BETA-GLUCURONIDE-LINKER DRUG CONJUGATES

1 . A compound having the structure of

or a salt thereof,

wherein D is a Drug Unit; and wherein one or more of the hydroxyl, amino and carboxylic acid functional groups are optionally protected.

2 . The compound of claim 1 wherein D is a DNA minor groove binding agent.

3 . The compound of claim 1 wherein D is anti-tubulin agent.

4 . The compound of claim 1 wherein D is an auristatin.

5 . The compound of claim 1 wherein D is of formula D E or D F :

wherein the wavy line indicates the point of covalent attachment to the remainder of the compound structure; and

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, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(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, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(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 subscript 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, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);

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;

R 10 is selected from the group consisting of aryl and C 3 -C 8 heterocycle;

Z is selected the group consisting of O, S, NH, and NR 12 , wherein R 12 is C 1 -C 8 alkyl;

R 11 is selected from the group consisting of H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(R 13 O) m —R 14 , and —(R 13 O) m —CH(R 15 ) 2 ;

subscript m is an integer ranging from 1-1000;

R 13 is C 2 -C 8 alkyl;

R 14 is is selected from the group consisting of H and C 1 -C 8 alkyl;

R 15 is independently selected from the group consisting of H, COOH, —(CH 2 ) n —N(R 16 ) 2 , —(CH 2 ) n —SO 3 H, and —(CH 2 ) n —SO 3 —C 1 -C 8 alkyl, wherein subscript n is an integer ranging from 0 to 6;

R 16 is independently selected from the group consisting of H, C 1 -C 8 alkyl, and —(CH 2 ) n —COOH;

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); and

X 1 is C 1 -C 10 alkylene.

6 . The compound of claim 5 wherein the compound has the structure of:

or a salt thereof.

7 . A method of preparing a Linker Unit precursor comprising the step of contacting a bi-functional Stretcher Unit having an activated carboxylic acid functional group and another functional group capable of forming a bond to a functional group of another Stretcher Unit, or to a functional group of a Ligand Unit, wherein the bond from said contact is an amide bond to the amino group of a suitably protected compound of formula 5,

wherein the Linker Unit precursor so prepared substantially retains the suitable protection of that protected compound.

8 . The method of claim 7 wherein the prepared Linker Unit precursor has the structure of formula 7:

9 . A method of preparing a drug-linker conjugate compound intermediate comprising

(a) converting the benzylic hydroxyl group of the Linker Unit precursor of claim 7 to an activated carbonate functional group;

(b) contacting the product of step a with a drug having an amino functional group to form a carbamate functional group so as to provide a drug-linker conjugate compound intermediate that substantially retains the suitable protection of the Linker Unit precursor and

(c) optionally deprotecting the protected drug-linker conjugate compound intermediate of step b.

10 . The method of claim 9 wherein the prepared drug-linker conjugate compound intermediate has the structure of:

wherein D is a Drug Unit from said contacting of the drug with the Ligand Unit precursor.

11 . The method of claim 10 , wherein D is a minor groove binder or antitubulin agent.

12 . The method of claim 10 , wherein D is an auristatin.

13 . The method of claim 12 , wherein D has the structure of:

wherein the wavy line indicates the point of covalent attachment to the remainder of the prepared drug-linker conjugate compound intermediate structure.