Compounds, conjugates and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines

Patent metadata

Field	Value
Publication number	US-2016354483-A1
Application number	US-201615150786-A
Country	US
Kind code	A1
Filing date	May 10, 2016
Priority date	Dec 4, 2012
Publication date	Dec 8, 2016
Grant date	—

Abstract

The present application provides, among other things, compounds, compositions and methods for treating various diseases including cancer.

First claim

1 - 2 . (canceled)

3 . 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, as valency permits;
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, 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 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, 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 ; 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 or 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, or 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 ; 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 —;
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.

4 . The compound of claim 3 , wherein the compound has the structure of formula II-a:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 3 , wherein M is an antibody.

7 . A compound having the structure of formula III:
M-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, as valency permits;
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, 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 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, 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 ; 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 or 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,

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

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

• A61K47/48384 Primary

  Human Necessities · mapped topic

• A61K47/6803

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

• C07D487/14 Primary

  Ortho-condensed systems · CPC title