Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment

1. A compound having the structure of formula II:

M L D) s ] t    II

or a pharmaceutically acceptable salt thereof, wherein:

M is a cell-specific ligand unit;

each L is independently a linker unit;

each D independently has the structure of formula I-c or I-d,

or a pharmaceutically acceptable salt thereof, wherein:

each is independently a single bond or a double bond;

each R 1 is independently R, —C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, —S(O) 2 OR, —C(R) 2 OR, or —S(O) 2 N(R) 2 ;

each R is independently hydrogen or an optionally substituted group selected from C 1-20 aliphatic, C 1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 2 is independently R, —[C(R) 2 ] q —OR, —[C(R) 2 ] q —N(R) 2 , —[C(R) 2 ] q —SR, —[C(R) 2 ] q —OSi(R) 3 , —[C(R) 2 ] q —OC(O)R, —[C(R) 2 ] q —OC(O)OR, —[C(R) 2 ] q —OC(O)N(R) 2 , —[C(R) 2 ] q —OC(O)N(R)—SO 2 R or —[C(R) 2 ] q —OP(OR) 2 ; or

R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R 1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

each q is independently 0, 1, 2, 3, or 4;

each R 3′ is independently R, or an electron-withdrawing group;

each R 4 is independently absent when is a double bond or is independently R or halogen;

each R 5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

each of R 6 and R 6′ is independently R, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, or —OSi(R) 3 ; or

R 6 and R 6′ are taken together to form ═O, ═C(R) 2 or ═NR;

each n is independently 0, 1, 2, 3, or 4;

each R 7 is independently R, halogen, —CN, —NO 2 , —OR, —OSi(R) 3 , —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 OR, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —P(R) 2 , —P(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , —P(O)[N(R) 2 ] 2 , —B(R) 2 , —B(OR) 2 , or —Si(R) 3 ; or

two R 7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 8 is independently —(S) m —R x wherein m is 1, 2, or 3, and R x is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;

each R 9 is independently —(S) p —R y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R y is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

R 8 and R 9 are taken together to form —S—, —(S) m —[C(R) 2 ] q —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —;

s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound of claim 1 , wherein the compound has the structure of formula II-a:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound has the structure of formula II-b:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein s is 1.

5. The compound of claim 1 , wherein L is self-immolative.

6. The compound of claim 1 , wherein M is an antibody.

7. The compound of claim 1 , wherein R 3′ is R.

8. The compound of claim 1 , wherein R 3′ is an electron-withdrawing group.

9. The compound of claim 1 , wherein

R 3′ is —S(O) 2 R, —S(O) 2 —[C(R) 2 ] q —R, —S(O) 2 —[C(R) 2 ] q —B(OR) 2 , —S(O) 2 —[C(R) 2 ] q —Si(R) 3 , —S(O) 2 OR, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —P(O)(R) 2 , —P(O)(OR) 2 , or —P(O)[N(R) 2 ] 2 .

10. The compound of claim 1 , wherein R 3′ is —SO 2 R.

11. The compound of claim 1 , wherein each R 4 is independently an optionally substituted group selected from phenyl, an 8-14 membered bicyclic or tricyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The compound of claim 1 , wherein

R 8 is —(S) m —R x wherein m is 1, 2, or 3, and R x is —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; and

R 9 is —(S) p —R y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R y is —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

R 8 and R 9 are taken together to form —S—, —(S) m —[C(R) 2 ] q —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —.

13. The compound of claim 1 , wherein R 8 and R 9 are taken together to form —S—, —(S) m —C(R) 2 —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —.

14. The compound of claim 1 , wherein:

R 8 is —(S) m —R x wherein m is 1 and R x is —SR or —C(O)R; and

R 9 is —(S) p —R y wherein p is 1 and R y is —SR or —C(O)R.

15. The compound of claim 1 , wherein R 8 and R 9 are taken together to form —(S) m —(S) p —, —S—C(O)—S—, or —S—C(S)—S—.

16. The compound of claim 1 , wherein:

each is independently a single bond;

each R 4 is independently R or halogen; and

each R 5 is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the cancer is lymphoma.

20. the method of claim 18 , wherein the cancer is cervical cancer, lung cancer, renal cancer, or breast cancer.

21. A compound having the structure of formula III:

H-L D) s    III

or a pharmaceutically acceptable salt thereof, wherein:

M is a cell-specific ligand unit;

L is a linker unit;

each D independently has the structure of formula I-c or I-d,

or a pharmaceutically acceptable salt thereof, wherein:

each is independently a single bond or a double bond;

each R 1 is independently R, —C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, —S(O) 2 OR, —C(R) 2 OR, or —S(O) 2 N(R) 2 ;

each R is independently hydrogen or an optionally substituted group selected from C 1-20 aliphatic, C 1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 2 is independently R, —[C(R) 2 ] q —OR, —[C(R) 2 ] q —N(R) 2 , —[C(R) 2 ] q —SR, —[C(R) 2 ] q —OSi(R) 3 , —[C(R) 2 ] q —OC(O)R, —[C(R) 2 ] q —OC(O)OR, —[C(R) 2 ] q —OC(O)N(R) 2 , —[C(R) 2 ] q —OC(O)N(R)—SO2R, or —[C(R) 2 ] q —OP(OR) 2 ; or

R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R 1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

each q is independently 0, 1, 2, 3, or 4;

each R 3′ is independently R, or an electron-withdrawing group;

each R 4 is independently absent when is a double bond or is independently R or halogen;

each R 5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

each of R 6 and R 6′ is independently R, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, or —OSi(R) 3 ; or

R 6 and R 6′ are taken together to form ═O, ═C(R) 2 or ═NR;

each n is independently 0, 1, 2, 3, or 4;

each R 7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R) 3 , —SR, —N(R) 2 , —S(O) 2 R,

—S(O) 2 OR, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —P(R) 2 , —P(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , —P(O)[N(R) 2 ] 2 , —B(R) 2 , —B(OR) 2 , or —Si(R) 3 ; or

two R 7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 8 is independently —(S) m —R x wherein m is 1, 2, or 3, and R x is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;

each R 9 is independently —(S) p —R y wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and R y is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(S)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

R 8 and R 9 are taken together to form —S—, —(S) m —[C(R) 2 ] q —(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, —(S) m —C(S)—(S) p —, —(S) m —S(O)—(S) p —, or —(S) m —S(O) 2 —(S) p —; and

s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

22. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 21 , or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein the cancer is lymphoma.

24. The method of claim 22 , wherein the cancer is cervical cancer, lung cancer, renal cancer, or breast cancer.