Substituted bicyclic fused ring compounds as indoleamine-2,3-dioxygenase inhibitors
View Patent ↗Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the general formula (I) detailed within.
1. A compound selected from one of the following formulae:
wherein:
each of X 1 and X 2 is C;
X 7 is selected from C and N;
each of R 1 and R 2 is H;
each of R 3 and R 5 is H;
R 4 is an organic group selected from halogen, an unsubstituted C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group substituted with 1-3 halogens, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, and a nitrile group;
R 31 is selected from:
H;
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, —(C O)Ph, —(CO)CH 2 Ph, —(CO)CH 2 OH, —(CO)CH 2 OCH 3 , —(CO)CH 2 NH 2 , —(CO)CH 2 N HMe, —(CO)CH 2 NMe 2 , —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl, —(CO)N H 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 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;
—NH—C(O)—C 1-4 alkyl;
—NH—SO 2 —C 1-4 alkyl;
a substituted or unsubstituted phenyl group selected from P-, 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)-Cl 2 -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)-Cl 2 -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-;
an aromatic heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, tetrazole-1yl, tetrazole-2-yl, tetrazole-3-yl, tetrazole-4-yl, tetrazole-5-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,3-thiazol)-2-yl, (1,3-thiazol)-4-yl, (1,3-thiazol)-5-yl, furan-2-yl, and furan-3-yl; and
a substituted or unsubstituted saturated heterocyclic group selected from piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl;
each R 34 is independently selected from:
H;
a halogen;
a nitrile group;
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 , —CI 3 , —CH 2 CF 3 , —CH 2 CCl 3 , —CH 2 CBr 3 , and —CH 2 CI 3 ;
an —NH 2 group,
a substituted or unsubstituted linear or branched primary, secondary or tertiary C 1 -C 6 amine group selected from —NMeH, —NMe 2 , —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)Cl 2 -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 C 3 -C 8 alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
—OH;
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, —(C O)Ph, —(CO)CH 2 Ph, —(CO)CH 2 OH, —(CO)CH 2 OCH 3 , —(CO)CH 2 NH 2 , —(CO)CH 2 N HMe, —(CO)CH 2 NMe 2 , —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl; —(CO)N HMe, —(CO)NMe 2 , —(CO)NHEt, —(CO)NEt 2 , —(CO)-pyrollidine-N-yl, —(CO)-morph oline-N-yl, —(CO)-piperazine-N-yl, —(CO)-N-methyl-piperazine-N-yl, —(CO)NHC H 2 CH 2 OH, —(CO)NHCH 2 CH 2 OMe, —(CO)NHCH 2 CH 2 NH 2 , —(CO)NHCH 2 CH 2 NH Me, 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 2 , —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-, 4Cl-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)-Cl 2 -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)-Cl 2 -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 substituted or unsubstituted saturated or unsaturated heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, tetrazole-1yl, tetrazole-2-yl, tetrazole-3-yl, tetrazole-4-yl, tetrazole-5-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,3-thiazol)-2-yl, (1,3-thiazol)-4-yl, (1,3-thiazol)-5-yl, furan-2-yl, furan-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl;
each R 313 is independently selected from absent, H, —OH, halogen, and C 1-6 alkyl;
and L is absent.
2. The compound of claim 1 , wherein R 31 is selected from:
—C(O)—C 1-4 alkyl;
—C(O)—NH—C 1-2 alkyl;
—SO 2 -C 1-4 alkyl;
—NH—C(O)—C 1-4 alkyl;
—NH—SO 2 —C 1-4 alkyl;
a substituted or unsubstituted phenyl group selected from Ph-, 2-F-Ph-, 3-F-Ph-, 4F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, and 4-Br-Ph-;
an aromatic heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, tetrazole-1yl, tetrazole-2-yl, tetrazole-3-yl, tetrazole-4-yl, tetrazole-5-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,3-thiazol)-2-yl, (1,3-thiazol)-4-yl, (1,3-thiazol)-5-yl, furan-2-yl, and furan-3-yl; and
a substituted or unsubstituted saturated heterocyclic group selected from piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl.
3. The compound of claim 1 , wherein each R 34 is independently selected from H and a group selected from:
a halogen;
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 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 linear or branched carbonyl group selected from —(CO)Me, —(CO)Et, —(CO)Pr, —(CO)iPr, —(CO)nBu, —(CO)iBu, —(CO)tBu, —(C O)Ph, —(CO)CH 2 Ph, —(CO)CH 2 OH, —(CO)CH 2 OCH 3 , —(CO)CH 2 NH 2 , —(CO)CH 2 N HMe, —(CO)CH 2 NMe 2 , —(CO)-cyclopropyl, —(CO)-1,3-epoxypropan-2-yl, —(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 2 , —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 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 CH2OCH 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, —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)-Cl 2 -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)-Cl 2 -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 ;
a substituted or unsubstituted saturated or unsaturated heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, tetrazole-1yl, tetrazole-2-yl, tetrazole-3-yl, tetrazole-4-yl, tetrazole-5-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,3-thiazol)-2-yl, (1,3-thiazol)-4-yl, (1,3-thiazol)-5-yl, furan-2-yl, and furan-3-yl; and
a substituted or unsubstituted saturated heterocyclic group selected from piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl.
4. A compound of the following formula, or a pharmaceutically acceptable salt thereof:
wherein each of X 1 and X 2 is C;
one of X 3 and X 4 is C and the other one of X 3 and X 4 is N;
each bond represented by a dotted line may be present or absent, provided that one of X 3 and X 4 has a double bond and the N between X 1 and X 2 has a double bond and the valencies of X 1 , X 2 , X 3 , X 4 and N are maintained;
each of R 1 and R 2 is H;
each of R 3 and R 5 is H;
R 4 is an organic group selected from halogen, an unsubstituted C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group substituted with 1-3 halogens, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, and a nitrile group; and
wherein R 6 is selected from one of the following groups:
wherein X 7 is C or N, one R 34 is H, R 31 and the other R 34 are selected from a —COR 311 group or an —SO 2 R 311 group:
wherein R 311 is selected from:
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, —CF 3 , —CH 2 CF 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, —NMe 2 , —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)Cl 2 -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 C 3 -C 8 alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
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 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 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)-Cl 2 -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)-Cl 2 -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-;
an aromatic heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, tetrazole-5-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,3-thiazol)-2-yl, (1,3-thiazol)-4-yl, (1,3-thiazol)-5-yl, furan-2-yl, furan-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl; and
each R 313 is independently selected from absent, H, —OH, halogen, and C 1-6 alkyl.
5. The compound of claim 1 , selected from one of the following:
6. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
7. A compound selected from formulae Ic and Id, or a pharmaceutically acceptable salt thereof:
wherein:
R 4 is selected from the group consisting of (1) halogen, (2)C 1 -C 4 alkyl, optionally substituted with 1-3 halogens, and (3)C 3 -C 6 cycloalkyl, optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl; and
Y is selected from the group consisting of:
wherein
L is a bond;
R 31 is selected from the group consisting of (1) H, (2) halogen, (3) —C(O)—C 1-4 alkyl, (5) —S(O) 2 —C 1-4 alkyl, (6) —NH—C(O)—C 1-4 alkyl, and (7) heterocyclyl, optionally substituted with 1-5 groups independently selected from C 1-6 alkyl, oxo, —C(O)—H, —C(O)—NH 2 , C(O)—NH—C 1-6 alkyl, —NH 2 , and —NH—C 1-6 alkyl;
R 34 is selected from the group consisting of (1) H, (2) halogen, (3) —C(O)—C 1-6 alkyl, (4) —S(O) 2 —C 1-4 alkyl, (5) —NH—C(O)—C 1-4 alkyl, and (6) heterocyclyl, optionally substituted with 1-5 groups independently selected from C 1-6 alkyl, oxo, —C(O)—H, —C(O)—NH 2 , C(O)—NH—C 1-6 alkyl, —NH 2 , and —NH—C 1-6 alkyl; and
each occurrence of R 313 is independently selected from the group consisting of (1) H and (2)C 1-4 alkyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein each heterocyclyl of R 31 and R 34 is independently selected from the group consisting of: 2,3-dihydro-1,4-dioxinyl, dihydropyranyl, dihydropyrazinyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, furanyl, imidazolyl, imidazolidinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, and triazolyl wherein each of the heterocyclyl is optionally substituted with 1-5 groups independently selected from C 1-6 alkyl, oxo, —C(O)—H, —C(O)—NH 2 , C(O)—NH—C 1-6 alkyl, —NH 2 , and —NH—C 1-6 alkyl.
9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of (1) halogen and (2)CF 3 ; and
Y is selected from the group consisting of:
wherein
L is a bond;
R 31 is selected from the group consisting of (1) —C(O)—CH 3 , (2) —S(O) 2 —CH 3 , (3) —NH—C(O)—CH 3 , (4) imidazolidinyl, (5) isoxazolyl, (6) tetrazolyl, and (7) 1,2,3,4-tetrahydropyrimidinyl; wherein each of (4), (5), (6) and (7) is optionally substituted with 1-5 groups independently selected from C 1-6 alkyl, oxo, —C(O)—H, —C(O)—NH 2 , C(O)—NH—C 1-6 alkyl, —NH 2 , and —NH—C 1-6 alkyl;
R 34 is selected from the group consisting of (1) H, (2) —C(O)—CH 3 , (3) —S(O) 2 —CH 3 , (4) —NH—C(O)—CH 3 , (5) imidazolidinyl, (6) isoxazolyl, (7) tetrazolyl, and (8) 1,2,3,4-tetrahydropyrimidinyl; wherein each of (5), (6), (7) and (8) is optionally substituted with 1-5 groups independently selected from C 1-6 alkyl, oxo, —C(O)—H, —C(O)—NH 2 , C(O)—NH—C 1-6 alkyl, —NH 2 , and —NH—C 1-6 alkyl; and
each occurrence of R 313 is independently selected from the group consisting of (1) H and (2) —CH 3 .