Patent ID: 11931414
Assignee: SEAGEN INC.
Field: Pharmaceuticals (Chemistry)
Classification: CPC A  C | IPC A  C

Claim 0:
1. A Ligand Drug Conjugate compound represented by Formula 1:, in salt form, wherein
L is a Ligand Unit which is an antibody or an antigen-binding fragment thereof,
W is a Peptide Cleavable Unit, or
W—Y is replaced by a Glucuronide Unit of formula —Y(W′), wherein W′ represents a carbohydrate moiety with glycosidic bonding to Y through an optionally substituted heteroatom; and
Y is a self-immolative Spacer Unit comprising a PAB or PAB-type moiety;
D+ is a quaternized NAMPT Drug Unit covalently attached to the remainder of the Formula 1 compound structure through a quaternized skeletal aromatic nitrogen atom of an optionally substituted C5-C24 heteroaryl of D+, or a quaternized skeletal non-aromatic nitrogen atom of a partially unsaturated or partially aromatic optionally substituted C9-C24 heterocyclyl of D+,
wherein the quaternized NAMPT Drug Unit is represented by the general structure of:, or a salt thereof, wherein
HN+ is a quaternized NAMPT Head Unit as the quaternized component of D+ wherein the optionally substituted C5-C24 heteroaryl or partially unsaturated or partially aromatic optionally substituted C9-C24 heterocyclyl of HN+ comprises a 5- or 6-membered nitrogen-containing partially unsaturated or heteroaromatic ring system, the skeletal nitrogen atom of which is the site of quaternization to LO, as indicated by the wavy line to HN+;
DA is a Donor-Acceptor Unit wherein the Donor-Acceptor Unit is or comprises a hydrogen bond donor or acceptor functional group and is bonded to a carbon skeletal atom at position 2 or 3 of the 5-membered nitrogen-containing partially unsaturated or heteroaromatic ring system or at position 3 or 4 of the 6-membered nitrogen-containing partially unsaturated or heteroaromatic ring system, with optional formal cyclization of DA back to an adjacent skeletal carbon atom of the 6-membered nitrogen-containing ring system through an introduced optionally substituted non-aromatic carbon atom or an optionally substituted nitrogen, oxygen or sulfur atom resulting in a partially unsaturated, partially aromatic or fully aromatic 6,5- or 6,6-fused ring system,
wherein said bonding of DA is in relation to a skeletal nitrogen atom of the 5- or 6-membered nitrogen-containing partially unsaturated or heteroaromatic ring system and wherein said formal cyclization to the adjacent carbon atom of the 6-membered nitrogen-containing partially unsaturated or heteroaromatic ring system substantially retains the hydrogen bonding ability of the donor or acceptor functional group of DA in absence of said cyclization;
IN is an Interconnecting Unit, wherein the Interconnecting Unit is or comprises —X1—[C(═O)]0,1—, —X1—S(═O)1,2—, —X2—C6-C24 arylene-[C(═O)]0,1—, —X2—C6-C24 arylene-[S(═O)1,2]0,1, —X2—C6-C24 arylene-O—, —X2—C5-C24 heteroarylene-[C(═O)0,1]-, —X2—C5-C24 heteroarylene-[S(═O)1,2]0,1, —X2—C5-C24 heteroarylene-O— or —X2—C3-C20 heterocyclo-[C(═O)0,1]-, wherein the arylene, heteroarylene and heterocyclo are optionally substituted;
X1 is optionally substituted C5-C7 alkylene;
X2 is absent or is an optionally substituted C1-C4 alkylene;
TN is a NAMPT Tail Unit, wherein the NAMPT Tail Unit is or comprises an optionally substituted amino-alcohol residue or a carboxylic acid-alcohol residue, the amino nitrogen or carbonyl carbon of which is bonded to IN, or
TN is or comprises an optionally substituted benzamide moiety or a bioisostere thereof, wherein the amide nitrogen atom of the benzamide moiety is bonded to IN with optional cyclization of that atom back to IN or to the remainder of TN, or
TN is or comprises an optionally substituted C6-C24 aryl, C5-C24 heteroaryl or a biaryl comprising two independently selected C6-C24 aryl or C5-C24 heteroaryl rings, each of which is optionally substituted, an aromatic atom of which is bonded to IN or the remainder of TN,
wherein TN or the remainder thereof is bonded to IN, wherein said remainder is an optionally substituted C2-C7 heteroalkylene or an optionally substituted C5-C6 heterocyclo, and
wherein non-enzymatic or enzymatic action on W/W′ of a drug linker moiety of a Ligand Drug Conjugate compound is capable of initiating release of the quaternized NAMPT Drug (D+) Unit as a NAMPTi compound of formula HN-DA-IN-TN, wherein HN is a NAMPT Head Unit that is a fully aromatic optionally substituted C5-C24 heteroaryl comprising a 5- or 6-membered nitrogen-containing heteroaromatic ring system having the previously quaternized skeletal nitrogen atom, and the other variable groups are as previously defined,
wherein HN— or HN-DA- of the NAMPTi compound is capable of interacting with enzymatically competent NAMPT homodimer at its nicotinamide binding site; and
LR is a primary linker that interconnects the Ligand Unit and the quaternized NAMPT Drug Unit through LO, wherein LO is a secondary linker;
subscripts a and b independently are 0 or 1, indicating the absence or presence, respectively, of A or B;
subscript n is 1, 2, 3 or 4;
A is a first optional Stretcher Unit;
B is a Branching Unit when subscript b is 1 and subscript n is 2, 3 or 4, and B is absent when subscript b is 0 and subscript n is 1,
wherein each of A and B is an independently selected single unit or optionally comprises or consists of two, three or four independently selected subunits; and
subscript p′ is an integer ranging from 1 to 24.