US 12,433,950 B2
Conjugation linkers, cell binding molecule-drug conjugates containing the linkers, methods of making and uses such conjugates with the linkers
Yongxin Robert Zhao, Hangzhou (CN); Qingliang Yang, Hangzhou (CN); Yuanyuan Huang, Hangzhou (CN); Hangbo Ye, Hangzhou (CN); and Huihui Guo, Hangzhou (CN)
Assigned to HANGZHOU DAC BIOTECH CO., LTD., Hangzhou (CN)
Filed by Hangzhou DAC Biotech Co., Ltd., Hangzhou (CN)
Filed on Jun. 8, 2022, as Appl. No. 17/835,395.
Application 17/835,395 is a division of application No. 16/348,749, previously published as PCT/CN2016/105799, filed on Nov. 14, 2016.
Prior Publication US 2022/0313838 A1, Oct. 6, 2022
Int. Cl. A61K 47/68 (2017.01)
CPC A61K 47/6803 (2017.08) [A61K 47/68031 (2023.08); A61K 47/68035 (2023.08); A61K 47/6829 (2017.08); A61K 47/6831 (2017.08); A61K 47/6855 (2017.08); A61K 47/6863 (2017.08); A61K 47/6883 (2017.08); A61K 47/6889 (2017.08)] 9 Claims
OG exemplary drawing
 
1. A linker compound of Formula (I) or (II):

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wherein
“custom character” and “custom character” represent a single bond, and “custom character” can be an enantiomer or stereoisomer bond when linked to a single or a double bond;
custom character represents either a single bond, or a double bond, or a triple bond;
provided that when custom character represents a single bond, both LV1 and LV2 are not H; when custom character represents a double bond, either LV1 or LV2 can be H, but they are not H at the same time; when custom character represents a triple bond, LV1 is absent and LV2 can optionally be H;
LV1 and LV2, represent H or a same or different leaving group that is optionally substituted by a thiol, and the leaving group is selected from the group consisting of a halide selected from fluoride, chloride, bromide, and iodide, methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethyl-sulfonyl (triflate), trifluoromethylsulfonate, nitrophenoxyl, N-succinimidyloxyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazole-1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl)oxyl, 2-ethyl-5-phenylisoxazolium-3′-sulfonyl, phenyloxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazolium-yl, phenyloxadiazol-yl (ODA), and oxadiazol-yl;
Y is a functional group that selected from the group consisting of following structures:

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 disulfide;

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 haloacetyl;

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 acyl halide (acid halide);

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 N-hydroxysuccinimide ester;

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 maleimide;

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 monosubstituted maleimide;

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 disubstituted maleimide;

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 monosubstituted succinimide;

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  disubstituted succinimide; —CHO aldehyde;

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 ethenesulfonyl;

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 acryl (acryloyl);

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 2-(tosyloxy)acetyl;

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 2-(mesyloxy)acetyl;

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 2-(nitrophenoxy)acetyl;

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 (dinitrophenoxy)acetyl;

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 2-(fluorophenoxy)-acetyl;

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 2-(difluorophenoxy)-acetyl;

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 2-(((trifluoromethyl)-sulfonyl)oxy)acetyl;

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 ketone, or aldehyde,

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 2-(pentafluorophenoxy)acetyl;

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 methylsulfonephenyloxadiazole (ODA);

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 acid anhydride,

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 alkyloxyamino;

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 azido,

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 alkynyl and

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 hydrazide, wherein X1′ is F, Cl, Br, I or LV3; X2′ is O, NH, N(Ria), or CH2; R3 and R5 are independently H, R1a, aromatic, heteroaromatic, or aromatic group wherein one or several H atoms are replaced independently by —R1a, -halogen, —OR1a, —SR1a, —NR1aR2, —NO2, —S(O)R1a, —S(O)2R1a, or —COOR1a; LV3 is a leaving group selected from the group consisting of nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3′-sulfonate, and anhydrides formed its self, or formed with acetyl anhydride, or formyl anhydride; R1a is selected from the group consisting of H, C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; C2-C8 ester, ether, amide, amine, imine, polyamine, hydrazine, hydrazone, urea, semicarbazide, carbazide, alkoxyamine, alkoxylamine, urethane, amino acid, acyloxylamine, glycoside, or hydroxamic acid: peptide containing 1-8 amino acids, or polyethyleneoxy unit of formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 1000, and a combination thereof;
R1 is absent;
T is

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 wherein custom character is the site of linkage,
X2, X3, and X5 each are NHNH;
m, m1, m2, m3, m4 and m5 are independently an integer from 1 to 10,
L1 is alkylcarbonyl;
L2, and X1 are absent.