Sulfonamide compounds and their use as STAT5 inhibitors
The present disclosure relates to compounds having the Formula (Formula (I)) which are inhibitors of STAT5.
1. A compound of the Formula
wherein
R 1 is —(CH 2 ) n —(C 6 -C 10 )-aryl or —C(═O)—(CH 2 ) n —(C 6 -C 10 )-aryl, wherein the aryl groups are optionally substituted with one to five substituents selected from halo, OH, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, halo-substituted-(C 1 -C 4 )-alkyl, -(cyclopropyl)-CF 3 , —NO 2 , CN, —SO 3 R′ and —COOR′, wherein R′ is H or (C 1 -C 4 )-alkyl;
R 2 is —(CH 2 ) n —(C 6 -C 10 )-aryl, wherein the aryl groups are substituted with one to five substituents selected from halo, OH, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, halo-substituted-(C 1 -C 4 )-alkyl, -(cyclopropyl)-CF 3 , —NO 2 , CN, —SO 3 R′ and —COOR′, wherein R′ is H or (C 1 -C 4 )-alkyl;
R 3 is —(CH 2 ) n —(C 6 -C 10 )-aryl, wherein the aryl groups are substituted with one to five halo substituents;
X is —COOR″, —P(O)(OR″) 2 , tetrazole, —C(═O)NR″—OH, or —CF 2 OH, wherein R″ is H or (C 1 -C 4 )-alkyl or —CH 2 —(C 6 -C 10 )benzyl;
R 4 and R 5 are independently or simultaneously H or CF 3 , wherein one of R 4 or R 5 is H, or taken together R 4 and R 5 are —C(═O) or —C(═S);
R is H, OH, halo, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy;
n is independently or simultaneously 0, 1, 2, 3, 4, 5, or 6; and
m is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt, solvate, prodrug and/or stereoisomer thereof.
2. The compound according to claim 1 , wherein R 1 is —(C 6 -C 10 )-aryl, —(CH 2 )—(C 6 -C 10 )-aryl or —C(═O)—(C 6 -C 10 )-aryl.
3. The compound according to claim 2 , wherein R 1 is phenyl, naphthyl, —CH 2 -phenyl, —CH 2 -naphthyl, —C(═O)-phenyl or —C(═O)-naphthyl.
4. The compound according to claim 1 , the optional substituents on the aryl group of R 1 are selected from one to five of halo, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy.
5. The compound according to 4 , the optional substituents on the aryl group of R 1 are selected from one to three substituents selected from fluoro, methyl or t-butyl.
6. The compound of claim 1 wherein R 1 is —(CH 2 ) n —(C 6 -C 10 )-aryl or —C(=O)—(CH 2 ) n —(C 6 -C 10 )-aryl, wherein the aryl groups are optionally substituted with one to five substituents selected from methyl, ethyl, propyl, cyclopropyl, butyl, t-butyl, isobutyl, pentyl, —O-methyl, —O-ethyl, —O-propyl, —O-butyl, —O-isobutyl, —O-pentyl, and OCH 2 -cyclopropyl.
7. The compound of claim 6 wherein R is —O-CH 3 , —O-cyclopropyl, —O-cyclopentyl, or cyclopropyl.
8. The compound of claim 6 wherein R 2 is —(CH 2 ) n -(C 6 -C 10 )-aryl, wherein the aryl groups are optionally substituted with one to five substituents selected from F, Cl and CF 3 .
9. The compound according to claim 1 , wherein R 1 is
10. The compound according to claim 1 , wherein R 2 is —or —(CH 2 )—(C 6 -C 10 )-aryl.
11. The compound according to claim 10 , wherein R 2 is phenyl or —CH 2 -phenyl.
12. The compound according to claim 10 , wherein the substituents on the aryl group of R 2 are selected from one to five of halo, halo-substituted-(C 1 -C 4 )-alkyl, -(cyclopropyl)-CF 3 , —NO 2 , CN, —SO 3 R′ and —COOR′, wherein R′ is H or (C 1 -C 4 )-alkyl.
13. The compound according to claim 12 , wherein the substituents on the aryl group of R 2 are one to three chloro groups.
14. The compound according to claim 1 , wherein R 3 is —(C 6 -C 10 )-aryl or —(CH 2 )—(C 6 -C 10 )-aryl, and wherein the aryl is substituted with one to five halo substituents.
15. The compound according to claim 1 , wherein R is H, OH, fluoro, chloro, bromo, or (C 1 -C 4 )-alkyl.
16. The compound according to claim 1 , wherein X is COOR″, wherein R″ is H or (C 1 -C 4 )-alkyl.
17. The compound according to claim 1 , wherein the compound has the following structure:
18. A method for the treatment of a disease or condition mediated by signal transducer and activator of transcription 5 (STAT5) protein, comprising administering a pharmaceutically effective amount of a compound of claim 1 to a subject in need thereof.
19. A method for the treatment of hematopoietic malignancies, skin conditions, non-melanoma skin cancer, prostate cancer or inflammation, the method comprising administering a pharmaceutically effective amount of a compound of claim 1 to a subject in need thereof.
20. The method of claim 19 , wherein the hematopoietic malignancies is leukemia.
21. The method of claim 19 , wherein the skin condition is psoriasis or dermatitis.