# US 10,118,896 B2 · Antagonists of the kappa opioid receptor

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- Number: US 10,118,896 B2
- Document ID: US10118896B2
- Status: Granted
- Kind: B2
- Application number: 15/529,290
- Filed: 2015-11-25
- Published: 2017-09-14
- Granted: 2018-11-06
- Earliest claimed: 2014-11-26
- Assignees: University of Kansas; The Scripps Research Institute
- Applicants: University of Kansas
- Inventors: Jeffrey Aube; Kevin Frankowski; Thomas Prisinzano; Laura Bohn
- Web page: https://patentgrep.com/patent/US10118896B2

## CPC

- C07D 217/08: with a hetero atom directly attached to the ring nitrogen atom
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present technology is directed to compounds, compositions, and methods related to non-morphinan-like kappa opioid receptor (KOR) antagonists. The technology is suited to treat addiction, diuresis, depression, post traumatic stress disorder, an eating disorder, panic disorder, social anxiety disorder, general anxiety disorder, obsessive compulsive disorders, excessive or unreasonable specific phobias, and/or other conditions related to anxiety or aversion-reward responses.

## Claims

### Claim 1

A compound according to formula I
or stereoisomers, tautomers, solvates, and/or salts thereof; wherein
G1 and G2 are each independently C═O or S(O)2;
R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, C1-C6 alkanoyl, C1-C8 alkanoyloxy, aryloyl, or aryloyloxy group, where any two adjacent R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 may join to form a 5-membered or 6-membered substituted or unsubstituted heteroalkyl group;
R6 is a branched C1-C8 alkyl group or a substituted or unsubstituted cycloalkyl or aryl group; and
R12 and R13 are each independently H or a substituted or unsubstituted C1-C8 alkyl or C5-C7 cycloalkyl group; and
n is 0, 1, or 2;
provided that when G1 is S(O)2, G2 is C═O, R1, R2, R4, R5, R7, R8, R9, R10, R11, R12, R13 are each H, R6 is isopropyl, and n is 1, then R3 is not methyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein at least one of R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 is halo, hydroxy, cyano, trifluoromethyl, thiol, alkylthio, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, aryloyl, or aryloyloxy group.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least one of R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 is hydroxy or a substituted or unsubstituted C1-C6 alkoxy or C1-C6 alkanoyloxy group.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least one of R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 is hydroxy or an unsubstituted C1-C6 alkoxy group.

### Claim 5 (depends on 1)

The compound of claim 1, wherein at least one of R1, R2, R3, R4, and R5 is halo, hydroxy, carboxylate, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, or C1-C6 alkanoyloxy group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein at least one of R7, R8, R9, R10, and R11 is halo, hydroxy, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, aryloyl, or aryloyloxy group.

### Claim 7 (depends on 1)

The compound of claim 1, wherein at least one of R7, R8, R9, R10, and R11 is hydroxy or an unsubstituted C1-C6 alkoxy group.

### Claim 8 (depends on 1)

The compound of claim 1, wherein at least two of R1, R2, R3, R4, R5, R7, R8, R9, R10, and R11 are each independently halo, hydroxy, cyano, trifluoromethyl, nitro, pentafluorosulfanyl, carboxylate, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, aryloyl, or aryloyloxy group.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
G1 is S(O)2;
G2 is C═O;
R1, R4, R5, R7, R10, and R11 are each H;
R2, R3, R8, and R9 are each independently halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, C1-C6 alkanoyl, C1-C8 alkanoyloxy, aryloyl, or aryloyloxy group, where any two adjacent R2, R3, R8, and R9 may join to form a 5-membered or 6-membered substituted or unsubstituted heteroalkyl group;
R6 is a branched C1-C8 alkyl group;
R12 and R13 are each H; and
n is 1.

### Claim 10 (depends on 1)

The compound of claim 1, wherein
G1 is S(O)2;
G2 is C═O;
R1, R4, R5, R7, R10, and R11 are each H;
one of R2 and R3 is halo, hydroxy, or a unsubstituted C1-C6 alkyl, C1-C6alkoxy, C1-C6 alkanoyl, or C1-C8 alkanoyloxy group and the other R2 or R3 is H;
one of R8 and R9 is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, or a substituted or unsubstituted C1-C6 alkoxy, C1-C6 alkanoyl, or C1-C8 alkanoyloxy group, and the other R8 or R9 is H;
R6 is a branched C1-C8 alkyl group;
R12 and R13 are each H; and
n is 1.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R6 is a branched C1-C8 alkyl group or a substituted or unsubstituted cycloalkyl group.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R6 is isopropyl, sec-butyl, tert-butyl, isopentyl, neopentyl, or adamantyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R6 is tert-butyl, neopentyl, or adamantyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of

### Claim 15 (depends on 1)

A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

A method comprising inhibiting β-arrestin recruitment in a subject by administering an effective amount of a compound of claim 1.

### Claim 17 (depends on 16)

The method of claim 16, wherein the subject is suffering from depression, alcohol addiction, or cocaine addiction.

### Claim 18 (depends on 1)

A method of inhibiting β-arrestin recruitment wherein the method comprises contacting a kappa opioid receptor with a compound of claim 1.