Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof

1. A compound having a structure represented by formula (II)

wherein

n is 0, 1, or 2;

R 1 , R 2 and R 3 are independently H, unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted aryl, unsubstituted or to substituted heteroaryl, unsubstituted or substituted (CH 2 ) 1-2 O(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkynyl), (CH 2 ) 1-2 OC(═O)(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted C(═O)(C 1 -C 10 alkyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, or unsubstituted or substituted alkylaryl;

R 4 is

R 5 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, CO(C 1 -C 5 alkyl), CO(C 2 -C 5 alkenyl), or CO(C 2 -C 5 alkynyl);

or a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable amide thereof at the carboxyl group of R 4 with the α-amino group of an α-amino acid, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , having a structure represented by formula (II-a)

wherein R 4a is

3. A compound according to claim 2 , having a structure represented by formula (II-a′):

wherein

R 2 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, CH 2 O(C 1 -C 5 alkyl), CH 2 O(C 2 -C 5 alkenyl), CH 2 O(C═O)(C 1 -C 5 alkyl), or CH 2 OC(═O)(C 2 -C 5 alkenyl); and

R 3 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C(═O)C 1 -C 5 alkyl, or C(═O)C 2 -C 5 alkenyl.

4. A compound according to claim 1 , having a structure represented by formula (II-b):

5. A compound according to claim 4 , having a structure represented by formula (II-b′):

wherein

R 2 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, CH 2 O(C 1 -C 5 alkyl), CH 2 O(C 2 -C 5 alkenyl), CH 2 O(C═O)(C 1 -C 5 alkyl), or CH 2 OC(═O)(C 2 -C 5 alkenyl); and

R 3 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C(═O)C 1 -C 5 alkyl, or C(═O)C 2 -C 5 alkenyl.

6. A compound according to claim 1 , having a structure according to formula (III-a), III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III j), (III-k), (III-l), (III-m), (III-n), (III-o), (III-p), (III-q), (III-r), (III-s), (III-t), (III-u), (III-v), (III-w), or (III-y):

7. A compound having a structure represented by formula (II-c)

where R 13 is Me, n-Pr, CH 2 OMe, or CH 2 OC(═O)CH 2 CH(Me) 2 ; R 14 is Me or C(═O)Me; and R 15 is H or C 1 -C 5 alkyl.

8. A conjugate comprising a compound according to claim 1 conjugated to an antibody.

9. A conjugate having a structure represented by formula (IV):

[D(X D ) a C(X Z ) b ] m Z  (IV)

wherein

D is a compound according to claim 1 ;

Z is an antibody;

X D and X Z are spacer groups;

C is a group cleavable at the site of intended biological action of D;

each of a and b is independently 0 or 1; and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

10. A composition of matter having a structure represented by formula (V-a)

D-(X D ) a C(X Z ) b —R 31   (V-a)

wherein

R 31 is a functional group suitable for reacting with a functional group on an antibody;

D is a compound according to claim 1 ;

X D and X Z are spacer groups;

C is a group cleavable at the site of intended biological action of D; and

each of a and b is independently 0 or 1.

11. A composition of matter having a structure represented by formula (V-b)

wherein

n is 0, 1, or 2;

R 1 , R 2 and R 3 are independently H, unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH 2 ) 1-2 O(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkynyl), (CH 2 ) 1-2 OC(═O)(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted C(═O)(C 1 -C 10 alkyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, or unsubstituted or substituted alkylaryl;

R 4′ is

wherein R 12 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, or C 2 -C 5 alkynyl; and

R 5 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, CO(C 1 -C 5 alkyl), CO(C 2 -C 5 alkenyl), or CO(C 2 -C 5 alkynyl);

X D and X Z are spacer groups;

C is a cleavable group; and

a and b are independently 0 or 1;

wherein group R 4′ is linked via a carboxyl or amine group therein to either group X D in the event a is 1 or to group C in the event a is 0.

12. A composition of matter having a structure represented by formula (V-d):

where R 13 is Me, n-Pr, CH 2 OMe, or CH 2 OC(═O)CH 2 CH(Me) 2 ; R 14 is Me or C(═O)Me; R 15 is H or C 1 -C 5 alkyl; R 16 is (CH 2 ) 4 NH 2 or (CH 2 ) 3 NHC(═O)NH 2 ; R 17 is C(Me) 2 or Me; and p is 0 or 1.

13. A composition of matter according to claim 11 , having a structure represented by formula (V-c)

wherein each AA independently is a natural amino acid and X Z is CH 2 CH 2 NHC(═O)(CH 2 ) 2-5 or C(═O)(CH 2 ) 2-5 .

14. A composition of matter having a structure represented by any of formulae (VI-a) through (VI-t):

15. A composition of matter according to claim 14 , having a structure represented by formula (VI-b):

16. A composition of matter according to claim 14 , having a structure represented by formula (VI-n):

17. A composition of matter according to claim 14 , having a structure represented by formula (VI-r):

18. A compound according to claim 1 , having a structure represented by formula (III-b):

19. A compound according to claim 1 , having a structure represented by formula (III-r):

20. A compound according to claim 1 , having a structure represented by formula (III-s):

21. A compound according to claim 1 , having a structure represented by formula (III-y):

22. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

23. A compound according to claim 1 , wherein R 4 is

24. A compound according to claim 1 , wherein R 4 is

25. A compound according to claim 1 , wherein R 4 is

26. A compound according to claim 1 , wherein R 4 is