US 12,144,864 B2
Tubulysins and protein-tubulysin conjugates
Amy Han, Hockessin, DE (US); Marcus Kelly, New York, NY (US); and William Olson, Yorktown Heights, NY (US)
Assigned to Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed on Dec. 20, 2019, as Appl. No. 16/724,164.
Claims priority of provisional application 62/784,325, filed on Dec. 21, 2018.
Prior Publication US 2021/0260208 A1, Aug. 26, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/65 (2017.01); A61K 31/454 (2006.01); A61K 47/54 (2017.01); A61K 47/68 (2017.01)
CPC A61K 47/6803 (2017.08) [A61K 31/454 (2013.01); A61K 47/545 (2017.08); A61K 47/65 (2017.08)] 33 Claims
 
1. A compound having the following Formula B or C

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
BA is a binding agent;
L is a linker;
wherein
R1 is C1-C10 alkyl;
R3 is —C(O)C1-C5 alkyl, —C(O)N(H)C1-C10 alkyl, or —(C1-C10 alkylene)-NR3aR3b,
wherein R3a and R3b are independently in each instance, hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, C6-C20 aryl, 5- to 20-membered heteroaryl, and C2-C20 acyl, wherein C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, C6-C20 aryl, 5- to 20-membered heteroaryl, and C2-C20 acyl are unsubstituted or substituted with C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, C6-C20 aryl, 5- to 20-membered heteroaryl, and/or C2-C20 acyl;
R4 and R5 are, independently in each instance, hydrogen or C1-C5 alkyl;
R6 is —OH, —O—, —NHNH2, or —NHNH—;
R7 is, independently in each instance, hydrogen, —OH, —O—, halogen, or —NR7aR7b,
wherein R7a and R7b are independently in each instance, a bond, hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, C6-C20 aryl, 5- to 20-membered heteroaryl, acyl, and amino acid residue, wherein C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, aryl, heteroaryl, and acyl are unsubstituted or substituted with C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, aryl, heteroaryl, and/or acyl;
R8 is, independently in each instance, hydrogen, deuterium, —NHR9, or halogen,
wherein R9 is hydrogen, —C1-C5 alkyl, or —C(O)C1-C5 alkyl; and
m is one or two;
Q is oxygen;
R2 is C1-C10 alkyl, C3-C10 alkynyl, —C1-C10 alkylene-(5-membered heteroaryl), —C1-C3 alkylene-Q1-(CH2)naryl, or C1-C3 hydroxyalkyl; and
Q1 is —CH2— or —O—;
wherein said heteroaryl is unsubstituted or substituted with C1-C20 alkyl, aminoalkyl, -alkylene-NH—, hydroxylalkyl, -alkylene-O—, carboxyalkyl, -alkylene-COO—, benzyl, or phenyl;
wherein said aryl is unsubstituted or substituted with nitro, amino, or —NH—; and
wherein n is an integer from one to five; and
k is an integer from one to thirty.