Ubiquitination inhibitors
Disclosed are sulfonamidoquinoline compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , R 2 , R 3 and R 4 are as described herein. In certain embodiments, a compound disclosed herein inhibits ubiquitination, and can be used to treat disease by blocking the degradation of tumor suppressors.
1. A compound having structural formula (Ia),
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
R 1 is -hydrogen, —O—Ar, or —O-Het, wherein —O—Ar and —O-Het are each optionally substituted with one or more —(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN;
R 2 is -hydrogen, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN, wherein —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), and —O—(C 1 -C 6 haloalkyl) are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN;
R 3 is -hydrogen, —Ar, or -Het, wherein —Ar and -Het are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkyl)—Ar, -halogen, —NO 2 or —CN; and
R 4 is —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het or —(C 0 -C 6 alkyl)-Cak, wherein —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het and —(C 0 -C 6 alkyl)-Cak are each optionally substituted with one or more —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkyl), N(R 5 )(R 6 ), -halogen, —NO 2 or —CN, wherein R 5 and R 6 are independently -hydrogen, —(C 1 -C 6 alkyl) or —C(O)—(C 1 -C 6 alkyl),
provided that at least one of R 1 and R 3 is not hydrogen.
2. The compound of claim 1 ,
wherein
R 1 is optionally substituted —O—Ar.
3. The compound of claim 1 ,
wherein
R 3 is optionally substituted —Ar.
4. The compound of claim 1 ,
wherein
R 1 is optionally substituted —O-Het.
5. The compound of claim 1 ,
wherein
R 3 is optionally substituted -Het.
6. The compound of claim 1 , wherein
R 2 is -hydrogen, —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN.
7. The compound of claim 1 , wherein
R 2 is —(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 haloalkyl), -halogen, —NO 2 or —CN.
8. The compound of claim 1 , wherein R 2 is hydrogen.
9. The compound of claim 1 , wherein R 2 is halogen.
10. The compound of claim 1 , having the structure of formula (II),
wherein R 1 is —O—Ar or —O-Het.
11. The compound of claim 1 , having the structure of formula (III),
wherein R 3 is —Ar, or -Het.
12. The compound of claim 1 having structural formula (IV),
or a pharmaceutically acceptable salt, or N-oxide thereof, or solvate or hydrate thereof,
wherein
R 1 is -hydrogen or optionally substituted —O—Ar,
R 4 is optionally substituted —(C 0 -C 6 alkyl)-Ar or —(C 0 -C 6 alkyl)-Het.
13. The compound of claim 1 , wherein
R 1 is —O—Ar.
14. The compound of claim 1 , wherein
R 1 is —O-Het.
15. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, carrier, or excipient and a compound according to claim 1 .
16. A method for inhibiting Cks1-Skp2 PPI, comprising administering an effective Cks1-Skp2 PPI inhibiting amount of a compound according to claim 1 .