Hypoxia inducible factor-1 pathway inhibitors and uses as anticancer and imaging agents

1. A compound of the formula

or salts thereof, wherein

X is selected from hydroxy and methoxy, wherein X is optionally substituted with one or more, the same or different R 1 ;

Y is selected from alkyl, isopropyl, and isobutyl wherein Y is optionally substituted with one or more, the same or different R 1 ;

Z is 2-pyridinyl, 4-pyridinyl wherein Z is optionally substituted with one or more, the same or different R 1 ;

R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 2 ; and

R 2 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The compound of claim 1 wherein the compound comprises a carbon 11 or fluorine 18 radionuclide.

3. The compound of claim 1 selected from:

N-((8-hydroxy-2,2-dimethyl-2H-chromen-6-yl)methyl)-N-isobutylpyridine-4-sulfonamide;

N-((8-hydroxy-2,2-dimethyl-2H-chromen-6-yl)methyl)-N-isobutylpyridine-2-sulfonamide;

N-[(8-Methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide;

N-[(8-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide; and

N-[(8-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-4-sulfonamide.

4. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

5. A method of treating cancer comprising administering an effective amount of a pharmaceutical composition of claim 4 .

6. The method of claim 5 , wherein the cancer is selected from glioblastoma (GBM), breast, pancreatic, colon, metastatic lung cancers, bladder cancer, lung cancer, breast cancer, melanoma, colon and rectal cancer, non-hodgkin lymphoma, endometrial cancer, pancreatic cancer, kidney cancer, prostate cancer, leukemia, thyroid cancer, and brain cancer.

7. The method of claim 6 , wherein the composition is administered in combination with a second anti-cancer agent.

8. The method of claim 7 , wherein the second anti-cancer agent is temozolamide, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, docetaxel, cis-platin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin, vinblastine, vindesine, vinorelbine, taxol, taxotere, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide, and/or lenalidomide or combinations thereof.

9. A method of imaging a tumor comprising administering a compound of claim 2 to a subject and viewing the compound by PET.