Indenyl compounds, pharmaceutical compositions, and medical uses thereof
Disclosed are compounds, for example, compounds of formula (I), (Formula (I) wherein R, R 0 , R 1 -R 8 , n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition, for example, cancer.
1. A compound, (Z)- or (E)-isomer thereof, of formula IIa:
wherein:
R 1 , R 3 , R 4 , R 13 and R 15 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, and alkoxy;
R 2 is selected from hydrogen, halogen, alkyl, cycloalkyl and haloalkyl;
R 7 and R 8 are independently selected from hydrogen and alkyl;
R 14 is a cleavable alcohol prodrug moiety; and
R′ is selected from the group consisting of heterocyclyl and heterocyclylalkyl, wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl is selected from the group consisting of azepanyl, oxazepanyl, thiazepanyl, azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl, thiazepinyl, oxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl, dioxanyl, dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, thiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl, wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is optionally substituted with one or more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido; or
a pharmaceutically acceptable salt thereof.
2. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 14 is a substituted or unsubstituted group selected from phosphonooxy, phosphonooxyalkyloxy, formyloxy, alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate, arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy, and heterocyclylalkylcarbonyloxy.
3. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from the group consisting of diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, pyrrolyl, thiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, and oxadiazolyl.
4. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from diazinyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dioxolanyl, pyrazolyl and imidazolyl, wherein the heterocyclyl is optionally substituted with one or more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, and carboxamido.
5. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 4 , wherein the heterocyclyl of the heterocyclyl and heterocyclylalkyl of the R′ is selected from pyrrolyl, oxazolyl, isoxazolyl, and dioxolanyl, wherein the heterocyclyl is optionally substituted with one or more of halo, alkyl, haloalkyl, hydroxyl, and alkoxy.
6. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 4 , wherein R′ is selected from 2-pyrrolylmethyl and (1-methyl-1H-pyrrol-2-yl)methyl.
7. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, alkoxy, alkyl, and haloalkyl.
8. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein R 1 , R 3 and R 4 are each hydrogen, and R 2 is selected from halogen, alkyl, and haloalkyl.
9. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 8 , wherein R 2 is fluoro.
10. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 7 is hydrogen and R 8 is alkyl.
11. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 13 and R 15 are each alkoxy.
12. The compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 1 , R 3 and R 4 are independently selected from halogen, alkoxy, alkyl and haloalkyl; R 7 is hydrogen; R 8 is alkyl; and R 13 and R 15 are each alkoxy.
13. The compound of claim 1 , which is selected from:
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl benzoate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methy)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl nicotinate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl (4-nitrophenyl) carbonate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl (2-(dimethylamino)ethyl)carbamate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl morpholine-4-carboxylate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl (1-methylpiperazine-4-yl)carbamate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyI-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl 4-methylpiperazine-1-carboxylate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyI-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6- dimethoxyphenyl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxyIate,
(Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl dihydrogen phosphate, and
(Z)-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl dihydrogen phosphate,
or the corresponding E-isomer thereof, or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable carrier.
15. A method of therapeutically treating a human or nonhuman mammalian patient with cancer, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, head and neck cancer, endocrine cancer, uterine cancer, breast cancer, sarcoma cancer, gastric cancer, hepatic cancer, esophageal cancer, central nervous system cancer, brain cancer, hepatic cancer, germline cancer, lymphoma, and leukemia, comprising administering to said patient an anticancer effective amount of at least one compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein said at least one compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof is administered alone or in combination with an antitumor drug or radiation, wherein said antitumor drug is not a compound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 .