same or different and is selected from H and a substituted or unsubstituted organic group; R 35 is selected from a substituted or unsubstituted alcohol group or ether group; each R 36 may be the same or different and is selected from H and a substituted or unsubstituted organic group; X 7 may be selected from C and N; X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 and X 16 may be the same or different and each is independently selected from C, N, O and S; each bond represented by a dotted line may be present or absent; and each R 313 may be the same or different and is selected from H and a substituted or unsubstituted organic group.
1. A compound having a formula selected from one of the following, or a pharmaceutically acceptable salt thereof:
wherein L is absent;
R 4 is selected from hydrogen, halogen, C 1 -C 6 alkyl, —CF 3 , —OCF 3 , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, nitrile, —N(CH 3 )—C(O)CH 3 , —N(CH 3 )—SO 2 CH 3 , an aromatic group, and a heterocyclic group,
each R 34 is independently selected from H and a group selected from the following groups:
a halogen selected from —F, —Cl, —Br and —I,
a substituted or unsubstituted linear or branched C 1 -C 6 alkyl group selected from Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl;
a substituted or unsubstituted linear or branched C 1 -C 6 alkyl-aryl group selected from —CH 2 Ph, —CH 2 (2,3 or 4)F-Ph, —CH 2 (2,3 or 4)Cl-Ph, —CH 2 (2,3 or 4)Br-Ph, —CH 2 (2,3 or 4)I-Ph, —CH 2 CH 2 Ph, —CH 2 CH 2 CH 2 Ph, —CH 2 CH 2 CH 2 CH 2 Ph, —CH 2 CH 2 CH 2 CH 2 CH 2 Ph, and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Ph;
a substituted or unsubstituted linear or branched C 1 -C 6 halogenated alkyl group selected
from —CH 2 F, —CH 2 Cl, —CF 3 , —CCl 3 -CBr 3 , —Cl 3 , —CH 2 CF 3 , —CH 2 CCl 3 , —CH 2 CBr 3 , and —CH 2 Cl 3 );
an —NH 2 group, or a substituted or unsubstituted linear or branched primary, secondary or tertiary C 1 -C 6 amine group selected from —NMeH, —NEtH, —NEtMe, —NEt 2 , —NPrH, —NPrMe, —NPrEt, —NPr 2 , —NBuH, —NBuMe, —NBuEt, —CH 2 —NH 2 , —CH 2 —NMeH, —CH 2 —NMe 2 , —CH 2 —NEtH, —CH 2 —NEtMe, —CH 2 —NEt 2 , —CH 2 —NPrH, —CH 2 —NPrMe, and —CH 2 —NPrEt;
a substituted or unsubstituted amino-aryl group selected from —NH-Ph, —NH-(2,3 or 4)F-Ph, —NH-(2,3 or 4)Cl-Ph, —NH-(2,3 or 4)Br-Ph, —NH-(2,3 or 4)I-Ph, —NH-(2,3 or 4)Me-Ph, —NH-(2,3 or 4)Et-Ph, —NH-(2,3 or 4)Pr-Ph, —NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph, —NH-(2,3 or 4)OEt-Ph, —NH-(2,3 or 4)OPr-Ph, —NH-(2,3 or 4)OBu-Ph, —NH-2, (3,4,5 or 6)F 2 -Ph, —NH-2, (3,4,5 or 6)C12-Ph, —NH-2, (3,4,5 or 6)Br 2 -Ph, —NH-2, (3,4,5 or 6)I 2 -Ph, —NH-2, (3,4,5 or 6)Me 2 -Ph, —NH-2, (3,4,5 or 6)Et 2 -Ph, —NH-2, (3,4,5, or 6)Pr 2 -Ph, and —NH-2, (3,4,5 or 6)Bu 2 -Ph;
a substituted or unsubstituted cyclic amine or amido group selected from pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl;
a substituted or unsubstituted cyclic C3-C8 alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
an —OH or a substituted or unsubstituted linear or branched C 1 -C 6 alcohol group selected from —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 CH 2 OH, —CH(CH 3 )CH(CH 3 )OH, —CH(CH 2 CH 3 )CH 2 OH, —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 CH 2 OH, and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH);
a substituted or unsubstituted linear or branched C 1 -C 6 carboxylic acid group selected from —COOH, —CH 2 COOH, —CH 2 CH 2 COOH, —CH 2 CH 2 CH 2 COOH, —CH 2 CH 2 CH 2 CH 2 COOH, and —CH 2 CH 2 CH 2 CH 2 CH 2 COOH;
a substituted or unsubstituted linear or branched carbonyl group selected from —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu, —(CO)iBu,
—(CO)tBu, —(CO)Ph, —(CO)CH 2 Ph, —(CO)CH 2 OH, —(CO)CH 2 OCH 3 , —(CO)CH 2 NH 2 ,
—(CO)CH 2 NHMe, —(CO)CH 2 NMe, —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl,
—(CO)NH 2 , —(CO)NHMe, —(CO)NMe 2 , —(CO)NHEt, —(CO)NEt 2 , —(CO)-pyrollidine —N-yl, —(CO)-morpholine-N-yl, —(CO)-piperazine-N-yl, —(CO)—N-methyl-piperazine-N-yl,
—(CO)NHCH 2 CH 2 OH, —(CO)NHCH 2 CH 2 OMe, —(CO)NHCH 2 CH 2 NH 2 ,
—(CO)NHCH 2 CH 2 NHMe, and —(CO)NHCH 2 CH 2 NMe 2 ;
a substituted or unsubstituted linear or branched C 1 -C 6 carboxylic acid ester group selected from —COOMe, —COOEt, —COOPr, —COO-i-Pr, —COO-n-Bu, —COO-i-Bu, —COO-t-Bu, —CH 2 COOMe, —CH 2 CH 2 COOMe, —CH 2 CH 2 CH 2 COOMe, and —CH 2 CH 2 CH 2 CH 2 COOMe);
a substituted or unsubstituted linear or branched C 1 -C 6 amide group selected from —CO—NH 2 , —CO—NMeH, —CO—NMe, —CO—NEtH, —CO—NEtMe, —CO—NEt 2 , —CO—NPrH, —CO—NPrMe, and —CO—NPrEt;
a substituted or unsubstituted linear or branched C 1 -C 7 amino carbonyl group selected from —NH—CO-Me, —NH—CO-Et, —NH—CO-Pr, —NH—CO-Bu, —NH—CO-pentyl, —NH—CO-hexyl, —NH—CO-Ph, —NMe-CO-Me, —NMe-CO-Et, —NMe-CO-Pr, —NMe-CO-Bu, —NMe-CO-pentyl, —NMe-CO-hexyl, and —NMe-CO-Ph;
a substituted or unsubstituted linear or branched C 1 -C 7 alkoxy or aryloxy group selected from —OMe, —OEt, —OPr, —O-i-Pr, —O-n-Bu, —O-i-Bu, —O-t-Bu, —O-pentyl, —O-hexyl, —OCH 2 F, —OCHF 2 , —OCF 3 , —O-Ph, —O-CH 2 -Ph, —O-CH 2 -(2,3 or 4)-F-Ph, —O-CH 2 -(2,3 or 4)-Cl-Ph, —CH 2 OMe, —CH 2 OEt, —CH 2 OPr, —CH 2 OBu, —CH 2 CH 2 OMe, —CH 2 CH 2 CH 2 OMe, —CH 2 CH 2 CH 2 CH 2 OMe, and —CH 2 CH 2 CH 2 CH 2 CH 2 OMe;
a substituted or unsubstituted linear or branched aminoalkoxy group selected from —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NHMe, —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 NHEt, and —OCH 2 CH 2 NEt 2 ;
a substituted or unsubstituted sulphonyl group selected from —SO 2 Me, —SO 2 Et, —SO 2 Pr, —SO 2 iPr, —SO 2 Ph, —SO 2 -(2,3 or 4)-F-Ph, —SO 2 —
cyclopropyl, —SO 2 CH 2 CH 2 OCH 3 ), —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NMe 2 , —SO 2 NHEt, —SO 2 NEt 2 , —SO 2 -pyrrolidine-N-yl, —SO 2 -morpholine-N-yl, —SO 2 NHCH 2 OMe, and —SO 2 NHCH 2 CH 2 OMe;
a substituted or unsubstituted aminosulphonyl group selected from —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Pr, —NHSO 2 iPr, —NHSO 2 Ph, —NHSO 2 -(2,3 or 4)-F-Ph, —NHSO 2 -cyclopropyl, and —NHSO 2 CH 2 CH 2 OCH 3 ;
a substituted or unsubstituted aromatic group selected from Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2, (3,4,5 or 6)-F 2 -Ph-, 2, (3,4,5 or 6)-C12-Ph-, 2, (3,4,5 or 6)-Br 2 -Ph-, 2, (3,4,5 or 6)-I 2 -Ph-, 2, (3,4,5 or 6)-Me 2 -Ph-, 2, (3,4,5 or 6)-Et 2 -Ph-, 2, (3,4,5 or 6)-Pr 2 -Ph-, 2, (3,4,5 or 6)-Bu 2 -Ph-, 2, (3,4,5 or 6)-(CN) 2 -Ph-, 2, (3,4,5 or 6)-(NO 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(NH 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(MeO) 2 -Ph-, 2, (3,4,5 or 6)-(CF 3 ) 2 -Ph-, 3, (4 or 5)-F 2 -Ph-, 3, (4 or 5)-C12-Ph-, 3, (4 or 5)-Br 2 -Ph-, 3, (4 or 5)-I 2 -Ph-, 3, (4 or 5)-Me 2 -Ph-, 3, (4 or 5)-Et 2 -Ph-, 3, (4 or 5)-Pr 2 -Ph-, 3, (4 or 5)-Bu 2 -Ph-, 3, (4 or 5)-(CN) 2 -Ph-, 3, (4 or 5)-(NO 2 ) 2 -Ph-, 3, (4 or 5)-(NH 2 ) 2 -Ph-, 3, (4 or 5)-(MeO) 2 -Ph-, 3, (4 or 5)-(CF 3 ) 2 -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO 2 )-Ph-, 3-(NO 2 )-Ph-, 4-(NO 2 )-Ph-, 2-(NH 2 )-Ph-, 3-(NH)-Ph-, 4-(NH)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH 2 —CO)-Ph-, 3-(NH 2 —CO)-Ph-, 4-(NH 2 —CO)-Ph-, 2-CF 3 -Ph-, 3-CF 3 -Ph-, 4-CF 3 -Ph-, 2-CF 3 O-Ph-, 3-CF 3 O-Ph-, and 4-CF 3 O-Ph-; and
a saturated or unsaturated, substituted or unsubstituted heterocyclic group selected from pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, tetrazole-1-yl, tetrazole-2-yl, and tetrazole-5-yl;
each R 313 is independently selected from H, —OH, halogen and C 1 -C 6 alkyl;
or alternatively, two R 313 groups attached to the same atom together form a carbonyl group (=O).
X 9 , X 10 , X 12 and X 15 are independently selected from C, N and O, and
at least one of X 9 , X 10 , X 12 and X 15 is an N, in which the N is substituted by —R″;
wherein R″ is selected from H and any of the following groups:
a substituted or unsubstituted linear or branched C 1 -C 6 alkyl group selected from Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);
a substituted or unsubstituted linear or branched C 2 -C 6 alcohol group selected from —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 CH 2 OH, —CH(CH 3 )CH(CH 3 )OH, —CH(CH 2 CH 3 )CH 2 OH, —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 CH 2 OH, and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH;
a substituted or unsubstituted linear or branched C 1 -C 7 alkoxy or aryloxy group linked through —O via at least two further C atoms selected from —CH 2 CH 2 OPh, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 OPr, —CH 2 CH 2 OBu, —CH 2 CH 2 CH 2 OPh, —CH 2 CH 2 CH 2 OMe, —CH 2 CH 2 CH 2 CH 2 OMe, and —CH 2 CH 2 CH 2 CH 2 CH 2 OMe;
a substituted or unsubstituted linear or branched C 1 -C 6 halogenated alkyl group selected from —CH 2 F, —CF 3 , and —CH 2 CF 3 ;
a substituted or unsubstituted cyclic amine or amido group selected from pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl; which group is attached via a —CH 2 — or a —CH 2 CH 2 — group;
a substituted or unsubstituted cyclic C 3 -C 8 alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
a substituted or unsubstituted aromatic group selected from Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2, (3,4,5 or 6)-F 2 -Ph-, 2, (3,4,5 or 6)-C12-Ph-, 2, (3,4,5 or 6)-Br 2 -Ph-, 2, (3,4,5 or 6)-I 2 -Ph-, 2, (3,4,5 or 6)-Me 2 -Ph-, 2, (3,4,5 or 6)-Et 2 -Ph-, 2, (3,4,5 or 6)-Pr 2 -Ph-, 2, (3,4,5 or 6)-Bu 2 -Ph-, 2, (3,4,5 or 6)-(CN) 2 -Ph-, 2, (3,4,5 or 6)-(NO 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(NH 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(MeO) 2 -Ph-, 2, (3,4,5 or 6)-(CF 3 ) 2 -Ph-, 3, (4 or 5)-F 2 -Ph-, 3, (4 or 5)-C12-Ph-, 3, (4 or 5)-Br 2 -Ph-, 3, (4 or 5)-I 2 -Ph-, 3, (4 or 5)-Me 2 -Ph-, 3, (4 or 5)-Et 2 -Ph-, 3, (4 or 5)-Pr 2 -Ph-, 3, (4 or 5)-Bu 2 -Ph-, 3, (4 or 5)-(CN) 2 -Ph-, 3, (4 or 5)-(NO 2 ) 2 -Ph-, 3, (4 or 5)-(NH 2 ) 2 -Ph-, 3, (4 or 5)-(MeO) 2 -Ph-, 3, (4 or 5)-(CF 3 ) 2 -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO 2 )-Ph-, 3-(NO 2 )-Ph-, 4-(NO 2 )-Ph-, 2-(NH 2 )-Ph-, 3-(NH 2 )-Ph-, 4-(NH 2 )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH 2 —CO)-Ph-, 3-(NH 2 —CO)-Ph-, 4-(NH 2 —CO)-Ph-, 2-CF 3 -Ph-, 3-CF 3 -Ph-, 4-CF 3 -Ph-, 2-CF 3 O-Ph-, 3-CF 3 O-Ph-, and 4-CF 3 O-Ph; and
a saturated or unsaturated, substituted or unsubstituted, heterocyclic group selected from pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazole-5-yl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the following formula:
wherein Y is selected from the following formulae:
in which L is absent;
wherein R″ is selected from H and any of the following groups:
a substituted or unsubstituted linear or branched C 1 -C 6 alkyl group selected from Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl;
a substituted or unsubstituted linear or branched C 2 -C 6 alcohol group selected from —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 CH 2 OH, —CH(CH 3 )CH(CH 3 )OH, —CH(CH 2 CH 3 )CH 2 OH, —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 CH 2 OH, and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH;
a substituted or unsubstituted linear or branched C 1 -C 7 alkoxy or aryloxy group linked through —O via at least two further C atoms selected from —CH 2 CH 2 OPh, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 OPr, —CH 2 CH 2 OBu, —CH 2 CH 2 CH 2 OPh, —CH 2 CH 2 CH 2 OMe, —CH 2 CH 2 CH 2 CH 2 OMe, and —CH 2 CH 2 CH 2 CH 2 CH 2 OMe;
a substituted or unsubstituted linear or branched C 1 -C 6 halogenated alkyl group selected from —CH 2 F, —CF 3 , and —CH 2 CF 3 ;
a substituted or unsubstituted cyclic amine or amido group selected from pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl; which group is attached via a —CH 2 — or a —CH 2 CH 2 — group;
a substituted or unsubstituted cyclic C3-C8 alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; which group is attached via a —CH 2 — or a —CH 2 CH 2 — group;
a substituted or unsubstituted aromatic group selected from Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2, (3,4,5 or 6)-F 2 -Ph-, 2, (3,4,5 or 6)-C12-Ph-, 2, (3,4,5 or 6)-Br 2 -Ph-, 2, (3,4,5 or 6)-I 2 -Ph-, 2, (3,4,5 or 6)-Me 2 -Ph-, 2, (3,4,5 or 6)-Et 2 -Ph-, 2, (3,4,5 or 6)-Pr 2 -Ph-, 2, (3,4,5 or 6)-Bu 2 -Ph-, 2, (3,4,5 or 6)-(CN) 2 -Ph-, 2, (3,4,5 or 6)-(NO 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(NH 2 ) 2 -Ph-, 2, (3,4,5 or 6)-(MeO) 2 -Ph-, 2, (3,4,5 or 6)-(CF 3 ) 2 -Ph-, 3, (4 or 5)-F 2 -Ph-, 3, (4 or 5)-C12-Ph-, 3, (4 or 5)-Br 2 -Ph-, 3, (4 or 5)-I 2 -Ph-, 3, (4 or 5)-Me 2 -Ph-, 3, (4 or 5)-Et 2 -Ph-, 3, (4 or 5)-Pr 2 -Ph-, 3, (4 or 5)-Bu 2 -Ph-, 3, (4 or 5)-(CN) 2 -Ph-, 3, (4 or 5)-(NO 2 ) 2 -Ph-, 3, (4 or 5)-(NH 2 ) 2 -Ph-, 3, (4 or 5)-(MeO) 2 -Ph-, 3, (4 or 5)-(CF 3 ) 2 -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO 2 )-Ph-, 3-(NO 2 )-Ph-, 4-(NO 2 )-Ph-, 2-(NH 2 )-Ph-, 3-(NH 2 )-Ph-, 4-(NH 2 )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH 2 —CO)-Ph-, 3-(NH 2 —CO)-Ph-, 4-(NH 2 —CO)-Ph-, 2-CF 3 -Ph-, 3-CF 3 -Ph-, 4-CF 3 -Ph-, 2-CF 3 O-Ph-, 3-CF 3 O-Ph-, and 4-CF 3 O-Ph-; which group is attached via a —CH 2 — or a —CH 2 CH 2 — group; and
a saturated or unsaturated, substituted or unsubstituted, heterocyclic group selected from pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl, and tetrazole-5-yl; which group is attached via a —CH 2 — or a —CH 2 CH 2 — group.
3. A compound selected from one of the following, or a pharmaceutically acceptable salt thereof:
4. A compound selected from the following formulae, or a pharmaceutically acceptable salt thereof:
5. A pharmaceutical composition comprising a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive and/or excipient, and/or wherein the compound is in the form of a pharmaceutically acceptable salt of the compound.
6. The pharmaceutical composition according to claim 5 for treating a cancer, further comprising a further agent for treating cancer; wherein the further agent is selected from an anti-microtubule agent, a platinum coordination complexe, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone or hormone analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis inhibitor, an anti-tumor vaccine, an oncolytic virus, an immune stimulatory antibody, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, a tumor microenvironment modulator, an anti-angiogenic agent, a proapoptotic agent and a cell cycle signalling inhibitor.
7. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises:
(a) a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof; and
(b) a further agent for treating cancer; wherein the further agent for treating cancer is selected from an anti-microtubule agent, a platinum coordination complexe, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone or hormone analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis inhibitor, an anti-tumor vaccine, an oncolytic virus, an immune stimulatory antibody, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, a tumor microenvironment modulator, an anti-angiogenic agent, a proapoptotic agent and a cell cycle signaling inhibitor;
wherein the compound and the further agent are suitable for administration simultaneously, sequentially or separately.
8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having the following formula:
wherein R 4 is selected from hydrogen, halogen, and C 1 -C 6 alkyl; and
Y is one of the following formula:
wherein L is absent;
R 11 is selected from H and C 1 -C 6 alkyl.
9. A compound having the following formula, or a pharmaceuticallly acceptable salt thereof:
wherein R 4 is selected from halogen and C 1 -C 6 alkyl; and
Y is of the following formula:
wherein L is absent;
each R 313 is independently selected from H, halogen, and C 1 -C 6 alkyl; and
R 11 is selected from H and C 1 -C 6 alkyl.
10. The compound of claim 9 , or a pharamaceutically acceptable salt thereof, wherein:
R 4 is halogen selected from -f, -Cl, and -Br;
each R 313 is independently selected from H, Me, Et, Pr and i-Pr; and;
R 11 is selected from H and Me.