# US 10,118,915 B2 · Kappa opioid ligands

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- Number: US 10,118,915 B2
- Document ID: US10118915B2
- Status: Granted
- Kind: B2
- Application number: 15/595,436
- Filed: 2017-05-15
- Published: 2018-04-12
- Granted: 2018-11-06
- Earliest claimed: 2012-08-16
- Assignees: The Scripps Research Institute
- Applicants: The Scripps Research Institute
- Inventors: Edward Roberts; Miguel A. Guerrero; Mariangela Urbano; Hugh Rosen
- Web page: https://patentgrep.com/patent/US10118915B2

## CPC

- C07D 405/14: containing three or more hetero rings
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/58: attached in position 4
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides novel ligands of Kappa (κ) opioid receptors, such as can be used to modulate a Kappa opioid receptor. Methods of synthesis and methods of use are also provided. Compounds of the invention can be used therapeutically in the treatment of dissociative disorders or pain, or to provide neuroprotection, or to induce diuresis, or to modulate the immune system, or for treatment of one or more of an affective disorders comprising depression or stress/anxiety; an addictive disorder; alcoholism, epilepsy; a cognition deficiency; schizophrenia; Alzheimer's disease; or pain.

## Claims

### Claim 1

A method of treating a patient having a condition, wherein the condition is one or more of an affective disorder, an addictive disorder, alcoholism, epilepsy, a cognition deficiency, schizophrenia, Alzheimer's disease, or pain, comprising administering to the patient a therapeutically effective amount of a compound of the following formula:
wherein
Y is H, halo, (C1-C6)alkyl, or (C3-C9)cycloalkyl;
Z is heteroaryl;
W and X taken together with the atoms to which they are bonded form a fused cycloalkyl or aryl, either of which can be mono- or independently multi-substituted with (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NRaRb, N(Ra)C(═O)(C1-C6)alkyl, CO2R, or heteroaryl;
wherein any alkyl, cycloalkyl, aryl, or heteroaryl of W, X, Y, or Z, can be unsubstituted or can be mono- or independently multi-substituted with (C1-C6)alkyl, (C3-C9)cycloalkyl, halo, nitro, NRaRb, N(Ra)C(═O)(C1-C6)alkyl, CO2R, or heteroaryl;
Ra and Rb are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, is substituted with 0, 1, 2, 3, or 4 independently selected J, and wherein any heterocyclyl or cycloalkyl is mono-, bi-, or tri-cyclic;
or Ra and Rb together with the nitrogen atom to which they are bonded form a heterocyclyl ring substituted with 0, 1, 2, 3, or 4 independently selected J;
n=0, 1, or 2; and
J is independently at each occurrence OR, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C9)cycloalkyl, CO2R, or halo;
wherein each independently selected R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6)alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the condition is an affective disorder.

### Claim 3 (depends on 2)

The method of claim 2, wherein the affective disorder is depression or anxiety.

### Claim 4 (depends on 3)

The method of claim 3, wherein the anxiety is stress related anxiety.

### Claim 5 (depends on 1)

The method of claim 1, wherein the condition is an addictive disorder.

### Claim 6 (depends on 1)

The method of claim 1, wherein the condition is alcoholism.

### Claim 7 (depends on 1)

The method of claim 1, wherein the condition is epilepsy.

### Claim 8 (depends on 1)

The method of claim 1, wherein the condition is a cognition deficiency.

### Claim 9 (depends on 1)

The method of claim 1, wherein the condition is schizophrenia.

### Claim 10 (depends on 1)

The method of claim 1, wherein the condition is Alzheimer's disease.

### Claim 11 (depends on 1)

The method of claim 1, wherein the condition is pain.

### Claim 12 (depends on 1)

The method of claim 1, wherein Y is H.

### Claim 13 (depends on 1)

The method of claim 1, wherein Y is (C1-C6)alkyl.

### Claim 14 (depends on 1)

The method of claim 1, wherein Y is halo.

### Claim 15 (depends on 1)

The method of claim 1, wherein Z is 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, or 3-cyclopropyl-1,2,4-oxadiazol-5-yl.

### Claim 16 (depends on 1)

The method of claim 1, wherein W and X taken together with the atoms to which they are bonded form a fused aryl which can be mono- or independently multi-substituted with (C1-C6)alkyl, (C3-C9)cycloalkyl, or halo.

### Claim 17 (depends on 1)

The method of claim 1, wherein n is 0 or 1; Ra is ethyl, 2-pentyl, 4-methyl-2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bornyl, or adamantyl, any of which is substituted with 0, 1, 2, 3, or 4 J; and Rb is H.

### Claim 18 (depends on 1)

The method of claim 1, wherein n is 0 or 1; and Ra and Rb together with the nitrogen atom to which they are bonded form a pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, or thiomorpholinyl ring, any of which is substituted with 0, 1, 2, 3, or 4 J.

### Claim 19 (depends on 1)

The method of claim 1, wherein n is 0.

### Claim 20 (depends on 1)

The method of claim 1, wherein n is 0; Ra is heterocyclyl; and Rb is H.

### Claim 21 (depends on 1)

The method of claim 1, wherein W and X taken together with the atoms to which they are bonded form a fused aryl which can be mono- or independently multi-substituted with (C1-C6)alkyl or halo; Y is H or (C1-C6)alkyl; and Z is 3-methyl-1,2,4-oxadiazol-5-yl.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound is any of the following:
or any pharmaceutically acceptable salt thereof;
wherein rac denotes a racemic mixture, trans-rac denotes a ring trans compound as a racemic mixture, and cis-rac indicates a ring cis compound as a racemic mixture.

### Claim 23 (depends on 20)

The method of claim 20, wherein Ra is tetrahydropyranyl.

### Claim 24 (depends on 23)

The method of claim 23, wherein Ra is

### Claim 25 (depends on 20)

The method of claim 20, wherein Ra is tetrahydrofuranyl.

### Claim 26 (depends on 25)

The method of claim 25, wherein Ra is

### Claim 27 (depends on 20)

The method of claim 20, wherein Ra is oxetanyl.

### Claim 28 (depends on 27)

The method of claim 27, wherein Ra is

### Claim 29 (depends on 19)

The method of claim 19, wherein Ra is cycloalkylalkyl and Rb is H.

### Claim 30 (depends on 29)

The method of claim 29, wherein Ra is

### Claim 31 (depends on 20)

The method of claim 20, wherein Y is H; and W and X taken together with the atoms to which they are bonded form the fused aryl quinoline mono- or independently multi-substituted with (C1-C6)alkyl or halo.

### Claim 32 (depends on 31)

The method of claim 31, wherein Z is 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl or 3-cyclopropyl-1,2,4-oxadiazol-5-yl.

### Claim 33 (depends on 20)

The method of claim 20, wherein Y is methyl; and W and X taken together with the atoms to which they are bonded form the fused aryl quinoline mono- or independently multi-substituted with (C1-C6)alkyl or halo.

### Claim 34 (depends on 33)

The method of claim 33, wherein Z is 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl or 3-cyclopropyl-1,2,4-oxadiazol-5-yl.