Benzodiazepine derivatives and uses thereof

1. A compound having the structure of Formula (II), (IIa), or (IIb)

or a pharmaceutically acceptable salt thereof,

wherein:

A 1 and A 2 each independently represent a heterocyclic ring;

R 1 and R 2 are each independently an alkyl group;

Z 1 is a linking group;

n 1 and n 2 are each independently an integer having a value of 1 to 5;

Z 2 is a linking group;

L 1 , when present, is a linking group attached to the SO 2 via a heteroatom selected from O, S, and N, and is selected such that cleavage of the bond between L 1 and SO 2 promotes cleavage of the bond between L 1 and Z 1 , A 1 , or A 2 to release the active agent;

X 1 is —O—, —CR b 2 —, or —NR a —;

Ar is selected from aryl or heteroaryl;

Y 1 is —(CR b 2 ) y N(R a )—, —(CR b 2 ) y O—, or —(CR b 2 ) y S—, positioned such that the N, O, or S atom is attached to TG if y is 1-10; wherein X 1 and Y 1 are positioned on adjacent atoms of Ar;

TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO 2 to displace Z 1 , A 1 , or A 2 and form a 5-6-membered ring including X 1 —SO 2 and the intervening atoms of Ar;

w and x are each independently an integer having a value of 0 or 1;

each R a is independently hydrogen or lower alkyl;

each R b is independently hydrogen or lower alkyl; or

two R b , together with the carbon atom to which they are attached, form a 3-5-membered ring; and

y is an integer having a value of 0-10.

2. The compound of claim 1 , wherein X 1 is —O—.

3. The compound of claim 1 , wherein Ar is phenyl or naphthyl.

4. The compound of claim 1 , wherein Z 2 is a linking group comprising one or more groups selected from isocyanide, isothiocyanide, 2-pyridyl disulfide, haloacetamide (—NHC(O)CH 2 -halo), maleimide, diene, alkene, halide, tosylate (TsO-), aldehyde, sulfonate (R—SO 3 − ),

phosphonic acid (—P(═O)(OH) 2 ), ketone, C8-C10 cycloalkynyl, —OH, —NHOH, —NHNH 2 , —SH, carboxylic acid (—COOH), acetylene (—C≡CH), azide (—N 3 ), amino (—NH 2 ), sulfonic acid (—SO 3 H), an alkynone derivative (—C(O)C≡CR a wherein R a is C 1-10 alkyl), and dihydrogen phosphate (—OP(═O)(OH) 2 ).

5. The compound of claim 1 , wherein x is 0.

6. The compound of claim 5 , wherein TG is —NO 2 , —OC(O)(CH 2 ) r C(O)R 1 , NHNH 2 , —BR 2 R 3 , or

wherein:

R 1 is C 1 -C 6 alkyl;

R 2 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy;

R 4 , R 5 , R 6 , and R 7 are each independently hydrogen or C 1 -C 6 alkyl; and

r is an integer having a value of 1, 2, 3, 4, or 5.

7. The compound of claim 1 , wherein TG is selected from:

wherein:

each R 21 is independently hydrogen or acetyl; and

R 22 is hydrogen or lower alkyl.

8. The compound of claim 1 , wherein TG is selected from —NO 2 , —C(O)—(CH 2 ) 2 C(O)-alkyl, and nitrobenzyl.

9. A conjugate having the structure of Formula (III):

(D-L) dl -LG-(CB) cb    (III)

or a pharmaceutically acceptable salt thereof,

wherein:

LG is a linking group;

CB is a cell-binding agent;

cb and dl are each independently integers having a value of 1 to about 20; and

each D-L independently is a group having the structure of a compound of claim 1 .

10. The conjugate of claim 9 , wherein LG is a C 10 -C 100 linear or branched, saturated or unsaturated alkylene moiety comprising at least two of the following:

(i) at least one heteroatom selected from —NH—, —C(═O), —O—, —S— and —P—;

(ii) at least one heteroarylene;

(iii) at least one amino acid moiety, sugar bond, peptide bond, or amide bond; and

(iv) one or more substitutents selected from the group consisting of C 1 -C 20 alkyl, C 6 -C 20 aryl C 1 -C 8 alkyl, —(CH 2 ) s COOH, and —(CH 2 ) p NH 2 , s is an integer having a value of 0 to 10, and p is an integer having a value of 1 to about 10.

11. The conjugate of claim 9 , wherein LG is a functional group that can be produced through a click chemical reaction.

12. The conjugate of claim 9 , wherein LG is:

wherein:

* represents the point to attachment to (D-L) dl ;

** represent the point of attachment to CB;

each V is independently a single bond, —O—, —S—, —NR 21 —, —C(O)NR 22 —, —NR 23 C(O)—, —NR 24 SO 2 —, or —SO 2 NR 25 —;

R 21 , R 22 , R 23 , R 24 , and R 25 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl, or (C 1 -C 6 )alkyl(C 3 -C 20 )heteroaryl;

r is an integer having a value of 1 to about 10;

p is an integer having a value of 0 to about 10;

q is an integer having a value of 1 to about 10; and

L 3 is a single bond.

13. The conjugate of claim 9 , wherein LG comprises (CH 2 ) b , L c , (P 1 ) a , W a1 , W a2 , W a3 , Y 3 and Y 4 groups connected to each other in a linear chain by covalent bonds,

wherein:

W a1 , W a2 , and W a3 are each independently —NH—, —C(O)—, or —CH 2 —;

P 1 is an amide bond, an amino acid residue, or a peptide;

L c is alkylene;

Y 3 is —(CH 2 ) q —(CH 2 CH 2 X 4 ) o — or —(CH 2 ) q —(X 4 CH 2 CH 2 X 3 ) o —;

X 3 and X 4 are each independently —O—, —S—, —NH— or —CH 2 —;

Y 4 is a single bond or a group selected from:

W b2 is an amide bond or triazolylene;

a is 0 to 10;

b, c, and d are each independently an integer having a value of 1 to about 10; and

and q are each independently an integer having a value of 1 to about 10.

14. The conjugate of claim 9 , wherein LG is a linking group of Formula (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIj):

wherein:

* represents the point to attachment to (D-L) dl :

** represent the point of attachment to CB:

R e is alkyl:

L 4 is a spacer moiety, unsubstituted or substituted with one or more C 1 -C 6 alkyl, C 5 -C 14 aryl, and C 3 -C 8 heteroaryl, wherein the alkyl, aryl and heteroaryl are unsubstituted or substituted with one or more substituents selected from C 1 -C 10 alkyl, —(CH 2 ) u NH 2 , —(CH 2 ) u NR u1 R u2 , —(CH 2 ) u CO 2 H, —(CH 2 ) u CO 2 R u1 , and —(CH 2 ) u SO 2 R u3 , wherein R u1 , R u2 , and R u3 are each independently hydrogen, C 1 -C 15 alkyl, C 6 -C 20 aryl or C 3 -C 10 heteroaryl; and u is an integer having a value of 1 to 10:

W b1 and W b2 are each independently —C(O)NH—, —NHC(O)—,

R 12 is hydrogen, alkyl, an amino acid side chain, —(CH 2 ) s C(O)R 13 or —(CH 2 ) p NR 14 R 15 ;

R 13 is OH or —NH(CH 2 ) s′ (X 4 CH 2 CH 2 ) s″ Z″—(CB) m ;

R 14 and R 15 are each independently hydrogen or —C(O)(CH 2 ) s′ (X′″CH 2 CH 2 ) s″ Z″—(CB) m ;

Z″ is a linking group connecting CB to the remainder of R 14 or R 15 : or Z″ is a linking group comprising a reactive group:

X′″ is —O—, —S—, —NH—, or —CH 2 —;

s and s″ are each independently an integer having a value of 0 to about 10;

m is an integer having a value of 0 or 1;

X 4 and X 5 are each independently —O—, —S—, —NH—, or —CH 2 —; and

a, b, c, d, e, o, p, s′ and qq are each independently an integer having a value of 1 to about 10.

15. The conjugate of claim 9 , wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing the CD4, CD6, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD56, EpCAm, CanAg, CALLA, or Her-2 antigens; Her-3 antigens or cells expressing insulin growth factor receptor, epidermal growth factor receptor, and folate receptor.

16. The conjugate of claim 15 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells.

17. The conjugate of claim 15 , wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds to the a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.

18. The conjugate of claim 17 , wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment; a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof; a chimeric antibody fragment, a domain antibody, or a domain antibody fragment; a humanized antibody, a humanized single chain antibody, or a humanized antibody fragment.

19. A pharmaceutical composition comprising the conjugate of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of treating a cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of the conjugate of claim 9 , or a pharmaceutically acceptable salt thereof.