# US 2021/0275499 A1 · Heterocyclic sulfonamide derivatives and pharmaceutical uses thereof

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- Number: US 2021/0275499 A1
- Document ID: US20210275499A1
- Status: Published application
- Kind: A1
- Application number: 17/258,273
- Filed: 2019-07-05
- Published: 2021-09-09
- Earliest claimed: 2018-07-06
- Assignees: Metrion Biosciences Limited
- Applicants: Metrion Biosciences Limited
- Inventors: Marc ROGERS; Robert KIRBY; Gakujun SHOMI; Takuya MATSUO; Satoru KOBAYASHI; Junichiro KANAZAWA; Nobutaka YAMAOKA; Makoto TORIZUKA; Koichi SUZAWA
- Web page: https://patentgrep.com/patent/US20210275499A1

## CPC

- A61K 31/4164: 1,3-Diazoles
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 233/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 235/02: condensed with carbocyclic rings or ring systems
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- 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 471/08: Bridged systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- 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 invention relates to heterocyclic sulfonamide derivatives and their use in the treatment and prophylaxis of autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases, and to compositions containing said derivatives and processes for their preparation.

## Claims

### Claim 1

A compound of formula (I):
or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:
R1 represents C1-6 alkyl, C1-6 alkoxy, C1-6 alkanol, —X—C3-8 cycloalkyl, haloC1-6 alkyl, aryl, heterocyclyl or heteroaryl, wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl groups may be optionally substituted by one or more (e.g. 1, 2, 3 or 4) Ra groups;
Ra represents C1-6 alkyl, halogen, haloC1-6 alkyl, hydroxy, cyano, nitro, oxo, CONRxRy or C3-8 cycloalkyl;
Rx and Ry independently represent hydrogen or C1-6 alkyl;
X represents a bond, —CH2— or —(CH2)2—;
R2 represents halogen, haloC1-6 alkyl or cyano;
n represents an integer selected from 0 to 4;
R3 represents hydrogen, C1-6 alkyl, —X—C3-8 cycloalkyl, haloC1-6 alkyl or —X-aryl,
wherein said alkyl may be optionally substituted by one or more cycloalkyl groups,
wherein said cycloalkyl may be optionally substituted by one or more C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, halogen, hydroxy or cyano groups,
wherein said haloalkyl may be optionally substituted by one or more hydroxy groups,
wherein said aryl may be optionally substituted by one or more halogen groups,
wherein R3 and R4 together with the nitrogen atom to which they are attached may join to form a heterocyclyl ring optionally substituted by one or more C1-6 alkyl, haloC1-6 alkyl, or halogen;
R4 represents hydrogen, C1-6 alkyl or C3-8 cycloalkyl;
R5 represents C1-6 alkyl or —X-aryl; and
m represents an integer selected from 0 to 4, such that when m represents 2, said R5 groups may join to form a C3-8 cycloalkyl group.

### Claim 2 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 represents:
C1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl or i-pentyl);
C1-6 alkoxy (such as propoxy);
X—C3-8 cycloalkyl (such as —(CH2)-cyclopropyl, —(CH2)2-cyclopropyl, -cyclobutyl, —(CH2)-cyclobutyl, -cyclopentyl or -cyclohexyl);
haloC1-6 alkyl (such as trifluoromethyl, fluoropropyl, difluoropropyl, trifluoropropyl, fluorobutyl, difluorobutyl or trifluorobutyl);
aryl (such as phenyl);
heterocyclyl (such as pyrrolidinyl or tetrahydropyranyl); or
heteroaryl (such as furanyl, thiophenyl, pyrazolyl, pyridinyl or imidazolyl);
wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl groups may be optionally substituted by one or more (e.g. 1, 2, 3 or 4) Ra groups, such as:
haloC1-6 alkyl (such as trifluoromethyl, fluoropropyl, difluoropropyl, trifluoropropyl, fluorobutyl, difluorobutyl or trifluorobutyl);
aryl (such as phenyl); or
heteroaryl (such as furanyl, thiophenyl, pyrazolyl, pyridinyl or imidazolyl);
wherein said aryl or heteroaryl groups may be optionally substituted by one or more (e.g. 1, 2, 3 or 4) Ra groups, in particular:
haloC1-6 alkyl (such as fluoropropyl);
aryl (such as phenyl, in particular unsubstituted phenyl); or
heteroaryl (such as pyridinyl, in particular unsubstituted pyridyl).

### Claim 3 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein Ra represents C1-6 alkyl (such as methyl), halogen (such as fluorine or chlorine), haloC1-6 alkyl (such as trifluoromethyl), hydroxy, cyano, nitro, oxo, CONRxRy (such as CONH2) or C3-8 cycloalkyl (such as cyclopropyl).

### Claim 4 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 represents halogen (such as fluorine or chlorine), haloC1-6 alkyl (such as difluoromethyl or trifluoromethyl) or cyano, such as halogen (in particular fluorine or chlorine).

### Claim 5 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n represents an integer selected from 0 to 3, such as 1 or 2.

### Claim 6 (depends on 5)

A compound of formula (I) as defined in claim 5, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n represents an integer selected from 0.

### Claim 7 (depends on 5)

A compound of formula (I) as defined in claim 5, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n represents 1 and R2 represents halogen (such as fluorine or chlorine), haloC1-6 alkyl (such as difluoromethyl or trifluoromethyl) or cyano, such as n represents 1 and R2 represents 3-fluorine, 4-fluorine, 3-chlorine, 4-chlorine, 4-difluoromethyl, 4-trifluoromethyl or 4-cyano, in particular n represents 1 and R2 represents 4-chlorine.

### Claim 8 (depends on 5)

A compound of formula (I) as defined in claim 5, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n represents 2 and R2 represents halogen (such as fluorine or chlorine), haloC1-6 alkyl (such as trifluoromethyl) or cyano, such as n represents 2 and R2 represents: 2-fluoro, 4-chloro; 3-fluoro, 4-chloro; 3-chloro, 4-fluoro; 3-fluoro, 4-trifluoromethyl; 3-chloro, 4-trifluoromethyl; 3-cyano, 4-chloro; 3,4-difluoro; or 3,4-dichloro, in particular n represents 2 and R2 represents 3-fluoro, 4-chloro.

### Claim 9 (depends on 5)

A compound of formula (I) as defined in claim 5, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n represents 3 and R2 represents halogen (such as fluorine or chlorine), such as n represents 3 and R2 represents 3,5-difluoro, 4-chloro.

### Claim 10 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 represents:
hydrogen;
C1-6 alkyl (such as methyl, n-propyl, i-propyl, dimethylpropyl, n-butyl or t-butyl) optionally substituted by one or more cycloalkyl groups (such as cyclopropyl);
X—C3-8 cycloalkyl (such as cyclopropyl, —CH2-cyclopropyl, —(CH2)2-cyclopropyl, -cyclobutyl, —CH2-cyclobutyl, —(CH2)2-cyclobutyl, —C(H)(CH3)-cyclobutyl, cyclohexyl, —CH2-cyclohexyl or bicyclo[1.1.1]pentanyl) optionally substituted by one or more C1-6 alkyl (such as methyl), C1-6 alkoxy (such as methoxy), haloC1-6 alkyl (such as difluoromethyl, trifluoromethyl or trifluoroethyl), halogen (such as fluorine), hydroxy or cyano groups;
haloC1-6 alkyl (such as trifluoroethyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, fluorobutyl, trifluorobutyl or trifluoropentyl) optionally substituted by one or more hydroxy groups;
X-aryl (such as -phenyl or —CH2-phenyl) optionally substituted by one or more halogen (such as fluorine) groups;
or R3 and R4 together with the nitrogen atom to which they are attached join to form a heterocyclyl ring (such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepinyl, 1-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[3.4]octyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.0]hexyl, octahydrocyclopenta[c]pyrrolyl, 2-azaspiro[3.3]heptyl, 3-azabicyclo[3.2.1]octyl, 6-azaspiro[3.4]octyl, 5-azaspiro[2.5]octyl or 2-oxa-6-azaspiro[3.4]octyl) optionally substituted by one or more C1-6 alkyl (such as methyl), haloC1-6 alkyl (such as difluoromethyl or trifluoromethyl) or halogen (such as fluorine), such as:
X—C3-8 cycloalkyl (such as cyclopropyl, —CH2-cyclopropyl, —(CH2)2-cyclopropyl, -cyclobutyl, —CH2-cyclobutyl, —(CH2)2-cyclobutyl, —C(H)(CH3)-cyclobutyl, cyclohexyl, —CH2-cyclohexyl or bicyclo[1.1.1]pentanyl) optionally substituted by one or more C1-6 alkyl (such as methyl), C1-6 alkoxy (such as methoxy), haloC1-6 alkyl (such as difluoromethyl, trifluoromethyl or trifluoroethyl), halogen (such as fluorine), hydroxy or cyano groups; or
haloC1-6 alkyl (such as trifluoroethyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, fluorobutyl, trifluorobutyl or trifluoropentyl) optionally substituted by one or more hydroxy groups, in particular:
X—C3-8 cycloalkyl (such as bicyclo[1.1.1]pentanyl, in particular unsubstituted bicyclo[1.1.1]pentanyl; or
haloC1-6 alkyl (such as trifluoropropyl, in particular unsubstituted trifluoropropyl).

### Claim 11 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein R4 represents hydrogen, C1-6 alkyl (such as methyl or ethyl) or C3-8 cycloalkyl (such as cyclopropyl), such as R4 represents hydrogen.

### Claim 12 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein m represents an integer selected from 0 to 3, such as 2.

### Claim 13 (depends on 12)

A compound of formula (I) as defined in claim 12, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein m represents 0.

### Claim 14 (depends on 1)

A compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 represents C1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl or i-butyl) or —X-aryl (such as —CH2-phenyl) or m represents 2 and said two R5 groups join to form a C3-8 cycloalkyl group (such as cyclopropyl or cyclobutyl), such as R5 represents C1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl or i-butyl), in particular R5 represents C1-6 alkyl (such as methyl).

### Claim 15 (depends on 12)

A compound of formula (I) as defined in claim 12, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein m represents 1 and R5 represents C1-6 alkyl (such as methyl, n-propyl, i-propyl or i-butyl) or —X-aryl (such as —CH2-phenyl).

### Claim 16 (depends on 12)

A compound of formula (I) as defined in claim 12, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein m represents 2 and R5 represents C1-6 alkyl (such as methyl or ethyl) or said two R5 groups join to form a C3-8 cycloalkyl group (such as cyclopropyl or cyclobutyl), such as m represents 2 and R5 represents C1-6 alkyl (such as methyl or ethyl), in particular m represents 2 and R5 represents C1-6 alkyl (such as methyl).

### Claim 17 (depends on 12)

A compound of formula (I) as defined in claim 12, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein m represents 3 and R5 represents C1-6 alkyl (such as methyl).

### Claim 18 (depends on 1)

A compound of formula (I) as defined in claim 1, which is the free base of a compound of Examples 1-295, such as Example 1, Example 48 or Example 92, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, in combination with one or more therapeutic agents.

### Claim 21

(canceled)

### Claim 22 (depends on 1)

A method of treating a disease or condition mediated by potassium channel inhibition, such as inhibition of Kv1.3, in particular an autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal or metabolic mediated disease, said method comprising administering to a subject a therapeutically effective amount of a compound as defined in claim 1 or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

### Claim 23 (depends on 1)

A process for preparing a compound of formula (I) as herein defined in claim 1, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, which comprises:
(a) reacting a compound of formula (II):
wherein R1, R2, n, R5 and m are as defined in claim 1, with a compound of formula HNR3R4;
(b) deprotection of a protected derivative of a compound of formula (I);
(c) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and
(d) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).