1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof
Provided herein are compounds according to Formula I and pharmaceutically acceptable salts thereof, and compositions comprising the same, for use in various methods, including treating cancers such as colon, ovarian, pancreatic, breast, liver, prostate and hematologic cancers:
1. A method of treating a disorder or disease selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, psoriasis, glomerulonephritis, and systemic lupus erythematosus in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ib, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 , R 3 , R 6 , and R 8 are H;
R 2 is pyridylR 12 ;
R 5 is selected from the group consisting of -arylR 12 and -heteroarylR 12 ;
each R 9 is independently selected from the group consisting of H, C 1-6 alkyl, —CF 3 , —(C 1-9 alkyl) n carbocyclyl, and —(C 1-9 alkyl) n aryl;
alternatively, two adjacent R 9 , may be taken together to form a fused ring with the nitrogen;
each R 12 is 1-5 substituents each selected from the group consisting of H, C 1-6 alkyl, halide, —CF 3 , —CN, —NHC(═O)R 9 , and —NHC(═O)N(R 9 ) 2 ;
Y 1 , Y 2 , and Y 4 are carbon;
Y 3 is nitrogen and R 7 is absent; and
each n is 0 or 1.
2. The method of claim 1 , wherein n is 0.
3. The method of claim 1 , wherein R 12 is selected from the group consisting of halide and —NHC(═O)R 9 .
4. The method of claim 3 , wherein R 9 is selected from the group consisting of —C 1-4 alkyl, carbocyclyl, and -heterocyclyl.
5. The method of claim 4 , wherein R 9 is selected from the group consisting of ethyl, isopropyl, and isobutyl.
6. The method of claim 4 , wherein R 9 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl.
7. The method of claim 1 , wherein R 5 is -arylR 12 .
8. The method of claim 7 , wherein R 5 is -phenylR 12 .
9. The method of claim 8 , wherein R 12 is selected from the group consisting of H and halide.
10. The method of claim 9 , wherein R 12 is selected from the group consisting of H and fluorine.
11. The method of claim 1 , wherein:
R 2 is 3-pyridylR 12 , wherein R 12 is one substituent attached to the pyridine ring and the substituent is —NHC(═O)R 9 , wherein R 9 is selected from the group consisting of —C 2-4 alkyl, cyclopropyl, and cyclobutyl; and
R 5 is -phenylR 12 , wherein R 12 is F and wherein there are 1 or 2 R 12 groups present, each attached to the phenyl ring.
12. The method of claim 1 , wherein:
R 2 is 3-pyridylR 12 , wherein R 12 is one substituent attached to the pyridine ring and the substituent is —NHC(═O)N(R 9 ) 2 , wherein each R 9 is independently selected from —C 1-3 alkyl, alternatively, each R 9 , may be taken together to form a fused 6-membered heterocyclyl ring with the nitrogen; and
R 5 is -phenylR 12 , wherein R 12 is F and wherein there are 1 or 2 R 12 groups present, each attached to the phenyl ring.
13. The method of claim 1 , wherein the compound of Formula Ib is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the compound of Formula (Ib) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the disorder or disease is inflammatory bowel disease.
16. The method of claim 1 , wherein the disorder or disease is rheumatoid arthritis.
17. The method of claim 1 , wherein the disorder or disease is psoriasis.
18. The method of claim 1 , wherein the disorder or disease is systemic lupus erythematosus.
19. The method of claim 1 , wherein the disorder or disease is glomerulonephritis.
20. The method of claim 1 , wherein the subject is a human.