Conjugates for selective responsiveness to vicinal diols

1 . A compound represented by Formula I:

Z—R  (Formula I)

wherein, in Formula I,

R is selected from Formulae FF1-FF24; and

Z is selected from one of:

a) NH 2 or OH,

b) a covalent linkage, either directly or via an optional linker, to a drug substance, wherein the drug substance is insulin, a polypeptide, Drug substance, or a human peptide hormone, and wherein the insulin comprising human insulin or an analog thereof comprising 2 to 10 amino acids that are each independently modified as described by Formula I

c) a covalent linkage, either directly or via the optional linker, to an N-terminal amine or an epsilon amino group of one or more amino acids in a polypeptide drug substance, and

d) a group represented by J—SCH 2-ø , J—S(CH 2 ) 2 —ø, J—NH—ø, J—NH—(the optional linker)-ø, J—S(CH 2 ) k NH—ø, or J-triazole(CH 2 ) k NH—ø;

wherein —ø is the covalent bond towards R;

index k is an integer in the range of 3 to 14; and

J is an amino acid or one or more amino acids in a polypeptide drug substance, wherein each of the one or more amino acids in the polypeptide drug substance is represented by Formula I′:

wherein, in Formula I′,

indicate points of attachment to remaining portions of the polypeptide drug substance;

* indicates the point of attachment to the remaining portion of Z; and

index n is an integer in the range of 1 to 8,

wherein for Formulae FF1-FF24:

X represents a covalent linkage, either directly or via the optional linker, towards Z in Formula I;

index i is an integer in the range of 1 to 20;

B 1 and B 2 are identical or different, and each independently represent a group selected from Formulae F1-F9; and

B 3 represents a group selected from Formulae F1-F11,

wherein, for each of Formulae F1-F9:

one R 1 represents (C═O)—, S(═O)(═O)—, (CH 2 ) m (C═O)—, or (CH 2 ) m —, wherein —represents a covalent bond to the remainder of R in Formula I;

none, one, or two R 1 each independently represent F, Cl, Br, OH, CH 2 —NH 2 , NH 2 , (C═O)—NH 2 , SO 2 CH 3 , CF 3 , NO 2 , CH 3 , OCH 3 , O(CH 2 ) m CH 3 , —(SO 2 )NH CH 3 , —(SO 2 )NH(CH 2 ) m CH 3 , or OCF 3 ,

index m is an integer in the range of 1 to 14;

one R 1 in F5 represents B(OH) 2 , and

all remaining R 1 represent H, and

in Formula F10, index j is an integer in the range of 1 to 13.

2 . The compound of claim 1 , wherein the optional linker is an L- or D-amino acid having at least one functional group directly conjugated to R, or the optional linker is selected from Formulae FL1-FL9:

wherein, in Formulae FL1-FL9:

Z″ represents a covalent bond towards Z;

R″ represents a covalent bond towards R;

p is an integer in the range of 1 to 5;

q is an integer in the range of 1 to 5; and

r is an integer in the range of 1 to 5.

3 . The compound claim 1 , wherein the compound is a drug substance that is additionally modified as described by claim 1 and/or wherein one or more amines are each independently acetylated or alkylated.

4 . The compound of claim 1 , wherein the insulin comprises an A-chain and/or the B-chain comprising one or two peptide sequences added to the A-chain and/or the B-chain of the insulin, and each peptide sequence independently comprises 1 to 20 continuous residues.

5 . The compound of any one of claim 1 , wherein the insulin is further conjugated either directly or through the optional linker to a polypeptide including up to 31 amino acids.

6 . The compound of any one of claim 1 , wherein the insulin conjugated at the N- or C-terminus of the A- or B-chain to a polypeptide including up to 31 amino acids.

7 . The compound of any one of claim 4 , wherein the insulin is conjugated at the N- or C-terminus of the A- or B-chain to a polypeptide including up to 31 amino acids and the polypeptide is connected to the insulin through a peptide bond.

8 . The compound of any one of claim 1 , wherein between 1-10 amino acids are appended to the polypeptide sequence of insulin and these are appended N-terminal to residue 1 of the B-chain of insulin and wherein the residue that is inserted at N-terminal to residue 1 is a modified amino acid described by Formulae I.

9 . The compound of any one of claim 1 wherein the insulin has 4 or 5 intramolecular disulfide bonds.

10 . The compound of any one of claim 1 , wherein the insulin is linked to a polypeptide including up to 31 amino acids and the side chains of at least two amino acids in the polypeptide sequence are covalently linked together or through the optional linker.

11 . The compound of any one of claim 1 , wherein the insulin is covalently conjugated using an amide bond to structures described by Formulae F411-F416 or structures comprising a structure in which F411 is further covalently conjugated using amide bonds to structures described by Formulae F412-F416,

wherein R represents a primary or secondary amine either in the N-terminus of the insulin, or, a primary or secondary amine in the side chains of a subset of amino acids in the insulin, and wherein the attachment to R is the point of attachment towards the insulin; index n represents an integer in the range of 1 to 14, index m represents an integer in the range of 1 to 12, index o represent an integer in the range of 1 to 6, index p represents an integer in the range of 1 to 12, Z represents one of —(C═O)—OH, —NH 2 , a cholesterol, 7-OH cholesterol, 7,25-dihydroxycholesterol, cholic acid, chenodeoxycholic acid, lithocholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, glycolithocholic acid, glycochenodeoxycholic acid, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, αtocotrienol, β-tocotrienol, γ-tocotrienol or δ-tocotrienol.

12 . The compound of any one of claim 1 , wherein the drug substance includes one or more of structures represented by Formulae FX15-FX28:

wherein,

each R 1 is independently selected from H, NH 2 , NO 2 , Cl, CF 3 , I, COCH 3 , CN, C≡CH, N 3 , or Br;

each R 2 is independently selected from CF 3 , H, or CH 3 ;

each R 3 is independently selected from C≡CH, H, N 3 , or a vinyl group;

each R 4 is independently selected from NH 2 , R 2 or R 3 ;

each R 5 is independently selected from S or NH; and

the index n is an integer in the range of 1 to 4.