Indazole based compounds and associated methods of use
Bifunctional compounds, which find utility as modulators of leucine-rich repeat kinase 2 (LRRK2), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
1 . A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
2 . A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
3 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
4 . A pharmaceutical composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5 . The pharmaceutical composition of claim 3 , wherein the composition further comprises an additional bioactive agent.
6 . The pharmaceutical composition of claim 4 , wherein the composition further comprises an additional bioactive agent.
7 . The pharmaceutical composition of claim 5 , wherein the additional bioactive agent is an anti-inflammatory agent, a chemotherapy agent, or an immunomodulatory agent.
8 . The pharmaceutical composition of claim 6 , wherein the additional bioactive agent is an anti-inflammatory agent, a chemotherapy agent, or an immunomodulatory agent.
9 . A method of treating a disease, a disorder, or a symptom causally related to LRRK2 in a subject, comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of claim 1 , or a pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
10 . A method of treating a disease, a disorder, or a symptom causally related to LRRK2 in a subject, comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of claim 2 , or a pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11 . The method of claim 9 , wherein the disease or disorder is Parkinson's disease (PD) primary tauopathies, Lewy body dementia, Crohn's Disease, leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP-43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington's disease, any of spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy (DRPLA), or Kennedy's disease.
12 . The method of claim 11 , wherein the PD is idiopathic PD or LRRK2 mutation associated PD.
13 . The method of claim 10 , wherein the disease or disorder is Parkinson's disease (PD) primary tauopathies, Lewy body dementia, Crohn's Disease, leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP-43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington's disease, any of spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy (DRPLA), or Kennedy's disease.
14 . The method of claim 13 , wherein the PD is idiopathic PD or LRRK2 mutation associated PD.
15 . A method of treating a subject having PD, a primary tauopathy, Lewy body dementia, Crohn's Disease, leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP-43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington's disease, any of SCAs 1, 2, 3, 6, 7, and 17, DRPLA or Kennedy's disease, the method comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of claim 1 , or a pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16 . The method of claim 15 , wherein the subject has PD.
17 . The method of claim 16 , wherein the subject has Progressive Supranuclear Palsy.
18 . A method of treating a subject having PD, a primary tauopathy, Lewy body dementia, Crohn's Disease, leprosy, neuroinflammation, Progressive Supranuclear Palsy, Picks disease, FTDtau, TDP-43 Frontal Temporal Dementia, TDP-43 ALS, c9orf ALS, Huntington's disease, any of SCAs 1, 2, 3, 6, 7, and 17, DRPLA or Kennedy's disease, the method comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of claim 2 , or a pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19 . The method of claim 18 , wherein the subject has PD.
20 . The method of claim 19 , wherein the subject has Progressive Supranuclear Palsy.