# US 8,772,293 B2 · Chemical compounds

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- Number: US 8,772,293 B2
- Document ID: US8772293B2
- Status: Granted
- Kind: B2
- Application number: 13/178,534
- Filed: 2011-07-08
- Published: 2012-01-12
- Granted: 2014-07-08
- Earliest claimed: 2010-07-09
- Assignees: Pfizer Inc.; Icagen, Inc.
- Applicants: Alan Daniel Brown; Marcel John De Groot; Brian Edward Marron; David James Rawson; Thomas Ryckmans; Robert Ian Storer; Paul Anthony Stupple; Nigel Alan Swain; Christopher William West
- Inventors: Alan Daniel Brown; Marcel John De Groot; Brian Edward Marron; David James Rawson; Thomas Ryckmans; Robert Ian Storer; Paul Anthony Stupple; Nigel Alan Swain; Christopher William West
- Web page: https://patentgrep.com/patent/US8772293B2

## CPC

- C07D 237/20: Nitrogen atoms (nitro radicals C07D237/12)
- A61K 31/427: 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)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to new sulfonamide Nav1.7 inhibitors of formula (I): or pharmaceutically acceptable salts thereof, wherein Z1, Ra, Rb, R1, R2, R3, R4 and R5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted on a ring carbon atom by F or CI; or
R1 is a ‘C-linked’ 5-membered heteroaryl comprising one or two nitrogen atoms and one sulphur atom, wherein said heteroaryl is optionally substituted on a ring carbon atom by F or CI;
R2, R3 and R4 are independently H, F, CI or —OCH3;
R5 is CN, F, CI or R6;
Ra is phenyl optionally substituted by one to three substituents that are independently F, CI, CN, H2N(C1-C4)alkylene-, (C1-C4)alkylNH(C1-C4)alkylene-, (C3-C8)cycloalkyl or R6; or
Ra is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted by R7 or R8, or both R7 and R8;
Rb is H, F, CI, CN or R6;
R6 is (C1-C4)alkyl or (C1-C4)alkyloxy, each optionally substituted by one to eight F;
Z1 is phenyl optionally substituted by one to three substituents that are independently F, CI or R6; or
Z1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted by R7 or R8, or both R7 and R8;
R7 is attached to a Z1 ring carbon and is F, CI, NR9R10, R6, (C3-C8)cycloalkyl or Het';
R8 is attached to a Z1 ring nitrogen and is (C1-C4)alkyl or (C3-C8)cycloalkyl, each optionally substituted by, one to three F; or
R8 is attached to a Z1 ring nitrogen and is a ‘C-linked’ Het1;
Het1 ‘is a 3- to 8-membered saturated monoheterocycloalkyl comprising one or two ring members selected from —N(R11)— and —O—, wherein said monoheterocycloalkyl is optionally substituted on a ring carbon atom by one to three substituents that are independently F, (C1-C6)alkyl, (C1-C4)alkyloxy(Co-C4)alkylene or (C3-C8)cycloalky; and .
R9, R10 and R11 are independently H, (C1-C6)alkyl or (C3-C8)cycloalkyl; or, when Het1 is ‘N-linked’, R11 is absent from that nitrogen atom.

### Claim 2 (depends on 1)

The compound according to claim 1 of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted on a ring carbon atom by F or Cl; or
R1 is a ‘C-linked’ 5-membered heteroaryl comprising one or two nitrogen atoms and one sulphur atom, wherein said heteroaryl is optionally substituted on a ring carbon atom by F or CI;
R2, R3 and R4 are independently H, F, CI or —OCH3;
R5 is CN, F, CI or R6;
Ra is phenyl optionally substituted by one to three substituents that are independently from F, CI or R6;
Rb is H, F, CI or R6;
R6 is (C1-C4)alkyl or (C1-C4)alkyloxy, each optionally substituted by one to three F;
Z1 is phenyl optionally substituted by one to three substituents that are independently F, CI or R6; or
Z1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted by R7 or R8, or both R7 and R8;
R7 is attached to a Z1 ring carbon and is F, CI, NR9R10, R6, (C3-C8)cycloalkyl or Het1;
R8 is attached to a Z1 ring nitrogen and is (C1-C4)alkyl, (C3-C8)cycloalkyl or ‘C-linked’ Het1;
Het1 is a 3- to 8-membered saturated monoheterocycloalkyl comprising one or two ring members selected from —N(R11)— and —O—, wherein said monoheterocycloalkyl is optionally substituted on a ring carbon atom by one to three substituents that are independently F, (C1-C6)alkyl, (C1-C4)alkyloxy(Co-C4)alkylene or (C3-C8)cycloalky; and
R9, R10 and R11 are independently H, (C1-C6)alkyl or (C3-C8)cycloalkyl; provided that when Het1 is ‘N-linked’, R11 is absent from that nitrogen atom.

### Claim 3 (depends on 2)

The compound according to claim 2 wherein R1 is a ‘C-linked’ heteroaryl selected from thiazolyl, thiadiazolyl, pyridazinyl or pyrimidinyl, wherein said heteroaryl is optionally substituted on a ring carbon atom by F or Cl.

### Claim 4 (depends on 2)

The compound according to claim 2 wherein R1 is a ‘C-linked’ heteroaryl selected from thiazolyl or thiadiazolyl, wherein said heteroaryl is optionally substituted on a ring carbon atom by F.

### Claim 5 (depends on 4)

The compound according to claim 4 wherein R2, R3 and R4 are independently H or F.

### Claim 6 (depends on 5)

The compound according to claim 5 wherein R5 is CN, F or Cl.

### Claim 7 (depends on 6)

The compound according to claim 6 wherein Ra is phenyl, optionally substituted by R6.

### Claim 8 (depends on 7)

The compound according claim 7 wherein Rb is H.

### Claim 9 (depends on 8)

The compound according to claim 8 wherein Z1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl is optionally substituted by R7 or R8, or both R7 and R8.

### Claim 10 (depends on 8)

The compound according claim 8 wherein Z1 is a ‘C-linked’ 5- or 6-membered heteroaryl comprising one or two nitrogen atoms, wherein said heteroaryl being is optionally substituted by R8.

### Claim 11 (depends on 10)

The compound according to claim 10 wherein said ‘C-linked’ 5- or 6-membered heteroaryl is pyrazolyl or pyridazinyl, wherein said heteroaryl is optionally substituted by R8.

### Claim 12 (depends on 10)

The compound according to claim 10 wherein said ‘C-linked’ 5- or 6-membered heteroaryl is pyridazinyl or pyrazolyl, wherein said pyrazolyl is optionally substituted by methyl or a ‘C-linked’ 3- to 4-membered saturated monoheterocycloalkyl comprising one —N((C1-C2)alkyl)- ring member.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13 further comprising one or more additional therapeutic agents.

### Claim 15 (depends on 1)

The compound according to claim 1 that is
3-Cyano-4-{[3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-pyrimidin-2-ylbenzenesulfonamide;
3-Chloro-N-pyridazin-3-yl-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide;
5-Chloro-2-fluoro-4-{[3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-{[3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-Cyano-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-Fluoro-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}-N-1,3-thiazol-2-ylbenzenesulfonamide;
3-Chloro-4-[(3-pyridazin-4-ylbiphenyl-4-yl)oxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-Cyano-4-[(3-pyridazin-4-ylbiphenyl-4-yl)oxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-[(3-pyridazin-4-ylbiphenyl-4-yl)oxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-Cyano-4-[(3-pyridazin-4-ylbiphenyl-4-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-({3-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]-2′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-({3-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide; -4-ylloxy)-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-Cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}benzenesulfonamide;
3-Cyano-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-Cyano-4-{[3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-Cyano-4-{[3′-methoxy-3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-Cyano-4-{[2′-methoxy-3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-Cyano-N-(5-fluoropyridin-2-yl)-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}benzenesulfonamide;
4-{[3′-(Aminomethyl)-3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}-3-cyano-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}benzenesulfonamide;
3-Cyano-4-({2′-[(methylamino)methyl]-3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl}oxy)-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-Chloro-4-{[2-chloro-4′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
4-{[3-(3-Amino-1H-pyrazol-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-4-{[2-chloro-3′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-4-{[2-chloro-2′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-4-{[2-chloro-5-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-4-{[4′-chloro-3-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-4-{2-(pyridazin-4-yl)-4-[6-(trifluoromethyl)pyrid in-3-yl]phenoxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-4-{2-(pyridazin-4-yl)-4-[6-(trifluoromethyl)pyrid in-2-yl]phenoxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
4-{[3-(5-Amino-1H-pyrazol-4-yl)-3′-cyanobiphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-4-{2-(pyridazin-4-yl)-4-[2-(trifluoromethyl) pyridin-4-yl]phenoxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-4-({3-[2-(piperazin-1-yl)pyridin-4-yl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
5-Chloro-2-fluoro-4-({3-[2-(piperazin-1-yl)pyridin-4-yl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide;
5-Chloro-4-[(6-chloro-3′-fluoro-4-pyridazin-4-ylbiphenyl-3-yl)oxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-4-[(6-chloro-4′-fluoro-4-pyridazin-4-ylbiphenyl-3-yl)oxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-Chloro-4-[(6-chloro-2′-fluoro-4-pyridazin-4-ylbiphenyl-3-yl)oxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-chloro-4-[(3′-cyano-3-pyridazin-4-ylbiphenyl-4-yl)oxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-{[3-(2-piperazin-1-ylpyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-pyrimidin-2-ylbenzenesulfonamide;
or a ;pharmaceutically acceptable salt thereof.