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

Patent metadata

Field	Value
Publication number	US-10918735-B2
Application number	US-201916293443-A
Country	US
Kind code	B2
Filing date	Mar 5, 2019
Priority date	Dec 4, 2012
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

The synthesis of various pyrazino[1′,2′:1,5]pyrrolo[2,3-B]-indole-1,4-dione analogs has been successfully implemented in the present application. From these efforts, compounds having the structure of Formula I-a or Formula I-b:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, are provided herein. These biologically active derivatives have been used to effectively treat 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 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 subs

Assignees

• Massachusetts Inst Technology
• Univ Illinois

Inventors

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

Classifications

• A61K47/6803 Primary

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

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• C07K5/12

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

• C07D513/22

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