Isoquinolidinobenzodiazepines

1. A method of treating acute myeloid leukemia (AML) comprising administering to a subject having AML a therapeutically effective amount of a compound having a structure of Formula (I):

wherein:

the dotted bond shown between —C(R a )— and —N(R b )— or —C(R a′ )— and —N(R b′ )— is independently a single bond or a double bond;

each of R a and R a′ is independently H or OH;

each of R b and R b′ is not present or is H;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ and R 6 are each independently selected from H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl;

each of R 5 or R 5′ is independently NH 2 , CO 2 H, H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl;

each of R 7 and R 7′ is H;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, NH 2 or CO 2 H; and

J is CH or N;

each of Y and Y′ is independently O, S, or NH;

each of Z and Z′ is independently H, R, OH, OR, SH, SR, NH 2 , or NHR, where each R is independently unsubstituted C 1 -C 12 alkyl.

2. The method according to claim 1 , wherein Y and Y′ are each O.

3. The method according to claim 1 , wherein Z and Z′ are each independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl.

4. The method according to claim 1 , wherein X is —CH 2 —.

5. The method according to claim 1 , wherein

each of R a and R a′ is independently H, or OH;

if present, each of R b and R b′ is H;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6′ , R 6 , R 7 and R 7′ , are each H;

X is C 1-12 alkylene;

each of Y and Y′ is O;

each of Z and Z′ is independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl.

6. The method according to claim 1 , wherein the compound has the structure:

7. A method of treating acute myeloid leukemia (AML) comprising administering to a subject having AML a therapeutically effective amount of an antibody-drug conjugate having a structure of Formula III:

wherein:

is an antibody or antibody fragment that binds to a cancer marker on an AML cell;

W—R M is a linking moiety formed by W and R x , wherein W is a moiety attached to a natural or unnatural amino acid residue of the antibody/antibody fragment and R x is a reactive moiety linking L-IQB to the antibody wherein R x is selected from iodoacetamide, succinimidyl, maleimidyl, cyclooctynyl, aminooxy, bisulfonyl, sulfonyl, or isothiocyanate moiety, such that W—R M is a disulfide, a thiolated succinimidyl, an amino substituted succinimidyl, a (cyclooctyl)-1, 4 triazolyl, oxime substituted N-glycan, oxime, a substituted bis-sulfopropyl, a sulfonamidyl, an amide, or a thiocarbamate moiety;

L is a linker comprising polyethylene glycol and 1-10 amino acid moieties; and,

IQB is a compound having a structure of Formula (I):

wherein:

the dotted bond shown between —C(R a )— and —N(R b )— or —C(R a′ )— and —N(R b′ )— is independently a single bond or a double bond;

each of R a and R a′ is independently H, OH, or —O—P, where P is a protecting group;

each of R b and R b′ is not present or is independently H, or -L;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ and R 6 are each independently selected from H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl;

each of R 5 or R 5′ is independently NH 2 , CO 2 H, H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or -L;

each of R 7 and R 7′ is H;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, NH 2 , CO 2 H, -L; and

J is CH or N;

each of Y and Y′ is independently O, S, or NH;

each of Z and Z′ is independently H, R, OH, OR, SH, SR, NH 2 , or NHR, where each R is independently unsubstituted C 1 -C 12 alkyl; and

wherein only one of R b , R b′ , R 5 , R 5′ , R 9 , R 10 , and R 11 is -L.

8. The method of claim 7 , wherein IQB is a moiety having the structure:

9. The method of claim 7 wherein —W—R M -L-IQB is a moiety having a structure of Formula IV:

10. The method of claim 7 wherein the antibody is a cysteine substituted antibody.

11. The method of claim 7 wherein the cancer marker is selected from GPR114, CLL-1, IL1RAP, CD33 and CD123/IL3Ra.

12. The method according to claim 1 , wherein

each of R a and R a′ is independently H, or OH;

if present, each of R b and R b′ is H;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ , R 6 , R 7 and R 7′ , are each H;

each of R 5 and R 5′ is H;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, or -L-R x ; and

J is CH;

each of Y and Y′ is O;

each of Z and Z′ is independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl.

13. The method according to claim 7 , wherein

each of R a and R a′ is independently H, or OH;

if present, each of R b and R b′ is independently H, or L-R x ;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ , R 6 , R 7 and R 7′ , are each H;

each of R 5 and R 5′ is independently H, or L-R x ;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, or -L-R x ; and

J is CH;

each of Y and Y′ is O;

each of Z and Z′ is independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl; and

-L-R x is the linker L attached to the reactive moiety R x ;

wherein only one of R b , R b′ , R 5 , R 5′ , R 9 , R 10 , and R 11 is L-R x .

14. The method of claim 7 , wherein the antibody or antibody fragment specifically binds to CLL-1.

15. The method of claim 7 , wherein W is a thiol of a cysteine residue, an amino group of a lysine residue, an azide group substituted on an amino acid or an aldehyde or ketone substituted on an amino acid.

16. The method of claim 7 , wherein Y and Y′ are each O.

17. The method of claim 7 , wherein Z and Z′ are each independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl.

18. The method of claim 7 , wherein X is —CH 2 —.

19. An antibody-drug conjugate having a structure of Formula III:

wherein:

is an antibody or antibody fragment that binds to a cancer marker on an AML cell;

W—R M is a linking moiety formed by W and R x , wherein W is a moiety attached to a natural or unnatural amino acid residue of the antibody/antibody fragment and R x is a reactive moiety linking L-IQB to the antibody wherein R x is selected from iodoacetamide, succinimidyl, maleimidyl, cyclooctynyl, aminooxy, bisulfonyl, sulfonyl, or isothiocyanate moiety, such that W—R M is a disulfide, a thiolated succinimidyl, an amino substituted succinimidyl, a (cyclooctyl)-1, 4 triazolyl, oxime substituted N-glycan, oxime, a substituted bis-sulfopropyl, a sulfonamidyl, an amide, or a thiocarbamate moiety;

L is a linker comprising polyethylene glycol and 1-10 amino acid moieties; and,

IQB is a compound having a structure of Formula (I):

wherein:

the dotted bond shown between —C(R a )— and —N(R b )— or —C(R a′ )— and —N(R b′ )— is independently a single bond or a double bond;

each of R a and R a′ is independently H, OH, or —O—P, where P is a protecting group;

each of R b and R b′ is not present or is independently H, or -L;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ and R 6 are each independently selected from H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl;

each of R 5 or R 5′ is independently NH 2 , CO 2 H, H, OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or -L;

each of R 7 and R 7′ is H;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, NH 2 , CO 2 H, -L; and

J is CH or N;

each of Y and Y′ is independently O, S, or NH;

each of Z and Z′ is independently H, R, OH, OR, SH, SR, NH 2 , or NHR, where each R is independently unsubstituted C 1 -C 12 alkyl; and

wherein only one of R b , R b′ , R 5 , R 5′ , R 9 , R 10 , and R 11 is -L.

20. The antibody-drug conjugate of claim 19 , wherein IQB is a moiety having the structure:

21. The antibody-drug conjugate of claim 19 , wherein —W—R M -L-IQB is a moiety having a structure of Formula IV:

22. The antibody-drug conjugate of claim 19 , wherein the antibody is a cysteine substituted antibody.

23. The antibody-drug conjugate of claim 19 , wherein the cancer marker is selected from GPR114, CLL-1, IL1RAP, CD33 and CD123/IL3Ra.

24. The antibody-drug conjugate of claim 19 , wherein

each of R a and R a′ is independently H, or OH;

if present, each of R b and R b′ is independently H, or L;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 6′ , R 6 , R 7 and R 7′ , are each H;

each of R 5 and R 5′ is independently H, or L;

X is:

C 1-12 alkylene, optionally wherein the alkylene chain is interrupted by one or more hetero atoms selected from the group consisting of O, S, and NH; or

—(CH 2 ) m -Q-(CH 2 ) p —, wherein m and p are each independently 0, 1 or 2;

Q has a structure of formula:

wherein each of R 9 , R 10 and R 11 is H, or -L; and

J is CH;

each of Y and Y′ is O;

each of Z and Z′ is independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl; and

L is the linker;

wherein only one of R b , R b′ , R 5 , R 5′ , R 9 , R 10 and R 11 is L.

25. The antibody-drug conjugate of claim 16 , wherein the antibody or antibody fragment specifically binds to CLL-1.

26. The antibody-drug conjugate of claim 19 , wherein W is a thiol of a cysteine residue, an amino group of a lysine residue, an azide group substituted on an amino acid or an aldehyde or ketone substituted on an amino acid.

27. The antibody-drug conjugate of claim 19 , wherein Y and Y′ are each O.

28. The antibody-drug conjugate of claim 19 , wherein Z and Z′ are each independently OR, where each R is independently unsubstituted C 1 -C 3 alkyl.

29. The antibody-drug conjugate of claim 19 , wherein rein X is —CH 2 —.

30. A compound of the formula: