# US 12,594,264 B2 · Modulators of alpha-synuclein proteolysis and associated methods of use

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- Number: US 12,594,264 B2
- Document ID: US12594264B2
- Status: Granted
- Kind: B2
- Application number: 18/309,867
- Filed: 2023-09-18
- Published: 2024-03-21
- Granted: 2026-04-07
- Earliest claimed: 2018-08-20
- Assignees: Arvinas Operations, Inc.
- Applicants: Arvinas Operations, Inc.
- Inventors: Andrew P. Crew; Hanqing Dong; Michael Berlin; Steven M. Sparks
- Web page: https://patentgrep.com/patent/US12594264B2

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- C07D 417/14: containing three or more hetero rings
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/4245: Oxadiazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 47/555: {pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 401/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon. Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

## Claims

### Claim 1

A bifunctional compound having the chemical structure:
ULM-L-PTM,
or a pharmaceutically acceptable salt thereof,
wherein:
(a) ULM is;
wherein:
X1, X2 are each independently selected from a bond, O, NRY3, CRY3RY4, C═O, C═S, SO, and SO2;
RY3, RY4 are each independently selected from H, linear or branched C1-C6 alkyl optionally substituted by 1 or more halo, and C1-C6 alkoxyl optionally substituted by 0-3 RP groups;
RP is independently selected from H, halo, —OH, C1-C3 alkyl, and C═O;
W3 is selected from an optionally substituted T, an optionally substituted -T-N(R1aR1b)X3, an optionally substituted -T-N(R1aR1b), an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted T-biheteroaryl, an optionally substituted -T-heterocycle, an optionally substituted -T-biheterocycle, an optionally substituted —NR1-T-aryl, an optionally substituted —NR1-T-heteroaryl and an optionally substituted —NR1-T-Heterocycle;
X3 is selected from C═O, R1, R1a, and R1b;
each of R1, R1a, R1b is independently selected from H, linear or branched C1-C6 alkyl group optionally substituted by 1 or more halo or —OH groups, RY3C═O, RY3C═S, RY3SO, RY3SO2, N(RY3RY4) C═O, N(RY3RY4) C═S, N(RY3RY4) SO, and N(RY3RY4) SO2;
T is selected from an optionally substituted alkyl, —(CH2)n— group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from halogen, methyl, optionally substituted alkoxy, and a linear or branched C1-C6 alkyl group optionally substituted by 1 or more halogen, C(O) NR1R1a, or NR1R1a or R1 and R1a are joined to form an optionally substituted heterocyclyl, or —OH groups or an amino acid side chain optionally substituted; and
n is 0, 1, 2, 3, 4, 5, or 6,
W4 is
R14a and R14b, are each independently selected from H, haloalkyl, and optionally substituted alkyl;
W5 is an optionally substituted phenyl or an optionally substituted 5-10-membered heteroaryl,
R15 is selected from H, halogen, CN, OH, NO2, N R14aR14b, OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cyclo-heteroalkyl; and
is the attachment of a chemical linker moiety (L);
(b) PTM is selected from:
wherein:
A, B, C, D, and E are independently selected from an optionally substituted 5- or 6-membered aryl or an optionally substituted 5- or 6-membered heteroaryl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, C1-C6 alkyl, O, N, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO2— or an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, alkyl, O, N, halogen, C1-C6 haloalkyl, alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO2—, wherein contact between circles indicates ring fusion;
M1, M2, and M3 are independently selected from a single bond; O—; —S—; —NR100—; —SO2—; —S(O)—; —SO2NH—; —C(O)—; —C(O) NH—; and an optionally substituted C1-C6 alkyl or C1-C6 haloalkyl, wherein a carbon of the alkyl group may be replaced with a group independently selected from —O—, —S—, —NR100—, —SO2—, —S(O)—, —SO2NH—, —C(O)— or —C(O)NH—, and the optional substitutions are selected from halogen, amino, alkyl or a haloalkyl, and a two to four carbon conjugated alkenyl fragment; an alkynyl fragment; and a two to four carbon conjugated alkenyl or alkynyl fragment, wherein at least one of the carbon of the alkenyl or alkynyl group may be part of A, B, C, or D;
each R100 is independently selected from H, C1-C6 alkyl, and an optionally substituted C1-C6 haloalkyl;
indicates the attachment of a chemical linker moiety (L); and
(c) L is a chemical linker moiety comprising an optionally substituted C1-C50 alkyl, wherein:
each carbon is optionally substituted with CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1═CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11 cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13 spirocycloalkyl optionally substituted with 0-9 RL1 and/or RL2 groups, C3-11 heteocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13 spiroheterocyclyl optionally substituted with 0-8 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, and heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups, where RL1 or RL2, each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 RL5 groups; and
RL1, RL2, RL3, RL4 and RL5 are, each independently selected from H, halo, C1-C8 alkyl, O C1-C8 alkyl, S C1-C8 alkyl, NH C1-C8 alkyl, N(C1-C8 alkyl)2, C3-C11 cycloalkyl, aryl, heteroaryl, C3-C11 heterocyclyl, OC3-C8 cycloalkyl, SC3-C8 cycloalkyl, NHC3-C8 cycloalkyl, N(C3-C8 cycloalkyl)2, N(C3-C8 cycloalkyl) (C1-C8 alkyl), OH, NH2, SH, SO2C1-C8alkyl, P(O)(OC1-C8 alkyl) (C1-C8 alkyl), P(O)(OC1-C8 alkyl)2, CC≡C1-C8 alkyl, CCH, CH═CH(C1-C8 alkyl), C(C1-C8 alkyl)=CH(C1-C8 alkyl), C(C1-C8 alkyl)=C(C1-C8 alkyl)2, Si(OH)3, Si(C1-C8 alkyl)3, Si(OH)(C1-C8 alkyl)2, COC1-C8 alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-C8alkyl, SO2N(C1-C8 alkyl)2, SONHC1-C8 alkyl, SON(C1-C8 alkyl)2, CONHC1-C8 alkyl, CON(C1-C8 alkyl)2, N(C1-C8 alkyl)CONH(C1-C8 alkyl), N(C1-C8 alkyl)CON(C1-C8 alkyl)2, NHCONH(C1-C8 alkyl), NHCON(C1-C8 alkyl)2, NHCONH2, N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), N(C1-C8alkyl) SO2N(C1-C8 alkyl)2, NHSO2NH(C1-C8 alkyl), NHSO2N(C1-C8 alkyl)2, and NHSO2NH2.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the ULM is:
wherein:
W3 is selected from an optionally substituted aryl, optionally substituted heteroaryl, and
R9 and R10 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R11 is selected from an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
R12 is H or optionally substituted alkyl;
R13 is selected from H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, and optionally substituted aralkyl;
R14a R14b are each independently selected from H, haloalkyl, and optionally substituted alkyl;
W5 is selected from an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl;
R15 is selected from H, halogen, CN, OH, NO2, N R14aR14b, OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cyclo-heteroalkyl;
each R16 is independently selected from H, CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R18 is independently selected from H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, and haloalkoxy; and
p is 0, 1, 2, 3, or 4; and
is the site of attachment of the chemical linker moiety (L).

### Claim 3 (depends on 1)

The compound of claim 1, wherein the ULM is selected from:
wherein:
R1 is selected from H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl;
R14a is selected from H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, and cyclopropyl;
R15 is selected from H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl;
X is C, CH2, or C═O
R3 is absent or an optionally substituted 5 or 6 membered heteroaryl; and
wherein indicates the site of attachment of a chemical linker moiety (L).

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the ULM is:
wherein:
R14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, and cyclopropyl;
R9 is H;
R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R11 is
and optionally substituted heteroaryl;
p is 0, 1, 2, 3, or 4;
each R18 is independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, and haloalkoxy;
R12 is H or C═O;
R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, and optionally substituted aralkyl;
R15 is selected from H, halogen, Cl, CN, OH, NO2, optionally substituted heteroaryl, an optionally substituted aryl;
and
wherein indicates the site of attachment of the chemical linker moiety (L).

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the unit AL of linker (L) is selected from:
wherein:
each m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and
N* of the heterocycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein the unit AL of linker (L) is:
wherein:
each m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and
N* of the heterocycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein the unit AL of linker (L) is selected from:
wherein N* of the hetero-cycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the linker (L) is:
wherein:
WL1 and WL2 are each independently absent, a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
YL1 is each independently a bond, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms are replaced with O; or optionally substituted linear or branched C1-C6 alkoxy;
n is 0, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
indicates the attachment point to the PTM or ULM moieties.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the linker (L) is:
wherein:
WL1 and WL2 are each independently selected from absent, aryl, heteroaryl, cyclic, heterocyclic, C1-C6 alkyl and optionally one or more C atoms are replaced with O, C1-C6 alkene and optionally one or more C atoms are replaced with O, C1-C6 alkyne and optionally one or more C atoms are replaced with O, bicyclic, bi-aryl, bi-heteroaryl, or bi-heterocyclic, each optionally substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C2-6alkenyl, C2-6alkynyl, optionally substituted linear or branched C1-C6 alkyl, C1-C6 alkoxy (linear, branched, optionally substituted), optionally substituted linear or branched OC1-3alkyl, OH, NH2, NRY1RY2, CN, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
YL1 is each independently selected from a bond, NRYL1, O, S, NRYL2, CRYL1RYL2, C═O, C═S, SO, SO2, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms are replaced with O; and optionally substituted linear or branched C1-C6 alkoxy;
QL is selected from a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 RQ, each RQ is independently H, optionally substituted linear or branched C1-C6 alkyl, or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
RYL1 and RYL2 are each independently selected from H, OH, and optionally substituted linear or branched C1-C6 alkyl, or R1, R2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
indicates the attachment point to the PTM or the ULM moieties.

### Claim 10

A compound selected from

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the composition further comprises at least one additional bioactive agent.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, wherein the additional bioactive agent is anti-neurodegenerative agent.

### Claim 14 (depends on 1)

A method of treating a disease or disorder, comprising administering an effective amount of a compound of claim 1 to a subject;
wherein the disease or disorder is associated with α-synuclein accumulation and aggregation.

### Claim 15 (depends on 14)

The method of claim 14, wherein the disease or disorder is a α-synucleinopathies or a neurodegenerative disease associated with α-synuclein accumulation and aggregation.

### Claim 16 (depends on 14)

The method of claim 14, wherein the disease or disorder is Parkinson Disease, Alzheimer's Disease, dementia, dementia with Lewy bodies, or multiple system atrophy.

### Claim 17 (depends on 14)

The method of claim 14, wherein the disease or disorder is Parkinson's Disease.

### Claim 18 (depends on 10)

A pharmaceutical composition comprising the compound of claim 10, and a pharmaceutically acceptable carrier.