# US 2013/0158034 A1 · Trpm8 antagonists and their use in treatments

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- Number: US 2013/0158034 A1
- Document ID: US20130158034A1
- Status: Published application
- Kind: A1
- Application number: 13/529,880
- Filed: 2012-06-21
- Published: 2013-06-20
- Earliest claimed: 2011-06-24
- Assignees: Amgen Inc.
- Inventors: James BROWN; Jian J. CHEN; Vijay Keshav GORE; Scott HARRIED; Daniel B. Horne; Matthew R. KALLER; Qingyian LIU; Holger MONENSCHEIN; Thomas T. NGUYEN; Nobuko NISHIMURA; Wenge ZHONG
- Web page: https://patentgrep.com/patent/US20130158034A1

## CPC

- C07D 213/53: Nitrogen atoms
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/22: for herpes viruses
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 275/30: being further substituted by halogen atoms, or by nitro or nitroso groups
- C07D 213/40: Acylated substituent nitrogen atom
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

## Claims

### Claim 1

A compound of Formula I having the structure:
or a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof, or a mixture thereof, wherein:
m is 0, 1, 2 or 3;
n is 0 or 1;
X1 is C(R4) or N;
X2 is CH or N;
Y is NH, NR1a, or O;
Z is O or S;
R1 is C1-6alk, —(C═O)—O—C1-6alk, or a direct-bonded, C1-6alk-linked, C1-2alkO-linked, —C(═O)—O linked, —C(═O)— linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, the C1-6alk, the C1-6alk of the C1-6alk-link, and the monocyclic or bicyclic ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, C1-6alk, C1-6alkOH, C1-6alk-C(═O)Ra, C1-6alk-C(═O)ORa, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Ra, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, ═S, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Ra, —S(═O)2N(Ra)C(═O)ORa, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Ra, —N(Ra)C(═O)ORa, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Ra, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, wherein the ring is additionally substituted by 0 or 1 directly bonded, SO2 linked, C(═O) linked or CH2 linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, and substituted by 0, 1, 2 or 3 groups selected from halo, C1-6alk, C1-4haloalk, cyano, oxo, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —NRaRa, and —N(Ra)C(═O)Ra; or R1a and R1, together with the N atom to which they are attached, form a saturated, partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclic or a 9- or 10-membered bicylic ring containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, wherein the ring formed by R1a and R1 is substituted with 0, 1, or 2 substituents independently selected from halo, oxo, C1-6alk, C1-6alkOH, C1-6alk-C(═O)Ra, C1-6alk-C(═O)ORa, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, or —C(═O)NRaRa;
R2 is H, halo, cyano, Rc, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa; or R2 is C1-6alk substituted by 0, 1, 2 or 3 substituents selected from C1-4haloalk, halo, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, or R2 is C1-6alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from Rc;
R3 is H, C1-8alk, C1-8alkOH, C1-4haloalk, halo, cyano, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NIONRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa or —NRaC2-6alkORa;
R4 is independently, at each instance, H, C1-6alk, —C1-3haloalk, —OC1-6alk, —OC1-3haloalk, —N(C1-6alk)C1-6alk, —NHC1-6alk, —NC(═O)C1-6alk, —N(C1-6alk)C1-6alk, F, Cl, Br, CN, OH or NH2; or R3 and R4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R5 substituents;
R5 is independently, in each instance, Cl, Br, F, CH3, CF3, or ORa;
R6 is F, CF3, C1-6alk, or ORa;
Ra is independently, at each instance, H or Rb;
Rb is independently, at each instance, phenyl, benzyl or C1-6alk, the phenyl, benzyl and C1-6alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C1-4alk, C1-3haloalk, —OC1-4alk, —OH, —NH2, —OC1-4alk, —OC1-4haloalk, —NHC1-4alk, and —N(C1-4alk)C1-4alk; and
Rc is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the C1-6alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from C1-8alk, C1-4haloalk, halo and cyano.

### Claim 2 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein the compound of Formula I has the Formula IA:

### Claim 3 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein the compound of Formula I has the Formula IB:
wherein Y is NH or O.

### Claim 4 (depends on 3)

The compound of claim 3 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein the compound of Formula I has the Formula IC:
or any pharmaceutically-acceptable salt thereof, wherein:
m is 0, 1, 2 or 3;
n is 0 or 1;
X1 is C(R4) or N;
X2 is CH or N;
R1 is selected from C1-6alk or a direct-bonded, C1-2alk-linked, C1-2alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom, the C1-6alk and ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, C1-6alk, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Ra, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Ra, —S(═O)2N(Ra)C(═O)ORa, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Ra, —N(Ra)C(═O)ORa, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Ra, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, wherein the ring is additionally substituted by 0 or 1 directly bonded, SO2 linked, C(═O) linked or CH2 linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3 groups selected from halo, C1-6alk, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —NRaRa, and —N(Ra)C(═O)Ra;
R2 is selected from H, halo, cyano, Rc, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa; or R2 is C1-6alk substituted by 0, 1, 2 or 3 substituents selected from C1-4haloalk, halo, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, or R2 is C1-6alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from Rc;
R3 is H, C1-8alk, C1-4haloalk, halo, cyano, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa or —NRaC2-6alkORa;
R4 is independently, at each instance, H, C1-6alk, —C1-3haloalk, —OC1-6alk, —OC1-3haloalk, —N(C1-6alk)C1-6alk, —NHC1-6alk, —NC(═O)C1-6alk, —N(C1-6alk)C1-6alk, F, Cl, Br, CN, OH or NH2; or R3 and R4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R5 substituents;
R5 is independently, in each instance, F, CH3 or CF3;
R6 is F;
Ra is independently, at each instance, H or Rb;
Rb is independently, at each instance, phenyl, benzyl or C1-6alk, the phenyl, benzyl and C1-6alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C1-4alk, C1-3haloalk, —OC1-4alk, —OH, —NH2, —OC1-4alk, —OC1-4haloalk, —NHC1-4alk, and —N(C1-4alk)C1-4alk; and
Rc is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C1-6alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from C1-8alk, C1-4haloalk, halo and cyano.

### Claim 5 (depends on 4)

The compound of claim 4 or the pharmaceutically-acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein the compound of Formula I has the Formula ID:
wherein Y is NH or O.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Y is NR1a.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R1a and R1, together with the N to which they are attached, form a 6 membered unsaturated ring.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R1a and R1, together with the N to which they are attached, form a morpholine ring, a piperidine ring, or a piperazine ring.

### Claim 10 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the monocyclic or bicyclic ring is independently substituted by 0, 1, 2 or 3 substituents.

### Claim 11 (depends on 10)

The compound of claim 10 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is selected from phenyl, pyridyl, pyridinonyl, piperidinonyl, pyrimidinyl, tetradyrofuranyl, tetrahydropyranyl, oxetanyl, furanyl, tetrahydrothiophenyl, thiophenyl, isoxazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl, tetrahydronaphthalenyl, dihydroindenyl, indolinonyl, indolinyl, or benzofuranyl independently substituted by 0, 1, 2, or 3 substituents.

### Claim 12 (depends on 11)

The compound of claim 11 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is substituted with 0, 1, 2, or 3 substituents independently selected from F, Cl, Br, I, CN, CF3, NO2, oxo, C1-6alk, OCH3, OCH2CH3, COCH3, CO2H, CO2CH3, CO2CH2CH3, SCH3, SO2CH3, oxadiazolyl, a methyl-substituted oxadiazolyl, or oxadiazolonyl.

### Claim 13 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is C1-6alk, wherein the C1-6alk is independently substituted by 0, 1, 2 or 3 substituents.

### Claim 14 (depends on 13)

The compound of claim 13 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is substituted with 0, 1, 2, or 3 substituents independently selected from F, Cl, Br, I, CN, CF3, NO2, oxo, C1-6alk, OCH3, OCH2CH3, COCH3, CO2H, CO2CH3, CO2CH2CH3, SCH3, SO2CH3, oxadiazolyl, a methyl-substituted oxadiazolyl, or oxadiazolonyl.

### Claim 15 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is a C1-6alk-linked, C1-2alkO-linked, —C(═O)—O linked, or —C(═O)— linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the monocyclic or bicyclic ring is substituted by 0, 1, 2 or 3 substituents.

### Claim 16 (depends on 15)

The compound of claim 15 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is a —C1-2alk-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the monocyclic or bicyclic ring is substituted by 0, 1, 2 or 3 substituents.

### Claim 17 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is a group of formula
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 18 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is a group of formula
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 19 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 20 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 21 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R1 is
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 22 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein Y is NH.

### Claim 23 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein Y is O.

### Claim 24 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R5 is independently, in each instance F or CF3.

### Claim 25 (depends on 24)

The compound of claim 24 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R5 is F.

### Claim 26 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R6 is F or CF3.

### Claim 27 (depends on 26)

The compound of claim 26 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R6 is CF3.

### Claim 28

The compound of claim for the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein n is 1.

### Claim 29 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein m is 0 or 1.

### Claim 30 (depends on 29)

The compound of claim 29 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein m is 1.

### Claim 31 (depends on 29)

The compound of claim 29 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein m is 0.

### Claim 32 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein n is 0.

### Claim 33 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —H, halo, or C1-6alk substituted by 0, 1, 2 or 3 halo substituents.

### Claim 34 (depends on 33)

The compound of claim 33 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —H, —F, —Br, —CF3, or C1-6alk.

### Claim 35 (depends on 34)

The compound of claim 34 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —F, —Br, —CF3, or C1-6alk.

### Claim 36 (depends on 35)

The compound of claim 35 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —F.

### Claim 37 (depends on 35)

The compound of claim 35 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —CF3.

### Claim 38 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R2 is —CH3, —CH2CH3, —CH2CH2CH3, —C(CH3)3, —CH(CH3)2, —CH2—C(CH3)3, —CH═CH2, —CH2CH═CH2, —C≡C—CH3, or a group of formula
or
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 39 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is H, C1-8alk, C1-4haloalk, halo, or —ORa.

### Claim 40 (depends on 39)

The compound of claim 39 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is H, —CH3, —CH2CH3, F, Cl, —OCH3, —OCF3, or —CF3.

### Claim 41 (depends on 40)

The compound of claim 40 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is —CH3, —CH2CH3, F, Cl, —OCH3, —OCF3, or —CF3.

### Claim 42 (depends on 41)

The compound of claim 41 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is —OCF3 or —CF3.

### Claim 43 (depends on 42)

The compound of claim 42 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is —OCF3.

### Claim 44 (depends on 42)

The compound of claim 42 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is —CF3.

### Claim 45 (depends on 40)

The compound of claim 40 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 is —H.

### Claim 46 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R4 is H.

### Claim 47 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R4 is F, Cl, C1-6alk, —OC1-6alk, or —C1-3haloalk.

### Claim 48 (depends on 47)

The compound of claim 47 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R4 is F, Cl, CF3, CH3, or OCH3.

### Claim 49 (depends on 48)

The compound of claim 48 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R4 is F.

### Claim 50 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R3 and R4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R5 substituents.

### Claim 51 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X2 is N.

### Claim 52 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X2 is CH.

### Claim 53 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X1 is N.

### Claim 54 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X1 is C(R4).

### Claim 55 (depends on 54)

The compound of claim 54 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X1 is CH.

### Claim 56 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X1 is C(R4) and X2 is N.

### Claim 57 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X1 is N and X2 is N.

### Claim 58 (depends on 1)

The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein X2 is N; R2 is F or CF3; m is 0; X1 is CH; R4 is F or H; R3 is CF3 or OCF3; Y is NH; Z is 0; and R1 is
and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

### Claim 59 (depends on 1)

The compound of claim 1, wherein the compound is
(S)-1-((3-fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)-3-(pyridin-3-yl)urea;
(S)-1-((4-methoxy-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-chlorophenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-methoxy-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-fluoro-4-methoxy-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(pyridin-3-yl)-3-(quinolin-3-yl(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-methylphenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-fluorophenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((5-chloroquinolin-3-yl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(naphthalen-2-yl(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((8-chloroquinolin-3-yl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3,4-dichlorophenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((8-fluoroquinolin-3-yl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((8-methoxy-quinolin-3-yl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(pyridin-3-yl)-3-(quinolin-6-yl(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-((7-methoxy-quinolin-3-yl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((4-fluorophenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(phenyl(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
1-((4-fluoro-3-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
1-((4-fluoro-3-(trifluoro-methyl)-phenyl)(3-fluoropyridin-2-yl)methyl)-3-(pyridin-3-yl)-urea;
1-((3-chloro-5-fluorophenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
1-((3-chloro-5-fluorophenyl)-(3-fluoro-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
1-(pyridin-3-yl)-3-(3-(trifluoro-methyl)-pyridin-2-yl)(6-(trifluoro-methyl)-pyridin-3-yl)-methyl)urea;
(S)-1-((4-chlorophenyl)-(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(4-ethylphenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(3-bromopyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(3-fluoro-4-(trifluoro-methyl)-phenyl)(3-fluoropyridin-2-yl)methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(pyridin-2-yl(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-phenyl-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-isopropyl-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-1-(naphthalen-1-yl)ethyl)-3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-phenylpropyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(phenyl formate)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-(benzo[d][1,3]dioxol-5-yl)-ethyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-bromophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-ethyl 2-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-acetate;
(S)-1-(benzofuran-5-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-cyanophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-((3-bromopyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(tert-butyl)urea;
(S)-1-(tert-butyl)-3-(3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)urea;
(S)-1-((3-allylpyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(pyridin-3-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(tert-butyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-cyanophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-fluoro-phenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,4-difluoro-phenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3,5-difluoro-phenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,6-difluoro-phenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(3-methoxy-phenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-(methylsulfonyl)phenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-(tetrahydro-2H-pyran-3-yl)-3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3,5-dimethylisoxazol-4-yl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-(tetrahydro furan-3-yl)-3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(pyrimidin-5-yl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(quinolin-6-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(quinolin-3-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(quinolin-4-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((3-neopentylpyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(2,6-dibromo-4-fluorophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((3-Sulfonylcyclopentyl)methyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-3-methylbutan-2-yl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-ethyl 3-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-propanoate;
(S)—N-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methylcarbamoyl)benzamide;
(S)-ethyl 4-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-butanoate;
(S)-1-(3-methyl-5-phenylisoxazol-4-yl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((R)-1-phenylethyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-tert-butylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-fluoro-benzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-chlorobenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3,4-dimethoxy-phenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-benzyl 4-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-piperidine-1-carboxylate;
(S)-1-(2,6-dichloropyridin-4-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-methyl 4-(methylthio)-2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-butanoate;
(S)-methyl 2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-propanoate;
1-((S)-1-(4-methoxy-phenyl)ethyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)—N-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methylcarbamoyl)ethylamide;
(S)-1-(2,3-dimethoxy-phenethyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-hexan-2-yl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-1-(3-methoxy-phenyl)ethyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-methylbenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-acetylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-fluoro-benzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,6-diethylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-ethyl-6-methylphenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-ethyl 3-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-benzoate;
(S)-1-(2-ethyl-6-isopropylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-isopropyl-6-methylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3,5-dimethoxy-phenethyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-ethyl 2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-propanoate;
(S)-1-(3,4-dimethoxy-phenethyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-methyl 3-methyl-2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-butanoate;
(S)-1-(3-cyanophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
ethyl 3-methyl-2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-butanoate;
(3S)-methyl 3-methyl-2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-pentanoate;
(S)-1-(3-nitrophenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-(1-(4-bromophenyl)-ethyl)-3-4S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-methyl 3-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-benzoate;
(S)-dimethyl 5-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-isophthalate;
(S)-butyl 2-(3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-acetate;
(S)-1-(2-(3-(prop-1-en-2-yl)phenyl)-propan-2-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3,5-dimethylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-1-phenylethyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,5-dimethylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-benzyl-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,5-dimethoxy-phenethyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(3,4,5-trimethoxy-benzyl)urea;
(S)-1-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(3,4,5-trimethoxy-phenyl)urea;
(S)-1-(thiophen-2-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((2-bromopyridin-3-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-((2-bromophenyl)-(4-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(2-bromophenyl)-(4-(trifluoro-methyl)-phenyl)-methyl)-3-tert-butylurea;
(R)-1-((3-fluoro-4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-methyl 2-(3-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)ureido)-benzoate;
(S)-1-(pyridin-3-yl)-3-(4-(trifluoro-methyl)-phenyl)(4-(trifluoro-methyl)-pyridin-3-yl)-methyl)urea;
(S)-1-((3-fluoro-4-(trifluoro-methyl)-phenyl)(2-(trifluoro-methyl)-phenyl)-methyl)-3-(pyridin-3-yl)-urea;
(S)-1-(pyridin-3-yl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-thiourea;
(S)-1-tert-butyl-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-thiourea;
(S)-1-(3-iodophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-bromobenzyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-ethoxyphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(cyclohexylmethyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((R)-1-(3-methoxy-phenyl)ethyl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((S)-2,3-dihydro-1H-inden-1-yl)-3-(S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
1-((R)-1-(4-methoxy-phenyl)ethyl)-3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(2,4,4-trimethylpentan-2-yl)urea;
(S)-1-(2,6-dichlorophenethyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-ethoxybenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-chlorobenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2,4-dichlorobenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-methyl 3-phenyl-2-(3-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)ureido)-propanoate;
(S)-1-(2-(methylthio)-phenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-acetylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-fluoro-3-nitrophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-methyl-3-nitrophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-methoxy-4-nitrophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea
(S)-1-(2-methyl-3-nitrophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(5-methyl-2-nitrophenyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-fluoro-benzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(o-tolyl)-3-((4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(2-fluoro-5-methylphenyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(3-methylbenzyl)-3-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)urea;
(S)-1-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-3-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea;
(S)-1-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-(2-oxoindolin-5-;
1-((S)-(3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(3-fluoro-4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(3-fluoro-4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(R)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(2-bromophenyl)-(4-(trifluoro-methyl)-phenyl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
(S)-1-((3-fluoro-4-(trifluoro-methyl)-phenyl)(3-(trifluoro-methyl)-pyridin-2-yl)-methyl)-3-(pyrimidin-5-yl)urea;
1-((S)-(3-fluoropyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(3-bromopyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
1-((S)-(3-allylpyridin-2-yl)(4-(trifluoro-methyl)-phenyl)-methyl)-3-((S)-1,1,1-trifluoro-propan-2-yl)-urea;
(S)-1-(2-methoxypyrimidin-5-yl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(2-methoxy-pyrimidin-5-yl)-urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(2-oxo-1,2-dihydropyridin-4-yl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)urea;
(S)-1-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-(2-oxoindolin-6-yl)urea;
(S)-1-(3-propylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-3-(pyridin-3-yl)-urea;
(S)-tert-butyl(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)carbamate;
(S)-ethyl 44-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-carbamate;
1-(4-fluorophenyl)-3-(phenyl(4-(trifluoromethyl)phenyl)methyl)urea;
(S)-benzyl(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)carbamate 2,2,2-trifluoroacetate; or
(S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-carbamate; or
the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 60 (depends on 1)

The compound of claim 1, wherein the compound is
(S)-tert-butyl((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamate;
(S)-isopropyl((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamate;
(S)-tetrahydro-2H-pyran-4-yl((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamate;
(S)-oxetan-3-yl((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamate;
6-oxopiperidin-3-yl((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamate;
(S)-1-(quinolin-5-yl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea;
(S)-4-(3-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)ureido)benzoic acid;
(S)-1-(2-chlorophenyl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea (2,2,2-trifluoro-acetate);
(S)-methyl 2-methyl-3-(3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)ureido)benzoate (2,2,2-trifluoro-acetate);
(S)-1-(2-methoxy-5-methylphenyl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea (2,2,2-trifluoro-acetate);
(S)-1-(3,4-dichlorobenzyl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea (2,2,2-trifluoro-acetate); 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-3-((S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea (2,2,2-trifluoro-acetate);
(S)-1-mesityl-3-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea (2,2,2-trifluoro-acetate);
(S)-ethyl 4-(3-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)ureido)benzoate (2,2,2-trifluoro-acetate); or
(S)-1-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-3-(pyridin-3-yl)urea; or
the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 61 (depends on 1)

The compound of claim 1, wherein the compound is
(S)-1-(3-fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)-3-(pyridin-3-yl)urea;
(S)-1-(pyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea;
(S)-1-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-3-(pyridin-3-yl)urea;
1-((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-3-(pyridin-3-yl)urea;
(S)-1-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-3-(pyridin-3-yl)urea; or
1-((S)-(3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-3-((S)-1,1,1-trifluoropropan-2-yl)urea; or
the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 62 (depends on 1)

The compound of claim 1, wherein the compound is (S)-1-((3-fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)-3-(pyridin-3-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 63 (depends on 1)

The compound of claim 1, wherein the compound is (S)-1-(pyridin-3-yl)-3-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 64 (depends on 1)

The compound of claim 1, wherein the compound is (S)-1-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-3-(pyridin-3-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 65 (depends on 1)

The compound of claim 1, wherein the compound is 1-((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-3-(pyridin-3-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof

### Claim 66 (depends on 1)

The compound of claim 1, wherein the compound is (S)-1-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)ethyl)-3-(pyridin-3-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 67 (depends on 1)

The compound of claim 1, wherein the compound is 1-((S)-(3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-3-((S)-1,1,1-trifluoropropan-2-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 68 (depends on 1)

The compound of claim 1, wherein the compound is (S)-1-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-3-(pyridin-3-yl)urea or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 69 (depends on 1)

The compound of claim 1, wherein the compound is (S)—N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)morpholine-4-carboxamide or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof.

### Claim 70 (depends on 1)

The compound or tautomer of claim 1 in a neutral form.

### Claim 71 (depends on 1)

The compound of claim 1 in a neutral form.

### Claim 72 (depends on 1)

The pharmaceutically-acceptably salt of the compound or the pharmaceutically acceptable salt of the tautomer of claim 1.

### Claim 73 (depends on 1)

The pharmaceutically-acceptably salt of the compound of claim 1.

### Claim 74 (depends on 73)

The pharmaceutically-acceptable salt of the compound of claim 73, wherein the salt is a trifluoroacetate or bis trifluoroacetate salt.

### Claim 75 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, and a pharmaceutically-acceptable diluent or carrier.

### Claim 76 (depends on 1)

A method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders in a subject, the method comprising administering the compound according to claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof to the subject.

### Claim 77 (depends on 76)

The method of claim 76, wherein the subject is suffering from neuropathic pain.

### Claim 78 (depends on 76)

The method of claim 76, wherein the subject is suffering from migraine pain.