DK2753606T3 - Pyrimidiner som natriumkanalblokkere - Google Patents

Pyrimidiner som natriumkanalblokkere Download PDF

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DK2753606T3
DK2753606T3 DK12770217.3T DK12770217T DK2753606T3 DK 2753606 T3 DK2753606 T3 DK 2753606T3 DK 12770217 T DK12770217 T DK 12770217T DK 2753606 T3 DK2753606 T3 DK 2753606T3
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amino
alkyl
phenyl
pyrimidine
carboxamide
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DK12770217.3T
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Chiyou Ni
Minnie Park
Bin Shao
Jiangchao Yao
Mark Youngman
Laykea Tafesse
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Purdue Pharma Lp
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Claims (13)

1. Forbindelse med formlen I:
I eller et farmaceutisk acceptabelt salt, eller solvat deraf, hvor: W1 og W2 er N og W3 er CR3; eller A1 er substitueret pyridyl med én eller to substituenter, eller substitueret phenyl med én, to eller tre substituenter; hvor pyridyl er substitueret med én eller to substituenter uafhængigt udvalgt fra halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydr oxy alley 1, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl og (heteroaryl)alkyl; hvor phenyl er substitueret med én, to eller tre substituenter uafhængigt udvalgt fra halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido) al kyl, mercaptoalkyl, (heterocyclo)alkyl eller (heteroaryl)alkyl; X er -O-; A2 er udvalgt fra gruppen bestående af: a) eventuelt substitueret aryl; b) eventuelt substitueret heteroaryl; c) eventuelt substitueret heterocyklus; og d) eventuelt substitueret cycloalkyl; E er udvalgt fra gruppen bestående af: a) hydroxy; b) alkoxy og c) -NR'R2; R1 er udvalgt fra gruppen bestående af: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo) alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl og m) heteroalkyl; R2 er udvalgt fra gruppen bestående af hydrogen og alkyl; eller R1 og R2 taget sammen med det nitrogenatom, hvortil de er bundet, danner en 3- til 8-leddet eventuelt substitueret heterocyklus; R3 er hydrogen; Z er udvalgt fra gruppen bestående af -NR5- og -O-; R4 er udvalgt fra gruppen bestående af:
a) b) c) hydroxyalkyl; d) hydroxy(cycloalkyl) alkyl og e) (heterocyclo)alkyl; hver R10a, R10b, R10c og R10d uafhængigt er udvalgt fra gruppen bestående af: a) hydrogen; b) hydroxy; c) eventuelt substitueret alkyl; d) aralkyl; e) (heterocyclo)alkyl; f) (heteroaryl)alkyl; g) (amino)alkyl; h) (alkylamino)alkyl; i) (dialkylamino)alkyl; j) (carboxamido)alkyl; k) (cyano)alkyl; l) alkoxyalkyl; m) hydroxy alkyl; n) heteroalkyl; o) eventuelt substitueret cycloalkyl; p) eventuelt substitueret aryl; q) eventuelt substitueret heterocyklus og r) eventuelt substitueret heteroaryl; eller R10a og R10b taget sammen med det carbonatom, hvortil de er bundet, danner en 3- til 8-leddet eventuelt substitueret cycloalkyl eller en 3- til 8-leddet eventuelt substitueret heterocyklus; r er 1, 2 eller 3; s er 1, 2 eller 3; R11 er udvalgt fra gruppen bestående af: a) hydroxy; b) alkoxy og c) -NRlaR2a; Rla er udvalgt fra gruppen bestående af: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxy alkyl; l) hydroxyalkyl og m) heteroalkyl; R2a er udvalgt fra gruppen bestående af hydrogen og alkyl; eller Rla og R2a taget sammen med det nitrogenatom, hvortil de er bundet, danner en 3- til 8- leddet eventuelt substitueret heterocyklus; R12 er udvalgt fra gruppen bestående af: a) hydrogen; b) eventuelt substitueret alkyl; c) (amino)alkyl; d) (alkylamino)alkyl; e) (dialkylamino)alkyl; f) (carboxamido)alkyl; g) (cyano)alkyl; h) alkoxyalkyl; i) hydroxyalkyl og j) heteroalkyl; R5 er udvalgt fra gruppen bestående af: a) hydrogen b) alkyl; c) hydroxyalkyl og d) alkylsulfonyl eller R4 og R5 taget sammen med det nitrogenatom, hvortil de er bundet, danner en 3- til 8-leddet eventuelt substitueret heterocyklus; hvor den eventuelt substituerede alkyl enten er usubstitueret eller substitueret med én, to eller tre substituenter uafhængigt udvalgt fra nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl og cycloalkyl; hvor eventuelt substitueret aryl enten er usubstitueret eller substitueret med én til fem substituenter uafhængigt udvalgt fra halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl eller (heteroaryl)alkyl; hvor eventuelt substitueret heteroaryl enten er usubstitueret eller substitueret med én til fire substituenter uafhængigt udvalgt fra halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl og (heteroaryl)alkyl; hvor den eventuelt substituerede cycloalkyl enten er usubstitueret eller substitueret med én, to eller tre substituenter uafhængigt udvalgt fra hafo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl og (heteroaryl)alkyl; hvor den eventuelt substituerede heterocyklus enten er usubstitueret eller substitueret med én til fire substituenter uafhængigt udvalgt fra halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyklus, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl og (heteroaryl)alkyl; med det forbehold, at når R4 og R5 taget sammen med det nitrogenatom, hvortil de er bundet, danner en 3- til 8-leddet eventuelt substitueret heterocyklus, så er R1 udvalgt fra gruppen bestående af: a) hydrogen; b) (heterocyclo)alkyl; c) (heteroaryl)alkyl; d) (amino)alkyl; e) (alkylamino)alkyl; f) (dialkylamino)alkyl; g) (carboxamido)alkyl; h) (cyano)alkyl; i) alkoxyalkyl; j) hydroxyalkyl og k) heteroalkyl.
2. Forbindelse ifølge krav 1 med formlen II: II eller et farmaceutisk acceptabelt salt, eller solvat deraf, hvor: R6a og R6b er uafhængigt udvalgt fra gruppen bestående af: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; m) carboxy og n) alkoxycarbonyl.
3. Forbindelse ifølge et hvilket som helst af kravene 1-2 med formlen IV:
IV eller et farmaceutisk acceptabelt salt, eller solvat deraf.
4. Forbindelse ifølge krav 1 med formlen VII: VII eller et farmaceutisk acceptabelt salt, eller solvat deraf.
5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor Z er i) -NR5- eller ii) -O-, eller et farmaceutisk acceptabelt salt, eller solvat deraf.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor: R4 er udvalgt fra gruppen bestående af: a)
b) hydroxyalkyl og c) hydroxy(cycloalkyl)alkyl; R10a er udvalgt fra gruppen bestående af: a) hydrogen; b) hydroxy; c) eventuelt substitueret alkyl; d) aralkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; k) alkoxyalkyl og l) hydroxyalkyl; R10b er udvalgt fra gruppen bestående af hydrogen og alkyl; eller R10a og R10b taget sammen med det carbonatom, hvortil de er bundet, danner en 3- til 6-leddet cycloalkyl; r er 1 eller 2; eller et farmaceutisk acceptabelt salt, eller solvat deraf. . Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R4 og R5 taget sammen med det nitrogen, hvortil de er bundet, danner en 5- eller 6-leddet eventuelt substitueret heterocyklus, eller et farmaceutisk acceptabelt salt, eller solvat deraf, og hvor fortrinsvis den eventuelt substituerede 5- eller 6-leddet heterocyklus er udvalgt fra gruppen bestående af:
hvor: Rlja, R13b, R13c, R13d, R13e og R13f er uafhængigt udvalgt fra gruppen bestående af: a) hydrogen; b) hydroxy; c) hydroxyalkyl; d) carboxy; e) alkoxycarbonyl og f) carboxamido; Y er udvalgt fra gruppen bestående af O, S og NR14; og R14 er udvalgt fra gruppen bestående af hydrogen og alkyl, eller et farmaceutisk acceptabelt salt, eller solvat deraf. . Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor i) R4 er: R" er-NR'"Η2"
eller et farmaceutisk acceptabelt salt, eller solvat deraf; eller ii) R4 er:
R10a og R10b taget sammen med det carbonatom, hvortil de er bundet, danner en 3- til 6-leddet cycloalkyl; og R11 er -NRlaR2a, eller et farmaceutisk acceptabelt salt, eller solvat deraf; eller iii) R4 er udvalgt fra gruppen bestående af:
R10a er udvalgt fra gruppen bestående af hydrogen og alkyl; og R10b er udvalgt fra gruppen bestående af: a) hydrogen; b) hydroxy og c) alkyl, eller et farmaceutisk acceptabelt salt, eller solvat deraf; eller iv) R4 er hydroxyalkyl eller hydroxy(cycloalkyl)alkyl, eller et farmaceutisk acceptabelt salt, eller solvat deraf, og hvor fortrinsvis hydroxyalkyl eller hydroxy(cycloalkyl)alkyl er udvalgt fra gruppen bestående af:
9. Forbindelse ifølge et hvilket som helst af kravene 1-8, hvor A1 er udvalgt fra gruppen bestående af substitueret phenyl med én eller to substituenter og substitueret pyridyl med én substituent, hvor hver substituent uafhængigt er udvalgt fra gruppen bestående af halo, cyano, hydroxy, amino, haloalkyl, alkoxy, haloalkoxy og alkyl.
10. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvor E er -NH2, og W1 og W2 er N og W3 er CH; eller et farmaceutisk acceptabelt salt eller solvat deraf.
11. Forbindelse ifølge krav 4 med formlen XIV eller formlen XV:
XV eller et farmaceutisk acceptabelt salt, eller solvat deraf, hvor fortrinsvis: W1 og W2 er N og W3 er CH; A1 er substitueret pyridyl med én eller to substituenter, eller substitueret phenyl med én, to eller tre substituenter; og Z er -NH-, eller et farmaceutisk acceptabelt salt, eller solvat deraf, og hvor mere fortrinsvis A1 er udvalgt fra gruppen bestående af substitueret phenyl med én eller to substituenter og substitueret pyridyl med én substituent, hvor hver substituent uafhængigt er udvalgt fra gruppen bestående af halo, cyano, hydroxy, amino, haloalkyl, alkoxy, haloalkoxy og alkyl.
12. Forbindelse ifølge krav 1 udvalgt fra gruppen bestående af: (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(4fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((2-amino-2-oxoethyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4carboxamid; (S)-6-((l-amino-4-methyl-l-oxopentan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl) pyrimidin-4-carboxamid; (S)-6-((l-amino-3-hydroxy-l-oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl) pyrimidin-4-carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-3-( 1 -methyl-1 H-imidazol-4-yl)-1 -oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-2-(4-(4-fluorphenoxy)phenyl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidin-4-carboxamid; 6-((l-carbamoylcyclopropyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((l-carbamoylcyclobutyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((l-amino-2-methyl-l-oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(4-cyano-3-(trifluormethyl)phenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(3-cyano-4-(trifluormethyl) phenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((5-(trifluormethyl)pyridin-2-yl) oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(4-(trifluormethyl)phenoxy)phenyl)pyrimidin-4-carboxamid; (S)-methyl l-(6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)pyrrolidin-2- carboxylat; (S)-ethyl l-(6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)indolin-2carboxylat; ethyl l-((6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)amino) cyclopropancarboxylat; methyl 2-((6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)amino)-2- methylpropanoat; 6-((3-amino-3-oxopropyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyriinidin-4carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)(methyl)amino)-2-(4-(4-fluorphenoxy)phenyl) pyrimidin-4-carboxamid; (R) -6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(4fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((1 -amino- l-oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((4-amino-4-oxobutan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-cai'boxamid; 6-(3-carbamoylpiperidin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 4-(6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)morpholin-3-carboxamid; 4-(6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)morpholin-2- carboxamid; 6-(2-carbamoylpiperazin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S) -2-((6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-yl)amino)propionsyre; (S)-6-(2-carboxypyrrolidin-l-yl)-2-(4-(4-lluorphenoxy)phenyl)pyrimidin-4-carboxylsyre; (S)-l-(6-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-}4)pyrrolidin-2-carboxylsyre; (S)-l-(6-carbamoyl-2-(4-(4-lluorphenoxy)phenyl)pyrimidin-4-yl)indolin-2-carboxylsyre; (S)-tert-butyl 2-(4-(4-fluorphenoxy)phenyl)-6-(( 1 -methoxy-1 -oxopropan-2- yl)amino)pyrimidin-4-carboxylat; (S)-2-(4-(4-fluorphenoxy)phenyl)-6-((l-methoxy-l-oxopropan-2-yl)amino)pyrimidin-4- carboxylsyre; (S)-tert-butyl6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin- 4-carboxylat; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(4fluorphenoxy)phenyl)pyrimidin-4-carboxylsyre; (S)-l-(6-carbamoyl-2-(4-(4-iluorphenoxy)phenyl)pyrimidin-4-yl)indolin-2- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-((5 -cyanopyridin-2-yl)oxy)phenyl)pyrimidin-4-carboxamid; S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-(5-chlor-2-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; (S)-methyl 2-(4-(4-fluorphenoxy)phenyl)-6-((l-methoxy-l-oxopropan-2-yl)amino)pyrimidin-4-carboxylat; (S)-6-((l-carboxyethyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxylsyre; 2-(4-(4-fluorphenoxy)phenyl)-6-(3-(hydroxymethyl)morpholino)pyrimidin-4-carboxamid; (S)-2-(4-(4-iluorphenoxy)phenyl)-6-((l-hydroxypropan-2-yl)amino)pyrimidin-4-carboxamid; (S)-2-(4-(4-tluorphenoxy)phenyl)-6-(2-(hydroxymethyl)pyrrolidin-l-yl)pyrimidin-4- carboxamid; 2-(4-(4-fluorphenoxy)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-carboxamid; 2-(4-(4-fluorphenoxy)phenyl)-6-(((l-hydroxycyclohexyl)methyl)amino)pyrimidin-4- carboxamid; (S)-6-((2,3-dihydroxypropyl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-((1,3-dihydroxypropan-2-yl)amino)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 2-(4-(4-fluorphenoxy)phenyl)-6-(2-(hydroxymethyl)piperazin-l-yl)pyrimidin-4-carboxamid; 6-(3,4-dihydroxypyrrolidin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-(4-(4-fiuorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-3-((6-carbamoyl-2-(4-(4-iluorphenoxy)phenyl)pyrimidin-4-yl)amino)-2-hydroxypropionsyre; 6-(N-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)methylsulfonamido)-2-(4-(4- fluorphenoxy)phenyl)pyrimidin-4-carboxamid; 6-(N-(2,3-dihydroxypropyl)methylsulibnamido)-2-(4-(4-iluorphenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(4-fluorphenoxy)phenyl)pyriimdin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((4-trifluormethyl)pyridin-2-yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-((3 -trifluormethyl)pyridin-2-yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((6-trifluormethyl)pyridin-2- yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((6-trifluormethyl)pyridin- 3- yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((6-fluorpyridin-2-yl)oxy)phenyl)pyrimidin-4- carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(4-((5-fluorpyridin-2-yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-((5 -chlorpyridin-2-yl)oxy)phenyl)pyrimidin-4-carboxamid; 6-((S)-l-carbamoyl-ethylamino)-2-[4-(4-cyano-phenoxy)-phenyl]-pyrimidin-4- carboxylsyreamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(2-(4-fluorphenoxy)pyridin-4-yl)pyrimidin-4-carboxamid; (S)-6-((l-amino-l-oxopropan-2-yl)amino)-2-(6-(4-iluorphenoxy)pyridin-3yl)pyrimidin-4- carboxamid; 6-(3-carbamoylpiperazin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-2-(4-(4-chlor-2-fluorphenoxy)phenyl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidin-4- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(4-(triiluormethoxy)phenoxy)phenyl)pyrimidin- 4- carboxamid; (S)-6-(( 1-amino-1-oxopropan-2-yl)oxy)-2-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-(4-chlor-2-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; 6-((3S,4S)-3,4-dihydroxypyrrolidin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; 6-((3R,4R)-3,4-dihydroxypyrrolidin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; 6-(2-carbamoyl-4-methylpiperazin-l-yl)-2-(4-(4-(trifluormethyl)phenoxy)phenyl)pyrimidin-4- carboxamid; 6-(2-carbamoyl-4-methylpiperazin-l-yl)-2-(4-(4-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; 6-(2-carbamoyl-4-methylpiperazin-l-yl)-2-(4-(4-chlor-2-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(4-(trifluormethoxy)phenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(benzo[d] [ 1,3]dioxol-5-yl)oxy)phenyl)pyrimidin-4-carboxamid; 6-(2-carbamoylpiperazin-l-yl)-2-(4-(4-(trifluormethyl)phenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-(5-chlor-2-fluorphenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-((5-(trifluormethyl)pyridin- 2-yl)oxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-carboxamid; (S)-2-(4-(benzo[d][l,31dioxol-5-yloxy)phenyl)-6-(2-carbamoylpyrrolidin-l-yl)pyrimidin-4- carboxamid; (S)-6-(2-carbamoylpyrrolidin-l-yl)-2-(4-(4(trifluormethyl)phenoxy)phenyl)pyrimidin-4- carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(5 -chlor-2-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(4-chlor-2-fluorphenoxy)phenyl)pyrimidin-4-carboxamid; (S)-2-(4-(4-fluorphenoxy)phenyl)-6-((l-((2-hydroxyethyl)amino)-l-oxopropan-2- yl)amino)pyrimidin-4-carboxamid; (S)-2-(4-(4-fluorphenoxy)phenyl)-6-((l-morpholin-l-oxopropan-2-yl)amino)pyrimidin-4- carboxamid; (S)-methyl 5-(4-((1-amino-1-oxopropan-2-yl)amino)-6-carbamoylpyrimidin-2-yl)-2(4- fluorphenoxy)benzoat; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(4-fluorphenoxy)-3 -(hydroxymethyl)phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(4-(trifluormethyl)phenoxy)phenyl)pyrimidin-4-carboxamid; (S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(4-((5-(trilluormethyl)pyridin-2-yl)oxy) phenyl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(4-cyanophenoxy)piperidin-l-yl)pyrimidin-4-carboxamid; (S)-6-(( 1 -amino-1 -oxopropan-2-yl)amino)-2-(3 -(4(triiluormethoxy)phenoxy)azetidin-l-yl)pyrimidin-4-carboxamid; 6-(((S)-2-oxopyrrolidin-3-yl)oxy)-2-(4-(4-(trifluormethyl)phenoxy)cyclohex-l-επί-yl)pyrimidin-4-cai'boxamid og 6-(((S)-1 -amino-1 -oxopropan-2-yl)amino)-2-(4-(4-(trifluormethyl)phenoxy)cyclohex-1 -en-1 -yl)pyrimidin-4-carboxamid, eller et farmaceutisk acceptabelt salt, eller solvat deraf, og fortrinsvis er udvalgt fra gruppen bestående af: (S)-6-(( 1 -amino-1 -oxopropan-2-yl)oxy)-2-(4-(4-(trifluormethyl)phenoxy)phenyl)pyrimidin-4-carboxamid; og (S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(4-((5-(trifluormethyl)pyridin-2- yl)oxy)phenyl)pyrimidin-4-carboxamid, eller et farmaceutisk acceptabelt salt eller solvat deraf.
13. Farmaceutisk sammensætning, der omfatter forbindelsen ifølge et hvilket som helst af kravene 1-12, eller et farmaceutisk acceptabelt salt, eller solvat deraf, og en farmaceutisk acceptabel bærer.
14. Forbindelse ifølge et hvilket som helst af kravene 1-12, eller et farmaceutisk acceptabelt salt eller solvat deraf til anvendelse i behandling af apopleksi, neuronskade som følge af hovedtraume, epilepsi, epileptiske anfald, neurontab efter global og fokal iskæmi, smerte, migræne, primær erythromelalgi, paroksysmal ekstrem smerteforstyrrelse, cerebellar atrofi, ataksi, mental retardering, en neurodegenerativ forstyrrelse, manisk depression, tinnitus, myotoni, en bevægelsesforstyrrelse, eller dysrytmi, eller tilvejebringelse af lokal bedøvelse hos et pattedyr, omfattende indgivelse af en effektiv mængde af forbindelsen til et pattedyr med behov for en sådan behandling, og hvor anvendelsen fortrinsvis er til behandling af smerte og hvor endnu mere fortrinsvis i) anvendelse til forebyggende eller palliativ behandling af smerte; eller ii) smerten er udvalgt fra gruppen bestående af kronisk smerte, inflammatorisk smerte, neuropatisk smerte, akut smerte og kirurgisk smerte.
15. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-12, eller et farmaceutisk acceptabelt salt, eller solvat deraf, i fremstilling af et medikament til behandling af apopleksi, neuronskade som følge af hovedtraume, epilepsi, epileptiske anfald, neurontab efter global og fokal iskæmi, smerte, migræne, primær erythromelalgi, paroksysmal ekstrem smerteforstyrrelse, cerebellar atrofi, ataksi, mental retardering, en neurodegenerativ forstyrrelse, manisk depression, tinnitus, myotoni, en bevægelsesforstyrrelse eller dysrytmi, eller tilvejebringelse af lokal bedøvelse hos et pattedyr, omfattende indgivelse af en effektiv mængde af forbindelsen og hvor anvendelsen fortrinsvis er til behandling af smerte, og hvor endnu mere fortrinsvis i) anvendelsen er til forebyggende eller palliativ behandling af smerte eller ii) smerten er udvalgt fra gruppen bestående af kronisk smerte, inflammatorisk smerte, neuropatisk smerte, akut smerte og kirurgisk smerte.
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