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 . (canceled)
2 . A compound or pharmaceutically acceptable salt or prodrug thereof having the structure 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 N or C;
with the proviso that if A is N then R 2 is nil;
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:
3 . The compound of claim 2 , wherein aryl is phenyl.
4 . The compound of claim 2 , wherein heteroaryl is pyridinyl.
5 . A compound or pharmaceutically acceptable salt or prodrug thereof having the structure of Formula II:
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 N or C;
with the proviso that if A is N then R 2 is nil;
each q is an integer of 1 to 5;
each n is an integer of 0 or 1; and
with the proviso that Formula II is not a structure selected from the group consisting of:
6 . The compound of claim 5 , wherein aryl is phenyl.
7 . The compound of claim 5 , wherein heteroaryl is pyridinyl.
8 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any of the claims 2 or 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
9 . A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, wherein the disorder or disease is cancer, diabetic retinopathy, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), rheumatoid arthritis, scleroderma, mycotic or viral infection, bone or cartilage disease, Alzheimer's disease, dementia, Parkinson's disease, lung disease, osteoarthritis, and a genetic disease caused by mutations in Wnt signaling components, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the claims 2 or 5 , or a pharmaceutically acceptable salt thereof, wherein the patient is a human.
10 . A method of claim 9 , wherein the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
11 . The method of claim 9 , wherein the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer leukemia, lymphoma, sarcoma and ovarian cancer.
12 . The method of claim 9 , wherein the compound inhibits one or more proteins in the Wnt pathway.
13 . The method of claim 9 , wherein the compound inhibits signaling induced by one or more Wnt proteins.
14 . The method of claim 13 , wherein the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
15 . The method of claim 9 , wherein the compound inhibits a kinase activity.