US 12,084,403 B2
Linkers for antibody drug conjugates
Kyoji Tsuchikama, Houston, TX (US); Yasuaki Anami, Houston, TX (US); Chisato Tsuchikama, Houston, TX (US); Ningyang Zhang, Houston, TX (US); and Zhiqiang An, Houston, TX (US)
Assigned to THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM, Austin, TX (US)
Filed by THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM, Austin, TX (US)
Filed on Feb. 23, 2023, as Appl. No. 18/173,413.
Application 18/173,413 is a continuation of application No. 16/616,148, granted, now 11,629,122, previously published as PCT/US2018/034363, filed on May 24, 2018.
Claims priority of provisional application 62/510,505, filed on May 24, 2017.
Claims priority of provisional application 62/639,894, filed on Mar. 7, 2018.
Prior Publication US 2024/0059647 A1, Feb. 22, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07C 247/04 (2006.01); A61K 31/40 (2006.01); A61K 45/06 (2006.01); A61K 47/68 (2017.01); A61P 35/00 (2006.01); C07D 209/20 (2006.01); C07D 403/12 (2006.01)
CPC C07C 247/04 (2013.01) [A61K 31/40 (2013.01); A61K 47/6889 (2017.08); A61P 35/00 (2018.01); C07D 209/20 (2013.01); C07D 403/12 (2013.01); A61K 45/06 (2013.01)] 19 Claims
 
1. A compound of the formula:

OG Complex Work Unit Chemistry
wherein:
X1 is a covalent bond, alkanediyl(C≤12), or substituted alkanediyl(C≤12);
R1 is hydrogen, —(OCH2CH2)n1ZR6, or substituted —(OCH2CH2)n1ZR6, wherein:
n1 is 0-50; and
R6 is hydrogen, hydroxy, amine, mercapto, hydroxylamine, hydrazine, or azide; or
alkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), alkylhydrazine(C≤12), or a substituted version of any of these groups;
a polyglycine comprising from 1 to 6 glycine units; or
a substructure of the formula:

OG Complex Work Unit Chemistry
wherein:
 A1 and A2 are each independently absent or arenediyl(C≤12), substituted arenediyl(C≤12), heteroarenediyl(C≤12), or substituted heteroarenediyl(C≤12), and form a fused arene(C≤12), substituted arene(C≤12), heteroarene(C≤12), or substituted heteroarene(C≤12);
 A4 or A5 are each independently selected from a covalent bond, alkanediyl(C≤8), or substituted alkanediyl(C≤8);
 Rd, Re, Re′, and Rh are each independently selected from hydrogen, halo, sulfate, tosylate, mesylate, aryl(C≤8), or substituted aryl(C≤8);
 Rf is halo;
 Rg is amine, hydrazine, alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), substituted dialkylamino(C≤8), alkylhydrazine(C≤8), or substituted alkylhydrazine(C≤8);
 X4 is O, N, CH2, or X4 is alkanediyl(C≤8) or substituted alkanediyl(C≤8);
 R16 is hydroxy, amino, or oxo;
 R17 is carboxy; or
 alkyl(C≤12), amido(C≤12), aryl(C≤12), heteroaryl(C≤12), —C(O)NR20R20′, or a substituted version of any of these groups wherein:
 R20 and R20′ are each independently hydrogen; or
 alkyl(C≤12), aryl(C≤12), or a substituted version of either of these groups;
 R18 and R19 are each independently hydroxy, amino, halo; or
 alkyl(C≤12), aryl(C≤12), or a substituted version of either of these groups;
Z is a covalent bond, alkanediyl(C≤12), —C(O)-alkanediyl(C≤12), —C(O)-alkanediyl(C≤12)-C(O)NH—, or a substituted version of any of these groups;
R2 is hydrogen, alkyl(C≤12), substituted alkyl(C≤12), acyl(C≤12), substituted acyl(C≤12), or a monovalent amino protecting group;
W is a covalent bond or a polyvalent polymer having 3-21 connection points;
n3 is 1 to 20 provided that when W is a covalent bond then n3 is 1 and when W is a polyvalent polymer then n3 is less than or equal to one less than the number of connection points;
each X is independently a covalent bond, alkanediyl(C≤12), or substituted alkanediyl(C≤12);
each X2 is independently alkanediyl(C≤12) or substituted alkanediyl(C≤12);
each R3 is independently hydroxy, or amino; or
alkoxy(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups; or
—X9—C(O)R7, wherein:
X9 is O, —NRb—, or a covalent bond;
 Rb is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
R7 is hydroxy or amino; or
 alkoxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), or a substituted version of any of these groups; or
-A3SO2NR21R21′, -A3P(O)(OH)OR22, or -A3SO2OR22′, wherein:
A3 is O, —NRc—, or a covalent bond;
 Rc is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or a monovalent amino protecting group;
R21, R21′, R22, and R22′ are each independently hydrogen, alkyl(C≤12), cycloalkyl(C≤12), aryl(C≤12), heteroaryl(C≤12), aralkyl(C≤12), heteroaralkyl(C≤12), or a substituted version of any of these groups;
each R23 is independently the side chain moiety of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, a hydroxyl-protected version of tyrosine, or an amino-protected version of tryptophan; and
each R24 is independently the side chain moiety of alanine, ornithine, lysine, arginine, citrulline, or an amino-protected version thereof;
each Q is independently a group of the formula:

OG Complex Work Unit Chemistry
wherein:
each R5 is independently hydrogen or —C(O)—R8, wherein:
R8 is a chemotherapeutic agent;
each X5 is independently a covalent bond, O, S, —NH—, alkanediyl(C≤12), substituted alkanediyl(C≤12), —(OCH2CH2)n2—, or substituted —(OCH2CH2)n2—, wherein:
n2 is 0-50; or
a group of the formula:

OG Complex Work Unit Chemistry
wherein:
 Ra and Ra′ are each independently hydrogen, alkyl(C≤12), or substituted alkyl(C≤12);
 X6 is O or —NR26R26′—, wherein:
 R26 and R26′ are each independently alkyl(C≤12) or substituted alkyl(C≤12);
X7 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—, wherein:
 n3 is 0-50; or
 a group of the formula:

OG Complex Work Unit Chemistry
 wherein:
 Y is O or S;
 Y2 is O, S, —NH—, or —NR27—, wherein:
 R27 is alkyl(C≤12) or substituted alkyl(C≤12); and
 X8 is a covalent bond, O, S, —NH—, —(OCH2CH2)n3—, or substituted —(OCH2CH2)n3—;
or a pharmaceutically acceptable salt thereof.