Indazolyl-spiro[2.2]pentane-carbonitrile derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
The present invention is directed to substituted certain reversed indazolyl-spiro[2.2]pentane-carbonitrile derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, X, Y, and Z are as defined herein, which are potent inhibitors of LRRK2 kinase and may be useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease and other diseases and disorders described herein. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.
1. A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or F;
X is C(R x ) or N;
R x is H, F, Cl, or —(C 1 -C 6 )alkyl;
═Y—Z═ is ═N—C(R Z )═, ═C(H)—C(R Z )═, or ═C(H)—N═;
R z is H, F, —(C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C-C 6 )alkyl) 2 , —O(C 1 -C 6 )alkyl, —S(C 1 -
C 6 )alkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl—O—(C 1 -C 6 )alkyl,
R 2 is —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OH,
wherein:
R 2A is H, F, —OH, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkyl, —C(OH)(C 1 -C 6 )alkyl) 2 ,
(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, —C(C 1 -C 6 )alkyl) 2 (OH), cyclopropyl, or
R 2 A is H, F, —OH, —(C 1 -C 6 )alkyl, —C((C 1 -C 6 )alkyl) 2 (OH), —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-
O—(C 1 -C 6 )alkyl, or
R 2BI is H, F, or —(C 1 -C 6 )alkyl;
R 2C is H, —(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl,
R 2D is H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OH, or —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, and
R 2E is H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl,
R 2F is H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )fluoroalkyl, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, and
R 2G is H, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )haloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C(R x ) and Formula has a structural Formula (IA):
wherein:
R X is H, F, Cl, or CH 3 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N and Formula (I) has a structural Formula (IB):
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
═Y—Z═is ═N—C(R z )═.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
═Y—Z═is ═C(H)—C(R z )═.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
═Y—Z═is ═C(H)—N═.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from;
8. A pharmaceutical composition comprising a compound of claim 1 , and pharmaceutically acceptable carrier.
9. A method of treating Parkinson's, Disease comprising administrating an effective amount of compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a person in need thereof.
10. A method for the treatment of an indication in which LRRK2 kinase is involved comprising administering a subject in need thereof an effective amount of a compound according to claim 1 , or pharmaceutically acceptable salt thereof, said indication selected from:
abnormal motor symptoms associated with Parkinson's disease, non-motor symptoms associated with Parkinson's disease, Lewy body dementia, L-Dopa induced dyskinesias,
Alzheimer's disease, mild cognitive impairment, the transition from mild cognitive impairment to Alzheimer's disease, tanopathy disorders characterized by hyperphosphorylation of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and Parkinson's disease linked to chromosome 17,
neuroinflammation associated with microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury and spinal cord injury,
lymphomas, leukemia, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic pupura (ITP), Evans Syndrome, vasculitis bullous skin disorder, type I diabetes mellitus, Sjorgen's syndrome, Delvic's disease, inflammatory myopathies, and ankylosing spondylitis,
renal cancer, breast cancer, lung cancer, prostate cancer, and acute myelogenous leukemia (AML) in subjects expressing the LRRK2 G2019S mutation,
papillary renal and thyroid carcinomas in a subject in whom LRRK2 is amplified or overexpressed,
Crohn's disease and leprosy.