Search

EP-4741018-A2 - SULPHONAMIDE COMPOUNDS

EP4741018A2EP 4741018 A2EP4741018 A2EP 4741018A2EP-4741018-A2

Abstract

This invention relates to compounds of formula (I) and salts, solvates, tautomers, N-oxides, stereoisomers, polymorphs and/or prodrugs thereof. Also disclosed is the use of the compounds of formula (I) to treat necroptosis and/or inhibit MLKL.

Inventors

  • BRZOZOWSKI, MARTIN
  • SCHUSTER-KLEIN, Carole Annie
  • POITEVIN, CHRISTOPHE
  • LESSENE, GUILLAUME LAURENT
  • GARDNER, CHRISTOPHER
  • CZABOTAR, PETER EDWARD
  • COWAN, Angus
  • DAVIES, Katherine
  • SHARMA, POOJA
  • GARNIER, Jean-Marc Daniel
  • FEUTRILL, JOHN THOMAS

Assignees

  • Anaxis Pharma Pty Ltd

Dates

Publication Date
20260513
Application Date
20210618

Claims (15)

  1. A compound of formula (I) wherein Q 1 and Q 2 are selected from N and NR 1 , wherein when Q 1 is N, Q 2 is NR 1 and when Q 2 is N, Q 1 is NR 1 ; R 1 and R 3 are independently selected from H and an optionally substituted C 1-6 -alkyl; R 2 is a 5-, 6- or 10-membered heteroaryl comprising 0, 1 or 2 substituents selected from fluoro, chloro, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoroethoxy, trifluoromethoxy, -OCH 2 CH 2 OCH 3 , cyclopropyl, nitrile, amido and morpholino; X is selected from optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl and C 3-6 cycloalkyl; Y and Z are independently selected from H and -OR 4 , wherein at least one of Y and Z is H; R 4 is selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted C 1-6 alkylaryl, optionally substituted heterocyclyl, optionally substituted C 1-6 alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1-6 alkylC 3-10 cycloalkyl, optionally substituted C 3-10 cycloalkylaryl, optionally substituted C 3-10 cycloalkylheterocyclyl, optionally substituted C 3-10 cycloalkylC 3-10 cycloalkyl, optionally substituted 3-6 membered non-aromatic heterocyclyl-aryl, optionally substituted 3-6 membered non-aromatic heterocyclylC 3-10 cycloalkyl and optionally substituted 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl; and R 5 is H or optionally substituted C 1-6 alkyl, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof.
  2. The compound of claim 1, or pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein X is selected from optionally substituted C 1-2 alkyl, optionally substituted haloC 1-2 alkyl and C 3 cycloalkyl.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein R 4 is selected from optionally substituted C 1 alkylC 6 aryl and optionally substituted C 1 alkylheteroaryl.
  4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein Z is H and Y is -OR 4 .
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein R 4 is an optionally substituted C 1 alkylC 6 aryl moiety represented by the following partial formula: wherein R a and R b are independently selected from H, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 alkylhydroxy, optionally substituted C 1-4 alkylnitrile, optionally substituted amino, optionally substituted C 1-4 alkylamino and optionally substituted (C 1-4 alkyl) 2 amino, or R a and R b together with the carbon atom to which they are attached form an optionally substituted C 3-6 cycloalkyl or a 3-6 membered non-aromatic heterocyclyl; R c is selected from halo and an optionally substituted C 1-4 alkyl; and m is 0, 1 or 2.
  6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein R 2 is selected from any one of the following radicals: methyl,
  7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein R 1 and R 3 are H.
  8. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (1A):
  9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, wherein the compound is selected from: 3-(3-((3,4-difluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((2-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((1-acetylpiperidin-4-yl)methoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)(methyl)amino)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(4-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((3,3-difluoropropyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(4-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((3-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-4-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((cyanomethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-3-ylmethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-isopropylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(cyclopentylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-isobutoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(benzyloxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((2,2-difluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((2-methoxyethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((2-(dimethylamino)ethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(cyclopropanesulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((1-methylethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((4-fluorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((3,4-dichlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((p-tolylmethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((2-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((3-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-methoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(pyridazin-3-ylamino)-1H-pyrazole-4-carboxamide 5-((6-chloroquinoxalin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-isopropylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(quinoxalin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(cyclopropanesulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((1,1-dimethylethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(((4-chlorophenyl)methyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((1-methylethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-((3-(trifluoromethyl)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(cyclohexanesulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-(((4-(trifluoromethyl)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((phenylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-((4-(trifluoromethoxy)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-((4-(trifluoromethyl)phenyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-(((4-(trifluoromethoxy)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((4-methoxyphenyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-(((3-(trifluoromethyl)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((4-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(naphthalen-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(isoquinolin-3-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(quinolin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-methylpyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((4-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-((6-ethoxypyridin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(propylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((2-ethoxypyrimidin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-((4-cyanophenyl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-(trifluoromethyl)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-((2-ethoxypyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-((2-(2,2-difluoroethoxy)pyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(prop-2-yn-1-ylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((cyanomethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-fluoro-2-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-((2,6-dimethylpyridin-4-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-((trifluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((2-(dimethylamino)ethyl)sulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(N-methylethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxy-5-methylpyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(methylamino)-1H-pyrazole-4-carboxamide 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-((2-methoxyethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-3-(4-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-methoxypyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(phenylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-methylpyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((6-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(((3-chlorophenyl)methyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-((5-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((2-phenylethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyridin-2-ylamino)-3-(4-((p-tolylmethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(phenylsulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((cyclobutylmethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyridin-2-ylamino)-3-(4-(((4-(trifluoromethoxy)phenyl)methyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((phenylmethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-((7-chloroquinolin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide 3-(2-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(2-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluoro-2,6-dimethylbenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(1-(4-fluorophenyl)cyclopropoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(4-fluorophenoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(4-fluorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(4-fluorophenoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(1-phenylcyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((5-fluoropyridin-2-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-((5-cyclopropylpyrazin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((3,4-difluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(1-phenylcyclopropoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chloro-3-fluorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(3-fluorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(4-chlorophenoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(cyclopropanesulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluoro-2-methylbenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(2-methoxyethoxy)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((3,4-difluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(4-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((2,2-difluoroethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 5-((6-(difluoromethyl)pyridin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((2,2-difluoroethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((5-(tert-butyl)pyrazin-2-yl)amino)-3-(4-(ethylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(4-chlorophenoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((2-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((1-methylpiperidin-3-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 5-((6-(trifluoromethyl)pyridin-2-yl)amino)-3-(4-((3,3,3-trifluoropropyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-methoxypyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide (R)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((2-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-methoxypyridin-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(2-((4-chlorobenzyl)oxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(cyclohexylmethoxy)-4-(ethylsulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-2-((4-fluorobenzyl)oxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((1-methylpiperidin-4-yl)methoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(3-fluorophenoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((6-(trifluoromethyl)pyridin-2-yl)amino)-3-(4-((trifluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-(2-chlorophenethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-2-((3-fluorobenzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-2-methoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-phenethoxyphenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(2-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(3-chlorophenethoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((4-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((3-(trifluoromethoxy)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-(trifluoromethoxy)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((4-(trifluoromethyl)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(3-fluorophenethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((6-chloroquinolin-2-yl)amino)-3-(4-(ethylsulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((N,N-dimethylsulfamoyl)amino)phenyl)-5-((2-(2-methoxyethoxy)pyridin-4-yl)amino)-1H-pyrazole-4-carboxamide 5-(4-(ethylsulfonamido)phenyl)-1-methyl-3-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3-chloro-4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 5-(pyrazin-2-ylamino)-3-(3-(pyridin-2-ylmethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((2-(4-fluorophenyl)propan-2-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-(ethylsulfonamido)-3-(1-(pyridin-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((5-fluoropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((1,2,3,4-tetrahydronaphthalen-1-yl)oxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)propoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-(cyclobutyl(4-fluorophenyl)methoxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 5-((6-cyanopyridin-2-yl)amino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-fluorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((5-fluoropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-((5-fluoropyridin-2-yl)methoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((5-chloropyridin-2-yl)methoxy)-4-(ethylsulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(2-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((4-fluorobenzyl)oxy)phenyl)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((6-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (R)-3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-chlorophenyl)ethoxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-5-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-3-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (R)-3-(2-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (R)-3-(4-((difluoromethyl)sulfonamido)-2-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(3-chlorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 6-((4-carbamoyl-3-(4-((difluoromethyl)sulfonamido)phenyl)-1H-pyrazol-5-yl)amino)picolinamide 5-((6-cyanopyridin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-chlorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(4-(ethylsulfonamido)-3-(pyridin-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-((5-chloropyridin-2-yl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(1-(4-fluorophenyl)propoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(3-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide 3-(3-(cyclobutyl(4-fluorophenyl)methoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-5-(pyrazin-2-ylamino)-3-(3-(1-(pyridin-2-yl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-(pyridin-2-ylamino)-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(3-((4-chlorobenzyl)oxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-(pyridin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-ethylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(thiazol-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-methylcyclopropyl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-5-((5-cyclobutylisoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-5-((5-(tert-butyl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((4,5-dimethylthiazol-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(3-((3,4-difluorobenzyl)oxy)-4-((difluoromethyl)sulfonamido)phenyl)-5-((5-methylpyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(3-methyloxetan-3-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(oxazol-2-yl)ethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methoxy-1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-5-((3-(tert-butyl)isoxazol-5-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(2-fluoropropan-2-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (R)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(4-methyltetrahydro-2H-pyran-4-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((3-methylisoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydro-2H-pyran-4-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-5-((5-(adamantan-1-yl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-((S)-1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-(tetrahydrofuran-3-yl)isoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)cyclopropoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((2-methylpyrimidin-4-yl)amino)-1H-pyrazole-4-carboxamide (S)-5-((5-cyclopropylisoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-3-(3-(1-(4-fluorophenyl)ethoxy)-4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide (S)-5-((5-(tert-butyl)pyrazin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(oxazol-2-ylmethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-5-((5-(difluoromethyl)isoxazol-3-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-6-((4-carbamoyl-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazol-5-yl)amino)nicotinic acid (S)-5-((5-cyclopropylpyrazin-2-yl)amino)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1H-pyrazole-4-carboxamide (S)-3-(4-(ethylsulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-(difluoromethanesulfonamido)-3-((1S)-1-(4-fluorophenyl)ethoxy)phenyl]-5-((5-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepin-2-yl)amino)-1H-pyrazole-4-carboxamide 3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)-2-methoxyethoxy)phenyl)-5-(pyrazin-2-ylamino)-1H-pyrazole-4-carboxamide (S)-3-(4-((difluoromethyl)sulfonamido)-3-(1-(4-fluorophenyl)ethoxy)phenyl)-1-methyl-5-((5-methylisoxazol-3-yl)amino)-1H-pyrazole-4-carboxamide
  10. A medicament comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof.
  11. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  12. A compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, for use in the treatment of necroptosis.
  13. An in-vitro or ex vivo method of inhibiting mixed lineage kinase domain-like protein (MLKL), comprising contacting a cell in-vitro or ex vivo with a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof.
  14. A compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, for use in the treatment and/or prevention of one or more disease(s), condition(s) and/or disorder(s) selected from: • diseases of the bones, joints, connective tissue and of cartilage, such as osteoporosis, osteomyelitis including chronic recurrent multifocal osteomyelitis, arthritises including for example osteoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, progressive fibrodysplasia ossificans, rickets, Cushing's syndrome; • muscular diseases such as muscular dystrophy, such as for example Duchenne's muscular dystrophy, myotonic dystrophies, myopathies and myasthenias; • diseases of the skin, such as dermatitis, eczema, psoriasis, aging or even alterations of scarring; • cardiovascular diseases such as cardiac and/or vascular ischemia, myocardial infarction, ischemic cardiopathy, chronic or acute congestive heart failure, cardiac dysrythmia, atrial fibrillation, ventricular fibrillation, paroxystic tachycardia, congestive heart failure, hypertrophic cardiopathy, anoxia, hypoxia, secondary effects due to therapies with anticancer agents; • circulatory diseases such as atherosclerosis, arterial scleroses and peripheral vascular diseases, strokes including cerebrovascular strokes, aneurisms; • haematological and vascular diseases such as: anemia, aplastic anemia, vascular amyloidosis, haemorrhages, drepanocytosis, red cell fragmentation syndrome, neutropenia, leukopenia, medullar aplasia, pantocytopenia, thrombocytopenia, haemophilia; • lung diseases including pneumonia, asthma; obstructive chronic diseases of the lungs such as for example chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema; • diseases of the gastro-intestinal tract, such as ulcers; inflammatory bowel diseases (IBD), including Crohn's disease, ulcerative colitis; • diseases of the liver such as for example hepatitis particularly hepatitis of viral origin or having as causative agent other infectious agents, auto-immune hepatitis, fulminating hepatitis, inflammatory hepatitis, certain hereditary metabolic disorders, Wilson's disease, cirrhoses, non-alcoholic fatty liver disease (NAFLD) including non-alcoholic hepatic steatosis and/or non-alcoholic steatohepatitis (NASH), diseases of the liver due to toxins and to drugs such as drug-induced liver injury, ethanol (or alcohol)-induced liver disease; • diseases of the pancreas such as for example acute or chronic pancreatitis; • metabolic diseases such as diabetes, including diabetes mellitus, pre-diabetes and insipid diabetes; thyroiditis; • diseases of the kidneys such as acute renal disorders (such as acute kidney injury (AKI), including ischaemic reperfusion injury (IRI)) or glomerulonephritis; • viral and bacterial infections such as septicemia; • severe intoxications by chemicals, toxins or drugs; • degenerative diseases associated with the Acquired Immune Deficiency Syndrome (AIDS); • disorders associated with aging such as the syndrome of accelerated aging; • inflammatory diseases such as Terminal ileitis including Crohn's disease, rheumatoid polyarthritis, TNF-induced systemic inflammatory syndrome; • auto-immune diseases such as erythematous lupus (including systemic lupus erythematosus), cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome; • dental disorders such as those resulting in degradation of tissues such as for example periodontitis; • ophthalmic diseases or disorders including diabetic retinopathies, glaucoma, macular degenerations, retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathies associated with trauma, inflammatory degenerations, post-surgical complications, medicinal retinopathies, cataract, cone cell degeneration; • disorders of the audition tracts, such as otosclerosis and deafness induced by antibiotics; • Ischemic reperfusion injury, including retinal ischaemic reperfusion injury; • Neuronal loss, including Alzheimer's disease and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS; also referred to as motor neuron disease (MND) and Charcot disease); • diseases associated with mitochondria (mitochondrial pathologies), such as Friedrich's ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson's syndrome), MIDD (mitochondrial diabetes and deafness) syndrome, Wolfram's syndrome, dystonia; • cancer and metastasis including but not limited to cancers of the lung and bronchus, including non-small cell lung cancer (NSCLC), squamous lung cancer, brochioloalveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); prostate cancer, including androgen-dependent and androgen-independent prostate cancer; breast cancer, including metastatic breast cancer; pancreatic cancer; cancers of the colon and rectum; thyroid cancer; cancers of the liver and intrahepatic bile duct; hepatocellular cancer; gastric cancer; endometrial cancer; melanoma; cancers of the kidney, renal pelvis, urinary bladder, uterine corpus and uterine cervix; ovarian cancer, including progressive epithelial or primary peritoneal cancer; multiple myeloma; oesophageal cancer, including squamous cell carcinoma and adenocarcinoma of the oesophagus; acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP); lymphocytic leukemia; myeloid leukemia; acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non- Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL); T-cell lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes; cancers of the brain, including glioma/glioblastoma, anaplastic oligodendroglioma, and adult anaplastic astrocytoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; cancers of the head and neck, including , e.g., squamous cell carcinoma of the head and neck, and nasopharyngeal cancer; cancers of the oral cavity, pharynx and small intestine; bone cancer; soft tissue sarcoma; and villous colon adenoma; and • diseases of the central nervous system (CNS), such as multiple sclerosis (MS).
  15. A compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, prodrug and/or stereoisomer thereof, for use in medicine.

Description

This application claims priority to Australian provisional application no. 2020902035 (filed on 19 June 2020), the entire contents of which is hereby incorporated by reference. Field The present disclosure relates to sulphonamide compounds which treat necroptosis and/or inhibit MLKL, and methods for their use. Background In many diseases, cell death is mediated through apoptotic and/or necrotic pathways. While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood. Understanding the mechanisms in respect of both necrosis and apoptosis in cells is essential to being able to treat conditions, such as neurodegenerative diseases, stroke, coronary heart disease, kidney disease, liver disease, AIDS and the conditions associated with AIDS. Cell death has traditionally been categorized as either apoptotic or necrotic based on morphological characteristics (Wyllie et al., Int. Rev. Cytol. 68:251, 1980). These two modes of cell death were also initially thought to occur via regulated (caspase-dependent) and non-regulated processes, respectively. More recent studies, however, demonstrate that the underlying cell death mechanisms resulting in these two phenotypes are much more complicated and under some circumstances interrelated. Furthermore, conditions that lead to necrosis can occur by either regulated caspase-independent or non-regulated processes. One regulated caspase-independent cell death pathway with morphological features resembling necrosis, called necroptosis, has been described (Degterev et al., Nat. Chem. Biol. 1:112, 2005). This cell death modality can be initiated with various stimuli (e.g., TNF-[alpha] and Fas ligand) and in an array of cell types (e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells and neurons). Necroptosis may represent a significant contributor to and in some cases predominant mode of cellular demise under pathological conditions involving excessive cell stress, rapid energy loss and massive oxidative species generation, where the highly energy-dependent apoptosis process is not operative. In WO2015/172203, we reported that particular compounds described in US2005/0085637 have been found to be suitable for inhibiting necroptosis. We also discussed particularly suitable compounds for inhibiting necroptosis in WO2016/127213. All publications, patents and patent applications that may be cited herein are hereby incorporated by reference in their entirety. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application. Summary As discussed above, certain compounds described in WO2016/127213, US2005/0085637 and WO2015/172203 have been found to be suitable for treating necroptosis. Surprisingly, the inventors of this invention have now discovered that other types of compounds are also suitable for treating necroptosis. Further, and equally surprising, the compounds described in this invention target a key effector of the necroptotic pathway, namely mixed lineage kinase domain-like protein (MLKL). The inventors have also found that the compounds described in this invention target human MLKL. In one aspect, there is provided a compound according to Formula (I) wherein Q1 and Q2 are selected from N and NR1, wherein when Q1 is N, Q2 is NR1 and when Q2 is N, Q1 is NR1;R1 and R3 are independently selected from H and an optionally substituted C1-6-alkyl;R2 is an optionally substituted C1-C6-alkyl, an optionally substituted aryl or an optionally substituted heterocyclyl;X is selected from optionally substituted C1-6alkyl, optionally substituted haloC1-6alkyl, optionally substituted C2-6alkynyl, optionally substituted cycloalkyl, optionally substituted halocycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted C1-6alkylcycloalkyl and optionally substituted amino;Y and Z are independently selected from H, R4, -OR4 and -NR4R5,wherein at least one of Y and Z is H;R4 is independently selected from optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted C1-6alkylaryl, optionally substituted heterocyclyl, C1-6alkylheterocyclyl, optionally substituted cycloalkyl, optionally substituted C1-6alkylC3-10cycloalkyl, optionally substituted C3-10cycloalkylaryl, optionally substituted C3-10cycloalkylheterocyclyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-6 membered non-aromatic heterocyclyl-aryl, optionally substituted 3-6 membered non-aromatic heterocyclylC3-10cycloalkyl and optionally substituted 3-6 membered non-aromatic heterocyclyl-3-10 membered heterocyclyl; andR5 is H or optionally substituted C1-6alkyl. In any aspect