Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics

1. A Drug-Linker Compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein

D is a hydrophobic Drug Unit corresponding in structure to a hydrophobic cytotoxic, cytostatic or immunosuppressive agent;

PEG is a Polyethylene Glycol Unit, wherein the Polyethylene Glycol Unit has the formula of:

wherein the wavy line indicates the site of covalent attachment to L P ;

R 20 is a PEG Attachment Unit, wherein the PEG Attachment Unit is —C(O)—, —O—, —S—, —S(O)—, —NH—, —C(O)O—, —C(O)C 1 -C 10 alkyl, —C(O)C 1 -C 10 alkyl-O—, —C(O)C 1 -C 10 alkyl-CO 2 —, —C(O)C 1 -C 10 alkyl-NH—, —C(O)C 1 -C 10 alkyl-S—, —C(O)C 1 -C 10 alkyl-C(O)—NH—, —C(O)C 1 -C 10 alkyl-NH—C(O)—, —C 1 -C 10 alkyl, —C 1 -C 10 alkyl-O—, —C 1 -C 10 alkyl-CO 2 —, —C 1 -C 10 alkyl-NH—, —C 1 -C 10 alkyl-S—, —C 1 -C 10 alkyl-C(O)—NH—, —C 1 -C 10 alkyl-NH—C(O)—, —CH 2 CH 2 SO 2 —C 1 -C 10 alkyl-, —CH 2 C(O)—C 1-10 alkyl-, ═N—(O or N)—C 1 -C 10 alkyl-O—, ═N—(O or N)—C 1 -C 10 alkyl-NH—, ═N—(O or N)—C 1 -C 10 alkyl-CO 2 —, ═N—(O or N)—C 1-10 alkyl-S—,

R 21 is a PEG Capping Unit; wherein the PEG Capping Unit is —C 1 -C 10 alkyl, —C 2 -C 10 alkyl-CO 2 H, —C 2 -C 10 alkyl-OH, —C 2 -C 10 alkyl-NH 2 , C 2 -C 10 alkyl-NH(C 1 -C 3 alkyl), or C 2 -C 10 alkyl-N(C 1 -C 3 alkyl) 2 ;

R 22 is an PEG Coupling Unit for coupling multiple PEG subunit chains together, wherein the PEG Coupling Unit is —C 1-10 alkyl-C(O)—NH—, —C 1-10 alkyl-NH—C(O)—, —C 2-10 alkyl-NH—, —C 2 -C 10 alkyl-O—, —C 1 -C 10 alkyl-S—, or —C 2 -C 10 alkyl-NH—;

subscript n is independently selected from 8 to 72;

subscript e is selected from 2 to 5;

each n′ is independently selected from 6 to 72;

Z′ is a Stretcher Unit, wherein the Stretcher Unit comprises maleimide moiety capable of reacting with a thiol functional group from an antibody or antigen-binding fragment thereof to form a thio-substituted succinimide moiety, or wherein the Stretcher Unit has the structure of:

wherein

the wavy line adjacent to R 17 indicates the site of covalent attachment to L P ; and

R 17 is —C 1 -C 10 alkylene-, —C 1 -C 10 heteroalkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 heteroalkylene-C(═O)—, —C 3 -C 8 carbocyclo-C(═O)—, —O—(C 1 -C 8 alkyl)-C(═O)—, -arylene-C(═O)—, —C 1 -C 10 alkylene-arylene-C(═O)—, -arylene-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-C(═O)—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 3 -C 8 heterocyclo-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-C(═O)—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-NH—, C 1 -C 10 heteroalkylene-NH—, —C 3 -C 8 carbocyclo-NH—, —O—(C 1 -C 8 alkyl)-NH—, -arylene-NH—, —C 1 -C 10 alkylene-arylene-NH—, -arylene-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-NH—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-NH—, —C 3 -C 8 heterocyclo-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-NH—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-S—, C 1 -C 10 heteroalkylene-S—, —C 3 -C 8 carbocyclo-S—, —O—(C 1 -C 8 alkyl)-S—, -arylene-S—, —C 1 -C 10 alkylene-arylene-S—, -arylene-C 1 -C 10 alkylene-S—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-S—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-S—, —C 3 -C 8 heterocyclo-S—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-S— or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-S—,

wherein R 17 is optionally substituted by —(CH 2 ) x NH 2 , —(CH 2 ) x NHR a or —(CH 2 ) x NR a 2 , wherein subscript x is an integer selected from 1-4 and each R a is independently C 1-6 alkyl, or two R a groups are combined with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl;

X is a Releasable Assembly Unit, wherein each Releasable Assembly Unit is capable of releasing free drug upon enzymatic cleavage of the Releasable Assembly Unit; and wherein the Releasable Assembly Unit has the formula of:

wherein Q CO is an optional Covalent Attachment Unit;

Q SP is an optional Spacer Unit;

Q CL is a Cleavable Unit; and

the asterisk indicates the site of covalent attachment to the Drug Unit; and the wavy line indicates covalent attachment to L P or A,

wherein the Cleavable Unit is a peptide Cleavable Unit comprising an amino acid or is a peptide sequence with a cleavable bond to Q SP or D, depending on the presence or absence, respectively, of Q SP , wherein said cleavable bond is capable of enzymatic cleavage by a tumor associated protease for said releasing of free drug; and

wherein the Spacer Unit when present comprises a para-aminobenzyl (PAB) moiety that is linked to the amino acid or peptide sequence of the peptide Cleavable Unit via the amino nitrogen atom of the PAB moiety, and is connected directly to the Drug Unit via a carbonate, carbamate or ether functional group, wherein the PAB moiety and the adjacent carbonyl group of the carbonate or carbamate functional group that is part of the Spacer Unit, or wherein the Spacer Unit has the formula of:

wherein Q is —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, -nitro or -cyano; and subscript m is an integer selected from 0-4; and

the wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the dipeptide of the peptide Cleavable Unit and the wavy line adjacent to carbonyl carbon atom indicates the site of covalent attachment to an oxygen or nitrogen atom of the Drug Unit,

or

wherein the Cleavable Unit has the formula of:

wherein Su is a Sugar moiety;

—O′— represents an oxygen glycosidic bond that is capable of enzymatic cleavable by a glycosidase for said free drug release;

each R is independently hydrogen, a halogen, —CN, or —NO 2 ; and wherein the wavy line indicates the site of covalent attachment to L P or A, depending on the absence or presence of A, respectively, either directly or indirectly through the Covalent Attachment Unit, and the asterisk indicates the site of covalent attachment to the Drug Unit, either directly or indirectly through the Spacer Unit; and

the Spacer Unit when present is —C(═O)—;

L P is a Parallel Connector Unit that connects the Stretcher Unit to the hydrophobic Drug Unit(s) through intermediacy of a Releasable Assembly Unit for each Drug Unit, and connects the Polyethylene Glycol Unit in parallel orientation relative to the hydrophobic Drug Unit(s) and wherein the Parallel Connector Unit or subunit thereof has the structure of:

wherein subscript n is an integer selected from 1 to 4;

X p is selected from the group consisting of —O—, —NH—, —S—, —S(═O)—, —C(═O)—, and —C 2 -C 8 heterocyclo-; and

R 1 and R 2 are independently selected from the group consisting of —H, —C 1 -C 3 alkyl, -phenyl and —C 2 -C 5 heterocycle; and

the wavy lines indicate the sites of covalent attachment within the Drug-Linker Compound, or

the Parallel Connector Unit or subunit thereof has the formula of:

wherein R 100 is independently selected from the group consisting of —H and —C 1 -C 3 alkyl; and

R 110 is selected from the group consisting of:

wherein the asterisk indicates the site of covalent attachment to the carbon labeled x and the wavy lines indicate the sites of covalent attachments within the Drug-Linker Compound, or

the Parallel Connector Unit or subunit thereof is a trifunctional amino acid residue, or has the structure of:

wherein the wavy lines indicate the sites of covalent attachment within the Drug-Linker compound;

A is an optional Branching Unit;

subscript m is an integer ranging from 1 to 4; and

subscript s is 0 or 1, with the proviso that when subscript s is 0, subscript m is 1 and when subscript s is 1, subscript m is 2, 3 or 4.

2. The Drug-Linker Compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Drug-Linker Compound has the structure of:

3. The Drug-Linker Compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Drug-Linker Compound has the structure of:

4. The Drug-Linker Compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Drug-Linker Compound has the structure of:

wherein R 21 is a PEG Capping Unit and subscript n is an integer ranging from 6 to 72.

5. The Drug-Linker Compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Drug-Linker Compound has the structure of

wherein R 21 is a PEG Capping Unit selected from the group consisting of methyl, ethyl, and propyl, and subscript n is an integer ranging from 6 to 72.

6. The Drug-Linker Compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Drug-Linker Compound has the structure of:

7. The Drug-Linker compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein

the PEG Capping Unit is methyl, ethyl, or propyl; and

subscript n is an integer ranging from 8 to 24.

8. A Drug-Linker Compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of:

9. A Drug-Linker Compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of:

10. A Ligand-Drug Conjugate compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

L is a Ligand Unit, which is an antibody or antigen-binding fragment thereof;

D is a hydrophobic Drug Unit corresponding in structure to a hydrophobic cytotoxic, cytostatic or immunosuppressive agent;

PEG is a Polyethylene Glycol Unit, wherein the Polyethylene Glycol Unit has the formula of:

wherein the wavy line indicates the site of covalent attachment to L P ;

R 20 is a PEG Attachment Unit, wherein the PEG Attachment Unit is —C(O)—, —O—, —S—, —S(O)—, —NH—, —C(O)O—, —C(O)C 1 -C 10 alkyl, —C(O)C 1 -C 10 alkyl-O—, —C(O)C 1 -C 10 alkyl-CO 2 —, —C(O)C 1 -C 10 alkyl-NH—, —C(O)C 1 -C 10 alkyl-S—, —C(O)C 1 -C 10 alkyl-C(O)—NH—, —C(O)C 1 -C 10 alkyl-NH—C(O)—, —C 1 -C 10 alkyl, —C 1 -C 10 alkyl-O—, —C 1 -C 10 alkyl-CO 2 —, —C 1 -C 10 alkyl-NH—, —C 1 -C 10 alkyl-S—, —C 1 -C 10 alkyl-C(O)—NH—, —C 1 -C 10 alkyl-NH—C(O)—, —CH 2 CH 2 SO 2 —C 1 -C 10 alkyl-, —CH 2 C(O)—C 1-10 alkyl-, ═N—(O or N)—C 1 -C 10 alkyl-O—, ═N—(O or N)—C 1 -C 10 alkyl-NH—, ═N—(O or N)—C 1 -C 10 alkyl-CO 2 —, ═N—(O or N)—C 1 -C 10 alkyl-S—,

R 21 is a PEG Capping Unit; wherein the PEG Capping Unit is —C 1 -C 10 alkyl, —C 2 -C 10 alkyl-CO 2 H, —C 2 -C 10 alkyl-OH, —C 2 -C 10 alkyl-NH 2 , C 2 -C 10 alkyl-NH(C 1 -C 3 alkyl), or C 2 -C 10 alkyl-N(C 1 -C 3 alkyl) 2 ;

R 22 is an PEG Coupling Unit for coupling multiple PEG subunit chains together, wherein the PEG Coupling Unit is —C 1-10 alkyl-C(O)—NH—, —C 1-10 alkyl-NH—C(O)—, —C 2-10 alkyl-NH—, —C 2 -C 10 alkyl-O—, —C 1 -C 10 alkyl-S—, or —C 2 -C 10 alkyl-NH—;

subscript n is independently selected from 8 to 72;

subscript e is selected from 2 to 5;

each n′ is independently selected from 6 to 72;

Z is a Stretcher Unit, wherein the Stretcher Unit comprises a succinimide moiety that is connected to a thiol functional group from the antibody or antigen-binding fragment thereof to form a thio-substituted succinimide moiety, or wherein the Stretcher Unit has the structure of:

wherein

the asterisk indicates covalent attachment of each Z to the Ligand Unit and the wavy line adjacent to R 17 indicates the site of covalent attachment to L P ; and

R 17 is —C 1 -C 10 alkylene-, —C 1 -C 10 heteroalkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 heteroalkylene-C(═O)—, —C 3 -C 8 carbocyclo-C(═O)—, —O—(C 1 -C 8 alkyl)-C(═O)—, -arylene-C(═O)—, —C 1 -C 10 alkylene-arylene-C(═O)—, -arylene-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-C(═O)—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 3 -C 8 heterocyclo-C(═O)—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-C(═O)—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-C(═O)—, —C 1 -C 10 alkylene-NH—, C 1 -C 10 heteroalkylene-NH—, —C 3 -C 8 carbocyclo-NH—, —O—(C 1 -C 8 alkyl)-NH—, -arylene-NH—, —C 1 -C 10 alkylene-arylene-NH—, -arylene-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-NH—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-NH—, —C 3 -C 8 heterocyclo-NH—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-NH—, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-NH—, —C 1 -C 10 alkylene-S—, C 1 -C 10 heteroalkylene-S—, —C 3 -C 8 carbocyclo-S—, —O—(C 1 -C 8 alkyl)-S—, -arylene-S—, —C 1 -C 10 alkylene-arylene-S—, -arylene-C 1 -C 10 alkylene-S—, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-S—, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-S—, —C 3 -C 8 heterocyclo-S—, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-S— or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-S—,

wherein R 17 is optionally substituted by —(CH 2 ) x NH 2 , —(CH 2 ) x NHR a or —(CH 2 ) x NR a 2 , wherein subscript x is an integer selected from 1-4 and each R a is independently C 1-6 alkyl, or two R a groups are combined with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl;

X is a Releasable Assembly Unit, wherein each Releasable Assembly Unit is capable of releasing free drug upon enzymatic cleavage of the Releasable Assembly Unit; and wherein the Releasable Assembly Unit has the formula of:

wherein Q CO is an optional Covalent Attachment Unit;

Q SP is an optional Spacer Unit;

Q CL is a Cleavable Unit; and

the asterisk indicates the site of covalent attachment to the Drug Unit; and the wavy line indicates covalent attachment to L P or A,

wherein the Cleavable Unit is a peptide Cleavable Unit comprising an amino acid or is a peptide sequence with a cleavable bond to Q SP or D, depending on the presence or absence, respectively, of Q SP , wherein said cleavable bond is capable of enzymatic cleavage by a tumor associated protease for said releasing of free drug; and

wherein the Spacer Unit when present comprises a para-aminobenzyl (PAB) moiety that is linked to the amino acid or peptide sequence of the peptide Cleavable Unit via the amino nitrogen atom of the PAB moiety, and is connected directly to the Drug Unit via a carbonate, carbamate or ether functional group, wherein the PAB moiety and the adjacent carbonyl group of the carbonate or carbamate functional group that is part of the Spacer Unit, or wherein the Spacer Unit has the formula of:

wherein Q is —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, -nitro or -cyano; and subscript m is an integer selected from 0-4; and

the wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the dipeptide of the peptide Cleavable Unit and the wavy line adjacent to carbonyl carbon atom indicates the site of covalent attachment to an oxygen or nitrogen atom of the Drug Unit,

or

wherein the Cleavable Unit has the formula of:

wherein Su is a Sugar moiety;

—O′— represents an oxygen glycosidic bond that is capable of enzymatic cleavable by a glycosidase for said free drug release;

each R is independently hydrogen, a halogen, —CN, or —NO 2 ; and wherein the wavy line indicates the site of covalent attachment to L P or A, depending on the absence or presence of A, respectively, either directly or indirectly through the Covalent Attachment Unit, and the asterisk indicates the site of covalent attachment to the Drug Unit, either directly or indirectly through the Spacer Unit; and

the Spacer Unit when present is —C(═O)—;

L P is a Parallel Connector Unit that connects the Stretcher Unit to the hydrophobic Drug Unit(s) through intermediacy of a Releasable Assembly Unit for each Drug Unit, and connects the Polyethylene Glycol Unit in parallel orientation relative to the hydrophobic Drug Unit(s) and wherein the Parallel Connector Unit or subunit thereof has the structure of:

wherein subscript n is an integer selected from 1 to 4;

X p is selected from the group consisting of —O—, —NH—, —S—, —S(═O)—, —C(═O)—, and —C 2 -C 8 heterocyclo-; and

R 1 and R 2 are independently selected from the group consisting of —H, —C 1 -C 3 alkyl, -phenyl and —C 2 -C 5 heterocycle; and

the wavy lines indicate the sites of covalent attachment within the Ligand-Drug Conjugate compound, or

the Parallel Connector Unit or subunit thereof has the formula of:

wherein R 100 is independently selected from the group consisting of —H and —C 1 -C 3 alkyl; and

R 110 is selected from the group consisting of:

wherein the asterisk indicates the site of covalent attachment to the carbon labeled x and the wavy lines indicate the sites of covalent attachments within the Ligand-Drug Conjugate compound, or

the Parallel Connector Unit or subunit thereof is a trifunctional amino acid residue, or has the structure of:

wherein the wavy lines indicate the sites of covalent attachment within the Ligand-Drug Conjugate compound;

A is an optional Branching Unit;

subscript m is an integer ranging from 1 to 4;

subscript s is 0 or 1, with the proviso that when subscript s is 0, subscript m is 1 and when subscript s is 1, subscript m is 2, 3 or 4; and

subscript p is an integer ranging from 1 to 14.

11. The Ligand-Drug Conjugate compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the PEG Unit is

12. The Ligand-Drug Conjugate compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 20 is —C(O)—, and R 21 is C 1 -C 10 alkyl.

13. The Ligand-Drug Conjugate compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Z is

14. The Ligand-Drug Conjugate compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

R 17 is —C 1 -C 10 alkylene-C(═O)—, optionally substituted by —(CH 2 ) x NH 2 .

15. The Ligand-Drug Conjugate compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein the Cleavable Unit has the formula:

16. The Ligand-Drug Conjugate compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the Spacer Unit is —C(═O)—.

17. The Ligand-Drug Conjugate compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein L P has the structure of:

18. The Ligand-Drug Conjugate compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 100 is H and R 110 has the structure of:

19. The Ligand-Drug Conjugate compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein D is an auristatin Drug Unit represented by the structure of formula D E :

wherein, independently at each location:

R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;

R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 5 is selected from the group consisting of H and methyl;

or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;

R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;

R 7 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

each R 8 is independently selected from the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 8 alkyl);

R 9 is selected from the group consisting of H and C 1 -C 8 alkyl; and

R 18 is selected from the group consisting of —C(R 8 ) 2 —C(R 8 ) 2 -aryl, —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8 heterocycle), and —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8 carbocycle).

20. The Ligand-Drug Conjugate compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of:

wherein

R PR is hydrogen or a protecting group; and

subscript n is 8, 10, 12, or 24.

21. A Ligand-Drug Conjugate compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of:

wherein L is a Ligand Unit, which in an antibody or antigen-binding fragment thereof, and

wherein subscript p is an integer ranging from 1 to 14.

22. A Ligand-Drug Conjugate compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of:

wherein L is a Ligand Unit, which in an antibody or antigen-binding fragment thereof, and

wherein subscript p is an integer ranging from 1 to 14.

23. A pharmaceutical composition comprising a population of Ligand-Drug Conjugate compounds or pharmaceutically acceptable salts thereof of claim 21 , wherein the average p value for the population of Ligand-Drug Conjugate compounds ranges from 1 to 14.

24. The pharmaceutical composition of claim 23 , wherein the average p value for the population of Ligand-Drug Conjugate compounds ranges from 6 to 12.

25. A pharmaceutical composition comprising a population of Ligand-Drug Conjugate compounds or pharmaceutically acceptable salts thereof of claim 22 wherein the average p value for the population of Ligand-Drug Conjugate compounds ranges from 1 to 14.

26. The pharmaceutical composition of claim 25 , wherein the average p value for the population of Ligand-Drug Conjugate compounds ranges from 6 to 12.