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US 12,144,864 B2Granted
Tubulysins and protein-tubulysin conjugates
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsAmy Han, Marcus Kelly, William Olson
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds, compositions, and methods for the treatment of diseases and disorders associated with cancer, including tubulysins and protein (e.g., antibody) drug conjugates thereof.
Claims33
A compound having the following Formula B or C
- 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.
22 more elements
An antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated to a compound selected from the group consisting of
A compound having the structure of Formula I
- or a pharmaceutically acceptable salt thereof, 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 or —NHNH2;
- R7 is, independently in each instance, hydrogen, —OH, halogen, or —NR7aR7b,
- wherein R7a and R7b 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, 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, hydroxylalkyl, carboxyalkyl, benzyl, or phenyl;
- wherein said aryl is unsubstituted or substituted with nitro or amino;
- and
- wherein n is an integer from one to five.
17 more elements
A linker-payload having the formula Formula LPb or LPc
- or a pharmaceutically acceptable salt thereof, wherein
- 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 unsubstitued or substituted with nitro, amino, or —NH—;
- and
- wherein n is an integer from one to five.
19 more elements
Dependencies are inferred from the claim text.