Monomethylvaline compounds having phenylalanine side-chain modification at the C-terminus

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:

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, 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, C 1 -C 8 alkyl-(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;

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, and C 3 -C 8 carbocycle;

each R 8 is independently O—(C 1 -C 8 alkyl);

the moiety —NR 9 Z 1 has the formula:

wherein

represents a single or double bond;

R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;

each R 16 is independently H or C 1 -C 20 alkyl;

the subscripts q, r and s are integers independently from 0 to 2;

Z 2 is COZ 3 R 19 ;

Z 3 is O;

R 19 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;

v is an integer ranging from 1-1000;

each X 1 is independently C 1 -C 10 alkylene;

R 22 is H or C 1 -C 8 alkyl;

each R 23 is independently H, COOH, —(CH 2 ) 1 —N(R 24 ) 2 , —(CH 2 ) 1 —SO 3 H or —(CH 2 ) 1 —SO 3 —C 1 -C 8 alkyl; and

each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) 1 —COOH; where 1 is an integer ranging from 0 to 6.

2. The compound of claim 1 , wherein the moiety —NR 9 Z 1 has the formula:

3. The compound of claim 1 , wherein the moiety —NR 9 Z 1 has the formula:

wherein Z 2 is CO 2 H; and the subscripts q, r and s are independently 1 or 2.

4. The compound of claim 1 , wherein the moiety —NR 9 Z 1 is

5. A compound having the formula:

L-((LU) 0-1 -(D) 1-4 ) p

or a pharmaceutically acceptable salt thereof

wherein,

L- is a Ligand Unit;

LU is a Linker Unit;

p is an integer ranging from 1 to about 20; and

D is a drug moiety having Formula D:

wherein,

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, 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, C 1 -C 8 alkyl-(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;

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, and C 3 -C 8 carbocycle;

each R 8 is independently O—(C 1 -C 8 alkyl);

the moiety —NR 9 Z 1 has the formula:

wherein

represents a single or double bond;

R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;

each R 16 is independently H or C 1 -C 20 alkyl;

the subscripts q, r and s are integers independently from 0 to 2;

Z 2 is COZ 3 R 19 ;

Z 3 is O;

R 19 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;

v is an integer ranging from 1-1000;

each X 1 is independently C 1 -C 10 alkylene;

R 22 is H or C 1 -C 8 alkyl;

each R 23 is independently H, COOH, —(CH 2 ) 1 —N(R 24 ) 2 , —(CH 2 ) 1 —SO 3 H or —(CH 2 ) 1 —SO 3 —C 1 -C 8 alkyl; and

each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) 1 —COOH; where 1 is an integer ranging from 0 to 6.

6. A compound of claim 5 , having the formula:

L-LU-D

or a pharmaceutically acceptable salt thereof.

7. A compound having the formula:

LU-(D) 1-4

or a pharmaceutically acceptable salt thereof

wherein,

LU- is a Linker Unit; and

D is a drug moiety having the Formula D:

wherein,

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, 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, C 1 -C 8 alkyl-(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;

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, and C 3 -C 8 carbocycle;

each R 8 is independently O—(C 1 -C 8 alkyl);

the moiety —NR 9 Z 1 has the formula:

wherein

represents a single or double bond;

R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;

each R 16 is independently H or C 1 -C 20 alkyl;

the subscripts q, r and s are integers independently from 0 to 2;

Z 2 is COZ 3 R 19 ;

Z 3 is O;

R 19 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;

v is an integer ranging from 1-1000;

each X 1 is independently C 1 -C 10 alkylene;

R 22 is H or C 1 -C 8 alkyl;

each R 23 is independently H, COOH, —(CH 2 ) 1 —N(R 24 ) 2 , —(CH 2 ) 1 —SO 3 H or —(CH 2 ) 1 —SO 3 —C 1 -C 8 alkyl; and

each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) 1 —COOH; where 1 is an integer ranging from 0 to 6.

8. The compound according to claim 5 , having Formula Ia′:

Ab-(A a -W w -Y y -(D) 1-4 ) p   Ia′

or a pharmaceutically acceptable salt thereof, wherein:

Ab is an antibody,

A is a Stretcher unit,

a is 0 or 1,

each W is independently an Amino Acid unit,

w is an integer ranging from 0 to 12,

Y is a Spacer unit, and

y is 0, 1 or 2.

9. The compound of claim 8 having the formula:

Ab-(D) p .

10. The compound of claim 8 , wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

11. The compound of claim 10 wherein p is 2 to 5.

12. The compound of claim 8 wherein p is 2 to 8.

13. The compound of claim 10 having the formula:

wherein L is an antibody and 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 —, or —(CH 2 CH 2 O) r —CH 2 —; and r is an integer of from 1-10.

14. The compound of claim 13 having the formula:

wherein w and y are each 0.

15. The compound of claim 13 wherein D has the formula:

16. The compound of claim 8 having the formula:

17. The compound of claim 8 having the formula:

18. The compound of claim 8 having the formula:

19. The compound of claim 16 wherein D has the formula:

20. The compound of claim 8 having the formula:

wherein n is 0 or 1.

21. The compound of claim 8 wherein w is an integer ranging from 2 to 12.

22. The compound of claim 8 wherein w is 2.

23. The compound of claim 22 wherein W w is -valine-citrulline-.

24. The compound of claim 8 , wherein the antibody is a monoclonal antibody.

25. The compound of claim 8 , wherein the antibody is a bispecific antibody.

26. The compound of claim 8 , wherein the antibody is a chimeric antibody.

27. The compound of claim 8 , wherein the antibody is a humanized antibody.

28. The compound of claim 8 , wherein the antibody is an antibody fragment.

29. The compound of claim 28 , wherein the antibody fragment is a Fab fragment.

30. The compound of claim 1 wherein the compound has the structure of: