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 D1:

wherein the dotted line between C2 and C3 or between C2 and C1 in D1 indicates the presence of a single or double bond;

m is 0, 1 or 2;

when D is D1, the dotted line between C2 and C3 is a double bond, and m is 1, then R 1 is:

(i) C 6-10 aryl, optionally substituted by one or more substituents selected from —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- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, bis-oxy-C 1-3 alkylene, —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 , and —NH(C═NH)NH 2 ;

(ii) C 1-5 alkyl;

(iii) C 3-6 cycloalkyl;

or

(viii) halo; or

when D is D1, the dotted line between C2 and C3 is a single bond, and m is 1, then R 1 is:

(i) —OH, ═O, ═CH 2 , —CN, —R 2 , —OR 2 , halo, ═CH—R 6 , ═C(R 6 ) 2 , —O—SO 2 R 2 , —CO 2 R 2 , —COR 2 , —CHO, or —COOH; or

or

when D is D1 and m is 2, then each R 1 independently is halo and either both R 1 are attached to the same carbon atom or one is attached to C2 and the other is attached to C3;

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, E1, E2, E3, or E4:

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

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;

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 R 6 independently is —H, —R 2 , —CO 2 R 2 , —COR 2 , —CHO, —CO 2 H, or halo;

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 13a , 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 ;

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;

R 31 , R 32 and R 33 are each independently —H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl or cyclopropyl, where the total number of carbon atoms in the R 1 group is no more than 5;

R 34 is —H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, cyclopropyl, or phenyl wherein the phenyl is optionally substituted by one or more of halo, methyl, methoxy, pyridyl or thiophenyl;

one of R 35a and R 35b is —H and the other is a phenyl group optionally substituted with one or more of halo, methyl, methoxy, pyridyl or thiophenyl;

R 36a , R 36b , R 36c are each independently —H or C 1-2 alkyl;

R 36d is —OH, —SH, —COOH, —C(O)H, —N═C═O, —NHNH 2 , —CONHNH 2 ,

or NHR N , where R N is —H or C 1-4 alkyl;

R 37a and R 37b are each independently is —H, —F, C 1-4 alkyl, C 2-3 alkenyl, wherein the alkyl and alkenyl groups are optionally substituted by C 1-4 alkyl amido or C 1-4 alkyl ester; or when one of R 37a and R 37b is —H, the other is —CN or a C 1-4 alkyl ester;

each X 1 independently is CR b , or N;

each Y 1 independently is NR a , O or S;

each Z 1 independently 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; and

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 the compound is of Formula (II), (II-1) or (II-2):

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

4. The compound of claim 1 , wherein R 1 is C 6-10 aryl, optionally substituted by one or more substituents selected from —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- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, bis-oxy-C 1-3 alkylene, —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 , and —NH(C═NH)NH 2 .

5. The compound of claim 1 , wherein each

independently is

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

wherein each X 1 independently is CH or N.

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 E is:

—OH,

10. 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 CH2) r —OR a .

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

12. 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 .

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

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

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

16. 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.

17. 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 13a , 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.

18. 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.

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

20. The compound of claim 3 , wherein the compound is of any of Formulae (II-a)-(II-p):

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

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

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

23. The compound of claim 20 , wherein the compound is:

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

24. The compound of claim 20 , wherein the compound is:

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

wherein:

R 13 is H;

R 14 is H or methyl; and

p is 1,2,3 or 4.

25. A compound, being

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