Hydrophilic linkers for antibody drug conjugates

1. A compound, pharmaceutically acceptable salt, stereoisomer, regioisomer, or a mixture of regioisomers thereof of Formula (Va), (Vb), (Vc) or (Vd) respectively:

wherein:

BA is an antibody or antigen binding fragment thereof;

RG 1 and RG 2 are independently a reactive group residue selected from the group consisting of

wherein the

indicates the atom through which the RG 1 or RG 2 is bonded to the adjacent groups in the formula;

PA is a payload residue;

AA 2 is a dipeptide, tripeptide, or tetrapeptide residue comprising amino acid residues selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline;

PAB is

wherein the

indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

subscript e is an integer from 0 to 6;

subscript n is an integer from 1 to 30;

subscript p is 0 or 1;

subscript q is 0 or 1; and

HG is selected from the following:

(a)

(b)

(c)

or

(d)

wherein the

indicates the atom through which the HG is bonded to the adjacent groups in the formula.

2. The compound of claim 1 , wherein subscript n is 1, 2, 3 or 4.

3. The compound of claim 1 , wherein RG 1 and RG 2 are independently, in each instance, selected from the group consisting of

wherein the

indicates the atom through which the RG 1 or RG 2 is bonded to the adjacent groups in the formula.

4. The compound of claim 1 , wherein HG is

wherein the

indicates the atom through which the HG is bonded to the adjacent groups in the formula.

5. The compound of claim 1 , wherein HG is

wherein the

indicates the atom through which the HG is bonded to the adjacent groups in the formula.

6. The compound of claim 1 , wherein HG is

wherein the

indicates the atom through which the HG is bonded to the adjacent groups in the formula.

7. The compound of claim 1 , wherein HG is

wherein the

indicates the atom through which the HG is bonded to the adjacent groups in the formula.

8. The compound of claim 1 , having a structure selected from the group consisting of:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein

each

is a bond to the antibody or antigen binding fragment thereof; and

each

is a bond to the payload residue.

9. The compound of claim 1 , having a structure selected from the group consisting of:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein

each

is a bond to the antibody or antigen binding fragment thereof; and

each

is a bond to the payload residue.

10. The compound of claim 1 , wherein AA 2 is

wherein R AA2 , R AA3 , R AA4 , and R AA5 are each, independently, an amino acid side chain residue selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline, wherein the

indicates the atom through which AA 2 is bonded to the adjacent groups in the formula.

11. The compound of claim 1 , wherein AA 2 is

wherein the

indicates the atom through which AA 2 is bonded to the adjacent groups in the formula.

12. The compound of claim 1 , wherein subscript e is 4.

13. The compound of claim 1 , wherein BA is an antibody.

14. The compound of claim 1 , wherein the binding agent (BA) is an antibody, or an antigen-binding fragment thereof, selective for an antigen selected from the group consisting of AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10 or f54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248,CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD46, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2, CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSFIR, CTLA4, CXCR1/2, CXCR4, CXCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HER2, HHLA2, HLA class II, HVEM, ICOSLG, IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, Integrins, LAG3, LIFR, MAG/Siglec-4, MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1, Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, TCR-list components/assoc, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, TROY, TSLPR, TYRO, VLDLR, VSIG4, and VTCN1.

15. The compound of claim 1 , wherein PA is the residue of a compound selected from the group consisting of a dolastatin, an auristatin, a maytansinoid, a plant alkaloid, a taxane, a vinca alkaloid, a steroid, and a liver X receptor (LXR) modulator.

16. The compound of claim 1 , selected from the group consisting of:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein

each Ab is the antibody, or an antigen-binding fragment thereof;

PA is the payload residue; and

subscript n is an integer from 1 to 30.

17. The compound of claim 1 , selected from the group consisting of:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein

each Ab is the antibody, or an antigen-binding fragment thereof; and

subscript n is an integer from 1 to 30.

18. The compound of claim 1 , wherein BA is a modified antibody of formula (Ab-1)

wherein the

indicates the atom through which Ab-1 is bonded to the adjacent groups in the formula.

19. A compound selected from the group consisting of:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein

each Ab is an antibody, or an antigen-binding fragment thereof; and

subscript n is an integer from 1 to 30.

20. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. The compound of claim 1 , wherein BA is an antigen binding fragment thereof.

22. The compound of claim 13 , wherein the antibody is the anti HER2 antibody.

23. The compound of claim 1 , wherein p is 1.

24. The compound of claim 1 , wherein AA 1 is L-lysine.

25. The compound of claim 1 , wherein AA 1 is D-lysine.

26. The compound of claim 1 , wherein AA 1 is L-glutamic acid.

27. The compound of claim 1 , wherein AA 1 is D-glutamic acid.

28. The compound of claim 1 , wherein AA 1 is L-aspartic acid.

29. The compound of claim 1 , wherein AA 1 is D-aspartic acid.