5-substituted indazole-3-carboxamides and preparation and use thereof
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, fibrotic disorders, cartilage (chondral) defects, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, and neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
1. A compound, or pharmaceutically acceptable salt thereof, of Formula V:
wherein:
R 1 is selected from the group consisting of H, halide, and C 1-3 alkyl;
R 2 is selected from the group consisting of 6-10-membered heteroaryl(R 4 ) and phenyl(R 5 ) m (R 6 );
R 3 is selected from the group consisting of
R 4 is 1 substituent attached to the 6-10-membered heteroaryl and is selected from the group consisting of H, halide, —CN, unsubstituted —C 1-6 haloalkyl, unsubstituted —C 1-6 alkyl, —(C 1-3 alkyl) n heterocyclyl(R 22 ) p , —O-aryl(R 23 ) q , —NHC(═O)R 24 , and —(C 1-6 alkyl) n N(R 25 ) 2 ;
each R 5 is a substituent attached to the phenyl ring and independently selected at each occurrence from the group consisting of H and halide;
R 6 is 1 substituent attached to the phenyl ring and selected from the group consisting of H, —(C 1-3 alkyl) n heterocyclyl(R 26 ) p , —O-aryl(R 27 ) q , —NHC(═O)R 28 , and —(CH 2 ) z N(R 29 ) 2 ;
each R 22 is a substituent attached to the heterocyclyl ring and is independently selected at each occurrence from the group consisting of H, halide, —CF 3 , —OH, —CH 2 OH, —CN, —N(R 25 ) 2 , and —C 1-6 alkyl;
each R 23 is a substituent attached to the aryl ring and is independently selected at each occurrence from the group consisting of H, halide, —CF 3 , —CN, and —C 1-6 alkyl;
R 24 is selected from the group consisting of —C 1-6 alkyl, —N(R 60 ) 2 , and —(C 1-3 alkyl) n carbocyclyl;
each R 25 is independently selected at each occurrence from the group consisting of H and —C 1-6 alkyl, alternatively, two adjacent R 25 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring;
each R 26 is a substituent attached to the heterocyclyl ring and is independently selected at each occurrence from the group consisting of H, halide, —CF 3 , —OH, —CN, and —C 1-6 alkyl;
each R 27 is a substituent attached to the aryl ring and is independently selected at each occurrence from the group consisting of H, halide, —CF 3 , —CN, and —C 1-6 alkyl;
R 28 is selected from the group consisting of —C 1-6 alkyl, —N(R 60 ) 2 , and —(C 1-3 alkyl) n carbocyclyl;
each R 29 is independently selected at each occurrence from the group consisting of H and —C 1-6 alkyl;
each R 36 is a substituent attached to the pyridyl ring and is independently selected at each occurrence from the group consisting of H, halide, —OH, —CF 3 , —CN, and —C 1-6 alkyl;
each R 60 is independently selected at each occurrence from the group consisting of H and —C 1-6 alkyl, alternatively, two adjacent R 60 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered heterocyclic ring;
m is an integer of 1 to 4;
each n is independently an integer of 0 to 1;
each p is independently an integer of 1 to 10;
each q is independently an integer of 1 to 5; and
z is an integer of 1 to 5.
2. The compound of claim 1 , wherein the compound of Formula V is selected from the group consisting of:
5-(pyridin-3-yl)-N-(quinolin-8-yl)-1H-indazole-3-carboxamide [43];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [71];
N-(6-(3,3-bis(hydroxymethyl)azetidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [72];
5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-N-(quinolin-8-yl)-1H-indazole-3-carboxamide [81];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide [207];
5-(5-aminopyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [226];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [262];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide [681];
5-(5-aminopyridin-3-yl)-N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [682];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [683];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [684];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide [685];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [686];
5-(5-(azetidin-1-ylmethyl)pyridin-3-yl)-N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [687];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [688];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [689];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [690];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(4-methylpiperidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [691];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(4-hydroxypiperidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [692];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(morpholinomethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [693];
5-(5-(azepan-1-ylmethyl)pyridin-3-yl)-N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [694];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-(3,3-dimethylureido)pyridin-3-yl)-1H-indazole-3-carboxamide [695];
5-(5-(cyclopropanecarboxamido)pyridin-3-yl)-N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [696];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(5-phenoxypyridin-3-yl)-1H-indazole-3-carboxamide [697];
N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-5-(2,3-difluorophenyl)-1H-indazole-3-carboxamide [698];
5-(2,3-difluoro-5-(piperidin-1-ylmethyl)phenyl)-N-(6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [699];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(piperidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide [1135];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide [1136];
5-(5-((dimethylamino)methyl)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1137];
5-(5-(azetidin-1-ylmethyl)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1138];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [1139];
5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1140];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [1141];
5-(5-((4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1142];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-((4-methylpiperidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [1143];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-((4-hydroxypiperidin-1-yl)methyl)pyridin-3-yl)-1H-indazole-3-carboxamide [1144];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(morpholinomethyl)pyridin-3-yl)-1H-indazole-3-carboxamide [1145];
5-(5-(azepan-1-ylmethyl)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1146];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-(3,3-dimethylureido)pyridin-3-yl)-1H-indazole-3-carboxamide [1147];
5-(5-(cyclopropanecarboxamido)pyridin-3-yl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1148];
N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-5-(5-phenoxypyridin-3-yl)-1H-indazole-3-carboxamide [1149];
-(2,3-difluorophenyl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1150]; and
5-(2,3-difluoro-5-(piperidin-1-ylmethyl)phenyl)-N-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-1H-indazole-3-carboxamide [1151]; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 1 is H.
4. The compound of claim 3 , wherein R 2 is pyridin-3-yl(R 4 ).
5. The compound of claim 4 , wherein R 4 is —(CH 2 )heterocyclyl(R 22 ) p .
6. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
7. The compound of claim 6 , wherein R 2 is pyridinyl(R 4 ).
8. The compound of claim 7 , wherein R 4 is —(C 1-3 alkyl) n heterocyclyl(R 22 ) p .
9. The compound of claim 8 , wherein R 22 is selected from the group consisting of H, halide, and —C 1-2 alkyl; wherein p is 1 or 2.
10. The compound of claim 8 , wherein R 4 is selected from the group consisting of
11. The compound of claim 7 , wherein R 4 is selected from the group consisting of H and halide.
12. The compound of claim 7 , wherein R 3 is selected from the group consisting of
13. The compound of claim 12 , wherein R 36 is selected from the group consisting of H and halide.
14. The compound of claim 7 , wherein R 3 is
15. The compound of claim 14 , wherein R 36 is selected from the group consisting of H and halide.
16. The compound of claim 7 , wherein R 3 is