γ-diketones as Wnt/β-catenin signaling pathway activators
The present disclosure provides γ-diketones or analogs thereof, that activate Wnt/β-catenin signaling and thus treat or prevent diseases related to signal transduction, such as osteoporosis and osteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries or spine injuries, brain atrophy/neurological disorders related to the differentiation and development of the central nervous system, including Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, schizophrenia; otic disorders like cochlear hair cell loss; eye diseases such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa and diseases related to differentiation and growth of stem cell, such as hair loss, hematopoiesis related diseases and tissue regeneration related diseases.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring C is a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R 4 is independently selected at each occurrence from the group consisting of H, unsubstituted —C 1-6 alkyl, —C 1-3 haloalkyl, halide, —OR 6 , CF 3 , and CN;
each R 5 is independently selected at each occurrence from the group consisting of H, unsubstituted —C 1-6 alkyl, —CH 2 OH, —CH 2 N(R 6b ) 2 , —C 1-3 haloalkyl, halide, —OR 6 , CF 3 , and CN;
each R 6 is independently selected from the group consisting of H, unsubstituted —C 1-6 alkyl, —C 1-3 haloalkyl, and CF 3 ;
each R 6b is independently selected from the group consisting of H and unsubstituted —C 1-3 alkyl;
p is an integer of 1 to 4; and
q is an integer of 1 to 5;
with the proviso that the compound of Formula II is not a compound selected from the group consisting of:
2. The compound of claim 1 , wherein Ring C is a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
3. The compound of claim 2 , wherein
is selected from the group consisting of
and p is 1 or 2.
4. The compound of claim 3 , wherein is
5. The compound of claim 1 , wherein Ring C is a 6-membered heteroaryl ring containing 1-2 nitrogens.
6. The compound of claim 5 , wherein
is selected from the group consisting of
and p is 1 or 2.
7. The compound of claim 6 , wherein
8. The compound of claim 1 , wherein each R 4 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF 3 and CN.
9. The compound of claim 1 , wherein Ring D is phenyl.
10. The compound of claim 9 , wherein
is selected from the group consisting of
and q is 1 or 2.
11. The compound of claim 10 , wherein
is selected from the group consisting of
12. The compound of claim 1 , wherein Ring D is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
13. The compound of claim 12 , wherein
is selected from the group consisting of
and q is 1 or 2.
14. The compound of claim 13 , wherein
is selected from the group consisting of
15. The compound of claim 1 , wherein Ring D is a 6-membered heteroaryl containing 1-2 nitrogen atoms.
16. The compound of claim 15 , wherein
is selected from the group consisting of
and q is 1 or 2.
17. The compound of claim 16 , wherein
is selected from the group consisting of
and R 5 is H.
18. The compound of claim 1 , wherein R 5 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF 3 , and CN.
19. The compound of claim 1 , wherein Ring D is a phenyl or 6-membered heteroaryl; R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho carbon of the 6-membered ring.
20. The compound of claim 19 , wherein Ring D is a phenyl, R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho position of the phenyl ring.
21. The compound of claim 19 , wherein Ring D is a pyridine, R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho carbon of the pyridine ring.
22. The compound of claim 1 , wherein the compound of Formula II is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.