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

1. A compound of the formula Ib:

L A a -W w -Y y -D) p   Ib

or a pharmaceutically acceptable salt thereof

wherein,

L- is a Ligand unit;

-A- is a Stretcher unit;

a is 0 or 1;

each -W- is independently an Amino Acid unit;

-Y- is a Spacer unit;

w is an integer ranging from 2 to 12;

y is 0, 1 or 2;

p ranges from 1 to about 20; and

-D is a Drug unit of the formula

wherein, independently at each location:

R 1 is selected from the group consisting of —H, —C 1 -C 8 alkyl and -C 3 -C 8 carbocycle; and R 2 is selected from the group consisting of 13 H and 13 C 1 -C 8 alkyl; or R 1 and R 2 join, 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 2, 3, 4, 5 or 6, and form a ring with the nitrogen atom to which they are attached;

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) wherein R 5 is —H or -methyl; or R 4 and R 5 join, 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 2, 3, 4, 5 or 6, and form a ring with the carbon atom to which they are attached;

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 —H or —C 1 -C 8 alkyl;

R 10 is selected from the group consisting of

wherein the wavy line adjacent to X indicates the point of attachment to Y when Y is present, or to W when Y is not present, and the remaining wavy line indicates the point of attachment to the nitrogen atom bearing R 10 ;

X is —O—, —S—, —NH— or —N(R 14 )—, where X is bonded to Y when y is 1 or 2, or X is bonded to W when y is 0;

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, —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);

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

R 15 is selected from the group consisting of -arylene-, —C 3 -C 8 carbocyclo and —C 3 -C 8 heterocyclo-.

2. A compound or a pharmaceutically acceptable salt of the compound of claim 1 where -D is a Drug unit having the structure

or a pharmaceutically acceptable salt thereof,

wherein, independently at each location:

R 1 is —H or -methyl;

R 2 is —H or -methyl;

R 3 is —H, -methyl, or -isopropyl;

R 5 is —H or -methyl; R 4 is -isopropyl, -isobutyl, -sec-butyl, -methyl or t-butyl or R 4 and R 5 join, have the formula —(CR a R b ) n —where 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 2, 3, 4, 5or 6, and form a ring with the carbon atom to which they are attached;

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

where X is —O—, —NH— or —N(R 14 )— and forms a bond with Y when y is 1 or 2, with W when y is 0,;

Z is —O—, —NH— or —N(R 14 )—;

R 13 is —H or -methyl;

R 14 is C 1 -C 8 alkyl; and

R 15 is -arylene-, —C 3 -C 8 carbocyclo- or —C 3 -C 8 heterocyclo-.

3. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein R 10 is selected from:

4. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein when R 1 is —H, R 10 is selected from the group consisting of

5. The compound or a pharmaceutically acceptable salt of the compound of claim 2 wherein when R 1 is —H, R 10 is selected from the group consisting of

6. A compound or a pharmaceutically acceptable salt of the compound of claim 1 where -D is a Drug unit having the structure:

wherein the wavy line indicates the point of attachment to the remainder of the compound.

7. A compound or a pharmaceutically acceptable salt of the compound of claim 1 where -D is a Drug unit having the structure

wherein the wavy line indicates the point of attachment to the remainder of the compound.

8. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where -A- is present and is

wherein the wavy line adjacent to the 5-membered ring indicates the point of attachment to L, and the wavy line adjacent to the carbonyl indicates the point of attachment to W, and r is an integer ranging from 1-10.

9. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where -A- is present and is

wherein the wavy line adjacent to the 5-membered ring indicates the point of attachment to L, and the wavy line adjacent to the carbonyl indicates the point of attachment to W.

10. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where -W W - is -Phenylalanine-Lysine- or -valine-citrulline-, the amino terminus of -W W forming a bond with a Stretcher unit when a is 1 or with a Ligand unit if a is 0, and the C- terminus of -W w - forming a bond with a Spacer unit when y is 1or 2, and with a Drug unit when y is 0.

11. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof,

where L- is Ligand unit, E is —CH 2 — or —CH 2 CH 2 O—; e is an integer ranging either from 0-10 when E is —CH 2 —, or 1-10 when E is —CH 2 CH 2 —O—; F is —CH 2 —; f is 0 or 1; and p ranges from 1 to about 20.

12. The compound of claim 1 having the structure

where p ranges from 1 to about 20, or a pharmaceutically acceptable salt thereof.

13. A compound or a pharmaceutically acceptable salt of the compound of claim 1 where the Ligand unit is an antibody unit.

14. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where the antibody unit is a monoclonal antibody unit.

15. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where the antibody unit is immunospecific for a cancer cell antigen.

16. The compound or a pharmaceutically acceptable salt of the compound of claim 1 where p ranges from about 3 to about 5.

17. A compound of the formula

or a pharmaceutically acceptable salt thereof

wherein, independently at each location:

R 1 is selected from —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle; and R 2 is selected from —H and —C 1 -C 8 alkyl; or R 1 and R 2 join, 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, and form a ring with the nitrogen atom to which they are attached;

R 3 is selected from —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 —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) wherein R 5 is selected from —H and -methyl; or R 4 and R 5 join, 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, and form a ring with the carbon atom to which they are attached;

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, —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 —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;

Z is —O—, —S—, —NH— or —N(R I4 )—;

X is —O—, —S—, —NH— or —N(R I4 )—;

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

R 13 is selected from —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);

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

R 15 is selected from -arylene-, —C 3 -C 8 carbocyclo- and —C 3 -C 8 heterocyclo-;

R 16 is -Yy-Ww-A′

wherein

each -W- is independently an Amino Acid unit;

-Y- is a Spacer unit;

w is an integer ranging from 2 to 12;

y is 0, 1 or 2; and

-A′ is selected from

wherein the wavy line adjacent to the carbonyl indicates the point of attachment to W;

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

J is selected from the group consisting of —C 1 , —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 alkylene)-, -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 —;

r is an integer ranging from 1-10; and

R 18 is —C 1 -C 8 alkyl or -aryl.

18. The compound of claim 17 having the structure

or a pharmaceutically acceptable salt or solvate thereof.

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

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