β-glucuronide-linker drug conjugates

1. A ligand drug conjugate compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L- is a Ligand unit;

-A a -W w —Y y — is a Linker unit (LU),

-A- is an optional Stretcher unit,

a is 0, 1 or 2,

each —W— is independently a Glucuronide unit having one of the formulae:

Su is a Sugar moiety

each R is independently hydrogen, a halogen, —CN, or —NO 2 ;

w is an integer ranging from 1 to 2,

—Y— is an optional self-immolative spacer unit,

y is 0, 1 or 2;

p ranges from 1 to 20;

-D is a Drug unit and wherein the wavy lines indicates covalent attachment within rest of the compound.

2. The ligand drug conjugate compound of claim 1 , wherein L is an antibody.

3. The ligand drug conjugate compound of claim 2 , wherein the antibody is a humanized, chimeric, or human antibody or an antigen binding antibody fragment of an antibody.

4. The ligand drug conjugate compound of claim 3 , wherein the antibody binds to CD19, CDD30, CD33, and CD70.

5. The ligand drug conjugate compound of claim 4 , wherein the antibody binds to CD30 or CD70.

6. The ligand drug conjugate compound of claim 1 ,

wherein w is 1.

7. The ligand drug conjugate compound of claim 6 , having one of the following formulae:

8. The ligand drug conjugate compound of claim 7 , having the formula:

9. The ligand drug conjugate compound of claim 8 , having the formula:

10. The ligand drug conjugate compound of claim 9 , having the formula:

wherein mAb is a monoclonal antibody.

11. The ligand drug conjugate compound of claims 1 , 6 , 7 , 8 , 9 or 10 , wherein the Drug moiety is selected from Formulas D E and D F :

or a pharmaceutically acceptable salt or solvate thereof; and the wavy line of D F and D E indicates a covalent attachment to a Linker Unit or a Ligand Unit;

wherein, independently at each location:

R 2 is selected from H or C 1 -C 8 alkyl;

R 3 is selected from 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 or X 1 —(C 3 -C 8 heterocycle);

R 4 is selected from 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 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 H, C 1 -C 8 alkyl or C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6;

R 6 is selected from H and C 1 -C 8 alkyl;

R 7 is selected from 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);

each R 8 is independently selected from H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle or O—(C 1 -C 8 alkyl);

R 9 is selected from H and C 1 -C 8 alkyl;

R 10 is selected from aryl and C 3 -C 8 heterocycle;

Z is O, S, NH, or NR 12 , wherein R 12 is C 1 -C 8 alkyl;

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

m is an integer ranging from 0-1000;

R 13 is C 2 -C 8 alkyl;

R 14 is H or C 1 -C 8 alkyl;

each occurrence of R 15 is independently H, COOH, —(CH 2 ) n —N(R 16 ) 2 , —(CH 2 ) n —SO 3 H, or —(CH 2 ) n —SO 3 —C 1 -C 8 alkyl;

each occurrence of R 16 is independently H, C 1 -C 8 alkyl, or —(CH 2 ) n —COOH;

R 18 is selected from —C(R 8 ) 2 —C(R 8 ) 2 -aryl, —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8 heterocycle), or —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8 carbocycle);

X 1 is C 1 -C 10 alkylene; and

n is an integer ranging from 0 to 6.

12. The ligand drug conjugate compound of claim 1 , wherein D is Formula D F :

and the wavy line of D F indicates a covalent attachment to a Linker Unit or a Ligand Unit.

13. The ligand drug conjugate compound of claim 1 , wherein D has the formula:

and the wavy line of D indicates a covalent attachment to a Linker Unit or a Ligand Unit.

14. The ligand drug conjugate compound of claim 1 , wherein D is has the Formula D E :

and the wavy line of D E indicates a covalent attachment to a Linker Unit or a Ligand Unit.

15. The ligand drug conjugate compound of claim 14 , wherein D has the formula:

and the wavy line of D indicates a covalent attachment to a Linker Unit or a Ligand Unit.

16. The ligand drug conjugate compound of claim 1 , wherein p is 2 to about 6.

17. The ligand drug conjugate compopund of claim 1 , wherein p is 2 to about 4.

18. The ligand drug conjugate compound of claim 6 wherein A is selected from the formulae:

wherein R 17 is C 1 -C 10 alkylene-, —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-, —(CH 2 CH 2 O) r —, —(CH 2 CH 2 O) r —CH 2 —; —(CH 2 CH 2 O) r — —CH 2 —CH 2 —; and r is an integer ranging from 1-10.

19. The ligand drug conjugate compound of claim 18 , wherein A is selected from the formulae:

20. The ligand drug conjugate compound of claim 1 , wherein D is doxorubicin, calicheamicin, staurosporine, amino CBI minor groove binder SN26597 or DM1.

21. A pharmaceutical composition comprising an effective amount of the ligand drug conjugate compound of claim 1 , and a pharmaceutically acceptable diluent, carrier or excipient.

22. The pharmaceutical composition of claim 21 further comprising a therapeutically effective amount of a chemotherapeutic agent.

23. The ligand drug conjugate compound of claim 6 , wherein a is 1 or 2.

24. The ligand drug conjugate compound of claim 1 , wherein Y is a carbonyl group (—CO)— or a p-aminobenzyl alcohol group whose phenylene portion is substituted with Q m wherein Q is C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, -nitro or -cyano; and m is an integer ranging from 0-4.

25. The ligand drug conjugate compound of claim 6 , having the formula:

26. The ligand drug conjugate compound of claim 25 , wherein D has the formula:

and the wavy line of D indicates a covalent attachment to a Linker Unit or a Ligand Unit.

27. The ligand drug conjugate compound of claim 25 , wherein D has the formula:

and the wavy line of D indicates a covalent attachment to a Linker Unit or a Ligand Unit.