US 11,858,940 B2
Selective modulators of mutant LRRK2 proteolysis and associated methods of use
Erika Araujo, Woodbridge, CT (US); Michael Berlin, Flemington, NJ (US); Steven M. Sparks, Guilford, CT (US); Jing Wang, Milford, CT (US); and Wei Zhang, Madison, CT (US)
Assigned to Arvinas Operations, Inc., New Haven, CT (US)
Filed by Arvinas Operations, Inc., New Haven, CT (US)
Filed on Mar. 19, 2021, as Appl. No. 17/207,330.
Claims priority of provisional application 62/992,951, filed on Mar. 21, 2020.
Prior Publication US 2022/0064168 A1, Mar. 3, 2022
Int. Cl. C07D 487/04 (2006.01); A61K 45/06 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 45/06 (2013.01); C07D 519/00 (2013.01)] 12 Claims
 
1. A compound having the chemical structure:
PTM-L-CLM,
or a pharmaceutically acceptable salt thereof,
wherein:
(a) the CLM is represented by the chemical structure:

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wherein:
W is selected from CH2, O, CHR, C═O, SO2, NH, N, optionally substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-alkyl;
W3 is C or N;
each X is independently selected from absent, O, S, and CH2,
Y is selected from CH2, —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
Z is selected from absent, O, S, and CH2;
G and G′ are independently selected from H, unsubstituted or substituted linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH2-heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q1, Q2, Q3, and Q4 represent C or N substituted with a group independently selected from H, R, N, and N-oxide;
A is independently selected from H, unsubstituted or substituted linear or branched alkyl, cycloalkyl, —Cl, and —F;
m′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R is a bond, H, —CONR′R″, —C(═O)R′, —OR′, —NR′R″, —SR′, —SO2R′, —SO2NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O)n′R″, optionally substituted heterocyclyl, aryl, optionally substituted alkyl-aryl, heteroaryl, unsubstituted or substituted linear or branched alkyl, optionally substituted alkoxyl group, optionally substituted heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF3, —CN, —NR′SO2NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO2)NR′R″, —SO2NR′COR″, —NO2, —CO2R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3, wherein at least one R or W is modified to be covalently joined to the PTM, or the CLM;
R′ and R″ are independently selected from a bond, H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted heterocyclyl;
n′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
custom character represents a single bond or a double bond; and
custom character represents a bond that may be stereospecific or non-stereospecific;
(b) the PTM has a chemical structure selected from:

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wherein the custom character of the PTM indicates the site of attachment with a chemical linking group; and
(c) the L is a bond or is a chemical linking group that covalently couples the CLM to the PTM and is selected from:

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wherein:
N* is a nitrogen atom that is covalently linked to the CLM or the PTM, or that is shared with the CLM or the PTM;
each m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and
the chemical linker group is optionally substituted with 1, 2, 3, or 4 substitutions independently selected from halogen and C1-4 alkyl.