HSP90 inhibitory carbazole derivatives, compositions containing same and use thereof
View Patent ↗The invention relates to the novel substances in Formula (I): wherein Het is a heterocycle optionally substituted by one or a plurality of radicals R1 or R′1; R is selected from the group comprising Formula (A′), (B), (C), (D), or (E), with R1 and/or R′1 selected from H, halogen, CF3, nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenylalcoxy, alkylhio, or carboxy that is free or esterified by an alkyl, carboxamide, CO—NH(alkyl), CON(alkyl)2, NH—CO-alkyl, sulfonamide, NH—S02-alkyl, S(0)2-NHalkyl, or S(02)-N(alkyl)2 radical; all these radicals are optionally substituted; W1, W2, and W3 independently are CH or N; X is 0, S, NR2, C(O), S(O), or S(0)2; Z is optionally substituted H, Hal, -0-R2 or —NH—R2 with R2 being H, alkyl, cycloalkyl, or heterocycloalkyl; and these substances are all isomeric forms and salts thereof, used as drugs.
1. A compound according to formula (I)
in which:
Het is selected from:
in which one of R′3 and R3 represents a hydrogen atom and the other is selected from —NH 2 , —CN, —CH 2 —OH, —CF 3 , —OH, —O—CH 2 -phenyl, —O—CH 3 and —CO—NH 2 ;
R is selected from:
R1 and R′1 are independently selected from: H, halogen, CF 3 , cyano, alkyl, hydroxyl, amino, alkoxy, phenylalkoxy, carboxamide, wherein said alkyl and alkoxy radicals are optionally and independently substituted with one or more radicals selected from halogen and hydroxyl;
W1 and W2 are independently CH or N;
Z is selected from a hydrogen atom, halogen atom, —O—R2 radical, and —NH—R2 radical, wherein:
R2 is selected from a hydrogen atom, C 1 -C 6 alkyl radical, C 3 -C 8 cycloalkyl radical, and C 3 -C 10 heterocycloalkyl radical, which is monocyclic or bicyclic wherein said alkyl, cycloalkyl, and heterocycloalkyl radicals are optionally and independently substituted with one or more radicals selected from:
halogen, hydroxyl, amino, carboxamide (CONH 2 ), carboxyl, and
heterocycloalkyl selected from piperidino, tetrahydropyrano, pyrrolidino; quinuclidino, cycloalkyl, heteroaryl, CO—NH(alkyl), —O—CO-alkyl, —NH—CO-alkyl, alkyl, alkoxy, and dialkylamino, wherein said alkyl and alkoxy radicals are optionally substituted with a hydroxyl, amino, dialkylamino, CO 2 alkyl, NHCO 2 alkyl; wherein said cyclic, cycloalkyl, heterocycloalkyl, and heteroaryl radicals are optionally and independently substituted with one or more radicals selected from hydroxyl, alkyl, and amino radicals;
or an addition salt thereof formed with an inorganic or organic acid or with an inorganic or organic base.
2. A compound according to claim 1 , wherein:
Het is selected from:
R is:
R1 is selected from H, F, Cl, Br, CH 3 , and OH;
R′ 1 is H;
W1 and W2 are selected from CH and N, provided that at least one of W1 and W2 is CH; and
Y is selected from OH, O—CO—CH 2 —CO 2 tBU, O—CO—CH 2 —NH 2 , and O—CO—CH 2 —N(Me) 2 .
3. A compound according to claim 1 , wherein:
Het is selected from:
R1 is selected from H, F, Cl, Br, CH 3 , and OH;
R′1 is H;
and R is selected from:
W1 and W2 are selected from CH and N, provided that at least one of W1 and W2 is CH;
R2 is selected from hydrogen, ethyl substituted in the 2-position with a substituent, and n-propyl substituted in the 3-position with a substituent, wherein said substituent is selected from OH, NH 2 , OMe, N(Me) 2 , and CONH 2 ; and
Y is selected from OH, O—CO—CH 2 —CO 2 tBu, O—CO—CH 2 —NH 2 , and O—CO—CH 2 —N(Me) 2 .
4. A compound according to claim 1 , wherein said compound is selected from:
4-[4-(6-fluoro-1H-benzimidazo 1-2-yl)-9H-carbazol-9-yl]-2-(4-trans-hydroxycyclohexylamino)benzamide;
2-(4-trans-hydroxycyclohexylamino)-4-[(4-quinolin-3-yl)-9H-carbazol-9-yl]benzamide;
2-(2-diethylaminoethylamino)-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzamide;
2-(4-trans-hydroxycyclohexylamino)-4-[4-(3H-imidazo[4,5-c]pyridin-2-yl)carbazol-9-yl]benzamide;
acetic acid 4-{2-carbamoyl-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}cyclohexyl ester;
2-cyclohexylamino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzamide;
4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-[2-(2-hydroxyethoxy)ethylamino]benzamide;
[[−]]4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-(3-hydroxypropylamino)benzamide;
4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-(4-cis-hydroxycyclohexylamino)benzamide;
2-amino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9,4-carbazol-9-yl]benzamide;
4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-(2-pyrrolidin-1-ylethylamino)benzamide;
3-(trans-4-hydroxycyclohexylamino)-5-[(4-quinolin-3-yl)-9H-carbazol-9-yl)pyridine-2-carboxamide;
4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-(tetrahydro-pyran-4-ylamino)benzamide;
4-[4-(6-cyanopyridin-3-yl)-9,1-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzamide;
aminoacetic acid 4-{[2-carbamoyl-5-(quinolin-3-yl)-9H-carbazol-9-yl]pyridin-3-ylamino}cyclohexyl ester;
4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzamide;
5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-3-(tetrahydropyran-4-yl)amino)pyridine-2-carboxamide;
2-[4-(quinolin-3-yl)-9H-carbazol-9-yl]-4-(tetrahydropyran-4-yl)-amino)pyridine-5-carboxamide;
2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino-4-[4-(quinolin-3-yl)-9H-carbazol-9-yl]benzamide; and
3-[(2-hydroxy-2-methylpropylamino)-5-[4-(quinolin-3-yl)-9H-carbazol-9-yl]pyridine-2-carboxamide.
5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
6. A pharmaceutical composition comprising a compound according to claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
7. A pharmaceutical composition comprising a compound according to claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition according to claim 5 , 6 , or 7 , further comprising an active ingredient for anticancer chemotherapy.