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 I-a:

or a pharmaceutically acceptable salt thereof,

wherein:

is a single bond or double bond;

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

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

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

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

when is a double bond, R 4 is absent; or

when is a single bond, R 4 is hydrogen or halogen; or

when is a single bond, R 4 is a substituent selected from the group consisting of:

(a) optionally substituted C 1-20 heteroalkyl;

(b) optionally substituted phenyl;

(c) an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;

(d) an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated, or aryl ring;

(e) an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(f) an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and

(g) an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

when is a double bond, R 5 is absent; or

when is a single bond, R 5 is hydrogen or an optionally substituted C 1-6 aliphatic group;

each of R 6 and R 6′ is independently R, halogen, —CN, —NO 2 , —C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —C(O)OR, —N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —OR, —OSi(R) 3 , —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

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

each R 7 is independently R, halogen, —CN, —NO 2 , —B(R) 2 , —B(OR) 2 , —C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —C(O)OR, —N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —OR, —OSi(R) 3 , —P(R) 2 , —P(O)[N(R) 2 ] 2 , —P(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O) 2 OR, or —Si(R) 3 ; or

two R 7 , taken together with their intervening atoms, form an optionally substituted 4-7 membered ring having 0, 1, or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

R 8 is —(S) m —R x ;

R 9 is —(S) p —R y ; or

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

R x is —C(O)R, —C(O)N(R) 2 , —C(O)OR, —C(S)R, —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

R x is a substituent selected from the group consisting of:

(a) optionally substituted C 1-20 heteroalkyl;

(b) optionally substituted phenyl;

(c) an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;

(d) an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring;

(e) an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(f) an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(g) an optionally substituted 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and

(h) an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

R y is R, —C(O)R, —C(O)N(R) 2 , —C(O)OR, —C(S)R, —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;

each R is independently hydrogen or a substituent independently selected from the group consisting of:

(a) optionally substituted C 1-20 aliphatic;

(b) optionally substituted C 1-20 heteroalkyl;

(c) optionally substituted phenyl;

(d) an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;

(e) an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated, or aryl ring;

(f) an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(g) an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(h) an optionally substituted 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and

(i) an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or

two R groups, taken together with their intervening atoms, form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0, 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

m is 1, 2, or 3;

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

p is 1, 2 or 3; and

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

with the proviso that the sum of m and p is 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 N(R) 2 , or —S(O) 2 OR.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —S(O) 2 R.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 4 is halogen; or

R 4 is a substituent selected from the group consisting of:

(a) optionally substituted phenyl;

(b) an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated, or aryl ring;

(c) an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and

(d) an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each R is independently hydrogen or a substituent independently selected from the group consisting of:

(a) optionally substituted C 1-20 aliphatic;

(b) optionally substituted C 1-20 heteroalkyl; and

(c) optionally substituted phenyl.

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

7. A method for generating reactive oxygen species in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

8. A method for inhibiting cellular proliferation in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

9. A method for inducing caspase-dependent apoptosis in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

10. A method for disrupting the tertiary structure of proteins containing a Zn 2+ -binding cysteine-histidine rich protein domain in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

11. A method for inhibiting a cellular protein in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

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

14. The method of claim 13 , wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, lung cancer, and renal cancer.

15. The method of claim 13 , wherein the cancer is lymphoma.

16. A compound having the structure of formula I-b:

or a pharmaceutically acceptable salt thereof,

wherein:

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

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

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

each R 3 is independently —C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —C(O)OR, —P(O)(R) 2 , —P(O)[N(R) 2 ] 2 , —P(O)(OR) 2 , —S(O)R, —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 N(R) 2 , or —S(O) 2 OR;

each R 5 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 , —C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —C(O)OR, —N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —OR, —OSi(R) 3 , —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; or

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

each R 7 is independently R, halogen, —CN, —NO 2 , —B(R) 2 , —B(OR) 2 , —C(O)R, —C(O)N(R) 2 , —C(O)N(R)OR, —C(O)OR, —N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —OR, —OSi(R) 3 , —P(R) 2 , —P(OR) 2 , —P(O)(R) 2 , —P(O)[N(R) 2 ] 2 , —P(O)(OR) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O) 2 OR, or —Si(R) 3 ; or

two R 7 , taken together with their intervening atoms, form an optionally substituted 4-7 membered, ring having 0, 1, or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

each R 8 is independently —(S) m —R;

each R 9 is independently —(S) p —R y ; or

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

R x is R, —C(O)R, —C(O)N(R) 2 , —C(O)OR, —C(S)R, —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;

R y is R, —C(O)R, —C(O)N(R) 2 , —C(O)OR, —C(S)R, —SR, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;

each R is independently hydrogen or a substituent independently selected from the group consisting of:

(a) optionally substituted C 1-20 aliphatic;

(b) optionally substituted C 1-20 heteroalkyl;

(c) optionally substituted phenyl;

(d) an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;

(e) an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated, or aryl ring;

(f) an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(g) an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

(h) an optionally substituted 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and

(i) an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or

two R groups, taken together with their intervening atoms, form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0, 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

m is 1, 2, or 3;

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

p is 1, 2, or 3; and

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

with the provisos that:

(1) R 3 is other than —C(O)CF 3 ; and

(2) the sum of m and p is 2, 3, or 4.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently —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 N(R) 2 , or —S(O) 2 OR.

18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently —S(O) 2 R.

19. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:

each R is independently hydrogen or a substituent independently selected from the group consisting of:

(a) optionally substituted C 1-20 aliphatic;

(b) optionally substituted C 1-20 heteroalkyl; and

(c) optionally substituted phenyl.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

21. A method for generating reactive oxygen species in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

22. A method for inhibiting cellular proliferation in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

23. A method for inducing caspase-dependent apoptosis in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

24. A method for disrupting the tertiary structure of proteins containing a Zn 2+ -binding cysteine-histidine rich protein domain in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

25. A method for inhibiting a cellular protein in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

26. A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

27. A method for treating cancer in a subject, comprising administering to the subject an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt thereof.

28. The method of claim 27 , wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, lung cancer, and renal cancer.

29. The method of claim 27 , wherein the cancer is lymphoma.