Substituted β-lapachones for treating cancer

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, —OR a , alkylamino, dialkylamino, or heterocyclyl;

R a is H, amido, heterocyclyl, or Si(alkyl) 3 ;

R 2 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —(CH 2 ) n -aryl, —(CH 2 ) n heteroaryl, C(O)OH, or C(O)OC 1 -C 6 alkyl;

R 3 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C(O)H, C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, amino, alkylamino, dialkylamino, —(CH 2 ) n -aryl, —(CH 2 ) n heteroaryl, or heterocyclyl;

R 4 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C(O)H, C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, amino, alkylamino, dialkylamino, —(CH 2 ) n -aryl, —(CH 2 ) n heteroaryl, or heterocyclyl;

R 5 and R 6 , together with the carbon atom to which they are attached, are —C(O)—;

R 7 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl, or heterocyclyl;

R 8 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl, or heterocyclyl;

R 9 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl, or heterocyclyl;

R 10 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl, or heterocyclyl;

X is —CH 2 —; and

n is 0, 1, 2, or 3;

with the proviso that covalently bonded to formula (I) at one of R 1 , R 2 , R 3 , or R 4 is a mitochondrial targeting group represented by the formula below:

wherein:

R 19 is —CH 2 —, —NH—, or —O—;

R 26 and R 27 are each independently H or an amine protecting group independently selected from the group consisting of:

R 28 is H or CH 3 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 26 and R 27 are each independently an amine protecting group independently selected from the group consisting of:

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 26 and R 27 are each independently an amine protecting group independently selected from the group consisting of:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the mitochondrial targeting group is covalently bonded to formula (I) at one of R 3 or R 4 .

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

R 26 is

and

R 27 is

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 28 is H.

7. The compound of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition further comprises a chemotherapeutic agent.

10. The pharmaceutical composition of claim 9 , wherein the chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, bosutinib, busulfan, cachectin, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, carboplatin, carmustine, cemadotin, chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxol, dolastatin, doxetaxel, doxorubicin, etoposide, etoposide phosphate, 5-fluorouracil, finasteride, flutamide, hydroxyurea, hydroxyurea taxanes, ifosfamide, imatinib, irinotecan, liarozole, lomustine, lonidamine, mechlorethamine, melphalan, methotrexate, mitomycin, mitoxantrone, mivobulin isethionate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, rhizoxin, sertenef, stramustine phosphate, streptozocin, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

11. A method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein the cancer is breast cancer.

13. The method of claim 11 , wherein the cancer is lung cancer.

14. The method of claim 11 , wherein the cancer is ovarian cancer.

15. The method of claim 11 , wherein the cancer is melanoma.

16. The method of claim 11 , wherein the method further comprises administering a chemotherapeutic agent to the patient.

17. The method of claim 16 , wherein the chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, bosutinib, busulfan, cachectin, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, carboplatin, carmustine, cemadotin, chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxol, dolastatin, doxetaxel, doxorubicin, etoposide, etoposide phosphate, 5-fluorouracil, finasteride, flutamide, hydroxyurea, hydroxyurea taxanes, ifosfamide, imatinib, irinotecan, liarozole, lomustine, lonidamine, mechlorethamine, melphalan, methotrexate, mitomycin, mitoxantrone, mivobulin isethionate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, rhizoxin, sertenef, stramustine phosphate, streptozocin, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

18. The method of claim 11 , wherein the method further comprises simultaneously administering radiation therapy to the patient while the compound, or a pharmaceutically acceptable salt thereof, is present in the patient.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:

or a pharmaceutically acceptable salt thereof.

20. A method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.