1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof
Provided herein are compounds according to Formulas (I) or (II) and pharmaceutically acceptable salts thereof, and compositions comprising the same, for use in various methods, including treating cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis, idiopathic pulmonary fibrosis and neurological conditions/disorders/diseases.
1. A compound, or pharmaceutically acceptable salt thereof, of Formula I:
wherein:
R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, halide, —(C 1-9 alkyl) n aryl(R 6 ) q , —(C 1-9 alkyl) n heteroaryl(R 7 ) q , —(C 1-9 alkyl) n heterocyclyl(R 8 ) q , —(C 1-9 alkyl) n N(R 9 ) 2 , —OR 10 and —NHC(═O)R 11 ;
R 3 is selected from the group consisting of H, halide and lower alkyl;
with the proviso that at least two of R 1 , R 2 and R 3 are H;
R 4 and R 5 are independently selected from the group consisting of H, —C(═O)N(R 12 ) 2 , -aryl(R 13 ) q , -heterocyclyl(R 14 ) q , and -heteroaryl(R 15 ) q ;
with the proviso that at least one of R 4 and R 5 is H;
each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, —C 1-9 alkyl, halide, CF 3 and CN;
each R 7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, —C 1-9 alkyl, halide, CF 3 and CN;
each R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, —(C 1-3 alkyl) n aryl(R 6 ) q , and —C 1-4 alkyl;
each R 9 is independently selected from the group consisting of H, —C 1-9 alkyl, —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl and —(C 1-9 alkyl)N(R 16 ) 2 ;
alternatively, two adjacent R 9 or two adjacent R 12 , may be taken together with the atoms to which they are attached to form a heterocyclyl(R 17 ) q ;
R 10 is selected from the group consisting of H, —CF 3 , —(C 1-3 alkyl) n aryl(R 6 ) q , and —C 1-9 alkyl;
R 11 is selected from the group consisting of —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl, —C 1-9 alkyl and —CF 3 ;
each R 12 is independently selected from the group consisting of H, —(C 1-9 alkyl) n aryl(R 6 ) q and —C 1-9 alkyl;
each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, —CF 3 , CN, —(C 1-3 alkyl) n heterocyclyl(R 8 ) q , —(C 1-9 alkyl) n N(R 9 ) 2 and —(C 1-9 alkyl) n NHSO 2 R 18 ;
each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 and CN;
each R 15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 , CN, —C(═O)(C 1-3 alkyl), —(C 1-9 alkyl) n N(R 9 ) 2 and —(C 1-9 alkyl) n NHSO 2 R 18 ;
each R 16 is independently selected from the group consisting of H and lower alkyl;
each R 17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, —(C 1-9 alkyl) n aryl(R 6 ) q , and —C 1-9 alkyl;
each R 18 is a lower alkyl;
A is C;
each q is an integer of 1 to 5;
each n is an integer of 0 or 1; and
with the proviso that Formula I is not a structure selected from the group consisting of:
2. The compound of claim 1 wherein heteroaryl is pyridinyl.
3. The compound of claim 1 wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
4. The compound of claim 1 wherein R 2 is selected from the group consisting of H, —(C 1-9 alkyl) n heterocyclyl(R 8 ) q , and —NHC(═O)R 11 and R 1 and R 3 are both H.
5. The compound of claim 4 wherein R 2 is —NHC(═O)R 11 .
6. The compound of claim 5 wherein R 11 is selected from the group consisting of —C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) q , and —CH 2 phenyl(R 6 ) q .
7. The compound as in any one of claims 5 - 6 , in which R 4 is -heterocyclyl(R 14 ) q .
8. The compound of claim 7 wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R 14 is H or Me.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of Formula I:
wherein:
R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, halide, —(C 1-9 alkyl) n aryl(R 6 ) q , —(C 1-9 alkyl) n heteroaryl(R 7 ) q , —(C 1-9 alkyl) n heterocyclyl(R 8 ) q , —(C 1-9 alkyl) n N(R 9 ) 2 , —OR 10 and —NHC(═O)R 11 ;
R 3 is selected from the group consisting of H, halide and lower alkyl;
with the proviso that at least two of R 1 , R 2 and R 3 are H;
R 4 and R 5 are independently selected from the group consisting of H, —C(═O)N(R 12 ) 2 , -aryl(R 13 ) q , -heterocyclyl(R 14 ) q , and -heteroaryl(R 15 ) q ;
with the proviso that at least one of R 4 and R 5 is H;
each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, —C 1-9 alkyl, halide, CF 3 and CN;
each R 7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, —C 1-9 alkyl, halide, CF 3 and CN;
each R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, —(C 1-3 alkyl) n aryl(R 6 ) q , and —C 1-4 alkyl;
each R 9 is independently selected from the group consisting of H, —C 1-9 alkyl, —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl and —(C 1-9 alkyl)N(R 16 ) 2 ;
alternatively, two adjacent R 9 or two adjacent R 12 , may be taken together with the atoms to which they are attached to form a heterocyclyl(R 17 ) q ;
R 10 is selected from the group consisting of H, —CF 3 , —(C 1-3 alkyl) n aryl(R 6 ) q , and —C 1-9 alkyl;
R 11 is selected from the group consisting of —(C 1-3 alkyl) n aryl(R 6 ) q , —(C 1-3 alkyl) n carbocyclyl, —C 1-9 alkyl and —CF 3 ;
each R 12 is independently selected from the group consisting of H, —(C 1-9 alkyl) n aryl(R 6 ) q and —C 1-9 alkyl;
each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, —CF 3 , CN, —(C 1-3 alkyl) n heterocyclyl(R 8 ) q , —(C 1-9 alkyl) n N(R 9 ) 2 and —(C 1-9 alkyl) n NHSO 2 R 18 ;
each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 and CN;
each R 15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, —CF 3 , CN, —C(═O)(C 1-3 alkyl), —(C 1-9 alkyl) n N(R 9 ) 2 and —(C 1-9 alkyl) n NHSO 2 R 18 ;
each R 16 is independently selected from the group consisting of H and lower alkyl;
each R 17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, —(C 1-9 alkyl) n aryl(R 6 ) q , and —C 1-9 alkyl;
each R 18 is a lower alkyl;
A is C;
each q is an integer of 1 to 5;
each n is an integer of 0 or 1; and
with the proviso that Formula I is not a structure selected from the group consisting of:
10. The pharmaceutical composition of claim 9 , wherein heteroaryl is pyridinyl.
11. The pharmaceutical composition of claim 9 , wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
12. The pharmaceutical composition of claim 9 , wherein R 2 is selected from the group consisting of H, —(C 1-9 alkyl) n heterocyclyl(R 8 ) q , and —NHC(═O)R 11 and R 1 and R 3 are both H.
13. The pharmaceutical composition of claim 12 , wherein R 2 is —NHC(═O)R 11 .
14. The pharmaceutical composition of claim 13 , wherein R 11 is selected from the group consisting of —C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) q , and —CH 2 phenyl(R 6 ) q .
15. The pharmaceutical composition as in any one of claims 13 - 14 , in which R 4 is -heterocyclyl(R 14 ) q .
16. The pharmaceutical composition of claim 15 , wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R 14 is H or Me.