Low affinity poly(AD-ribose) polymerase 1 dependent cytotoxic agents

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

A is NR 1 , CHR 1 , or O;

R 1 is H, alkoxy, aryl, —C(O)(aryl), —C(O)(cycloalkyl), or —C(O)(alkoxy);

t is 1, 2, or 3;

u is 1 or 2;

v is 0, 1, 2 or 3; and

w is 1 or 2;

or an isotopic variant thereof;

or a stereoisomer thereof, or a mixture thereof.

2. The compound of claim 1 , wherein A is NR 1 .

3. The compound of claim 1 , wherein A is CHR 1 .

4. The compound of claim 1 , wherein A is O.

5. The compound of claim 1 , wherein R 1 is H.

6. The compound of claim 1 , wherein R 1 is —C(O)(alkoxy).

7. The compound of claim 1 , wherein R 1 is —C(O)(cycloalkyl).

8. The compound of claim 1 , wherein R 1 is aryl.

9. The compound of claim 1 , wherein R 1 is —C(O)(aryl).

10. The compound of claim 1 , wherein R 1 is alkoxy.

11. The compound of claim 1 , wherein the heterocyclyl is substituted by, one or two substituents that are, independently, (i) C 1-6 alkoxy, or (iii) substituted phenyl optionally substituted with halo or heterocyclyl.

12. The compound of claim 1 , wherein:

t, u, v, and w are 1; or

t is 2, v is 0, and u and w are 1; or

t, u, and w is 1 and v is 2; or

t and v are 1, u and w are 2; or

t, u, and w are 2 and v is 0; or

t is 2, v is 1, u is 1 and w is 1; or

t is 2, v is 1, u is 2, and w is 1; or

t is 2, v is 1, u is 2, and w is 2; or

t and u are 1, and v and w are 2; or

t is 1 and v, U, and w are 2; or

t, v, u, and w are 2.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of the formula:

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, that is:

wherein X is 18 F, 19 F, 123 I, 124 I, 125 I, 131 I, 76 Br, 77 Br, or 211 At.

15. A compound that is an isotopic variant of claim 1 .

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

17. A method of preparing a pharmaceutical composition, comprising combining a compound of claim 1 , or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient.

18. A method modulating poly(ADP-ribose)polymerase-1 (PARP-1) in a subject, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the subject has been diagnosed with a neurodegenerative disease.

20. The method of claim 19 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, or Huntington's disease.

21. A method of

detecting a poly(ADP-ribose)polymerase-1-mediated cancer or neurodegenerative disease or disorder, comprising:

(a) administering an effective amount of an isotopically-labeled compound of claim 1 to a subject; and

(b) performing positron emission tomography or single photon emission computed tomography on said subject; and

(c) detecting the isotopically-labeled compound of claim 1 in the subject.

22. The method of claim 18 , wherein the subject has been diagnosed with a neurodegenerative disease or cancer.

23. The method of claim 22 , wherein the cancer is breast cancer, uterine cancer, lung cancer, ovarian cancer, and skin cancer, or non-Hodgkin's lymphoma.

24. A method of monitoring poly(ADP-ribose)polymerase-1-mediated cancer treatment in a subject, comprising:

(a) administering a chemotherapeutic or radiation to said subject;

(b) administering an effective amount of an isotopically-labeled compound of formula I of claim 1 to said subject;

(c) performing positron emission tomography or single photon emission computed tomography on said subject;

(d) and detecting the isotopically-labeled compound of claim 1 in the subject.