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, tautomer, or stereoisomer thereof, wherein:
each of X 1 , X 2 , X 3 and X 4 is independently selected from 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 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 O, S and N(R 3a );
Z is selected from C(R 4a )(N(R 5 )(R 6 )) and N(R 1 );
R 1 is selected from 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 hydrogen or C 1 -C 4 alkyl;
R 11 is selected from 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 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 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 2a and R 2c is independently selected from 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, ( 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 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 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 hydrogen and C 1 -C 6 alkyl;
each of R 5 and R 6 is independently selected from 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 hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, (C 0 -C 3 alkylene)-heterocyclyl;
R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, (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 independently C(R).
4. The compound of claim 1 , wherein each R is independently selected from 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 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 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 hydrogen or methyl.
9. The compound of claim 8 , wherein R 1 is selected from 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 10 , wherein:
R 2a is hydrogen;
R 2b is hydrogen; and
R 2c is selected from 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, any alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, or heteroaryl portion of R 2c is optionally substituted.
12. The compound of claim 10 , wherein R 2c is selected from 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 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 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 hydrogen and C 1 -C 3 alkyl;
each R 4b , if present, is C 1 -C 3 alkyl;
R 17 and R 14 are independently selected from hydrogen, halo, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 15 is selected from hydrogen, C 1 -C 3 alkyl, and —CH 2 —N(R 13a )(R 16 );
R 13a is selected from hydrogen and C 1 -C 3 alkyl;
R 16 is selected from 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 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 hydrogen and —CH 3 .
22. The compound of claim 18 , wherein R 17 is selected from hydrogen, chloro, and —CH 3 .
23. The compound of claim 18 , wherein R 14 is selected from hydrogen, —CH 3 and —CHF 2 .
24. The compound of claim 18 , wherein R 15 is selected from hydrogen, NHR 16 , and N(CH 3 )R 16 .
25. The compound of claim 18 , wherein R 16 is selected from -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 - 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, and
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 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, tautomer, or stereoisomer thereof.
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 28 , 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 28 , wherein the compound of claim 1 is selected from the group consisting of
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.