Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors

A Ligand Drug Conjugate (LDC) composition, wherein the composition is represented by the structure of:

• or a pharmaceutically acceptable salt thereof, wherein
• L is a Ligand Unit;
• D is a NAMPT Drug Unit represented by the general structure of:
• or a pharmaceutically acceptable salt thereof, wherein
• the wavy line indicates the site of covalent attachment to LO or LR, depending on the presence or absence of LO;
• HN is a NAMPT Head Unit, wherein the NAMPT Head Unit is a C5-C24 heteroaryl or partially aromatic C9-C24 heterocyclyl, optionally substituted, wherein the C5-C24 heteroaryl or partially aromatic C9-C24 heterocyclyl is comprised of an optionally substituted 5- or 6-membered nitrogen-containing heteroaromatic ring system corresponding to the heterocycle of nicotinamide, and is capable of interacting with enzymatically competent NAMPT homodimer at its nicotinamide mononucleotide binding site when the NAMPT Drug Unit is released from a Ligand Drug Conjugate compound of the composition as a NAMPT inhibitor (NAMPTi) compound or derivative thereof;
• DA is a Donor-Acceptor Unit wherein the Donor-Acceptor Unit is or is comprised of a hydrogen bond donor acceptor functional group and is bonded to a carbon skeletal atom at position 2 or 3 of the 5-membered nitrogen-containing heteroaromatic ring system or at position 3 or 4 of the 6-membered nitrogen-containing heteroaromatic ring system, with optional formal cyclization of DA back to an adjacent skeletal carbon atom of the 6-membered nitrogen-containing heteroaromatic ring system through an introduced optionally substituted non-aromatic carbon atom or an optionally substituted nitrogen, oxygen or sulfur atom resulting in a partially aromatic or fully aromatic fused 6,5- or 6,6-ring system,
• wherein said bonding of DA is in relation to a skeletal nitrogen atom of the 5- or 6 membered nitrogen-containing heteroaromatic ring system and wherein said formal cyclization to the adjacent carbon atom of the 6-membered nitrogen-containing heteroaromatic ring system substantially retains the hydrogen bonding capability of the donor acceptor functional group of DA in absence of said cyclization;
• IN is an Interconnecting Unit, wherein the Interconnecting Unit is or is comprised of —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 is comprised of an optionally substituted amino-alcohol residue or a carboxylic acid-alcohol residue, the —O— or optionally substituted nitrogen of which is the site of covalent attachment to LO, or LR, depending on the presence or absence of LO, or
• TN is or is comprised of an optionally substituted benzamide moiety, the amide nitrogen atom of which is bonded to IN with optional cyclization of that atom back to IN or to the remainder of TN, and the aromatic ring of which is at least substituted with a hydroxyl, thiol or amino residue, the —O—, —S— or optionally substituted nitrogen atom of which at position 3 or 4 relative to the site at which the amide carbonyl carbon atom is attached is the site of covalent attachment to LO or LR, depending on the presence or absence of LO, or
• TN is or is comprised of an optionally substituted aryl or biaryl moiety, an aromatic skeletal atom of which is bonded to IN, or to the remainder of TN, and wherein an aromatic ring of which is at least substituted with a hydroxyl, thiol or an amino residue, the —O—, —S— or optionally substituted nitrogen of which is the site of covalent attachment to LO or LR, depending on the presence or absence of LO, respectively;
• and
• 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,
• LR is a primary linker, which interconnects the Ligand Unit and Drug Unit optionally through LO, as indicated, which is an optional 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 an first optional Stretcher;
• and
• B is a Branching Unit, when subscript b is 1 and subscript n is 2, 3 or 4, or B is absent, so that subscript b is 0, when subscript n is 1,
• wherein each of A and B is an independently selected single unit or is optionally comprised or consists of at least two, three or four independently selected subunits;
• Y is a Spacer Unit;
• and subscript y is 0, 1 or 2, indicating the absence or presence of one or two of Y, respectively,
• provided that when subscript y is 1, Y is a Spacer Unit covalently attached to a heteroatom or moiety thereof of TN selected from the group consisting of —O—, —S— and optionally substituted nitrogen,
• provided that when subscript y is 2 so that Yy is —Y—Y, Y is a first Spacer Unit and Y′ is a second Spacer Unit or a functional group comprised of the optionally substituted heteroatom from TN;
• and
• provided that subscript y is 1 or 2 when W is a Glucuronide Unit of formula Y(W′), in which instance subscript y is inclusive of a first Spacer Unit Y, wherein that Spacer Unit is a required self-immolative Spacer Unit;
• and
• subscript w is 0 or 1, indicating the absence or presence, respectively, of W;
• wherein
• when subscript w is 1, W is a Peptide Cleavable Unit or said Glucuronide Unit in which W′ represents a carbohydrate moiety with glycosidic bonding to the required self-immolative Spacer Unit through an optionally substituted heteroatom, wherein enzymatic or non-enzymatic cleavage of either Unit initiates release of the NAMPT Drug Unit as a NAMPTi compound or derivative thereof from a drug linker moiety of a compound comprising the Ligand Drug Conjugate composition;
• and
• when subscript w is 0, which indicates the absence of a Cleavable Unit, enzymatic or non-enzymatic cleavage of the bond between LR and LO, when LO is present, or the bond between LR and D, when LO is absent, initiates release of the NAMPT Drug Unit as a NAMPTi compound or derivative thereof;
• subscript p is an average drug linker moiety loading when subscript n is other than 1 or an average drug loading when subscript n is 1, wherein subscript p in either instance is a number ranging from about 1 to about 24;
• and
• wherein a compound comprising the Ligand Drug Conjugate composition corresponds in structure to that of Formula 1 or Formula 2 in which p is replaced by p′, wherein p′ is an integer ranging from 1 to 24.