US 11,654,197 B2
Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
Ho Young Song, Daejeon (KR); Sung Min Kim, Daejeon (KR); Hyoungrae Kim, Daejeon (KR); Kyung Eun Park, Daejeon (KR); Chul-Woong Chung, Daejeon (KR); Yun Hee Park, Daejeon (KR); Hyo Jung Choi, Daejeon (KR); Su In Lee, Daejeon (KR); Juyuel Baek, Daejeon (KR); Hyeun Joung Lee, Daejeon (KR); Ju Young Lee, Daejeon (KR); Ji Hye Oh, Daejeon (KR); Jeiwook Chae, Daejeon (KR); Yeong Soo Oh, Daejeon (KR); and Yong Zu Kim, Daejeon (KR)
Assigned to LegoChem Biosciences, Inc., Youseong-gu (KR)
Appl. No. 16/328,256
Filed by LegoChem Biosciences, Inc., Daejeon (KR)
PCT Filed Mar. 29, 2018, PCT No. PCT/KR2018/003744
§ 371(c)(1), (2) Date Feb. 25, 2019,
PCT Pub. No. WO2018/182341, PCT Pub. Date Oct. 4, 2018.
Claims priority of application No. 10-2017-0039841 (KR), filed on Mar. 29, 2017; and application No. 10-2018-0036895 (KR), filed on Mar. 29, 2018.
Prior Publication US 2022/0218830 A1, Jul. 14, 2022
Int. Cl. A61K 47/55 (2017.01); A61P 35/00 (2006.01)
CPC A61K 47/552 (2017.08) [A61P 35/00 (2018.01)] 18 Claims
1. A conjugate of Chemical Formula IIIa, IIIb, or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
a dotted line represents an optional double bond;
ligand is an protein;
R1 is selected from H, OH, ═O, ═CH2, CN, Rm, ORm, halo, and dihalo;
Rm′ is selected from Rm, CO2Rm, CORm, CHO, CO2H, and halo;
Rm is selected from optionally substituted C1-12 alkyl, optionally substituted C6 aryl, optionally substituted C6 heteroaryl, and optionally substituted C3-6 cycloalkyl, wherein the optional substituent is C1-12 alkyl;
R2, R3, and R5 are each independently selected from H, Rm, OH, ORm, NH2, NHRm, NRmRm′, NO2, and halo;
R4 is selected from H, Rm, OH, ORm, NH2, NHRm, NRmRm, NO2, halo, C1-6 alkyl, or C1-6 alkoxy;
Rn, Ro, Rp, and Rq are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, and 5- to 7-membered heteroaryl;
X and X′ are each independently selected from —C(O)O—, —C(O)—, and —C(O)NR—;
Xa and Xa′ are each independently a bond or C1-6 alkylene;
Y and Y′ are each independently selected from O, S, and N(H);
R6 is a substituted or unsubstituted saturated or unsaturated C3-12 hydrocarbon chain, wherein the chain may comprise one or more heteroatoms, NMe, or a substituted or unsubstituted aromatic ring, the chain or aromatic ring may be substituted with —NH, —NRm, —NHC(O)Rm, —NHC(O)CH2—[OCH2CH2]n—R, or —[CH2CH2O]n—R, wherein
n is 1 to 12;
R7 is H or C1-6 alkyl;
Za and Zb are each independently O, N, or S;
R12a, R13a, and R14a are each independently H, C1-6 alkyl: or wherein R13a and R14a combine with the carbon to which they are attached to form a - to 7-membered heterocyclyl;
R1′, R2′, R3′, R4′, and R5′ are as defined for R1, R2, R3, R4, and R5, respectively;
G and G′ denote a glucuronide group;
each Z and Z′ is selected from H, C1-8 alkyl, halo, NO2, CN,

OG Complex Work Unit Chemistry
R9, R10, and R16 are each independently selected from H, C1-8 alkyl, C2-6 alkenyl, C1-6 alkoxy, and methyloxyalkyl;
n is an integer from 1 to 3;
W is —C(O)—, —C(O)NR″—, or —C(O)O—,
R″ is H or C1-8 alkyl;
L is one or more units selected from a branching unit, a connection unit, and a binding unit or a combination of these units: wherein the connection unit connects W with a binding unit, W with a branching unit, a branching unit with another branching unit, or a branching unit with a binding unit, and the branching unit connects a connection unit with W or the connection unit with another connection unit;
the branching unit is a C2-100 alkenyl (wherein a carbon atom of the alkenyl may be substituted with one or more heteroatoms selected from the group consisting of N, O, and S and the alkenyl may be further substituted with one or more C1-20 alkyls), a hydrophilic amino acid, —C(O)—, —C(O)NR″″—, —C(O)O—, —(CH2)s—NHC(O)—(CH2)t—, —(CH2)u—C(O)NH—(CH2)v—, —(CH2)s—NHC(O)—(CH2)t—C(O)—, —(CH2)u—C(O)NH—(CH2)v—C(O)—, —S(O)2NR″″—, —P(O)R′″″NR″″—, —S(O)NR″″—, or —PO2NR″″—;
R″″ and R′″″ each independently denote H, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, mono- or di-C1-8 alkylamino, C3-20 heteroaryl, or C5-20 aryl;
s, t, u, and v are each independently an integer from 0 to 10;
the connection unit is —(CH2)r(V(CH2)p)q—;
r is an integer from 0 to 10;
p is an integer from 0 to 12;
q is an integer from 1 to 20;
V denotes a single bond, —O—, or S—;
the binding unit is

OG Complex Work Unit Chemistry
L1 is a single bond or C2-30 alkenyl;
R11 is H or C1-10 alkyl; and
L2 denotes C2-30 alkenyl.