MONOMETHYLVALINE COMPOUNDS CAPABLE OF CONJUGATION TO LIGANDS

1 . A method for treating cancer comprising administering to a patient in need thereof an effective amount of an antibody-drug conjugate having Formula Ia′:

A b A a -W w —Y y -D) p   Ia′

or a pharmaceutically acceptable salt thereof, wherein:

Ab is an antibody that specifically binds to an antigen expressed by the cancer,

A is a Stretcher unit,

a is 1,

each W is independently an Amino Acid unit,

w is an integer ranging from 2 to 12,

Y is a Spacer unit, and

y is 1 or 2,

p ranges from 1 to about 20, and

D is a drug moiety of Formula D F :

wherein the wavy line of D F indicates the covalent attachment site to Y:

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

R 3 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 4 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(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 and 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, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

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

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

R 10 is selected from aryl or 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 1-1000;

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 ), —COOH; and

n is an integer ranging from 0 to 6.

2 . The method of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof, 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 —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1-10.

3 . The method of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 3 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

5 . The method of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

6 . The method of claim 1 , wherein Z is —O— and R 11 is —H, methyl or t-butyl

7 . The method of claim 6 , wherein R 11 is —H.

8 . The method of claim 1 , wherein R 2 and R 6 are each methyl, and R 9 is —H.

9 . The method of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof; wherein Val is valine, and Cit is citrulline.

10 . The method of claim 9 , wherein the antibody is a monoclonal antibody.