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

Patent metadata

Field	Value
Publication number	US-9353150-B2
Application number	US-201314096158-A
Country	US
Kind code	B2
Filing date	Dec 4, 2013
Priority date	Dec 4, 2012
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The present application provides, among other things, a compound of Formula I-a and/or I-b,

or a pharmaceutically acceptable salt thereof, wherein the variables are defined in the specification. The compounds of the invention are useful for treating various diseases including cancer.

First claim

The invention claimed is:

1. A compound having the structure of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:
is a single bond or a double bond, as valency permits;
R 1 is 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 a 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 mono cyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups are optionally taken together with their intervening atoms to form a 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is hydrogen, —[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 ;
each q is independently 0, 1, 2, 3, or 4;
R 3 is —SO 2 R or —COCF 3 ;
R 4 is absent when is a double bond or is R or halogen;
R 5 is absent when is a double bond or is hydrogen or a 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;
n is 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 ;
R 8 is —(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 ; 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 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 —.

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

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

4. The compound of claim 3 , wherein each of R 5 , R 6 and R 6′ is independently hydrogen.

5. The compound of claim 4 , wherein R 8 and R 9 are taken together to form —S—S—.

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

or a pharmaceutically acceptable salt thereof, wherein:
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 a 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, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups are optionally taken together with their intervening atoms to form a 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, or 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 ;
each q is independently 0, 1, 2, 3, or 4;
each R 3 is —SO 2 R;
each R 5 is independently hydrogen or a 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 ;
each R 8 is independently —(S) p —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 ; and

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 —.

7. The compound of claim 6 , wherein R 3 is —SO 2 Ph.

8. The compound of claim 7 , wherein R 8 and R 9 are taken together to form —S—, —(S) m —(CH 2 )—(S) p —, —(S) m —(S) p —, —(S) m —C(O)—(S) p —, or —(S) m —C(S)—(S) p —.

9. The compound of claim 8 , wherein each of R 5 , R 6 and R 6′ is independently hydrogen.

10. The compound of claim 9 , wherein R 8 and R 9 are taken together to form —S—S—.

11. A compound selected from the group consisting of:

Assignees

• Massachusetts Inst Technology
• Univ Illinois

Inventors

• Movassaghi Mohammad
• Kim Justin
• Hergenrother Paul J
• Morrison Karen
• Boyer Nicolas

Classifications

• C07D513/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07K5/12 Primary

  Cyclic peptides {with only normal peptide bonds in the ring} · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61K47/48384

  Human Necessities · mapped topic

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title