6-(5-membered heteroaryl)isoquinolin-3-yl-(5-membered heteroaryl) carboxamides and preparation and use thereof
Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an isoquinoline 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, inflammation, auto-immune diseases and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:
wherein:
R 1 , R 2 , R 4 , and R 5 are H;
R 3 is a 5-membered heteroaryl optionally substituted with 1-4 R 36 ;
R 6 is selected from the group consisting of
and
R 7 is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 44 and -carbocyclyl optionally substituted with 1-12 R 45 ;
R 15 is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 44 and -carbocyclyl optionally substituted with 1-12 R 45 ;
each R 36 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), and unsubstituted —(C 1-5 haloalkyl);
each R 43 is independently halide;
each R 44 is independently selected from the group consisting of unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), unsubstituted —(C 2-5 alkynyl), unsubstituted —(C 1-5 haloalkyl), and -carbocyclyl optionally substituted with 1-12 R 43 ; and
each R 45 is independently halide.
2. The compound of claim 1 , wherein R 3 is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, and oxazolyl, each optionally substituted with 1-4 R 36 .
3. The compound of claim 2 , wherein R 3 is selected from the group consisting of pyrazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, thiadiazol-2-yl, and oxazol-5-yl, each optionally substituted with 1-4 R 36 .
4. The compound of claim 3 , wherein R 3 is a pyrazol-4-yl substituted with one —(C 1-3 alkyl).
5. The compound of claim 3 , wherein R 3 is a imidazol-5-yl substituted with one —(C 1-3 alkyl).
6. The compound of claim 3 , wherein R 3 is a imidazol-5-yl substituted with two —(C 1-3 alkyl).
7. The compound of claim 3 , wherein R 3 is a 1,2,3-triazol-4-yl substituted with one —(C 1-3 alkyl).
8. The compound of claim 3 , wherein R 3 is an unsubstituted thiadiazol-2-yl.
9. The compound of claim 3 , wherein R 3 is a thiadiazol-2-yl substituted with one —(C 1-3 alkyl).
10. The compound of claim 3 , wherein R 3 is an unsubstituted oxazol-5-yl.
11. The compound of claim 3 , wherein R 3 is a oxazol-5-yl substituted with one —(C 1-3 alkyl).
12. The compound of claim 3 , wherein R is
13. The compound of claim 3 , wherein R 6 is
14. The compound of claim 12 , wherein R 7 is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, wherein each is optionally substituted with one unsubstituted —(C 1-3 alkyl).
15. The compound of claim 13 , wherein R 15 is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, wherein each is optionally substituted with one unsubstituted —(C 1-3 alkyl).
16. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a therapeutically effective amount of a a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
18. A method of treating a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of: chronic inflammation, systemic inflammation, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological condition/disorder/disease, osteoarthritis, lung disease, a fibrotic disorder, the method comprising administering to the patient a therapeutically effective amount a of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, wherein the patient is a human.
19. The method of claim 18 , wherein the cancer is selected from the group consisting of:
osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, and gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors, neurofibroma, meningioma, glioma, and sarcoma.
20. The method of claim 18 , wherein the disorder or disease is a neurological condition/disorder/disease, wherein the neurological condition/disorder/disease is selected from the group consisting of: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD), FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), Prion Diseases, globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, lewy body dementia, Parkinson's disease, Pick's disease, and diseases with pronounced neurodegeneration, autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury, chronic traumatic encephalopathy, traumatic brain injury, tumor, stroke, frontotemporal dementias, dementia with lewy bodies, prion diseases, multiple system atrophy, inclusion body myositis, degenerative myopathies, diabetic neuropathy, metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, and Charcot-Marie-Tooth disease.
21. The method of claim 18 , wherein the disorder or disease is a neurological condition/disorder/disease associated with tau protein, amyloid, alpha-synuclein, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS) pathology.
22. The method of claim 18 , wherein the disorder or disease is a fibrotic disorder, wherein the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease, and radiation fibrosis.
23. The method of claim 18 , wherein the disorder or disease is chronic inflammation associated eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders, multiple sclerosis, Parkinson's and dementia, Alzheimer's disease.
24. A method of reducing angiogenesis in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutical composition.