Pyrrolobenzodiazepines and conjugates thereof

1. A compound of Formula (I),

or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the tautomer, wherein:

D is D2:

T is C 1-10 alkylene linker;

A is

wherein the —NH group of A is connected to the —C(O)-T- moiety of Formula (I) and the C═O moiety of A is connected to E; and each

independently is

E is —OH, —NH—(C 1-6 alkylene)-R 13a , E1, E2, E3, or E4:

wherein the dotted line in E1 or E4 indicates the presence of a single or double bond;

R 4 , R 5 and R 7 are each independently —H, —R 2 , —OH, —OR 2 , —SH, —SR 2 , —NH 2 , —NHR 2 , —NR 2 R 3 , —NO 2 , —SnMe 3 , halo, or a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a ; or R 4 and R 7 together form bis-oxy-C 1-3 alkylene;

each occurrence of R 2 and R 3 independently is an optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 3- to 20-membered heterocycloalkyl, optionally substituted C 6-20 aryl, or optionally substituted 5- to 20-membered heteroaryl, and, optionally in relation to the group NR 2 R 3 , R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocycloalkyl or an optionally substituted 5- or 6-membered heteroaryl;

each R 8 independently is —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , —CONR 13 R 14 , C 1-10 alkyl, —CO—NH—(C 1-6 alkylene)-R 3a , C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , —SO x M, —OSO x M, —NR 9 COR 19 , —NH(C═NH)NH 2 , or —R 20 —R 21 —NR 13 R 14 ;

each R 9 independently is C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, or C 2-10 alkynyl;

R 10 is —H or a nitrogen protecting group;

R 11 is -QR Q or —SO x M;

or R 10 and R 11 taken together with the nitrogen atom and carbon atom to which they are respectively attached, form a N═C double bond;

each R 12 independently is C 1-7 alkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl, or C 6-20 aryl;

each occurrence of R 13 and R 14 are each independently H, C 1-10 alkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl, or C 6-20 aryl;

each R 13a independently is —OH or —NR 13 R 14 ;

R 15 , R 16 , R 17 , and R 18 are each independently —H, —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3-14 membered heterocycloalkyl, 5- to 12-membered heteroaryl, —NR 13 R 14 , —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , —SO x M, —OSO x M, —NR 9 COR 19 , or —NH(C═NH)NH 2 ;

each R 19 independently is C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, or C 2-10 alkynyl;

each R 20 independently is a bond, C 6-10 arylene, 3-14 membered heterocycloalkylene, or 5- to 12-membered heteroarylene;

each R 21 independently is a bond or C 1-10 alkylene;

each X 1 independently is CR b or N;

each Y 1 independently is CH, NR a , O or S, wherein when

then Y 1 is NR a , O, or S;

each Z 1 independently is CH, NR a , O or S, wherein when

then Z1 is NR a , O, or S;

each R a independently is H or C 1-4 alkyl;

each R b independently is H, OH, C 1-4 alkyl, or C 1-4 alkoxyl;

X 2 is CH, CH 2 , or N;

X 3 is CH or N;

X 4 is NH, O, or S;

Q is O, S, or NH;

when Q is S or NH, then R Q is —H or optionally substituted C 1-7 alkyl; or

when Q is O, then R Q is —H or optionally substituted C 1-7 alkyl or —SO x M;

each M independently is H or a monovalent pharmaceutically acceptable cation;

each r independently is an integer from 1 to 200;

s is 1, 2, 3, 4, 5, or 6;

t is 0, 1, or 2;

each x independently is 2 or 3, and

when E is E4, the dotted line indicates the presence of a double bond, X 3 is CH, and X 4 is O or S, then s is 2, 3, 4, 5, or 6.

2. The compound of claim 1 , wherein T is C 2-6 alkylene linker.

3. The compound of claim 1 , wherein T is C 2-4 alkylene linker.

4. The compound of claim 1 , wherein T is propylene.

5. The compound of claim 1 , wherein the compound is of Formula (III):

or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the tautomer.

6. The compound of claim 1 , wherein each

independently is

7. The compound of claim 1 , wherein A is:

wherein each X 1 independently is CH or N.

8. The compound of claim 1 , wherein A is:

wherein each X 1 independently is CH or N.

9. The compound of claim 1 , wherein A is

wherein each X 1 independently is CH or N.

10. The compound of claim 1 , wherein E is:

11. The compound of claim 1 , wherein R 4 , R 5 and R 7 are each independently —H, —R 2 , —OH, —OR 2 , —SH, —SR 2 , —NH 2 , —NHR 2 , —NR 2 R 3 , —NO 2 , halo, or a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a .

12. The compound claim 1 , wherein R 4 and R 7 together form bis-oxy-C 1-3 alkylene.

13. The compound of claim 1 , wherein each R 8 independently is —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , —CONR 13 R 14 , —CO—NH—(C 1-6 alkylene)-R 13a , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , —NH(C═NH)NH 2 , or —R 20 —R 21 —NR 13 R 14 .

14. The compound of claim 1 , wherein each of R 20 and R 21 is a bond.

15. The compound of claim 1 , wherein one of R 20 and R 21 is a bond and the other is not a bond.

16. The compound of claim 1 , wherein R 20 is a bond and R 21 is C 1-10 alkylene.

17. The compound of claim 1 , wherein R 21 is a bond and R 20 is C 6-10 arylene, 3-14 membered heterocycloalkylene or 5- to 12-membered heteroarylene.

18. The compound of claim 1 , wherein each R 8 independently is —OH, —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , —CONR 13 R 14 , —CO—NH—(C 1-6 alkylene)-R 13 a, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , or —R 20 —R 21 —NR 13 R 14 ;

wherein R 13 and R 14 are each independently —H or C 1-10 alkyl;

each R 20 is phenylene; and

each R 21 independently is C 1-4 alkylene.

19. The compound of claim 1 , wherein R 10 and R 11 taken together with the nitrogen atom and carbon atom to which they are respectively attached, form a N═C double bond.

20. The compound of claim 1 , wherein R 10 is —H or a nitrogen protecting group, and R 11 is -QR Q .

21. The compound of claim 1 , wherein R 15 , R 16 , R 17 , and R 18 are each independently —H, —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3-14 membered heterocycloalkyl, 5- to 12-membered heteroaryl, —NR 13 R 14 , —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , or —NH(C═NH)NH 2 .

22. The compound of claim 5 , wherein the compound is of any of Formulae (III-a)-(III-c):

or a tautomer thereof, or a A pharmaceutically acceptable salt or solvate of the compound or the tautomer.

23. The compound of claim 1 , wherein the compound contains at most one —SO x M or —OSO x M.

24. The compound of claim 1 , wherein R 11 is —OSO x M or —SO x M.

25. The compound of claim 22 , wherein the compound is:

or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the tautomer.