Sugar-linker-drug conjugates

1. A sugar-linker-drug conjugate of formula (I)

or a pharmaceutically acceptable salt thereof,

wherein A is:

R 1 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;

each R 4 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;

each R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;

R 2 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;

R 3 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;

R′ is selected from the group consisting of H, OH and NHR 4 ;

B is X-(L 1 -Y) m -L 2 -Z,

wherein X is CH 2 or O;

L 1 is C 2 -C 6 alkyl;

Y is O, S, or NR y , wherein R y is hydrogen or C 1 -C 6 alkyl;

m is an integer selected from 1 to 10;

L 2 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, heteroaryl, heterocyclyl, C 3 -C 5 cycloalkyl; and

Z is absent, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x ), wherein

each R x is independently hydrogen or C 1 -C 6 alkyl;

n is an integer selected from 1 to 3;

L is (E-L 3 -F-L 4 ) p -G,

wherein each E is bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x );

each L 3 is C 2 -C 6 alkyl;

each F is bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x );

each L 4 is C 0 -C 6 alkyl;

p is 1 or 2; and

G is a bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x ); and

D is a Drug Unit selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, methotrexate, amsacrin, cis-platin, mercaptopurine, etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine, bleomycin, teniposide, podophyllotoxin, esperamicin, 6-mercaptopurine, methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, nitrogen mustard drugs, chlorambucil, melphalan, cinnamaldehyde, inosine dialdehyde, diglycoaldehyde, anthracycline and epothilone.

2. The conjugate according to claim 1 , wherein A is

3. The conjugate according to claim 1 , wherein A is selected from the group consisting of:

4. The conjugate according to claim 1 , wherein R 1 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , OCONHR 4 , and OCONR 4 R 5 .

5. The conjugate according to claim 1 , wherein R 2 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 ,NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , OCONHR 4 , OCONR 4 R 5 , OCSNHR 4 , NHCONHR 4 , OCH 2 CONHR 4 , and OCH 2 CONR 4 R 5 .

6. The conjugate according to claim 1 , wherein R 3 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 ,NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , and OCONHR 4 .

7. The conjugate according to claim 1 , wherein R′ is H or OH.

8. The conjugate according to claim 1 , wherein each R 4 is selected from the group consisting of H, methyl and ethyl.

9. The conjugate according to claim 1 , wherein each R 5 is selected from the group consisting of methyl, ethyl, and isobutyl.

10. The conjugate according to claim 1 , wherein A is selected from the group consisting of:

11. The conjugate according to claim 1 , wherein E is NR x or C(O);

L 3 is C 4 -C 6 alkyl;

L 4 is C 0 -C 2 alkyl;

p is 1 or 2;

F is a bond, NR x , N(R x )C(O), OC(O), C(O)O or C(O)N(R x ); and

G is O, S, C(O) or NR x .

12. The conjugate according to claim 1 , wherein D is a drug selected from the group consisting of a cytotoxic drug, a cytostatic drug, antiproliferative drug, antitumor agent, an inhibitor of a cellular metabolic event and is an enzyme or protein inhibitor.

13. A pharmaceutical composition comprising a conjugate of formula (I) according to claim 1 , and a pharmaceutically acceptable carrier.

14. A method of treating cancer in a patient comprising administering to a patient in need thereof a conjugate according to claim 1 , or a pharmaceutical composition according to claim 13 .

15. A method of reducing the toxic side effects of administering a drug to treat cancer, comprising administering to a patient an effective amount of a conjugate according to claim 1 , or a pharmaceutical composition according to claim 13 .

16. A conjugate represented by formula:

17. A conjugate represented by formula:

or a pharmaceutically acceptable salt thereof.