N-heteroaryl indazole derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
The present invention is directed to substituted certain N-heteroaryl indazole derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , 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 diseases, such as Parkinson's disease, in which LRRK-2 kinase is involved.
1. A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from N, C—H, C—F, and C—Cl;
Y is selected from N, C—H, C—F, and C—Cl;
R 1 is selected from H, F, Cl, CN, —(C 1 -C 3 )alkyl, —O(C 1 -C 3 )alkyl, —(C 1 -C 3 )haloalkyl, —O(C 1 -C 3 )haloalkyl, and —(C 3 -C 6 )cycloalkyl;
R 2 is a moiety selected from:
wherein:
q is 1, 2, or 3;
r is 1 or 2;
t is 1 or 2;
Z is selected from O and N(R 2N );
R 2N is selected from H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl, C(O)NH 2 , C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, oxetanyl which is optionally substituted with R 2A , furanyl which is optionally substituted with 1 or 2 groups selected from OH and R 2A , pyranyl which is optionally substituted with 1 or 2 groups selected from OH and R 2A , and
each R 2A is independently selected from H and —(C 1 -C 4 )alkyl;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
R 3A is selected from H and CN;
R 4 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
ring A is 5-membered heteroaryl group comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S;
R 5 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl substituted with (C 1 -C 4 )alkyl, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , C(O)OR 5A , phenyl, heteroaryl, heterocycloalkyl and
and
each R 5A is independently selected from H and —(C 1 -C 4 )alkyl; and
R 5B is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, CN, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , and C(O)OR 5A .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from pyrazolyl, triazolyl, thiazolyl, oxazolyl, and oxadiazolyl;
R 5 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl substituted with (C 1 -C 4 )alkyl, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , C(O)OR 5A , phenyl, heteroaryl, heterocycloalkyl, and
R 5A is selected from H and —(C 1 -C 4 )alkyl; and
R 5B is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, CN, C(O)N(R 5A ) 2 , and C(O)OR 5A .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is:
wherein:
R 2N is selected from H,
—(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, —(C 1 -C 4 )alkyl, —(C 1 -C 6 )haloalkyl, and —(C 1 -C 6 )alkyl-OH.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a moiety selected from:
wherein R 3A is selected from H and CN.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is:
wherein:
R 2N is selected from
H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, —(C 1 -C 4 )alkyl, —(C 1 -C 6 )haloalkyl, and —(C 1 -C 6 )alkyl-OH.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a moiety selected from:
wherein:
q is 1, 2, or 3;
r is 1 or 2;
Z is 0 or NR 2N ;
R 2N is selected from
H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl, C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl; and
R 2B is selected from H and OH.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a moiety selected from:
wherein:
R 2N is selected from
H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
In an alternative of each of the preceding embodiments, in Formula (I):
R 2 is a moiety selected from:
wherein:
R 2N is selected from
H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is:
wherein:
t is 1 or 2;
Z is selected from O and NR 2N .
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C—H;
Y is C—H; and
R 1 is selected from H, Cl, —CH 3 , and CN.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y is selected from C—H, C—F, and C—Cl; and
R 1 is selected from H, Cl, —CH 3 , and CN.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y is C—F; and
is selected from H, Cl, —CH 3 , and CN.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method of treating Parkinson's Disease comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a person in need thereof.
15. A method for the treatment or prophylaxis of an indication in which LRRK2 kinase is involved comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 , or a 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, tauopathy 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 of microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury and spinal cord injury,
lymphomas, leukemias, 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.