Compounds for the modulation of myc activity

1. A compound of structural formula I:

or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein:

Y is S;

Z is N(R 1 );

R 1 is selected from hydrogen, C 1 -C 6 alkyl, and (C 0 alkylene)-carbocyclyl;

R 12 is hydrogen;

R 2 is —C(R 2a )(R 2b )[C(R 9a )(R 9b )] 1-7 —N(R 17 )(R 8 );

R 2a is selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 heteroalkyl;

R 2b is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 6 alkylene)-heteroaryl, and —CH 2 —NR 17 —(CH 2 ) 0-1 —(CH 2 CH 2 O) 3-20 —CH 2 CH 2 —R 20 , wherein:

each R 9a and each R 9b is independently selected from hydrogen, halogen, —CN, C 1 -C 8 alkyl, (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl;

each R 17 and R 8 is independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 6 heteroalkyl, (C 1 -C 4 alkylene)-heterocyclyl, (C 1 -C 4 alkylene)-heteroaryl, carbocyclyl, —(CH 2 CH 2 O) 3-20 —CH 2 CH 2 R 20 , and (C 1 -C 4 alkylene)-aryl;

R 20 is selected from —C(O)OH, —C(O)CH 3 , —C(O)CH 2 CH 3 , —NH 2 , —CH 2 NH 2 , —(CH 2 ) 2 —NH 2 , and —(CH 2 ) 3 —NH 2 ;

and

wherein any alkyl portion of R 2b optionally substituted with one or more methyl;

each R 4 is C 1 -C 8 alkyl;

each R 7 is independently selected from halogen, —CN, —OH, —S(O) 2 —C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 alkyl), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, heterocyclyl or heteroaryl portion of R 7 is optionally and independently substituted; or

two R 7 are taken together with the ring carbon atoms to which they are bound to form a heterocyclyl fused to rest of the compound;

R 3a is hydrogen;

R 3b is —S(O) 2 —C 1 -C 6 alkyl or heterocyclyl;

n is 1;

m is 1;

o is 0, 1, or 2; and

p is 0, 1, or 2.

2. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R 1 is hydrogen.

3. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R 1 is selected from ethyl and cyclopropyl.

4. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R 2a is C 1 -C 4 alkyl.

5. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein each R 4 is C 1 alkyl.

6. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein p is zero (0).

7. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein p is 1.

8. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein p is 2.

9. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein each R 7 is independently selected from —CN, —OH, halogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 1 -C 6 heteroalkyl, heteroaryl, heterocyclyl, and aryl, and wherein any alkyl, heteroalkyl, heterocyclyl or heteroaryl portion of R 7 is optionally and independently substituted.

10. The compound of claim 9 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein each R 7 is independently selected from fluoro, bromo, chloro, —CN, —OH, —CH 3 , —CH 2 CH 3 , —CF 3 , —CH(OH)CH 3 , —CH 2 OH, —OCH 3 , —CH═CH 2 , 1,2,5,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,5,6-tetrahydropyridin-4-yl, 4-(morpholin-4-ylcarbonyl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methyl sulfonylphenyl, 4-acetamidophenyl, 3-(N-(2-(dimethylamino)ethyl)aminocarbonyl)phenyl, 3-(dimethylaminocarbonyl)phenyl, 1H-1,2,4-triazol-1-yl, 1H-imidazol-1-yl, 5-chloro-1H-imidazol-1-yl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 1-isopropyl-1H-pyrazol-4-yl, 1-(1-ethoxycarbonylmethyl)-1H-pyrazol-4-yl, isoxazol-4-yl, 3-hydroxyazetidin-1-yl, oxetan-3-ylamino, pyrimidin-5-yl, 2-aminopyrimidin-5-yl, 2-methoxypyrimidin-5-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 4-methyl-1H-imidzaol-1-yl, morpholin-4-yl, pyridin-3-yl, pyridin-4-yl, 5-fluoropyridin-3-yl, 2-fluoropyridin-5-yl, 2-fluoropyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminopyridin-4-yl, 2-methoxycarbonylpyridin-5-yl, 2-acetamidopyridin-4-yl, 2-(piperazin-1-yl)pyridin-5-yl, 5-aminopyridin-3-yl, 2-cyanopyridin-5-yl, 5-methoxypyridin-3-yl, 3,6-dihydro-2H-pyran-4-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, and 2H-1,2,3,4-tetrazol-5-yl.

11. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein o is zero (0) or 1.

12. The compound of claim 11 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein o is zero (0).

13. The A compound of structural formula I:

or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein:

Y is S;

Z is N(R 1 );

R 1 is selected from hydrogen, C 1 -C 6 alkyl, and (C 0 alkylene)-carbocyclyl;

R 12 is hydrogen;

R 2 is —C(R 2a )(R 2b )[C(R 9a )(R 9b )] 1-7 —N(R 17 )(R 8 );

R 2a is selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 heteroalkyl;

R 2b is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 6 alkylene)-heteroaryl, and —CH 2 —NR 17 —(CH 2 ) 0-1 —(CH 2 CH 2 CH 2 O) 3-20 —CH 2 CH 2 —R 20 , wherein any alkyl portion of R 2b is optionally substituted with one or more methyl;

each R 9a and each R 9b is independently selected from hydrogen, halogen, —CN, C 1 -C 8 alkyl, (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl;

R 17 is selected from —CH(CH 3 )CH 2 CH 3 , —CH 3 , —CH 2 CH 2 OCH 3 , —(CH 2 ) 3 (OCH 2 CH 2 ) 3 CH 2 NH 2 , —CH 2 CH 2 N(CH 2 CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH 2 CH 2 OH, —C(CH 3 )CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —C(O)CH 2 CH 3 , —C(O)CH 3 , —CH 2 C(O)OCH 2 CH 3 , —(CH 2 ) 2 OCH 3 , and —CH 2 C(O)OH

R 8 is independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 6 heteroalkyl, (C 1 -C 4 alkylene)-heterocyclyl, (C 1 -C 4 alkylene)-heteroaryl, carbocyclyl, —(CH 2 CH 2 O) 3-20 —CH 2 CH 2 R 20 , and (C 1 -C 4 alkylene)-aryl;

R 20 is selected from —C(O)OH, —C(O)CH 3 , —C(O)CH 2 CH 3 , —NH 2 , —CH 2 NH 2 , —(CH 2 ) 2 —NH 2 , and —(CH 2 ) 3 —NH 2 ;

each R 4 is C 1 -C 8 alkyl;

each R 7 is independently selected from halogen, —CN, —OH, —S(O) 2 —C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 alkyl), (C 0 -C 6 alkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 0 -C 6 alkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 0 -C 6 alkylene)-aryl, (C 1 -C 6 heteroalkylene)-aryl, (C 0 -C 6 alkylene)-heteroaryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, wherein each alkyl is optionally substituted with halogen; or

two R 7 are taken together with the ring carbon atoms to which they are bound to form a heterocyclyl fused to rest of the compound;

R 3a is hydrogen;

R 3b is —S(O) 2 —C 1 -C 6 alkyl or heterocyclyl;

n is 1;

m is 1;

o is 0, 1, or 2; and

p is 0, 1, or 2.

14. A pharmaceutically acceptable composition comprising a compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof and a pharmaceutically acceptable carrier.

15. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof.

16. The method of claim 15 , wherein the cancer is a breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer.

17. The method of claim 16 , wherein the lung cancer is small cell lung cancer.

18. The method of claim 15 , wherein the subject has been determined to have deregulated c-Myc activity prior to administration of the compound or the pharmaceutically acceptable salt or isotopically labeled derivative thereof.

19. The method of claim 15 , wherein the subject has been diagnosed with a cancer associated with overexpression of Myc prior to administration of the compound or the pharmaceutically acceptable salt or isotopically labeled derivative thereof.

20. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein the compound is

or a pharmaceutically acceptable salt, tautomer, or stereoisomer or isotopically labeled derivative thereof.

21. The compound of claim 1 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof, wherein R 2a and R 2b are each hydrogen.

22. The compound of claim 1 , wherein the compound conforms to structural formula I and excludes the pharmaceutically acceptable salt or the isotopically labeled derivative thereof.

23. The compound of claim 1 , wherein the compound is in the form of the pharmaceutically acceptable salt.

24. The compound of claim 1 , wherein the compound is in the form of the isotopically labeled derivative.

25. A pharmaceutically acceptable composition comprising a compound of claim 13 or the pharmaceutically acceptable salt or isotopically labeled derivative thereof and a pharmaceutically acceptable carrier.