Compounds for the modulation of MYC activity
The present invention provides novel compounds of Formula (I) 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, angiogenesis, 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:
Y is S;
Z is N(R 5 );
R 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl;
R 2 is —C(R 2a )(R 2b )(R 2c ), wherein:
R 2a is halogen, CN, C 1 -C 4 alkyl, or C 1 -C 4 heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted;
each of R 2b and R 2c is, independently, 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), or C(O)N(R 3a )(R 3b ),
wherein any alkyl or heteroalkyl portion of R 2b and R 2c is optionally and independently substituted;
each R 3 is, independently, hydrogen, —C 1 -C 6 alkyl, or —C 1 -C 6 heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; or
two R 3 bound to a common nitrogen atom are optionally taken together with the nitrogen atom to which they are commonly bound to form a 4-11 member heterocyclyl or heteroaryl;
each R 4 is, independently, hydrogen, halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (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 5 is 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 8 , CH 2 C(O)N(R 10 )(R 9 ), or CH 2 CH 2 N(R 10 )(R 9 ), wherein:
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, (C 0 -C 3 alkylene)-carbocyclyl, or (C 0 -C 3 alkylene)-heterocyclyl;
R 9 is hydrogen or C 1 -C 4 alkyl; and
R 10 is 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), or C(O)—O—(C 1 -C 4 alkyl), or
R 10 and R 9 are taken together with the nitrogen atom to which they are commonly bound to form a 4- to 11-membered heterocyclyl or heteroaryl;
n is 1;
m is 1; and
p is 0, 1, 2, 3, 4, 5, or 6.
2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl.
4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 2 is —(CH 2 ) 2 —NH—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH—(CH 2 ) 2 —OCH 3 , or —(CH 2 ) 2 —NH—CH(CH 3 )—CH 2 CH 3 .
5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and p is 0.
6. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutically acceptable composition comprising a compound of claim 1 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. The compound of claim 6 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. The pharmaceutically acceptable composition of claim 7 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R is hydrogen.
10. The pharmaceutically acceptable composition of claim 7 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl.
11. The pharmaceutically acceptable composition of claim 7 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 2 is —(CH 2 ) 2 —NH—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH—(CH 2 ) 2 —OCH 3 , or —(CH 2 ) 2 —NH—CH(CH 3 )—CH 2 CH 3 .
12. The pharmaceutically acceptable composition of claim 7 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 3 is hydrogen and p is 0.
13. The pharmaceutically acceptable composition of claim 7 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The pharmaceutically acceptable composition of claim 7 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R is an unsubstituted heterocyclyl or heteroaryl; R 2a is halogen, CN, C 1 -C 4 alkyl, or C 1 -C 4 heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R 2b and R 2c is, independently, 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), or C(O)N(R 3a )(R 3b ), wherein any alkyl or heteroalkyl portion of R 2b and R 2c is unsubstituted; each R 3 is, independently, hydrogen, —C 1 -C 6 alkyl, or —C 1 -C 6 heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R 4 is, independently, hydrogen, halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4 is unsubstituted.
16. The pharmaceutically acceptable composition of claim 7 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1 is an unsubstituted heterocyclyl or heteroaryl; R 2a is halogen, CN, C 1 -C 4 alkyl, or C 1 -C 4 heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R 2b and R 2c is, independently, 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), or C(O)N(R 3a )(R 3b ), wherein any alkyl or heteroalkyl portion of R 2b and R 2c is unsubstituted; each R 3 is, independently, hydrogen, —C 1 -C 6 alkyl, or —C 1 -C 6 heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R 4 is, independently, hydrogen, halogen, —CN, C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, N(R 3 )(R 3 ), 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 3 )(R 3 ), (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, or (C 1 -C 6 heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R 4 is unsubstituted.
17. The compound of claim 15 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 5 is hydrogen.
18. The compound of claim 15 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or pyrimidin-5-yl.
19. The compound of claim 15 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 2 is —(CH 2 ) 2 —NH—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH—(CH 2 ) 2 —OCH 3 , or —(CH 2 ) 2 —NH—CH(CH 3 )—CH 2 CH 3 .
20. The compound of claim 15 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 3 is hydrogen and p is 0.
21. The pharmaceutically acceptable composition of claim 16 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 5 is hydrogen.
22. The pharmaceutically acceptable composition of claim 16 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or pyrimidin-5-yl.
23. The pharmaceutically acceptable composition of claim 16 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 2 is —(CH 2 ) 2 —NH—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH—(CH 2 ) 2 —OCH 3 , or —(CH 2 ) 2 —NH—CH(CH 3 )—CH 2 CH 3 .
24. The pharmaceutically acceptable composition of claim 16 , wherein, in the compound or the pharmaceutically acceptable salt thereof, R 3 is hydrogen and p is 0.