# US 2019/0167682 A1 · Pyridine sulfonamides

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- Number: US 2019/0167682 A1
- Document ID: US20190167682A1
- Status: Published application
- Kind: A1
- Application number: 16/319,783
- Filed: 2017-07-20
- Published: 2019-06-06
- Earliest claimed: 2016-07-20
- Assignees: Amgen Inc.
- Applicants: Amgen Inc.
- Inventors: Matthew WEISS; John R. BUTLER; Benjamin Charles MILGRAM; Gwenaella RESCOURIO; Alessandro BOEZIO; Brian Andrew SPARLING; Daniel LA
- Web page: https://patentgrep.com/patent/US20190167682A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 25/00: Drugs for disorders of the nervous system
- 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 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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

The present invention provides compounds of Formula (I), as defined in the specification, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders, cough, or itch. Also provided are pharmaceutical compositions containing compounds of the present invention.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X1 is N or CR3;
X2 is N or CR4;
X3 is N or CR5;
X4 is N or CR6;
X5 is N or CR7;
X6 is N or CR8;
X7 is CR9 or CL1;
X8 is CR10 or CL1;
X9 is N or CR11;
wherein 0, 1, 2, 3, or 4 of X1, X2, X3, X4, X5, X6 and X9 are N;
R1 is —NH-L2;
R2 is NH2, NHC1-8alk, NHC1-4haloalk, NH—ORa, NH—ORc, —ORa, or —ORc;
R3 is H, halo, CN, C1-8alk, or C1-4haloalk;
R4 is H, halo, CN, C1-8alk, or C1-4haloalk;
R5 is H, halo, CN, C1-8alk, or C1-4haloalk;
R6 is H, halo, CN, C1-8alk, or C1-4haloalk;
R7 is CN, halo, C1-8alk, or C1-8haloalk, —ORa, or —ORc;
R8 is H, halo, C1-8alk, or C1-8haloalk;
R9 is H, halo, C1-20alk, or C1-20haloalk;
R10 is H, halo, C1-8alk, or C1-8haloalk;
R11 is H, halo, C1-8alk, or C1-8haloalk;
L1 is C0-6alk-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 Rd groups selected from F, Cl, Br, C1-6alk —ORa, —ORc, CN, —C(═O)Rb, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —OC(═O)Rb, —OC(═O)NRaRa, —OC1-6alkNRaRa, —OC1-6alkORa, —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, —NRaC1-6alkNRaRa, —NRaC1-6alkORa, and oxo; wherein each of said C1-6alk is substituted by 0, 1, 2 or 3 substituents selected from halo, C1-3haloalk, —ORa, —NRaRa, —N(Ra)C(═O)Rb, —OC(═O)Rb, C(═O)NRaRa, or C(═O)ORa
L2 is C0-6alk-linked saturated, partially-saturated or unsaturated 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 Re groups selected from F, Cl, Br, C1-6alk, or C1-4haloalk;
Ra is independently, at each instance, H or Rb;
Rb is independently, at each instance, phenyl, benzyl or C1-6alk, wherein the phenyl, benzyl and C1-6alk is substituted by 0, 1, 2 or 3 substituents selected from halo, C1-4alk, C1-3haloalk, —OC1-4alk, —NH2, —NHC1-4alk, and —N(C1-4alk)C1-4alk; and
Rc is a C0-1alk-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 R13 groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, —ORa, —OC1-4haloalk, CN, —C(═O)Rb, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —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, —NRaC2-6alkORa, —C1-6alkNRaRa, —C1-6alkORa, —C1-6alkN(Ra)C(═O)Rb, —C1-6alkOC(═O)Rb, —C1-6alkC(═O)NRaRa, —C1-6alkC(═O)ORa and oxo.

### Claim 2 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein X3 is N.

### Claim 3 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein X7 is CR9 and X8 is CL1.

### Claim 4 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein X7 is CL1 and X8 is CR10.

### Claim 5 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein each of X1, X2 and X4 are CH and X3 is N.

### Claim 6 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein X5 is CR7; X6 is CR8; and X9 are CR11.

### Claim 7 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is NH2, NH(CH3), NH(OCH3), or —OCH3.

### Claim 8 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is —ORa.

### Claim 9 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is —OCH3.

### Claim 10 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein R10 is halo.

### Claim 11 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R3, R4, R6, R8, and R11 are H; R7 is —OCH3; and R9 is H, F, Cl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, vinyl, allyl, or longer linear or branched C9-20alk group.

### Claim 12 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is-N-L2, wherein L2 is unsaturated 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms.

### Claim 13 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein L2 is oxazolyl, imidazolyl, thiadiazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or pyridazinyl, each of which is substituted by 0, 1, 2 or 3 Re groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —ORa.

### Claim 14 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from:
each of which is substituted by 0, 1, 2 or 3 Re groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —O—C1-6alk.

### Claim 15 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, or unsaturated 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms.

### Claim 16 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is cyclopropyl, —C≡C-cyclopentyl, phenyl, or pyridinyl ring.

### Claim 17 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is phenyl ring having the formula:
wherein:
R14 is H, halo, C1-8alk, C1-4haloalk, —ORa or —ORc;
R15 is H, halo, C1-8alk, C1-4haloalk, —ORa or —ORc;
R16 is H, halo, C1-8alk, C1-4haloalk, —ORa or —ORc;
R17 is H, halo, C1-8alk, C1-4haloalk, —ORa or —ORc; and
R18 is H, halo, C1-8alk, C1-4haloalk, —ORa or —ORc.

### Claim 18 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein:
each of X1, X2, X4, X6, and X9 are CH;
X3 is N;
X5 is —C(OCH3);
X7 is CH, CF, CCl, or C-methyl;
X8 is CL1, wherein L1 is phenyl or pyridinyl ring, each of which is substituted by 0, 1, 2 or 3 Rd groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —ORa;
R1 is —N-L2, wherein L2 is unsaturated 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, each of which is substituted by 0, 1, 2 or 3 Re groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —ORa; and
R2 is NH2, NH(CH3), NH(OCH3), or —OCH3.

### Claim 19 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, wherein:
each of X1, X2, X4, X6, and X9 are CH;
X3 is N;
X5 is —C(OCH3);
X7 is CL1, wherein L1 is cyclopropyl, —C≡C-cyclopentyl, phenyl or pyridinyl ring, each of which is substituted by 0, 1, 2 or 3 Rd groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —ORa;
X8 is CH, CF, CCl, or C-methyl;
R1 is —N-L2, wherein L2 is unsaturated 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, each of which is substituted by 0, 1, 2 or 3 Re groups selected from F, Cl, Br, C1-6alk, C1-4haloalk, or —ORa; and
R2 is NH2, NH(CH3), NH(OCH3), or —OCH3.

### Claim 20 (depends on 1)

The compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
6-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridinesulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridine sulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′-chloro-2,5′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-2-fluoro-5,5′-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-fluoro-3′,5-dimethoxy-5′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-fluoro-3′,5-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-fluoro-3′,5-dimethoxy-5′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′,4′-dichloro-2-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((4′-chloro-2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′-cyclopropyl-2-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,3′-difluoro-5-methoxy-4′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-2-fluoro-5-methoxy-4′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,3′-difluoro-5-methoxy-5′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-2-fluoro-5-methoxy-5′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((4′-chloro-2,3′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-2,4′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
N-3-isoxazolyl-6-((methylcarbamoyl)(2,3′,4′-trifluoro-5-methoxy-4-biphenylyl)amino)-3-pyridinesulfonamide;
6-((2,4′-difluoro-3′,5,5′-trimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
N-3-isoxazolyl-6-((methylcarbamoyl)(2,3′,4′,5′-tetrafluoro-5-methoxy-4-biphenylyl)amino)-3-pyridine sulfonamide;
6-((3′-chloro-2,4′-difluoro-5,5′-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-dichloro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,3′-dichloro-5′-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,3′-dichloro-5,5′-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,4′-dichloro-3′,5-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,5′-dichloro-5-methoxy-2′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((4′-chloro-2-fluoro-3′,5-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′,5-dimethoxy-5′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-3′-cyclopropyl-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((5-chloro-2-methoxy-4-(2-methoxy-5-(trifluoromethyl)-3-pyridinyl)phenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((5-chloro-4-(5-chloro-2-methoxy-3-pyridinyl)-2-methoxyphenyl) (methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((5-chloro-2-methoxy-4-(2-methoxy-6-(trifluoromethyl)-4-pyridinyl)phenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((5-chloro-2-methoxy-4-(2-(trifluoromethyl)-4-pyridinyl)phenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-5-methoxy-4′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-3′,5-dimethoxy-4′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′-(difluoromethoxy)-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-5-methoxy-3′-(1-methylethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-3′-fluoro-5-methoxy-5′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-3′,5-dimethoxy-5′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′,5-dimethoxy-5′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-3′,4′,5′-trifluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,3′-dichloro-5′-cyano-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-dichloro-3′-cyano-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-2′-fluoro-5-methoxy-5′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-2′,5-dimethoxy-5′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((5-chloro-4-cyclopropyl-2-methoxyphenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,3′-dichloro-4′-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,3′-dichloro-5-methoxy-4′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′-fluoro-5-methoxy-4′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-dichloro-3′-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′,5,5′-trimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2-chloro-3′,4′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-4′-fluoro-3′,5,5′-trimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′-ethoxy-4′-fluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-3′,4′-difluoro-5,5′-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((2,4′-dichloro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((4′-fluoro-3-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-3,5′-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((4′-chloro-3-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((3′-chloro-5′-fluoro-3-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((2,4′-dichloro-3′-cyano-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2-chloro-3′,4′-difluoro-5-methoxy-4-biphenylyl) (methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2,4′-dichloro-3′,5-dimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2,3′-dichloro-5′-cyano-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2-chloro-3′,5,5′-trimethoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-fluoro-3′,5-dimethoxy-5′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((3′,4′-dichloro-2-fluoro-5-methoxy-4-biphenylyl) (methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridine sulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((methylcarbamoyl)(2,3′,4′,5′-tetrafluoro-5-methoxy-4-biphenylyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((4′-chloro-2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methoxycarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′-(difluoromethyl)-2,4′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((3′-chloro-2,4′-difluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((3′-(difluoromethyl)-2,4′,5′-trifluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridinesulfonamide;
6-((2-chloro-3′,4′,5′-trifluoro-5-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridinesulfonamide;
6-((5-chloro-2-methoxy-4-(2-methoxy-6-(trifluoromethyl)-4-pyridinyl)phenyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridinesulfonamide;
6-((4′-fluoro-3-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((4′-fluoro-3-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((3′-(difluoromethyl)-4′-fluoro-3-methoxy-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-(1-(5-Fluoro-2-methoxy-4-tetradecylphenyl)-3-methylureido)-N-(pyrimidin-2-yl)pyridine-3-sulfonamide;
6-(1-(2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-methylureido)-N-(4-methylisoxazol-3-yl)pyridine-3-sulfonamide;
6-(1-(2,4′-difluoro-5-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methylureido)-N-(4-methylisoxazol-3-yl)pyridine-3-sulfonamide;
6-(1-(2,4′-difluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-[1,1′-biphenyl]-4-yl)-3-methylureido)-N-(4-methylisoxazol-3-yl)pyridine-3-sulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-1,2,5-thiadiazol-3-yl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-(6-fluoro-2-pyridinyl)-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-1,3-oxazol-2-yl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-(2-methyl-4-pyrimidinyl)-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-4-pyrimidinyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-2-pyrimidinyl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-1,2,5-thiadiazol-3-yl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-(6-fluoro-2-pyridinyl)-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-1,3-oxazol-2-yl-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-(2-methyl-4-pyrimidinyl)-3-pyridinesulfonamide;
6-((2-chloro-4′-fluoro-5-methoxy-3′-(trifluoromethyl)-4-biphenylyl)(methylcarbamoyl)amino)-N-4-pyrimidinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-3-pyridazinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-1,3-oxazol-2-yl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-4-pyrimidinyl-3-pyridinesulfonamide;
6-((2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-4-biphenylyl)(methylcarbamoyl)amino)-N-(2-methyl-4-pyrimidinyl)-3-pyridinesulfonamide;
6-((3′-chloro-4,5′-dimethoxy-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
N-3-isoxazolyl-6-((4-methoxy-3′-(trifluoromethyl)-3-biphenylyl)(methylcarbamoyl)amino)-3-pyridinesulfonamide;
6-((3′-fluoro-4-methoxy-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′-chloro-5′-fluoro-4-methoxy-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′-chloro-4-methoxy-4′-methyl-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((6-chloro-4-methoxy-3′-(trifluoromethyl)-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((6-chloro-3′-fluoro-4-methoxy-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′,6-dichloro-4,5′-dimethoxy-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-((3′,6-dichloro-4-methoxy-4′-methyl-3-biphenylyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-(1-(2-chloro-5-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)-N-(isoxazol-3-yl)pyridine-3-sulfonamide;
6-(carbamoyl(2,4′-dichloro-3′-fluoro-5-methoxy-4-biphenylyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-(carbamoyl(2,3′-dichloro-5′-cyano-5-methoxy-4-biphenylyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-(carbamoyl(2-chloro-3′,5-dimethoxy-5′-(trifluoromethyl)-4-biphenylyl)amino)-N-3-isoxazolyl-3-pyridinesulfonamide;
6-(carbamoyl(2-chloro-5-methoxy-3′-(2,2,2-trifluoroethoxy)-4-biphenylyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
Methyl (2-chloro-5-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)(5-(N-(isoxazol-3-yl)sulfamoyl)pyridine-2-yl)carbamate;
6-((5-chloro-4-(cyclopentylethynyl)-2-methoxyphenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
6-((5-fluoro-2-methoxy-4-(3,3,3-trifluoropropyl)phenyl)(methylcarbamoyl)amino)-N-3-isoxazolyl-3-pyridine sulfonamide;
4-(1-(4′-chloro-3-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3methylureido)-N-(isoxazol-3-yl)benzenesulfonamide; and
4-(1-(2,4′-difluoro-5-methoxy-3′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-methylureido)-N-(isoxazol-3-yl)benzenesulfonamide.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising the compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 22 (depends on 1)

A method of treating pain, cough, or itch, comprising administering to a patient in need thereof a therapeutically effective amount of the compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof.