Modulators of alpha-synuclein proteolysis and associated methods of use

1. A bifunctional compound having the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt thereof,

wherein:

(a) the L is a chemical linking moiety connecting the ULM and the PTM, and is a C 1-35 alkyl, wherein:

each carbon is optionally substituted with —CR L1 R L2 —, —O—, —S—, —S(O 2 )—, —SO 2 NR L3 —, —SONR L3 —, —CONR L3 —, —NR L3 CONR L4 —, —NR L3 SO 2 NR L4 —, —C(O)—, —CR L1 ═CR L2 —, —C═C—, —NR L3 C(═NCN)NR L4 —, —NR L3 C(═NCN)—, —NR L3 C(═CNO 2 )NR L4 —, C 3-11 cycloalkyl optionally substituted with 1-9 R L1 and/or R L2 groups, C 5-13 spirocycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 5-13 spiroheterocyclyl optionally substituted with 1-8 R L1 and/or R L2 groups, phenyl optionally substituted with 1-6 R L1 and/or R L2 groups, 5- or 6-membered heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form a C 3-7 cycloalkyl or a C 3-7 membered heterocyclyl group, optionally substituted with 1-4 R L5 groups; and

each of R L1 , R L2 , R L3 , R L4 and R L5 is independently selected from H, halogen, —C 1-8 alkyl, —OC 1-8 alkyl, —SC 1-8 alkyl, —NHC 1-8 alkyl, —N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, C 3-11 heterocyclyl, —OC 3-8 cycloalkyl, —SC 3-8 cycloalkyl, —NHC 3-8 cycloalkyl, —N(C 3-8 cycloalkyl) 2 , —N(C 3-8 cycloalkyl)(C 1-8 alkyl), —OH, —NH 2 , —SH, —SO 2 C 1-8 alkyl, —C≡C(C 1-8 alkyl), —C≡CH, —CH═CH(C 1-8 alkyl), —C(C 1-8 alkyl)=CH(C 1-8 alkyl), —C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , —COC 1-8 alkyl, —CO 2 H, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NO 2 , —SF 5 , —SO 2 NHC 1-s alkyl, —SO 2 N(C 1-8 alkyl) 2 , —SONHC 1-8 alkyl, —SON(C 1-8 alkyl) 2 , —CONHC 1-8 alkyl, —CON(C 1-8 alkyl) 2 , —N(C 1-8 alkyl)CONH(C 1-8 alkyl), —N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , —NHCONH(C 1-8 alkyl), —NHCON(C 1-8 alkyl) 2 , —NHCONH 2 , —N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), —N(C 1-8 alkyl), —SO 2 N(C 1-8 alkyl) 2 , —NHSO 2 NH(C 1-8 alkyl), —NHSO 2 N(C 1-8 alkyl) 2 , and —NHSO 2 NH 2 ;

(b) the ULM is selected from:

wherein:

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

each X is independently absent, O, S, or CH 2 ,

Y is CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N—C 3-7 cycloalkyl, N—C 3-7 heterocyclyl, O, or S, wherein the aryl of Y is a 6-membered aryl and the heteroaryl of Y is a 5- or 6-membered heteroaryl;

Z is absent, O, S, or CH 2 ;

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

Q 1 , Q 2 , Q 3 , and Q 4 are each independently a CH group or a CR group;

A is H, optionally substituted linear or branched alkyl, C 3-7 cycloalkyl, Cl or F;

R is —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, —(CR′O) n′ R″, optionally substituted C 3-7 heterocyclyl, optionally substituted-aryl, optionally substituted alkyl-aryl, optionally substituted heteroaryl, optionally substituted linear or branched alkyl, optionally substituted alkoxy group, optionally substituted

optionally substituted C 3-7 cycloalkyl, —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 is covalently joined to the chemical linking moiety (L) coupling the PTM to the CLM, the aryl of R is a 6-membered aryl, and the heteroaryl of R is a 5- or 6-membered heteroaryl;

each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6;

n′ and n of Formulas (a) through (f) are each an integer from 1 to 10;

R′ and R″ are independently selected from a bond when the point of attachment, H, optionally substituted alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 5 or 6 membered aryl, optionally substituted 5- or 6-membered heteroaryl, and optionally substituted C3-7 heterocycloalkyl;

represents a single bond or a double bond; and

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

(c) the PTM is selected from:

wherein:

A, B, C, and D are independently an optionally substituted 6 membered aryl or an optionally substituted 5- or 6-membered heteroaryl wherein each heteroatom of each 5- or 6-membered heteroaryl is independently selected from O and N, and the optional substitutions are 1 or 2 substituents independently selected from H, C 1-6 alkyl, O, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, and nitro, wherein contact between circles indicates ring fusion;

M 1 and M 2 are independently selected from: a single bond; —O—; —S—; —NR 100 —; —SO 2 —; —S(O)—; —SO 2 NH—; —C(O)—; —C(O)NH—; an optionally substituted C 1-3 alkyl wherein a carbon of the alkyl group may be replaced with a group independently selected from —O—, —S—, —NR 100 —, and —C(O)—; and a two to four carbon conjugated alkenyl or alkynyl fragments, wherein at least one of the carbons of the alkenyl or alkynyl group may be part of A, B, C, or D;

each R 100 is independently selected from H, C 1-3 alkyl, and C 1-3 halolakyl; and

- - - indicates the attachment of the chemical linking moiety (L) or a ULM.

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

wherein - - - indicates the point of attachment of the chemical linking moiety (L) coupling to the PTM to the ULM.

3. The compound according to claim 2 , wherein the PTM includes at least one of:

(a) B of Formula IA PTM , or IB PTM includes optionally substituted

or optionally substituted

wherein - - - indicates a point of attachment with the chemical linking moiety (L);

(b) C of Formula IA PTM includes optionally substituted

or optionally substituted

wherein - - - indicates a point of fusion with B;

(c) at least one of A and C of Formula IB PTM includes

(d)

of Formula IIA PTM , or IIB PTM includes optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

or optionally substituted

wherein - - - indicates a point of attachment with C or the chemical linking moiety (L);

(e) C of Formula IIA PTM , IIB PTM , or IIC PTM includes optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

or optionally substituted

optionally substituted

wherein - - - indicates a point of attachment with A, B, or the chemical linking moiety (L);

(f)

of Formula IIIA PTM , IIIB PTM , IIIC PTM , and IIID PTM is optionally substituted

optionally substituted

optionally substituted

or optionally substituted

wherein - - - indicates a point of attachment with C or D;

(g) C of Formula IIIA PTM , IIIB PTM , IIIC PTM , and III PTM includes optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

or optionally substituted

wherein - - - indicates a point of attachment with A or B; and

(h) D of Formula IIIA PTM , IIIB PTM , IIIC PTM , and IIID PTM includes optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

optionally substituted

or optionally substituted

wherein - - - indicates a point of attachment with A or B.

4. The compound according to claim 1 , wherein PTM is selected from an optionally substituted:

wherein - - - indicates the point of attachment of the chemical linking moiety (L) coupling the PTM to the ULM.

5. The compound of claim 1 , wherein the CLM has a chemical structure represented by:

6. The compound according to claim 1 , wherein the chemical linking moiety (L) is a C 1 -C 20 alkyl wherein:

each carbon is optionally replaced with —CR L1 R L2 —, —O—, —S—, —S(O)—, —S(O 2 )—, —NR L3 —, —SO 2 NR L3 —, —NR L3 CONR L4 —, —C(O)—, —CR L1 ═CR L2 —, —C≡C—, C 3-11 cycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 5-13 spirocycloalkyl optionally substituted with 1-9 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 5-13 spiroheterocyclyl optionally substituted with 1-8 R L1 and/or R L2 groups, phenyl optionally substituted with 1-6 R L1 and/or R L2 groups, 5- or 6-membered heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form a C 3-7 cycloalkyl or a C 3-7 heterocyclyl group, optionally substituted with 1-4 R L5 groups; and

R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halo, —C 1-8 alkyl, —OC 1-8 alkyl, —NHC 1-8 alkyl, —N(C 1-8 alkyl) 2 , —C 3-11 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, —C 3-11 heterocyclyl, —OC 3-8 cycloalkyl, —SC 3-8 cycloalkyl, —NHC 3-8 cycloalkyl, —N(C 3-8 cycloalkyl) 2 , —N(C 3-8 cycloalkyl)(C 1-8 alkyl), —OH, —NH 2 , —C≡C—C 1-8 alkyl, —C≡CH, —CH═CH(C 1-8 alkyl), —C(C 1-8 alkyl)═CH(C 1-8 alkyl), —C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , —COC 1-8 alkyl, —CO 2 H, —CN, —CF 3 , —CHF 2 , —CH 2 F, or —NO 2 .

7. The compound according to claim 1 , wherein chemical linking moiety (L) has a chemical structure selected from:

wherein:

is the site of attachment with the ULM or the PTM;

each of m, n, o, p, q, r, or s of the chemical linking moiety are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and

N* of the C 4-6 heterocycloalkyl is (i) shared with the PTM or the ULM, or (ii) is linked to the PTM or the ULM via a bond.

8. The compound according to claim 1 , wherein the chemical linking moiety (L) has a chemical structure selected from:

wherein:

is the site of attachment with the ULM or the PTM;

each m and n of the chemical linking moiety is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and

N* of the C 4-6 heterocycloalkyl is (i) shared with the PTM or the ULM, or (ii) is linked to the PTM or the ULM via a bond.

9. The compound according to claim 1 , wherein the chemical linking moiety (L) is selected from:

is the site of attachment with the ULM or the PTM; and

N* of the C 4-6 heterocycloalkyl is (i) shared with the PTM or the ULM, or (ii) is linked to the PTM or the ULM via a bond.

10. The compound according to claim 1 , wherein the compound is selected from:

11. The bifunctional compound of claim 1 , wherein the compound is selected from

12. A pharmaceutical composition comprising an effective amount of a bifunctional compound of claim 1 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , wherein the composition further comprises at least one additional bioactive agent.

14. The pharmaceutical composition of claim 13 , wherein the additional bioactive agent is an anti-neurodegenerative agent.

15. A method for treating a α-synuclein accumulation and aggregation disease or disorder in a subject, comprising administering an amount of at least one compound of claim 1 to the subject.

16. The method of claim 15 , wherein treating the disease or disorder comprises treating or ameliorating at least one symptom of the α-synuclein accumulation and aggregation in the subject.

17. The method of claim 15 , wherein the disease or disorder is a α-synucleinopathy or a neurodegenerative disease associated with α-synuclein accumulation and aggregation.

18. The method of claim 15 , wherein the disease or disorder is Parkinson Disease, Alzheimer's Disease, dementia, dementia with Lewy bodies, or multiple system atrophy.

19. The method of claim 15 , wherein the disease or disorder is Parkinson's Disease.