Modulators of alpha-synuclein proteolysis and associated methods of use

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.