Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

1. A compound of the Formula Ia:

L A a -W w -Y y -D) p   Ia;

or a pharmaceutically acceptable salt thereof,

wherein,

L— is a Ligand unit;

—A— is a Stretcher unit;

a is 1;

each —W— is independently an Amino Acid unit;

—Y— is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 20; and

—D is a Drug unit of the formula:

the wavy line indicates the point of attachment to the Spacer unit, and

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, —O—(C 1 -C 8 alkyl), -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 the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -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 heterocyle); R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 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 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, —O—(C 1 -C 8 alkyl), -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 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:

Z is —O—, —S—, —NH— or —N(R 14 )—;

R 11 is selected from the group consisting of —H, —OH, —NH 2 , NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -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); or R 11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;

each R 12 is independently selected from the group consisting of -aryl and C 3 -C 8 heterocycle;

R 13 is selected from the group consisting —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and —C 1-8 alkyl-(C 3 -C 8 heterocycle); and

each R 14 is independently —H or —C 1 -C 8 alkyl.

2. A compound of the formula Ia:

L A a —W w —Y y —D) p   Ia;

or a pharmaceutically acceptable salt thereof,

wherein,

L— is a Ligand unit;

—A— is a Stretcher unit;

a is 1

each —W— is independently an Amino Acid unit;

—Y— is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 20; and

—D is a Drug unit having the structure:

the wavy line indicates the point of attachment to the Spacer unit, and independently at each location:

R 2 is selected from the group consisting of —H and -methyl;

R 3 is selected from the group consisting of —H, -methyl, and -isopropyl;

R 4 is selected from the group consisting of —H and -methyl;

R 5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 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 n is selected the group consisting of 2, 3, 4, 5 and 6;

R 6 is selected from the group consisting of —H and -methyl;

each R 8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;

R 10 is selected from the group consisting of:

R 24 is selected from the group consisting of H and —C(O)R 25 —; R 25 is selected from the group consisting of —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);

A is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR 28 C(O)—; R 28 is selected from the group consisting of —H and —C 1 -C 8 alkyl;

n is 0 or 1; and

R 27 is selected from the group consisting of —H, —N 3 , —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) when n is 0; and R 27 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 1 -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) when n is 1.

3. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —D is a Drug unit having the structure:

4. The compound or a pharmaceutically acceptable salt of the compound of claim 1 or claim 2 wherein the Ligand unit is an antibody.

5. The compound or a pharmaceutically acceptable salt of the compound of claim 4 wherein the antibody is a monoclonal antibody.

6. The compound or a pharmaceutically acceptable salt of the compound of claim 5 wherein the monoclonal antibody specifically binds the CD30 antigen, the CD20 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD38 antigen, the CEA antigen, CD19 antigen, the CA15-3 antigen or the epidermal growth factor antigen.

7. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —Yy- is:

Q is selected from the group consisting of —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, -nitro and -cyano; and

m is an integer ranging from 0-4, the amino terminus of —Yy- forming a bond with the Amino acid unit and the other terminus of —Yy- forming a bond with the Drug unit.

8. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A— is:

and r is an integer ranging from 1-10, the carbonyl terminus of —A— forming a bond with the Amino Acid unit and the succinimido terminus of —A— brining a bond with the Ligand unit.

9. The compound or a pharmaceutically acceptable salt at the compound of claim 1 wherein —A— is:

and r is an integer ranging from 1-10, the carbonyl terminus of —A— forming a bond with the Amino Acid unit and the amidomethyl terminus of —A— forming a bond with the Ligand unit.

10. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A— is:

and r is an integer ranging from 1-10, the carbonyl terminus of —A— forming a bond with the Amino acid unit and the succinimido terminus of —A— forming a bond with the Ligand unit.

11. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A— is:

and r is an integer ranging from 1-10, the carbonyl terminus of —A— forming a bond with the Amino acid unit and the succinimido terminus of —A— forming a bond with the Ligand unit.

12. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A— is:

and r is an integer ranging from 1-10, the carbonyl terminus of —A— forming a bond with the Amino acid unit and the amidomethyl terminus of —A— forming a bond with the Ligand unit.

13. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A— is:

the carbonyl terminus of —A— forming a bond with the Amino acid unit and the amidomethyl terminus of —A— forming a bond with the Ligand unit.

14. The compound or a pharmaceutically acceptable salt of the compound of claim 8 wherein —A— is:

the carbonyl terminus of —A— forming a bond with the Amino acid unit and the succinimido terminus of —A— forming a bond with the Ligand unit.

15. The compound or a pharmaceutically acceptable salt of the compound of claim 9 wherein —A— is:

the carbonyl terminus of —A— forming a bond with the Amino acid unit and the amidomethyl terminus of —A— forming a bond with the Ligand unit.

16. The compound or a pharmaceutically acceptable salt of the compound of claim 11 wherein —A— is:

the carbonyl terminus of —A— forming a bond with the Amino acid unit and the succinimido terminus of —A— forming a bond with the Ligand unit.

17. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —W w — is -Phenylalanine-Lysine-, the amino terminus of —W w — forming a bond with the Stretcher unit and the C-terminus of —W w — forming a bond with the Spacer unit.

18. A compound of the formula:

or a pharmaceutically acceptable salt thereof;

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, —O—(C 1 -C 8 alkoxy), -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 the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkoxy), -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 the group consisting of —H and -methyl: or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 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 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, —O—(C 1 -C 8 alkoxy), -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 the group consisting of —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkoxy);

R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;

R 11 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -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); or R 11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;

each R 12 is independently selected from the group consisting of -aryl and —C 3 -C 8 heterocycle;

R 13 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocyle, —O—(C 1 -C 8 alkoxy), -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 14 is independently —H or —C 1 -C 8 alkyl;

R 16 is A′a-Ww-Yy-

each —W— is independently an Amino Acid unit;

—Y— is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

—A′ is a Stretcher unit; and

a is 1.

19. The compound of claim 8 having the structure:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 18 having the structure:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 18 having the structure:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 18 having the structure:

a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 having the structure:

a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein L is a monoclonal antibody.

26. The compound or pharmaceutically acceptable salt thereof of claim 25 wherein L specifically binds the CD20 antigen.

27. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 or claim 2 , and a pharmaceutically acceptable carrier or vehicle.

28. The compound or a pharmaceutically acceptable salt thereof of claim 1 in an isolated or a purified form.

29. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —W w — is valine-citrulline, the amino terminus of —W w — forming a bond with the Stretcher unit, and the C-terminus of —W w — forming a bond with a the Spacer unit.

30. The Compound of claim 18 or a pharmaceutically acceptable salt of the Compound of claim 18 , wherein

—A′ is selected from the group consisting of:

G is selected from the group consisting of —Cl, —Br, —I, —O-mesyl and —O-tosyl;

J is selected from the group consisting of —Cl, —Br, —I, —F, —OH, —O—N-succinimide, —O-(4-nitrophenyl), —O-pentafluorophenyl, —O-tetrafluorophenyl and —O—C(O)—OR 18 ;

R 17 is selected from the group consisting of —C 1 -C 10 alkylene, —C 3 -C 8 carbocyclo, —O—(C 1 -C 8 alkoxy)-, -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 1 -C 10 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 —;

r is an integer ranging from 1-10; and

R 18 is —C 1 -C 10 or -aryl.

31. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 29 and a pharmaceutically acceptable carrier or vehicle.

32. The compound or a pharmaceutically acceptable salt thereof of claim 29 in an isolated or a purified form.

33. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein

—Aa-Ww-Yy- has the formula:

the succinimido terminus forming a bond with the Ligand unit and the other terminus forming a bond with the Drug unit.

34. The compound or a pharmaceutically acceptable salt of the compound of claim 2 wherein

—Aa-Ww-Yy- has the formula:

the succinimido terminus forming a bond with the Ligand unit and the other terminus forming a bond with the Drug unit.

35. The compound or a pharmaceutically acceptable salt of the compound of claim 33 or 34 wherein the ligand unit is a monoclonal antibody.

36. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein R 10 is

37. The compound or pharmaceutically acceptable salt thereof of claim 2 wherein R 10 is:

38. The compound or a pharmaceutically acceptable salt of the compound of claim 6 wherein the monoclonal antibody specifically binds the CD30 antigen.

39. The compound or a pharmaceutically acceptable salt of the compound at claim 6 wherein the monoclonal antibody specifically binds the CD19 antigen.

40. The compound or a pharmaceutically acceptable salt of the compound of claim 6 wherein the monoclonal antibody specifically binds the CD33 antigen.

41. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —A a — is:

R 17 is selected from the group consisting of —C 1 -C 10 alkylene, C 3 -C 8 carbocyclo, —O—(C 1 -C 8 alkyl)-, arylene-, —C 1 -C 10 alkylenearylene-, -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.

42. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein p ranges from 1 to about 5.

43. The compound of claim 33 having the structure:

or a pharmaceutically acceptable salt thereof.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein L is a monoclonal antibody.

45. The compound or pharmaceutically acceptable salt thereof of claim 25 wherein L specifically binds the CD20 antigen.

46. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 44 and a pharmaceutically acceptable carrier or vehicle.

47. The compound or a pharmaceutically acceptable salt thereof of claim 44 in an isolated or a purified form.

48. The compound or a pharmaceutically acceptable salt of the compound of claim 44 wherein p ranges from 1 to about 5.

49. The compound or a pharmaceutically acceptable salt of the compound of claim 43 wherein L is a monoclonal antibody that specifically binds the CD30 antigen, the CD20 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CEA antigen, the CA15-3 antigen or the epidermal growth factor antigen.

50. The compound or a pharmaceutically acceptable salt of the compound of claim 49 wherein the monoclonal antibody specifically binds the CD30 antigen.

51. A composition comprising drug-linker-ligand conjugates having Formula Ia:

L A a —W w —Y y —D) p   Ia

or a pharmaceutically acceptable sail thereof;

wherein,

L— is a Ligand unit;

—A— is a Stretcher unit;

a is 1;

each —W— is independently an Amino Acid unit;

—Y— is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 5 and is the average number of —A a —W w —Y y —D units per ligand in the composition; and

—D is a Drug unit of the formula:

the wavy line indicates the point of attachment to the Spacer unit, and 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, —O—(C 1 -C 8 alkyl), -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 the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -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 the group consisting of —H and -methyl; or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 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 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, —O—(C 1 -C 8 alkyl), -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 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:

Z is —O—, —S—, —NH— or —N(R 14 )—;

R 11 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -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); or R 11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;

each R 12 is independently selected from the group consisting of -aryl and —C 3 -C 8 heterocycle;

R 13 is selected from the group consisting of —H, —OH, —NHR 14 , N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and —C 1-8 alkyl-(C 3 -C 8 heterocycle); and

each R 14 independently —H or —C 1 -C 8 alkyl.

52. A composition comprising drug-linker-ligand conjugates having Formula Ia:

L A a —W w —Y y —D) p   Ia;

or a pharmaceutically acceptable salt thereof

wherein,

L— is a Ligand unit;

—A— is a Stretcher unit;

a is 1;

each —W— is independently an Amino Acid unit;

—Y— is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 5 and is the average number of —A a —W w —Y y —D units per ligand in the composition; and

—D is a Drug unit having the structure:

the wavy line indicates the point of attachment to the Spacer unit, and independently at each location:

R 2 is selected from the group consisting of —H and -methyl;

R 3 is selected from the group consisting of —H, -methyl, and -isopropyl;

R 4 is selected from the group consisting of —H and -methyl;

R 5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 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 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 -methyl;

each R 8 is independently selected from the group consisting —OH, -methoxy and -ethoxy;

R 10 is selected from the group consisting of:

R 24 is selected from the group consisting of H and —C(O)R 25 —; R 25 is selected from the group consisting of —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 2 -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);

Z is —O—, —NH—, —OC(O)—, NHC(O)—, or —NR 28 C(O)—: R 28 is selected from the group consisting of —H and —C 1 -C 8 alkyl;

n is 0 or 1; and

R 27 is selected from the group consisting of —H, —N 3 , —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) when n is 0; and

R 27 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,

—C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 1 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) when n is 1.

53. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R 10 is

54. The composition of claim 52 wherein in the drug-linker-ligand conjugates pharmaceutically acceptable salt thereof, R 10 is

55. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —D is a Drug unit having the structure:

56. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —Aa-Ww-Yy- has the formula:

the succinimido terminus forming a bond with the Ligand unit and the other terminus forming a bond with the Drug unit.

57. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —Aa-Ww-Yy- has the formula:

the succinimido terminus forming a bond with the Ligand unit and the other terminus forming a bond with the Drug unit.

58. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the ligand unit is a monoclonal anti body.

59. The composition of claim 58 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen, the CD20 antigen, the CD19 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD38 antigen, the CEA antigen, the CA15-3 antigen or the epidermal growth factor antigen.

60. The composition of 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD19 antigen.

61. The composition of claim 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

62. The composition of claim 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD33 antigen.

63. The composition of claim 57 wherein the drug-linker-ligand conjugates have the formula:

or a pharmaceutically acceptable salt thereof.

64. The composition of claim 63 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, L is a monoclonal antibody.

65. The composition of claim 64 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen, the CD30 antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CA15-3 antigen, the CEA antigen, or the epidermal growth factor antigen.

66. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

67. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD19 antigen.

68. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen.

69. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD33 antigen.

70. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, L is a monoclonal antibody.

71. The composition of claim 70 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen, the CD30 antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CA15-3 antigen, the CEA antigen, or the epidermal growth factor antigen.

72. The composition of claim 71 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

73. The composition of claim 64 wherein the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the antibody is attached to the drug moiety through a cysteine residue of the antibody.

74. The compound of claim 30 or a pharmaceutically acceptable salt of the compound of claim 20 , wherein

A a — is:

R 17 is selected from the group consisting of —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.

75. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein R 2 is —C 1 -C 8 alkyl.

76. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R 2 is —C 1 -C 8 alkyl.

77. The compound or a pharmaceutically acceptable salt of the compound of claim 2 wherein R 2 is -methyl.

78. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R 2 is -methyl.