# US 10,246,465 B2 · Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain

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- Number: US 10,246,465 B2
- Document ID: US10246465B2
- Status: Granted
- Kind: B2
- Application number: 15/315,486
- Filed: 2015-06-02
- Published: 2017-11-02
- Granted: 2019-04-02
- Earliest claimed: 2014-06-02
- Assignees: Laboratorios Del Dr. Esteve, S.A.
- Applicants: Laboratorios Del Dr. Esteve S.A.
- Inventors: Marina Virgili-Bernado; Monica Alonso-Xalma; Carlos Alegret-Molina; Carmen Almansa-Rosales; Monica Garcia Lopez
- Web page: https://patentgrep.com/patent/US10246465B2

## CPC

- C07D 498/10: Spiro-condensed systems
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

## Claims

### Claim 1

A compound of Formula I
wherein
R1 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C4-7 alkylcycloalkyl,
wherein the cycloalkyl in R1, if substituted, also in alkylcycloalkyl, is substituted with substituents selected from the group consisting of —R4′″, halogen, —SR4′″, —CN, haloalkyl, and —NR4′″R4′″,
wherein the alkyl, alkenyl and alkynyl in R1, if substituted, are substituted with substituents selected from the group consisting of halogen, —CN, and haloalkyl;
R2 is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heterocyclyl,
wherein the aryl or heterocyclyl in R2, if substituted, is substituted with substituents selected from the group consisting of —R4, —OR4, halogen, ═O, —OCH2CH2OH, —SR4, —S(O)R4, —S(O)2R4, —CN, haloalkyl, -haloalkoxy, —NR4R4′″, —NO2, —NR4C(O)R4′, —NR4SO2R4′, —C(O)OR4, —C(O)NR4R4′, —NR4C(O)NR4′R4″, —S(O)2NR4R4′, and —NR4S(O)2NR4′R4″,
R3 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C4-7 alkylcycloalkyl, substituted or unsubstituted C4-7 alkylaryl, substituted or unsubstituted C3-6 aryl, substituted or unsubstituted C3-6 heterocyclyl or substituted or unsubstituted C4-7 alkylheterocyclyl,
wherein the aryl, heterocyclyl or cycloalkyl in R3, if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, is substituted with substituents selected from the group consisting of —R4, —OR4, halogen, ═O, —OCH2CH2OH, —SR4, —S(O)R4, —S(O)2R4, —CN, haloalkyl, -haloalkoxy, —NR4R4′″, —NO2, —NR4C(O)R4′, —NR4S(O)2R4′, —C(O)OR4, —C(O)NR4R4′, —NR4C(O)NR4′R4′″, —S(O)2NR4R4′, and —NR4S(O)2NR4′R4′″
and wherein the alkyl, alkenyl and alkynyl as defined in R3, if substituted, are substituted with substituents selected from —OR4, halogen, —CN, and haloalkyl,
R3′ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl or unsubstituted C2-6 alkynyl,
alternatively R3 and R3′ taken together with the connecting C-atom form an substituted or unsubstituted C3-6 cycloalkyl,
wherein the cycloalkyl formed by R3 and R3′ taken together with the connecting C-atom, if substituted, is substituted with substituents selected from the group consisting of —R4, —OR4, halogen, ═O, —OCH2CH2OH, —SR4, —S(O)R4, —S(O)2R4, —CN, haloalkyl, -haloalkoxy, —NR4R4′″, —NO2, —NR4C(O)R4′, —NR4S(O)2R4′, —C(O)OR4, —C(O)NR4R4′, —NR4C(O)NR4′R4″, —S(O)2NR4R4′, and —NR4S(O)2NR4′R4″;
R4, R4′ and R4″ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl,
wherein the cycloalkyl in R4, R4′ or R4″, if substituted, is substituted with substituents selected from the group consisting of —R4′″, halogen, —SR4′″, —CN, haloalkyl, and —NR4′″R4′″,
wherein the alkyl, alkenyl and alkynyl in R4, R4′ or R4″, if substituted, are substituted with substituents selected from the group consisting of halogen, —CN, and haloalkyl;
R4′″ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl or -Boc;
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
R1 is unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted C3-6 cycloalkyl, unsubstituted C4-7 alkylcycloalkyl;
R2 is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heterocyclyl,
wherein the aryl or heterocyclyl, if substituted, is substituted with substituents selected from the group consisting of —R4, —OR4, halogen, ═O, —OCH2CH2OH, —SR4, —S(O)R4, —S(O)2R4, —CN, haloalkyl -haloalkoxy, —NR4R4′″, —NO2, —NR4C(O)R4′, —NR4S(O)2R4′, —C(O)OR4, —C(O)NR4R4′, —NR4C(O)NR4′R4″, —S(O)2NR4R4′, and —NR4S(O)2NR4′R4″;
R3 is unsubstituted C1-6 alkyl, unsubstituted C2-5 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted C3-6 cycloalkyl, unsubstituted C4-7 alkylcycloalkyl, unsubstituted C4-7 alkylaryl, unsubstituted C3-6 aryl, unsubstituted C3-6 heterocyclyl or unsubstituted C4-7 alkylheterocyclyl;
R3′ is hydrogen or unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl or unsubstituted C2-6 alkynyl,
alternatively R3 and R3′ taken together with the connecting C-atom form an unsubstituted C3-6 cycloalkyl;
R4, R4′ and R4″ are independently selected from the group consisting of hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, and unsubstituted C3-6 cycloalkyl;
R4′″ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl or -Boc;
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the compound of formula I is a compound of formula I′
wherein q is 1, 2, 3 or 4,
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein q is 1,
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 5 (depends on 1)

The Compound according to claim 1, wherein the compound of formula I is a compound of formula I″
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R1 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C4-7 alkylcycloalkyl:
R2 is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heterocyclyl, wherein
the monocyclic aryl is substituted or unsubstituted phenyl; and
the monocyclic heterocyclyl is a heterocyclic ring system of one saturated or unsaturated ring which contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur;
R3 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C4-7 alkylcycloalkyl, substituted or unsubstituted C4-7 alkylaryl, substituted or unsubstituted C3-6 aryl, substituted or unsubstituted C3-6 heterocyclyl or substituted or unsubstituted C4-7 alkylheterocyclyl; wherein
the aryl is phenyl, and
the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur;
R3′ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl or unsubstituted C2-6 alkynyl,
or R3 and R3′ taken together with the connecting C-atom form an substituted or unsubstituted C3-6 cycloalkyl;
R4, R4′ and R4″ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl, and substituted or unsubstituted C3-6 cycloalkyl;
R4′″ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl or -Boc;
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein
R1 is selected from the group consisting of substituted or unsubstituted methyl, ethyl, isopropyl; substituted or unsubstituted ethenyl, propenyl, butenyl, pentenyl, or hexenyl; substituted or unsubstituted ethyne, propyne, butyne, pentyne or hexyne; and substituted or unsubstituted cyclopropyl;
R2 is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, thiazole, tetrahydropyran, morpholine, furan, triazole, isoxazole, pyrazole, thiophene, pyrrole, pyrazine, oxopyrrolidine, or pyrimidine;
R3 is selected from the group consisting of substituted or unsubstituted methyl, ethyl, or isopropyl; substituted or unsubstituted ethenyl, propenyl, butenyl, pentenyl, or hexenyl; substituted or unsubstituted propyne; substituted or unsubstituted phenyl; substituted or unsubstituted imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole, oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole or quinazoline; and substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R3′ is selected from the group consisting of hydrogen, methyl, ethyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, ethyne, propyne, butyne, pentyne, and hexyne; or
R3 and R3′ taken together with the connecting C-atom form an substituted or unsubstituted cyclopropyl ring;
R4, R4′ and R4″ are independently selected from the group consisting of hydrogen; substituted or unsubstituted methyl; substituted or unsubstituted ethenyl, propenyl, butenyl, pentenyl, or hexenyl; substituted or unsubstituted ethyne, propyne, butyne, pentyne or hexyne; and substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R4′″ is hydrogen or -Boc.

### Claim 8 (depends on 6)

The compound according to claim 6, wherein
R1 is unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl or unsubstituted cyclopropyl;
R2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, or substituted or unsubstituted thiazole;
R3 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted propyne, substituted or unsubstituted benzyl, or —CH2CH2OH;
R3′ is hydrogen, methyl, or ethyl;
R4, R4′ and R4″ are independently selected from the group consisting of hydrogen and substituted or unsubstituted methyl;
R4′″ is hydrogen or -Boc.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R1 is unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted C3-6 cycloalkyl, unsubstituted C4-7 alkylcycloalkyl;
R2 is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heterocyclyl, wherein
the aryl is phenyl and
the heterocyclyl is a heterocyclic ring system of one saturated or unsaturated ring which contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur;
R3 is unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted C3-6 cycloalkyl, unsubstituted C4-7 alkylcycloalkyl, unsubstituted C4-7 alkylaryl, unsubstituted C3-6 aryl, unsubstituted C3-6 heterocyclyl or unsubstituted C4-7 alkylheterocyclyl, wherein
the aryl is phenyl;
the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur;
R3′ is hydrogen or unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl or unsubstituted C2-6 alkynyl;
or
R3 and R3′ taken together with the connecting C-atom form an unsubstituted C3-6 cycloalkyl;
R4, R4′ and R4″ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, and unsubstituted C3-6 cycloalkyl;
R4′″ is hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl or -Boc;
optionally as a stereoisomer, a racemate or in form of a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

### Claim 10 (depends on 9)

The compound according to claim 9, wherein
R1 is methyl, ethyl, isopropyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, ethyne, propyne, butyne, pentyne, hexyne, or cyclopropyl;
R2 is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, thiazole, tetrahydropyran, morpholine, furan, triazole, isoxazole, pyrazole, thiophene, pyrrole, pyrazine, oxopyrrolidine, or pyrimidine;
R3 is methyl, ethyl, isopropyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, propyne, phenyl; imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole, oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, or cyclopropyl;
R3′ is hydrogen, methyl, ethyl, isopropyl ethenyl, propenyl, butenyl, pentenyl, hexenyl, ethyne, propyne, butyne, pentyne, or hexyne; or
R3 and R3′ taken together with the connecting C-atom form a cyclopropyl or cyclopentyl ring;
R4, R4′ and R4′″ are independently selected from the group consisting of hydrogen, methyl; ethenyl, propenyl, butenyl, pentenyl, hexenyl, ethyne, propyne, butyne, pentyne, hexyne, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R4′″ is hydrogen or -Boc.

### Claim 11 (depends on 9)

The compound according to claim 9, wherein
R1 is methyl, ethyl, isopropyl, or cyclopropyl;
R2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, or substituted or unsubstituted thiazole;
R3 is methyl, ethyl, isopropyl, propyne, benzyl, or —CH2CH2OH;
R3′ is hydrogen, methyl, or ethyl;
R4, R4′ and R4′″ are independently selected from the group consisting of hydrogen and methyl;
R4′″ is hydrogen or -Boc.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein the compound is selected from the group consisting of:
12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
8-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
8-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-isopropyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride
12-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
(R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide
4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide
12-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
(R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
12-ethyl-8-(3-nitrophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(3-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
tert-butyl (4-(2-(12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate
methyl 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate
12-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(4-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(2-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile
4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide
8-[2-fluorophenethyl]-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
8-[2-fluorophenethyl]-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
(R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
8-(3-fluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride
(R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
2,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
12-methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
8-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide
[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea
4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide
12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3] tridecan-13-one hydrochloride
8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
2,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
8-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
8-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-One
10-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one
10-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one
(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
8-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(3-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
12-ethyl-8-(2-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one
(R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
4-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
4-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
4-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
4-cyclopropyl-9-(2,5-difluorophenethyl)-22-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one
(R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, and
(R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;
optionally in form of one of the stereoisomers, a racemate or in form of a mixture of at least two of the stereoisomers, in any mixing ratio, or a corresponding salt thereof.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein the compound is in the form of an enantiomer or diastereomer.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein the compound is in the form of a mixture of at least two enantiomers and/or diastereomers.

### Claim 15 (depends on 12)

The compound according to claim 12, wherein the compound is in the form of an enantiomer or diastereomer.

### Claim 16 (depends on 12)

The compound according to claim 12, wherein the compound is in the form of a mixture of at least two enantiomers and/or diastereomers.

### Claim 17 (depends on 1)

A pharmaceutical composition which comprises the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

### Claim 18 (depends on 1)

A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the pain is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia, and hyperalgesia.

### Claim 20 (depends on 1)

A process for the preparation of a compound of formula (I) according to claim 1,
which comprises the steps of
(a) reacting a compound of formula V
with a compound of formula VI
wherein W and LG are leaving groups, to obtain a compound of formula VII
(b) Carrying out a cyclisation of the resulting compound in a suitable solvent, in the presence of a strong base and at a temperature comprised between −78° C. and the reflux temperature.

### Claim 21 (depends on 3)

A process for the preparation of a compound of general formula (I′) according to claim 3:
which comprises the steps of
(a) reacting a compound of formula V
with a compound of formula XX
wherein W and LG are leaving groups, q is as defined in the preceeding claims;
to obtain a compound of formula XXI
wherein W and LG are leaving groups,
(b) carrying out a cyclisation of the resulting compound in a suitable solvent, in the presence of a strong base and at a temperature comprised between −78° C. and the reflux temperature; leading to a compound of formula XXII,
(c) and treating with a strong base, in an aprotic solvent, at a suitable temperature.