# US 12,005,054 B2 · Piperidinyl-3-(aryloxy)propanamides and propanoates

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- Number: US 12,005,054 B2
- Document ID: US12005054B2
- Status: Granted
- Kind: B2
- Application number: 17/320,574
- Filed: 2021-05-14
- Published: 2023-01-26
- Granted: 2024-06-11
- Earliest claimed: 2018-03-01
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Zacharia Cheruvallath; Jason Green; Ben Johnson; Kristin Schleicher; Huikai Sun; Mingnam Tang
- Web page: https://patentgrep.com/patent/US12005054B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4355: the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 211/58: attached in position 4
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 491/048: the oxygen-containing ring being five-membered
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are compounds of Formula 1, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein L, r, s, R5, R6, R7, R9, R10, R11, R12, X1, X2, X3, X4, X13, and X14 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with SSTR4.

## Claims

### Claim 1

A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of Formula 1,
or a pharmaceutically acceptable salt thereof in which:
X1 is selected from N and CR1;
X2 is selected from N and CR2;
X3 is selected from N and CR3; and
X4 is selected from N and CR4, provided no more than two of X1, X2, X3, and X4 are N;
X13 is NR13 and X14 is CR15R16 or X13 is CH2 and X14 is NR14;
L is selected from NR8 and O;
r is selected from 0 and 1;
s is selected from 0 and 1;
R1, R2, and R3 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;
R4 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;
R5 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo; or
R4 and R5, together with the carbon atoms to which they are attached, form a cyclopent-1-en-1,2-diyl or a furan-2,3-diyl;
R6 and R7 are each independently selected from halo and C1-3 alkyl, or R6 and R7, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R8 is selected from H and C1-4 alkyl;
R9 and R10 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano;
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and
(c) phenyl and C1-5 heteroaryl, each substituted with 0 to 3 optional substituents independently selected from halo, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-5 heteroaryl substituent is a monocyclic ring with 5 to 6 ring members in which 1 to 4 ring members are heteroatoms, each of the heteroatoms independently selected from N, O, and S, provided no more than one of the ring members is O or S, and wherein the C1-4 alkyl and C1-4 alkoxy optional substituents on phenyl and C1-5 heteroaryl are each independently substituted with 0 to 3 optional substituents independently selected from halo; or
R9 and R10, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R11 and R12 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or
R11 and R12, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R13 and R14 are each independently selected from
(a) hydrogen; and
(b) C1-4 alkyl, which is un substituted or substituted with a substituent selected from cyano and oxo; and
R15 and R16 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or
R15 and R16, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
wherein the disease, disorder or condition is pain.

### Claim 2 (depends on 1)

The method according to claim 1, wherein X1 is CR1, X2 is CR2, X3 is CR3, and X4 is CR4.

### Claim 3 (depends on 2)

The method according to claim 2, wherein R1, R2, R3, and R4 are each independently selected from
(a) hydrogen, halo, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 4 (depends on 1)

The method according to claim 1, wherein X1 is N, X2 is CR2, X3 is CR3, and X4 is CR4.

### Claim 5 (depends on 4)

The method according to claim 4, wherein R2, R3, and R4 are each independently selected from
(a) hydrogen, halo, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 6 (depends on 1)

The method according to claim 1, wherein R5 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 7 (depends on 1)

The method according to claim 1, wherein R6 and R7 are each independently selected from fluoro and methyl or together with the carbon atom to which they are attached form a cyclopropan-1,1-diyl or a cyclobutan-1,1-diyl.

### Claim 8 (depends on 1)

The method according to claim 1, wherein each of R6 and R7 is methyl.

### Claim 9 (depends on 1)

The method according to claim 1, wherein L is NR8.

### Claim 10 (depends on 9)

The method according to claim 9, wherein R8 is hydrogen.

### Claim 11 (depends on 1)

The method according to claim 1, wherein R9 and R10 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano;
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and
(c) phenyl and C1-5 heteroaryl, each substituted with 0 to 3 optional substituents independently selected from halo, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-5 heteroaryl substituent is a monocyclic ring with 5 to 6 ring members in which 1 to 4 ring members are heteroatoms, each of the heteroatoms independently selected from N, O, and S, provided no more than one of the ring members is O or S, and wherein the C1-4 alkyl and C1-4 alkoxy optional substituents on phenyl and C1-5 heteroaryl are each independently substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 12 (depends on 1)

The method according to claim 1, wherein R11 and R12 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 13 (depends on 1)

The method according to claim 1, wherein X13 is NR13 and X14 is CR15R16.

### Claim 14 (depends on 13)

The method according to claim 13, wherein R13 is selected from
(a) hydrogen; and
(b) C1-4 alkyl, which is unsubstituted or substituted with a substituent selected from cyano and oxo.

### Claim 15 (depends on 13)

The method according to claim 13, wherein R15 and R16 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

### Claim 16 (depends on 1)

The method according to claim 1, wherein r is 0.

### Claim 17 (depends on 1)

The method according to claim 1, wherein s is 0.

### Claim 18 (depends on 1)

The method according to claim 1, in which the compound is selected from the following compounds:
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide;
2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)-N-(1-methylpyrrolidin-3-yl)propanamide;
3-((3-cyanopyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-((5-cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
cis-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
cis-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(4-isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(4-isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
cis-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)propanamide;
trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide;
trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide;
trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
cis-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
trans-N-(3-isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
cis-N-(3-isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,5,5-trimethylpyrrolidin-3-yl)propanamide;
(R)-2,2-dimethyl-N-((1-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
(S)-2,2-dimethyl-N-((l-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
3-((3-chloropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3,5-difluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((4-(trifluoromethyl)pyridin-3-yl)oxy)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-4-yl)oxy)propanamide;
3-((4-chloro-3-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-chloro-5-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((6-chloro-2-methylpyridin-3-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((5-chloro-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-methoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-4-yl)oxy)propanamide;
3-((5-cyano-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)propanamide;
(R)-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-((3-ethoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide;
trans-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(1-methylpiperidin-4-yl)-1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropane-1-carboxamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide;
(R)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide;
3-(2-chlorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-(2-chlorophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
(R)-3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-(2-cyclopropylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-(2-cyclopropylphenoxy)-2,2,-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-(2-ethylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-phenoxypropanamide;
3-(3-cyano-2-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(o-tolyloxy)propanamide;
3-(2-cyano-6-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(2-ethoxyphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((2,3-dihydro-1H-inden-4-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-cyclopropylpyrazin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
1-((2-chlorophenoxy)methyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide;
3-((3-chloro-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3,6-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3-ethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
(R)-3-((3-ethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide;
3-((3-ethylpyrazin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((3,4-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
1-(((3-cyclopropylpyridin-2-yl)oxy)methyl)-N-(1-methylpiperidin-4-yl)cyclobutane-1-carboxamide;
3-((3-(difluoromethyl)pyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-3-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
trans-N-(4-ethoxy-1-methylpyrrolidin-3-yl)-3-(2-ethylphenoxy)-2,2-dimethylpropanamide;
trans-3-(2-ethylphenoxy)-N-(4-methoxy-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide;
3-(2-ethylphenoxy)-2,2-dimethyl-N-(1-methyl-4-phenylpyrrolidin-3-yl)propanamide;
3-((6-chloro-4-(trifluoromethyl)pyridazin-3-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(furo[3,2-c]pyridin-4-yloxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-3-((5-methyl-3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1-methylpiperidin-4-yl)propanamide;
2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(2-(trifluoromethoxy)phenoxy)propanamide;
trans-N-(1-(cyanomethyl)-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
cis-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyri din-2-yl)oxy)propanamide;
2,2-dimethyl-3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,3,3-trimethylpiperidin-4-yl)propanamide;
N-(3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(5-methyl-5-azaspiro[2.5]octan-8-yl)-3-((3-(trifluoromethyl)pyri din-2-yl)oxy)propanamide;
N-(trans-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
N-(cis-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyri din-2-yl)oxy)propanamide;
N-((3 S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(3,3-difluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(5-methyl-5-azaspiro[2.5]octan-8-yl)-3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
N-(3-chloro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3 S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
3-((3,5-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-N-((3 S,4 S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide;
N-((3 S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methylpiperidin-4-yl)-2,2-dimethyl-3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
trans-3-((3,5-dimethylpyridin-2-yl)oxy)-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide;
cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(4-fluoropyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(4,4-difluoropyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,2,2-trimethylpiperidin-4-yl)propanamide;
trans-N-(1,5-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
cis-N-(1,5-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
N-(2-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide;
N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
N-((3R,4R)-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3S,4S)-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(2-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
(R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N-(2-ethyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
(R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(5-methyl-5-azaspiro[3.4]octan-8-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((2S,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
(R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-(3-methylpyridin-2-yl)oxy)propanamide;
(R)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)propanamide;
N,2,2-trimethyl-N-(trans-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N,2,2-trimethyl-N-(cis-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(trans-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3S,4S)-3-fluoropiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(3,3-difluoropiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((3S,4S)-3-fluoropiperidin-4-yl)-N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(trans-1-methyl-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-N,2,2-trimethyl-N-(3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(cis-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(trans-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(cis-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(trans-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
trans-3-(o-tolyl)piperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate;
2,2-dimethyl-N-(trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-3-(2-methylpyridin-3-yl)piperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate;
trans-3-phenylpiperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate;
N,2,2-trimethyl-N-(trans-3-(2-methylpyridin-3-yl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
(S)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(4-methyl-4-azaspiro[2.5]octan-7-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-dimethyl-N-(4-methyl-4-azaspiro[2.5]octan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((2R,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((2S,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethylpropanamide;
N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide;
3-((3,5-dimethylpyridin-2-yl)oxy)-N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethylpropanamide;
trans-N-(1-(cyanomethyl)-3-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
3-((3-(chlorodifluoromethoxy)pyridin-2-yl)oxy)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
trans-3-(2-chlorophenoxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
3-(2-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)-2,2-dimethylpropanamide;
3-(2-chlorophenoxy)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide;
trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
3-(2-chlorophenoxy)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide;
cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-difluoropropanamide;
3-(2-chlorophenoxy)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoropropanamide;
3-(2-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(2-fluorophenoxy)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide;
2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide;
N-(trans-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanamide;
N-(trans-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide;
N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-3-(2-fluorophenoxy)-2,2-dimethylpropanamide;
3-(3-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
3-(4-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanamide;
N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide;
2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)propanamide;
2,2-difluoro-N42R,4R)-2-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide;
3-(2-chlorophenoxy)-2,2-dimethyl-N-(piperidin-4-yl)propanamide;
3-((3,5-dimethylpyridin-2-yl)oxy)-N43R,4R)-3-fluoropiperidin-4-yl)-2,2-dimethylpropanamide;
3-(2-chlorophenoxy)-2,2-difluoro-N-(1-methylpiperidin-4-yl)propanamide;
3-(2-chlorophenoxy)-2,2-difluoro-N43S,4S)-3-methylpiperidin-4-yl)propanamide;
3-(4-chlorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide;
N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; and
a pharmaceutically acceptable salt of any one of the aforementioned compounds.

### Claim 19 (depends on 1)

A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a pharmaceutical composition comprising:
a compound or pharmaceutically acceptable salt as defined in claim 1; and
a pharmaceutically acceptable excipient;
wherein the disease, disorder or condition is pain.