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

1. A method for treating a cancer in a subject suffering from such cancer, comprising administering to the subject a therapeutically effective amount of a compound having a structure represented by formula (II), or a conjugate thereof with a ligand that is an antibody,

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

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 method according to claim 1 , wherein the antibody is an anti-PSMA, anti-CD70, or anti-mesothelin antibody.

3. A method according to claim 1 , wherein the cancer is selected from the group consisting of colorectal cancer, liver cancer, prostate cancer, breast cancer, melanoma, glioblastoma, lung cancer, pancreatic cancer, ovarian cancer, multiple myeloma, renal cancer, leukemia, and lymphoma.

4. A method according to claim 1 , wherein the compound has 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 C(═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.

5. A method according to claim 4 , wherein the antibody is an anti-PSMA, anti-CD70, or anti-mesothelin antibody.

6. A method according to claim 4 , wherein the cancer is selected from the group consisting of colorectal cancer, liver cancer, prostate cancer, breast cancer, melanoma, glioblastoma, lung cancer, pancreatic cancer, ovarian cancer, multiple myeloma, renal cancer, leukemia, and lymphoma.

7. A method according to claim 1 , wherein the compound has a structure represented by formula (III-b):

8. A method according to claim 7 , wherein the antibody is an anti-PSMA, anti-CD70, or anti-mesothelin antibody.

9. A method according to claim 7 , wherein the cancer is selected from the group consisting of colorectal cancer, liver cancer, prostate cancer, breast cancer, melanoma, glioblastoma, lung cancer, pancreatic cancer, ovarian cancer, multiple myeloma, renal cancer, leukemia, and lymphoma.

10. A method according to claim 1 , wherein the compound has a structure represented by formula (III-r):

11. A method according to claim 10 , wherein the antibody is an anti-PSMA, anti-CD70, or anti-mesothelin antibody.

12. A method according to claim 10 , wherein the cancer is selected from the group consisting of colorectal cancer, liver cancer, prostate cancer, breast cancer, melanoma, glioblastoma, lung cancer, pancreatic cancer, ovarian cancer, multiple myeloma, renal cancer, leukemia, and lymphoma.

13. A method according to claim 11 , wherein the antibody is an anti-mesothelin antibody.