Patent ID: 11905291
Assignee: THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Field: nan (nan)
Classification: CPC nan | IPC C

Claim 0:
1. A bivalent compound comprising a WD40 repeat domain protein 5 (WDR5) ligand conjugated to a degradation/disruption tag through a linker, said linker selected from the group consisting of:, wherein
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′-R″, R′COR″, R′CO2R″, R′C(O)N(R1)R″, R′C(S)N(R1)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R1)R″, R′SR″, R′SOR″, R′SO2R″, R′SO2N(R1)R″, R′N(R1)R″, R′NR″COR″, R′NR1C(O)OR″, R′NR″CON(R2)R″, R′NR″C(S)R″, R′NR1S(O)R″, R′NR1S(O)2R″, and R′NR1S(O)2N(R2)R″, wherein
R′ and R″ are independently selected from null, optionally substituted Rr—(C1-C8 alkyl), or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C5 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C5 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R1 and R2 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R′ and R″, R1 and R2, R′ and R1, R1 and R2, R″ and R1, R″ and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
m is 0 to 15;, wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′-R″, R′COR″, R′CO2R″, R′C(O)N(R5)R″, R′C(S)N(R5)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR5R″, R′SR″, R′SOR″, R′SO2R″, R′SO2N(R5)R″, R′N(R5)R″, R′NR5COR″, R′NR5C(O)OR″, R′NR5CON(R6)R″, R′NR5C(S)R″, R′NR5S(O)R″, R′NR5S(O)2R″, and R′NR5S(O)2N(R6)R″, wherein
R′ and R″ are independently selected from null, optionally substituted Rr—(C1-C8 alkyl), or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R5 and R6 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R′ and R″, R5 and R6, R′ and R5, R′ and R6, R″ and R5, R″ and R6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m is 0 to 15;
n, at each occurrence, is 0 to 15; and
o is 0 to 15;, wherein
R1 and R2, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1 and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′-R″, R′COR″, R′CO2R″, R′C(O)NR3R″, R′C(S)NR3R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R3)R″, R′SR″, R′SOR″, R′SO2R″, R′SO2N(R3)R″, R′N(R3)R″, R′NR3COR″, R′NR3C(O)OR″, R′NR3CON(R4)R′, R′NR3C(S)R″, R′NR3S(O)R″, R′NR3S(O)2R″, and R′NR3S(O)2N(R4)R″, wherein
R′ and R″ are independently selected from null, optionally substituted Rr—(C1-C8 alkyl), or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R3 and R4 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R′ and R″, R3 and R4, R′ and R3, R′ and R4, R″ and R3, R″ and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m, at each occurrence, is 0 to 15; and
n is 0 to 15;, wherein
X is selected from O, NH, and NR7;
R1, R2, R3, R4, R5, and R6, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
A and B are independently selected from null, or bivalent moiety selected from R′-R″, R′COR″, R′CO2R″, R′C(O)N(R8)R″, R′C(S)N(R8)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R8)R″, R′SR″, R′SOR″, R′SO2R″, R′SO2N(R8)R″, R′N(R8)R″, R′NRBCOR″, R′NRBC(O)OR″, R′NRBCON(R9)R″, R′NRBC(S)R″, R′NRBS(O)R″, R′NRBS(O)2R″, and R′NRBS(O)2N(R9)R″, wherein
R′ and R″ are independently selected from null, optionally substituted Rr—(C1-C8 alkyl), or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7, R8 and R9 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R′ and R″, R8 and R9, R′ and R8, R′ and R9, R″ and R8, R″ and R9 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m, at each occurrence, is 0 to 15;
n, at each occurrence, is 0 to 15;
o is 0 to 15; and
p is 0 to 15;
(e) the linker comprises a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to 13 membered spiro ring;, wherein X is C═O or CH2,
Y is C═O or CH2, and
n is 0-15;, wherein X is C═O or CH2,
Y is C═O or CH2,
m is 0-15,
n is 0-6, and
o is 0-15; or, wherein
X is C═O or CH2,
Y is C═O or CH2,
R is —CH2—, —CF2—, —CH(C1-3 alkyl)-, —C(C1-3 alkyl)(C1-3 alkyl)-, —CH═CH—, —C(C1-3 alkyl)═C(C1-3 alkyl)-, —C═C—, —O—, —NH—, —N(C1-3 alkyl)-, —C(O)NH—, —C(O)N(C1-3 alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring,
m is 0-15, and
n is 0-15; and wherein the WDR5 ligand is selected from, wherein R24, R25, R26, R27, and R28 are independently selected from H and CH3;
B1 and B2 are independently selected from H and F; and
Y1 and Y2 are independently selected from CH and N;
and wherein the degradation/disruption tag is selected from, wherein
R1 and R2 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylaminoalkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, or C2-C8 alkynyl;
R3 is H, C(O)C1-C8 alkyl, C(O)C1-C8 alkoxyalkyl, C(O)C1-C8 haloalkyl, C(O)C1-C8 hydroxyalkyl, C(O)C1-C8 aminoalkyl, C(O)C1-C8 alkylaminoalkyl, C(O)C3-C7 cycloalkyl, C(O)C3-C7 heterocyclyl, C(O)C2-C5 alkenyl, C(O)C2-C5 alkynyl, C(O)OC1-C8 alkoxyalkyl, C(O)OC1-C8 haloalkyl, C(O)OC1-C8 hydroxyalkyl, C(O)OC1-C8 aminoalkyl, C(O)OC1-C8 alkylaminoalkyl, C(O)OC3-C7 cycloalkyl, C(O)OC3-C7 heterocyclyl, C(O)OC2-C8 alkenyl, C(O)OC2-C8 alkynyl, C(O)NC1-C8 alkoxyalkyl, C(O)NC1-C8 haloalkyl, C(O)NC1-C8 hydroxyalkyl, C(O)NC1-C8 aminoalkyl, C(O)NC1-C8 alkylaminoalkyl, C(O)NC3-C7 cycloalkyl, C(O)NC3-C7 heterocyclyl, C(O)NC2-C8 alkenyl, C(O)NC2-C8 alkynyl, P(O)(OH)2, P(O)(OC1-C8 alkyl)2, or P(O)(OC1-C8 aryl)2.