Selective modulators of mutant LRRK2 proteolysis and associated methods of use

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:

wherein:

W is selected from CH 2 , O, CHR, C═O, SO 2 , NH, N, optionally substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-alkyl;

W 3 is C or N;

each X is independently selected from absent, O, S, and CH 2 ,

Y is selected from CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

Z is selected from absent, O, S, and CH 2 ;

G and G′ are independently selected from H, unsubstituted or substituted linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;

Q 1 , Q 2 , Q 3 , and Q 4 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′, —SO 2 R′, —SO 2 NR′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, —CF 3 , —CN, —NR′SO 2 NR′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—NO 2 )NR′R″, —SO 2 NR′COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5 and —OCF 3 , 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;

represents a single bond or a double bond; and

represents a bond that may be stereospecific or non-stereospecific;

(b) the PTM has a chemical structure selected from:

wherein the 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:

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 C 1-4 alkyl.

2. The compound according to claim 1 , wherein PTM is:

wherein indicates a site of attachment of L or the CLM, and wherein each PTM is coupled to at least one L or the CLM.

3. The compound of claim 1 , wherein the CLM is:

4. The compound of claim 1 , wherein the CLM is:

5. The compound of to claim 1 , wherein PTM is:

wherein indicates a site of attachment of L or the CLM, and wherein each PTM is coupled to at least one or the CLM.

6. The compound claim 1 , wherein:

(a) the CLM is:

 wherein:

of the CLM indicates the point of attachment with L or the PTM; and

N* is a nitrogen atom that is shared with the L or the PTM;

(b) the PTM is:

 wherein

of the PTM indicates the point of attachment with L or the CLM;

(c) L is selected from:

 wherein or * indicates the site that is covalently linked to the CLM or the PTM, or that is shared with the CLM or the PTM; or

(d) a combination thereof.

7. The compound of claim 1 , wherein:

(a) the CLM is:

 wherein:

of the CLM indicates the point of attachment with L or the PTM; and

N* is a nitrogen atom that is shared with L or the PTM;

(b) the PTM is:

 wherein

of the PTM indicates the point of attachment with L or the CLM; and

(c) L is selected from:

 wherein or * indicates the site that is covalently linked to the CLM or the PTM, or that is shared with the CLM or the PTM.

8. The compound of claim 1 , wherein the compound is selected from:

9. A pharmaceutical composition comprising an amount of a compound of claim 1 , and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9 , wherein the composition further comprises an additional bioactive agent.

11. The pharmaceutical composition of claim 10 , wherein the additional bioactive agent is an anti-neurodegenerative, an anti-inflammatory, a chemotherapy agent, or an immunomodulatory agent.

12. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.