Compounds for the modulation of Myc activity
The present invention provides novel compounds of Formulas (I) and (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angio genesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of X 1 , X 2 , X 3 and X 4 is independently selected from the group consisting of C(R), N and N(O), wherein one or two of X 1 , X 2 , X 3 and X 4 is N or one of X 1 , X 2 , X 3 and X 4 is N(O);
each R is independently selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 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, and (C 0 -C 6 alkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R is optionally and independently substituted;
Y is selected from the group consisting of O, S and N(R 3a );
Z is selected from the group consisting of C(R 4a )(N(R 5 )(R 6 )) and N(R 1 );
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (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, (C 1 -C 6 heteroalkylene)-heteroaryl, CH 2 C(O)OR 7 , CH 2 C(O)N(R 10 )(R 11 ), and CH 2 CH 2 N(R 10 )(R 11 ) wherein:
R 10 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
R 11 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, (C 0 -C 4 alkylene)-carbocyclyl, (C 0 -C 4 alkylene)-heterocyclyl, (C 0 -C 4 alkylene)-aryl, (C 0 -C 4 alkylene)-heteroaryl, (C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), (C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl), and C(O)—O—(C 1 -C 4 alkyl), or
R 10 and R 11 are taken together with the nitrogen atom to which they are commonly bound to form a 4-11 membered heterocyclyl or heteroaryl; and any alkyl, alkylene, heteroalkyl, heteroalkylene, heterocyclyl, heteroaryl, aryl or carbocyclyl portion of R 1 is optionally substituted;
R 2 is selected from the group consisting of C(R 2a )(R 2b )(R 2c ), carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein any carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally substituted;
R 2a is selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl and C 1 -C 4 haloalkyl, wherein any alkyl, heteroalkyl or haloalkyl is optionally substituted;
each of R 2b and R 2c is independently selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C(O)(C 1 -C 6 alkyl), C(O)(C 1 -C 6 heteroalkyl), C(O)O(C 1 -C 6 alkyl), C(O)O(C 1 -C 6 heteroalkyl), C(O)N(R 3a )(R 3b ), (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, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 2b and R 2c is optionally and independently substituted;
each of R 3a and R 3b is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl, each of which is optionally substituted;
each R 4 is independently selected from the group consisting of halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 6 alkyl), C(O)(C 1 -C 6 heteroalkyl), C(O)O(C 1 -C 6 alkyl), C(O)N(R 3a )(R 3b ), (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, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4 is optionally and independently substituted;
R 4a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each of R 5 and R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, 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, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of each of R 5 and R 6 is optionally and independently substituted; or
R 5 and R 6 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl;
R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, and (C 0 -C 3 alkylene)-heterocyclyl;
R 12 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, and (C 0 -C 3 alkylene)-heterocyclyl;
n is 0, 1 or 2;
m is 0, 1 or 2;
n+m=1, 2 or 3; and
p is 0, 1, 2, 3, 4, 5 or 6.
2. The compound of claim 1 , wherein one of X 1 , X 2 , X 3 , and X 4 is N or N(O), and the others of X 1 , X 2 , X 3 , and X 4 are, independently, C(R).
3. The compound of claim 2 , wherein X 3 is N, and each of X 1 , X 2 , and X 4 is C(R).
4. The compound of claim 1 , wherein each R is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, N(R 3a )(R 3b ), C(O)(C 1 -C 4 optionally substituted alkyl), and C(O)O(optionally substituted C 1 -C 4 alkyl).
5. The compound of claim 1 , wherein each R is independently selected from the group consisting of hydrogen, chloro, —CH 3 and —CHF 2 .
6. The compound of claim 1 , wherein Y is S.
7. The compound of claim 1 , wherein Z is N(R 1 ).
8. The compound of claim 7 , wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, (C 0 -C 6 alkylene)-morpholin-4-yl, and CH 2 CH 2 N(R 10 )(R 11 ) wherein each of R 10 and R 11 is independently selected from the group consisting of hydrogen and methyl.
9. The compound of claim 8 , wherein R 1 is selected from the group consisting of hydrogen, isopropyl and ethyl.
10. The compound of claim 1 , wherein R 2 is C(R 2a )(R 2b )(R 2c ).
11. The compound of claim 8 , wherein:
R 2a is hydrogen;
R 2b is hydrogen; and
R 2c is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 1 -C 6 heteroalkylene)-carbocyclyl, (C 1 -C 6 heteroalkylene)-heterocyclyl, (C 1 -C 6 heteroalkylene)-aryl, and (C 1 -C 6 heteroalkylene)-heteroaryl, and any alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, or heteroaryl portion of R 2c is optionally substituted.
12. The compound of claim 11 , wherein R 2c is selected from the group consisting of C 1 -C 6 alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-O-alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-C(O)—O-alkyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-cycloalkyl, —(CH 2 )—N(R 13 )-cycloalkyl, —(CH 2 ) 2 —N-linked heterocyclyl, —(CH 2 )—N(R 13 )-heterocyclyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-heterocyclyl, —CH 2 —N-linked heterocyclyl, —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-heteroaryl, and —(CH 2 )—N(R 13 )—C 1 -C 4 alkylene-aryl, wherein R 13 is hydrogen or C 1 -C 4 alkyl, and any alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, or heteroaryl portion of R 2c is optionally substituted.
13. The compound of claim 12 , wherein any alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, or heteroaryl portion of R 2c is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, —CN, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkyl, —C 1 -C 4 hydroxyalkyl, —C(O)NH 2 , —C(O)OH, —C(O)O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —O—C 3 -C 6 cycloalkyl, phenyl, and halo-substituted phenyl.
14. The compound of claim 1 , wherein each R 4 is independently selected from the group consisting of halogen, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3a )(R 3b ), (C 0 -C 6 alkylene)-heterocyclyl, and (C 0 -C 6 alkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heterocyclyl or heteroaryl portion of each R 4 is optionally and independently substituted.
15. The compound of claim 14 , wherein each R 4 is optionally substituted C 1 -C 4 alkyl.
16. The compound of claim 15 , wherein each R 4 is methyl.
17. The compound of claim 1 , wherein p is 0, 1 or 2.
18. The compound of claim 1 , wherein the compound of Formula (I) has the structure of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 1a is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
each R 4b , if present, is C 1 -C 3 alkyl;
R 14 and R 17 are independently selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 15 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, and —CH 2 —N(R 13a )(R 16 );
R 13a is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
R 16 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, —(C 0 -C 2 alkylene)-heterocyclyl, —(C 0 -C 2 alkylene)-C 3 -C 6 cycloalkyl, or (C 1 -C 2 alkylene)-heteroaryl, wherein any heteroalkyl, alkylene, cycloalkyl, heterocyclyl or heteroaryl portion of R 11a is optionally substituted; or
R 13a and R 16 are taken together to form an optionally substituted heterocyclyl; and
p is 0, 1 or 2.
19. The compound of claim 18 , wherein R 1a is selected from the group consisting of hydrogen, ethyl and isopropyl.
20. The compound of claim 18 , wherein each R 4b , if present, is —CH 3 .
21. The compound of claim 18 , wherein R 13a is selected from the group consisting of hydrogen and —CH 3 .
22. The compound of claim 18 , wherein R 17 is selected from the group consisting of hydrogen, chloro, and —CH 3 .
23. The compound of claim 18 , wherein R H is selected from the group consisting of hydrogen, —CH 3 and —CHF 2 .
24. The compound of claim 18 , wherein R 15 is selected from the group consisting of hydrogen, NHR 16 , and N(CH 3 )R 16 .
25. The compound of claim 18 , wherein R 16 is selected from the group consisting of -heterocyclyl, —CH 2 -heterocyclyl, —(CH 2 ) 2 -heterocyclyl, —CH 2 -heteroaryl, —CH(CH 3 )-heteroaryl, —(CH 2 ) 2 -heteroaryl, —CH(CH 3 )—CH 2 -heteroaryl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH 2 —O—CH 3 , —(CH 2 ) 3 —C(O)OCH 3 , —CH(CH 2 OH)CH 2 CH(CH 3 ) 2 , —CH(CH(CH 3 ) 2 )CH 2 OCH 3 , —(C 3 -C 5 cycloalkyl), —CH 2 —(C 3 -C 5 cycloalkyl), and —CH(CH 3 )—(C 3 -C 5 cycloalkyl); or
wherein R 16 is taken together with R 13a and the nitrogen atom to which they are bound to form a N-linked heterocyclyl,
wherein each heterocyclyl, heteroaryl and cycloalkyl portion of R 16 or the N-linked heterocyclyl formed when R 16 is taken together with R 13a is optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, —CH 3 , —CH 2 OCH 3 , —OCH 3 , —NH 2 , —N(CH 3 ) 2 , —C(O)OH, and —O-cycloalkyl.
26. The compound of claim 1 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt of any one of the foregoing compounds.
27. A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
28. A method of treating small cell lung cancer in a subject in need thereof, the method comprising administering to the subject a compound of claim 1 or a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
29. The method of claim 27 , wherein the subject has been determined to have deregulated c-Myc activity prior to administration of the compound or composition.
30. The method of claim 27 , wherein the compound of claim 1 is selected from the group consisting of
or is a pharmaceutically acceptable salt of any of the foregoing compounds.