US 12,319,671 B2
1-pyrazolyl, 5-, 6-disubstituted indazole derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
Hua Zhou, Acton, MA (US); John J. Acton, III, Cranford, NJ (US); Michael J. Ardolino, Arlington, MA (US); Yi-Heng Chen, Whippany, NJ (US); Peter H. Fuller, Ashland, MA (US); Anmol Gulati, Watertown, MA (US); Rebecca Elizabeth Johnson, Oakland, CA (US); William P. Kaplan, Boston, MA (US); Solomon D. Kattar, Wakefield, MA (US); Mitchell H. Keylor, Malden, MA (US); Derun Li, West Roxbury, MA (US); Kaitlyn Marie Logan, Boston, MA (US); Min Lu, Brookline, MA (US); Gregori J. Morriello, Randolph, NJ (US); Santhosh F. Neelamkavil, Edison, NJ (US); Barbara Pio, West Orange, NJ (US); Nunzio Sciammetta, Sudbury, MA (US); Vladimir Simov, South Boston, MA (US); Jing Su, Scotch Plains, NJ (US); Luis Torres, Norwood, MA (US); and Xin Yan, Newton, MA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/614,732
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Jun. 1, 2020, PCT No. PCT/US2020/035505
§ 371(c)(1), (2) Date Nov. 29, 2021,
PCT Pub. No. WO2020/247298, PCT Pub. Date Dec. 10, 2020.
Claims priority of provisional application 62/858,137, filed on Jun. 6, 2019.
Prior Publication US 2022/0259188 A1, Aug. 18, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 405/14 (2006.01); A61P 25/16 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/14 (2006.01); C07D 409/14 (2006.01); C07D 471/04 (2006.01); C07D 471/10 (2006.01); C07D 487/04 (2006.01); C07D 487/08 (2006.01); C07D 487/10 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01); C07D 498/08 (2006.01)
CPC C07D 405/14 (2013.01) [A61P 25/16 (2018.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/14 (2013.01); C07D 409/14 (2013.01); C07D 471/04 (2013.01); C07D 471/10 (2013.01); C07D 487/04 (2013.01); C07D 487/08 (2013.01); C07D 487/10 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01); C07D 498/08 (2013.01)] 16 Claims
 
1. A compound having a structural Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R1 is selected from Cl, Br, F, CH3, CN, and CHF2;
R2 is selected from:
optionally substituted cycloalkyl, optionally mono, di, or tri-substituted heteroaryl, mono, di, or tri-substituted heterocycloalkyl, wherein each said optional substituent is independently selected from halogen, oxo, CN, —(O)0-1(C1-C3)alkyl, —(C3-C6)cycloalkyl, —(O)0-1(C1-C3)haloalkyl, NR2AR2B, CH2NHC(O)(C1-C3)alkyl, —C(O)OH, —C(O)O(C1-C3)alkyl, wherein the alkyl in —(O)0-1(C1-C3)alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, OH, (CH2)nO(C1-C3)alkyl, —(O)0-1(C1-C3)haloalkyl, NR2AR2B, and heterocycloalkyl, wherein n is 0-2, and C(O)NR2AR2B,
R2A is selected from H and —(C1-C3)alkyl,
R2B is selected from H and —(C1-C3)alkyl;
the moiety

OG Complex Work Unit Chemistry
is selected from:

OG Complex Work Unit Chemistry
or, alternatively, the moiety

OG Complex Work Unit Chemistry
is selected from:

OG Complex Work Unit Chemistry
or, alternatively, the moiety

OG Complex Work Unit Chemistry
is selected from:

OG Complex Work Unit Chemistry
or, alternatively, the moiety

OG Complex Work Unit Chemistry
is a fused bicyclic moiety selected from:

OG Complex Work Unit Chemistry
or, alternatively, the moiety

OG Complex Work Unit Chemistry
is a moiety selected from:

OG Complex Work Unit Chemistry
a is 0, 1, or 2;
each RA1 is independently selected from halogen, OH, —(C1-C6)alkyl, —(C1-C6)alkyl-OH, and —(C1-C6)alkyl-CN;
RA2 is selected from H, —(C1-C6)alkyl, —(C1-C6)alkyl-OH, —(C1-C6)alkyl-CN, S(O)2(C1-C3)alkyl, optionally mono-, di- or tri-substituted cyclopropyl, optionally mono-, di- or tri-substituted cyclobutyl, optionally mono-, di- or tri-substituted cyclopentyl, optionally mono-, di- or tri-substituted oxetanyl, optionally mono-, di- or tri-substituted tetrahydrofuranyl, optionally mono-, di- or tri-substituted thietanyl dioxide, optionally mono-, di- or tri-substituted tetrahydrothiophenyl dioxide, wherein each said optional substituent is independently selected from halogen, oxo, CN, OH, —O(C1-C3)alkyl, —(C1-C3)alkyl, and —(C1-C3)haloalkyl;
RA2C is selected from H and, —(C1-C6)alkyl;
b is 0, 1, 2, or 3; and
each RA3 is independently selected from H, halogen, CN, NH2, OH, oxo, —(C1-C3)alkyl, —(C1-C3)alkyl-OH, —(C1-C3)alkyl-CN, —(C1-C3)haloalkyl, O(C1-C3)alkyl, (C1-C3)alkylNHS(O)2(C1-C3)alkyl, S(O)2(C1-C3)alkyl, S(O)2(C1-C3) cyclopropyl, said cyclopropyl optionally mono-, di- or tri-substituted, optionally mono-, di- or tri-substituted cyclopropyl, optionally mono-, di- or tri-substituted cyclobutyl, optionally mono-, di- or tri-substituted cyclopentyl, optionally mono-, di- or tri-substituted azetidinyl, optionally mono-, di- or tri-substituted oxetanyl, optionally mono-, di- or tri-substituted tetrahydrofuranyl, optionally mono-, di- or tri-substituted thietanyl dioxide, optionally mono-, di- or tri-substituted tetrahydrothiophenyl dioxide, and optionally mono-, di- or tri-substituted heteroaryl, wherein each said optional substituent independently selected from halogen, oxo, OH, —(C1-C3)alkyl, and —(C1-C3)haloalkyl.