Gamma-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 IV:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring F is
Ring G is selected from the group consisting of
and a 5-6 membered heteroarylR 19d , wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R 18 is independently selected at each occurrence from the group consisting of H, —C 1-3 haloalkyl, halide, —OR 20 , CF 3 , and CN;
R 19a is selected from the group consisting of H, unsubstituted C 2-6 alkyl, —CH 2 OH, —CH 2 N(R 21 ) 2 , —C 1-3 haloalkyl, F, Br, I, —OR 20 , CF 3 , and CN;
each R 19b is independently selected at each occurrence from the group consisting of H, unsubstituted C 2-6 alkyl, —CH 2 OH, —CH 2 N(R 21 ) 2 , —C 1-3 haloalkyl, halide, —OR 20 , CF 3 , and CN;
R 19c is 2-5 substituents, each independently selected at each occurrence from the group consisting of H, —CH 2 OH, —CH 2 N(R 21 ) 2 , —C 1-3 haloalkyl, halide, —OR 20 , CF 3 , and CN;
R 19d is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, —CH 2 OH, —CH 2 N(R 21 ) 2 , —C 1-3 haloalkyl, halide, —OR 20 , CF 3 , and CN;
each R N is independently selected from the group consisting of H, unsubstituted —C 3-6 alkyl, —C 1-3 haloalkyl, and CF 3 ;
each R 21 is independently selected from the group consisting of H and unsubstituted —C 1-3 alkyl;
p is an integer of 1 to 13; and
r is an integer of 1 to 5.
2. The compound of claim 1 , wherein r is an integer of 2 to 4.
3. The compound of claim 2 , wherein R 18 is F and p is 1-2.
4. The compound of claim 2 , wherein R 18 is H.
5. The compound of claim 2 , wherein
is selected from the group consisting of:
6. The compound of claim 1 , wherein R 19b , R 19c , and R 19d are selected from the group consisting of H, F, Cl, Me, OMe, CF 3 , and CN.
7. The compound of claim 1 , is
selected from the group consisting of:
8. The compound of claim 7 ,
is selected from the group consisting of:
9. The compound of claim 8 ,
is selected from the group consisting of:
10. The compound of claim 1 , wherein the compound of Formula Ma is selected from the group consisting of: Formula IV is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.