# US 2016/0354483 A1 · Compounds, conjugates and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines

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- Number: US 2016/0354483 A1
- Document ID: US20160354483A1
- Status: Published application
- Kind: A1
- Application number: 15/150,786
- Filed: 2016-05-10
- Published: 2016-12-08
- Earliest claimed: 2012-12-04
- Assignees: Massachusetts Institute of Technology; The Board of Trustees of the University of Illinois
- Applicants: Massachusetts Institute of Technology; The Board of Trustees of the University of Illinois
- Inventors: Mohammad Movassaghi; Justin Kim; Paul J. Hergenrother; Karen Morrison; Nicolas Boyer
- Web page: https://patentgrep.com/patent/US20160354483A1

## CPC

- C07D 487/14: Ortho-condensed systems
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- C07D 513/22: in which the condensed system contains four or more hetero rings
- C07K 5/12: Cyclic peptides {with only normal peptide bonds in the ring}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

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

## Claims

### Claim at position 1

1-2. (canceled)

### Claim 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 R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
each R is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, C1-20 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 R2 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
R1 and R2 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 R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen or sulfur;
each q is independently 0, 1, 2, 3, or 4;
each R3′ is independently R or an electron-withdrawing group;
each R4 is independently absent when is a double bond or is independently R or halogen;
each R5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(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)2R, or —OSi(R)3; or
R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
each n is independently 0, 1, 2, 3, or 4;
each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(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)2R, —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 R7 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 R8 is independently —(S)m—Rx wherein m is 1, 2, or 3, and Rx is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; and
each R9 is independently —(S)p—Ry wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and Ry is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; or
R8 and R9 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.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the compound has the structure of formula II-a:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 3)

The compound of claim 3, wherein the compound has the structure of formula II-b:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 3)

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

### Claim 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 R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
each R is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, C1-20 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 R2 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
R1 and R2 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 R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen or sulfur;
each q is independently 0, 1, 2, 3, or 4;
each R3′ is independently R or an electron-withdrawing group;
each R4 is independently absent when is a double bond or is independently R or halogen;
each R5 is independently absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(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)2R, or —OSi(R)3; or
R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
each n is independently 0, 1, 2, 3, or 4;
each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(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)2R, —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 R7 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 R8 is independently —(S)m—Rx wherein m is 1, 2, or 3, and Rx is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; and
each R9 is independently —(S)p—Ry wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and Ry is R, —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; or
R8 and R9 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.

### Claim 8 (depends on 3)

The compound of claim 3, wherein R3′ is R.

### Claim 9 (depends on 3)

The compound of claim 3, wherein R3′ is an electron-withdrawing group.

### Claim 10

(canceled)

### Claim 11 (depends on 3)

The compound of claim 3, wherein L is self-immolative.

### Claim 12 (depends on 3)

The compound of claim 3, wherein s is 1.

### Claim 13 (depends on 3)

The compound of claim 3, wherein
R3′ is —S(O)2R, —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)2OR, —S(O)2N(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.

### Claim 14 (depends on 3)

The compound of claim 3, wherein
R8 is —(S)m—Rx wherein m is 1, 2, or 3, and Rx is —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; and
R9 is —(S)p—Ry wherein p is 1, 2, or 3, such that the sum of m and p is 2, 3, or 4, and Ry is —SR, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(S)R, —S(O)R, —S(O)2R, or —S(O)2N(R)2; or
R8 and R9 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—.

### Claim 15 (depends on 3)

The compound of claim 3, wherein R8 and R9 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—.

### Claim 16 (depends on 3)

A pharmaceutical composition comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 3)

A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 3.

### Claim at position 17

18-23. (canceled)

### Claim 24 (depends on 3)

The compound claim 3, wherein is a single bond, R4 is R or halogen, and R5 is hydrogen or an optionally substituted C1-6 aliphatic.

### Claim at position 19

25-26. (canceled)

### Claim 27 (depends on 3)

The compound claim 3, wherein:
R8 is —(S)m—Rx wherein m is 1 and Rx is —SR, —C(O)R; and
R9 is —(S)p—Ry wherein p is 1 and Ry is —SR, —C(O)R.

### Claim 28 (depends on 3)

The compound claim 3, wherein R8 and R9 are taken together to form —(S)m—(S)p—, —S—C(O)—S—, or —S—C(S)—S—.

### Claim 29 (depends on 3)

The compound claim 3, wherein R3 or R3′ is —SO2R.

### Claim 30 (depends on 3)

The compound claim 3, wherein each R4 is independently an optionally substituted group selected from phenyl, a 8-14 membered bicyclic or tricyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 31

(canceled)