JP-2022514348-A5 -

Dates

Publication Date

20221220

Application Date

20191220

Description

In other aspects, this specification also provides pharmaceutical compositions and methods for treating diseases using the TM-ADC described herein. [Invention 1001] Equation (I): Multiplexer linkage assembly (MLA) compounds having: During the ceremony, A1 is the first linking group; Each A2 is independently a bonded or independently selected second linking group; A1 and A2 each contain zero or one splitting group (Y ) covalently bonded to the first or second linking group, or a divalent linking component of the first or second linking group; M is a multiplicating group or a first thiol multiplicating group (T MC1 ); Each T MC2 is a second thiol multiplicating group; The subscript m is either 0 or 1; where, If the subscript m is 0, then M is either a first thiol multiplicating group in disulfide form (T MC1 ) or a first thiol multiplicating group (T MC1 ) bonded to two drug moieties (D M ) ; and If the subscript m is 1, each T MC2 is either in disulfide form or bound to two drug moieties (D M ). [Invention 1002] A 1 is, The MLA compound of the present invention 1001 has a formula selected from the group consisting of, where R is selected from the group consisting of H and amine protecting groups; Y is a splitting group; and the tilde indicates a covalent bond to M. [Invention 1003] M is T MC1 and An MLA compound of the present invention 1002, selected from the group consisting of the following. [Invention 1004] M is T MC1 and An MLA compound according to the present invention 1002, selected from the group consisting of the above, wherein the wavy line adjacent to the sulfur indicates a covalent bonding site to the -A 2 -T MC2 group. [Invention 1005] Each T MC2 , An MLA compound of the present invention 1004, selected from the group consisting of the following, where the wavy lines adjacent to each sulfur in each T MC2 indicate the binding site to the drug moiety (D M ). [Invention 1006] Each T MC2 , An MLA compound of the present invention 1004, selected from the group consisting of the following. [Invention 1007] A 1 is, The MLA compound of the present invention 1001, having a formula selected from the group consisting of the following, wherein the wavy line indicates bonding to M. [Invention 1008] M is T MC1 and An MLA compound of the present invention 1007, selected from the group consisting of the following. [Invention 1009] The subscript m is 1, and M is T MC1 , and Selected from the group consisting of; and T MC2 is An MLA compound of the present invention 1001 or 1007, selected from the group consisting of the following. [Invention 1010] (A 2 - T MC2 ) are, respectively, An MLA compound of the present invention 1001 or 1007 having a formula independently selected from the group consisting of, wherein the succinimide ring is in a hydrolyzed form and each R is independently selected from the group consisting of H and an amine protecting group; Y is a splitting group; and the wavy line to the left of the succinimide ring indicates a thioether bond to T MC1 . [Invention 1011] The subscript m is 0, and M is T MC1 , and An MLA compound of the present invention 1001 or 1007, selected from the group consisting of the following. [Invention 1012] The subscript m is 0, and M is T MC1 , andAn MLA compound of the present invention 1001 or 1007, selected from the group consisting of the following. [Invention 1013] I-1, I-2, I-1a, and I-2a:It has an expression selected from the group consisting of; During the ceremony, The subscript w is an integer from 0 to 8; Each W is independently a natural or non-natural amino acid; Each R is independently an H or an amine protecting group; and Y is a dividing group. MLA compound of the present invention 1001. [Invention 1014] The MLA compound of the present invention 1013, wherein the aforementioned splitting group Y contains a polyethylene glycol group. [Invention 1015] An MLA compound of the present invention 1001 having a formula selected from the following. [Invention 1015] An MLA compound according to the present invention 1001 or 1002, wherein A1 is selected from the group consisting of a maleimide group and a halomethylcarbonyl group. [Invention 1016] The MLA compound of the present invention 1001, further comprising the splitting group Y. [Invention 1017] The MLA compound of the present invention 1017, wherein the aforementioned splitting group Y contains a polyethylene glycol group. [Invention 1019] A 1 is, An MLA compound of the present invention 1001 or 1002 having a formula selected from the group consisting of, where R is selected from the group consisting of H and an amine protecting group; and Y is a resolving group. [Invention 1020] The MLA compound of the present invention 1017, wherein the dividing group is a PEG unit selected from the group consisting of PEG 3 , PEG 6 , PEG 12 , and PEG 24 , where the subscript indicates the number of linearly linked repeat polyethylene glycol subunits. [Invention 1021] A1 comprises an azide or alkyne functional group that c