Pyrridinobenzodiazepine and benzopyrridodiazecine compounds

1. A compound of formula (I):

and salts or solvates thereof, wherein:

the dotted lines indicates the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4;

R 4 is selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN;

R 5 , R 6 and R 8 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, CO 2 H, CH 2 —CO 2 H, CO 2 R, CH 2 —CO 2 R, NO 2 , Me 3 Sn and halo;

each R and R′ is independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl, C 3-20 heteroaryl, C 4-32 heteroaralkyl, C 5-20 aryl groups and C 6-32 aralkyl;

and either:

(i) R 9 and R 10 together form a double bond;

(ii) R 9 is H and R 10 is OH; or

(iii) R 9 is H and R 10 is OR A and R A is C 1-6 alkyl;

wherein each of m, n, u and w may be 0 or 1; and with the proviso that the compound of formula (I) is a compound according to (a), (b), (c) or (d) wherein:

(a) the compound is a dimer with each monomer being the same or different and being of formula (I) to give a dimer of formula:

where one of R 1 , R 2 , R 3 and R 7 of the first monomer and one of R′ 1 , R′ 2 , R′ 3 and R′ 7 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and m+n+u+w=1;

where the remaining groups m′, n′, u′, w′, R′ 4 , R′ 5 , R′ 6 , R′ 8 , R′ 9 and R′ 10 are independently selected from groups with the same meanings as for m, n, u, w, R 4 , R 5 , R 6 , R 8 , R 9 and R 10 respectively;

and the remaining of R 1 , R 2 and R 3 of the first monomer and the remaining of R′ 1 , R′ 2 and R′ 3 of the second monomer that do not form the bridge are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

and the remaining of R 7 of the first monomer and R′ 7 of the second monomer that do not form the bridge are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

or

(b) the compound is a dimer with each monomer being the same or different and being of formula (I) to give a dimer of formula (A1), (A2), (A3), (A5), (A6), (A7), (A9), (A10) or (A11); where the remaining groups m′, n′, u′, w′, R′ 4 , R′ 5 , R′ 6 , R′ 8 , R′ 9 and R′ 10 are independently selected from groups with the same meanings as for m, n, u, w, R 4 , R 5 , R 6 , R 8 , R 9 and R 10 respectively;

where one of R 1 , R 2 and R 3 of the first monomer and one of R′ 1 , R′ 2 , and R′ 3 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and m=n=u=w=0;

and the remaining of R 1 , R 2 and R 3 of the first monomer and the remaining of R′ 1 , R′ 2 and R′ 3 of the second monomer that do not form the bridge are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

and that R 7 of the first monomer and R′ 7 of the second monomer are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

or

(c) one of R 1 , R 2 and R 3 has the formula:

-X-L-X′-D; or

-(CH 2 ) f —O—R 14 ;

wherein R 14 is selected from H and R;

f is 0 or 1;

and m+n+u+w=0 or 1;

and the remaining of R 1 , R 2 and R 3 are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, ═O, ═CH—R, CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

and R 7 is selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

or

(d) R 7 has the formula:

-X-L-X′-D; or

-(CH 2 ) g —O—R 15 ;

wherein R 15 is selected from H and R;

g is 0 or 1;

and m+n+u+w=1;

and R 1 , R 2 and R 3 are independently selected from H, R, OH, OR, NH 2 , NHR, NRR′, CH 2 —OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 R, CO 2 R, CO 2 H, COR, CN, (C 1-12 alkylene)-C(O)NR″,R′″ and (C 2-12 alkenylene)-C(O)NR′R″ and halo;

wherein:

X is selected from O, S, NR″, ═CR″—, CR″R′″, CR″R′″O, C(═O), C(═O)NR″, NR″C(═O), O—C(O) and C(O)—O;

L is selected from an amino acid, a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 1 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain (OCH 2 ) 1-12 —, a polyethylene glycol chain —(OCH 2 CH 2 ) 1-6 —, which chains may be interrupted by one or more hetero-atoms and/or C 3-20 heteroaryl and/or C 5-20 aryl groups;

X′ is selected from O, S, NR″, ═CR″—, CR″R′″, CR″R′″O, C(═O), C(═O)NR′, NR″C(═O), O—C(O) and C(O)—O or is absent; and

D has the formula (II) or (III):

p is 0 or 1;

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

r is o or 1;

t is o or 1

Y 3 is N or CH;

Y 4 is N or CH; wherein at least one of Y 3 and Y 4 is CH;

R 13 is H, Z—R″, Z—CO 2 R″, Z—C(═O)—NH—(CH 2 ) 1-6 —NR″R′″, and Z—C(═O)—NH—(CH 2 ) 1-6 —C(═NH)NR″R′″;

Z is absent or is selected from C 3-20 heteroaryl, C 1-6 alkyl substituted C 3-20 heteroaryl, —(CH 2 ) k —C 3-20 heterocyclyl, and —O—(CH 2 ) k —C 3-20 heterocyclyl group;

k is 0, 1, 2, 3 or 4;

each R″ and R′″ is independently selected from H, and optionally substituted C 1-12 alkyl;

R 11 is an optionally substituted C 3-20 heteroaryl; and

R 12 is an optionally substituted C 3-20 heteroaryl.

2. A compound of formula (I) according to claim 1 , wherein m=n=u=w=0 and wherein the compound is represented by formula (IV):

3. A compound of formula (I) according to claim 1 , wherein m=n=u=0 and w=1 and wherein the compound is represented by formula (VIII):

4. A compound of formula (I) according to claim 1 , wherein R 5 is H.

5. A compound of formula (I) according to claim 1 , wherein R 6 is selected from H, R, OH, OR and halo.

6. A compound of formula (I) according to claim 1 , wherein R 8 is H.

7. A compound of formula (I) according to claim 1 , wherein X is selected from O, ═CR″—, C(═O)NR″ and NR″C(═O).

8. A compound of formula (I) according to claim 1 , wherein X′ is selected from O, ═CR″—, C(═O)NR″ and NR″C(═O).

9. A compound of formula (I) according to claim 1 , wherein L is an alkylene chain containing from 1 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds.

10. A compound of formula (I) according to claim 1 , wherein R 2 is selected from H, CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 OH, CH 2 OR.

11. A compound of formula (I) according to claim 1 , wherein D has the formula (II) or (III) and R 11 is selected from N-methylpyrrolylene, furanylene, thiophenylene, N-methylimidazolylene, oxazolylene, thiazolylene, indolylene, N-methylindolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, N-methylbenzoimidazolylene, benzooxazolylene and benzothiazolylene.

12. A compound of formula (I) according to claim 1 , wherein D has the formula (II) or (III) and R 12 is selected from N-methylpyrrolylene, furanylene, thiophenylene, N-methylimidazolylene, oxazolylene, thiazolylene, indolylene, N-methylindolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, N-methylbenzoimidazolylene, benzooxazolylene and benzothiazolylene.

13. A compound of formula (I) according to claim 1 , wherein D has the formula (II) or (III), Z is absent and R 13 is CO 2 R″.

14. A compound of formula (I) according to claim 1 , wherein the compound of formula (I) is:

wherein q is selected from 1, 2, 3, 4, 5 or 6; L is an alkylene chain containing from 1 to 12 carbon atoms; Y, Y 1 and Y 2 are CH, N—CH 3 and CH or are N, N—CH 3 and CH; Y 12 is selected from O, S, NH and N—CH 3 ; Y 13 is selected from CH and N; and R″ is selected from H and C 1-6 alkyl.

15. A compound of formula (I) according to claim 1 , wherein the compound is a dimer with each monomer being the same and being of formula (I).

16. A compound of formula (I) according to claim 1 , wherein the compound has the following structure:

and salts or solvates thereof, wherein:

the dotted lines indicates the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4;

R 6 is selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, OCH 2 Ph, NH 2 , NH(C 1-12 alkyl), ═O, ═CH—C 1-12 alkyl, ═CH 2 , CO 2 H, C(O)—O—C 1-12 alkyl;

and either:

(i) R 9 and R 10 together form a double bond;

(ii) R 9 is H and R 10 is OH; or

(iii) R 9 is H and R 10 is O—C 1-6 alkyl;

wherein w may be 0 or 1; and

(a) the compound is a dimer with each monomer being the same or different and being of formula (I) where one of R 1 , R 2 and R 7 of the first monomer and one of R′ 1 , R′ 2 and R′ 7 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and w=1;

and the remaining of R 1 and R 2 of the first monomer and the remaining of R′ 1 , and R′ 2 of the second monomer that do not form the bridge are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, NH 2 , NH(C 1-12 alkyl), ═O, ═CH—C 1-12 alkyl, ═CH 2 , CO 2 H and C(O)—O—C 1-12 alkyl;

and the remaining of R 7 of the first monomer and R′ 7 of the second monomer that do not form the bridge are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, OCH 2 Ph, NH 2 , NH(C 1-12 alkyl), CO 2 H and C(O)—O—C 1-12 alkyl;

or

(b) the compound is a dimer with each monomer being the same or different and being of formula (I) where one of RI and R 2 of the first monomer and one of R′ 1 and R′ 2 of the second monomer form together a bridge having the formula —X-L-X′— linking the monomers and w=0;

and the remaining of R 1 , and R 2 of the first monomer and the remaining of R′ 1 and R′ 2 of the second monomer that do not form the bridge are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, NH 2 , NH(C 1-12 alkyl), ═O, —CH—C 1-12 alkyl, ═CH 2 , CO 2 H and C(O)—O—C 1-12 alkyl;

and that R 7 of the first monomer and R′ 7 of the second monomer are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, OCH 2 Ph, NH 2 , NH(C 1-12 alkyl), CO 2 H and C(O)—O—C 1-12 alkyl;

or

(c) one of R 1 and R 2 has the formula: —X-L-X′-D; or —(CH 2 ) f —O—R 14 ;

wherein R 14 is selected from H and C 1-12 alkyl;

f is 0 or 1;

and w is o or 1;

and the remaining of R 1 and R 2 is selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, NH 2 , NH(C 1-12 alkyl), ═O, ═CH—C 1-12 alkyl, ═CH 2 , CO 2 H and C(O)—O—C 1-12 alkyl;

and R 7 is selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, OCH 2 Ph, NH 2 , NH(C 1-12 alkyl), CO 2 H and C(O)—O—C 1-12 alkyl;

or

(d) R 7 has the formula:

—X-L-X′-D;

or

(CH 2 ) g —O—R 15 ;

wherein R 15 is selected from H and C 1-12 alkyl;

g is 0 or 1;

and m+n+u+w=1;

and R 1 and R 2 are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, NH 2 , NH(C 1-12 alkyl), ═O, ═CH—C 1-12 alkyl, ═CH 2 , CO 2 H and C(O)—O—C 1-12 alkyl;

wherein:

X is selected from O, ═CH—, C(═O)NH and NHC(═O);

L is selected from a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 1 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds, —(OCH 2 ) 1-12 —, and —OCH 2 CH 2 ) 1-6 —;

X′ is selected from O, ═CH—, C(═O)NH and NHC(═O) or is absent; and

D is selected from formula (D1):

formula (D2):

formula (D3):

and formula (D4):

p is 0 or 1;

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

r is o or 1;

t is o or 1;

Y, Y 1 and Y 2 are selected from CH, CH and N—CH 3 ; CH, N—CH 3 and CH; N, CH and N—CH 3 ; N, N—CH 3 and CH; CH, S and CH; CH, CH and S; N, S and CH; N, CH and S; N, O and CH; N, CH and O; CH, CH and O; CH O and CH; COH, N—CH 3 and CH; and COH, CH and N—CH 3 ;

Y 3 is N or CH;

Y 4 is N or CH; wherein at least one of Y 3 and Y 4 is CH;

Y 5 , Y 6 and Y 7 are selected from CH, CH and N—CH 3 ; CH, N—CH 3 and CH; N, CH and N—CH 3 ; N, N—CH 3 and CH; CH, S and CH; CH, CH and S; N, S and CH; N, CH and S; N, O and CH; N, CH and O; CH, CH and O; CH O and CH; COH, N—CH 3 and CH; and COH, CH and N—CH 3 ;

Y 8 is selected from O, S, NH and N—CH 3 ;

Y 9 is selected from CH and N;

Y 10 is selected from O, S, NH and N—CH 3 ;

Y 11 is selected from CH and N;

R 13 is H, Z—R″, Z—CO 2 R″, Z—C(═O)—NH—(CH 2 ) 1-6 —NR″R′″, and Z—C(═O)—NH—(CH 2 ) 1-6 —C(═NH)NR″R′″;

Z is absent or is selected from benzofuranylene, benzothiophenylene, indolylene, N-methyl indolylene, N-methylbenzimidazolylene, benzoxazolylene and benzothiazolylene;

k is 0, 1, 2, 3 or 4; and

each R″ and R′″ is independently selected from H, and C 1-12 alkyl.

17. A compound of formula (I) according to claim 1 , wherein the compound has the following structure:

or is a dimer with the following structure:

and salts or solvates thereof, wherein:

R 1 and R′ 1 are independently selected from H, C 1-12 alkyl, C 2-12 alkenyl, OH, O—C 1-12 alkyl, NH 2 , NH(C 1-12 alkyl), ═O, ═CH—C 1-12 alkyl, ═CH 2 , CO 2 H and C(O)—O—C 1-12 alkyl;

R 6 , R 7 , R′ 6 , and R 7 are independently selected from H, C 1-12 alkyl, O—C 1-12 alkyl, OCH 2 Ph;

and either:

(i) R 9 and R 10 together form a double bond, and R′ 9 and R′ 10 together form a double bond;

(ii) R 9 is H and R 10 is OH, and R′ 9 is H and R′ 10 is OH; or

(iii) R 9 is H and R 10 is OR A and R A is C 1-6 alkyl, and R′ 9 is H and R′ 10 is O—C 1-6 alkyl;

wherein:

R 2 has the formula:

—X-L-X′-D;

or is:

—(CH 2 ) f —O—R 14 ;

R 14 is selected from H and C 1-12 alkyl;

f is 0 or 1;

X is selected from O, ═CH—, C(═O)NH and NHC(═O);

L is selected from a peptide chain having from 2 to 5 amino acids; an alkylene chain containing from 1 to 11 carbon atoms which may contain one or more carbon-carbon double or triple bonds; —(OCH 2 ) 1-12 — and —(OCH 2 CH 2 ) 1-5 —;

X′ is selected O, ═CH—, C(═O)NH and NHC(═O) or is absent;

D is:

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

r is o or 1;

t is o or 1

Y, Y 1 and Y 2 are selected from CH, CH and N—CH 3 ; CH, N—CH 3 and CH; N, CH and N—CH 3 ; N, N—CH 3 and CH;

Y 3 is N or CH;

Y 4 is N or CH; wherein at least one of Y 3 and Y 4 is CH;

Y 5 , Y 6 and Y 7 are selected from CH, CH and N—CH 3 ; CH, N—CH 3 and CH; N, CH and N—CH 3 ; N, N—CH 3 and CH;

R 13 is H, Z—H, Z—C 1-6 alkyl, Z—CO 2 H and Z—CO 2 C 1-6 alkyl; and

Z is absent or is selected from benzofuranylene, benzothiophenylene, indolylene, N-methyl indolylene, N-methylbenzimidazolylene, benzoxazolylene and benzothiazolylene.

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

19. A method of treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .