US2009253676A1PendingUtilityA1
Heteroaryl Benzamide Derivatives for Use as GLK Activators in the Treatment of Diabetes
Est. expiryJun 5, 2024(expired)· nominal 20-yr term from priority
A61P 3/04A61P 43/00C07D 231/40C07D 417/12A61P 3/10C07D 285/08C07D 413/12C07D 277/46C07D 403/12A61P 3/08A61K 31/425C07D 231/14A61K 31/54A61K 31/415
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Claims
Abstract
Compounds of Formula (I): wherein: R 1 is hydroxymethyl; R 2 is selected from —C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , —S(O) p R 4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R 3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R 4 is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R 5 is hydrogen or (1-4C)alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro-drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.
Claims
exact text as granted — not AI-modified1 - 17 . (canceled)
18 . A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
wherein:
R 1 is hydroxymethyl;
R 2 is selected from —C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , and —S(O) p R 4 ;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R 6 ;
R 3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
R 4 is selected from hydrogen and (1-4C)alkyl;
R 5 is hydrogen or (1-4C)alkyl;
R 6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O) p (1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
p is independently at each occurrence 0, 1, or 2;
m is 0 or 1;
n is 0, 1, or 2;
provided that when m is 0, then n is 1 or 2.
19 . A compound of Formula (I), as claimed in claim 18 , which is selected from:
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-[4-(methoxymethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-(5-methyl-1,3-thiazol-2-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1H-pyrazol-3-ylbenzamide;
3-chloro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
3-({4-[(dimethylamino)carbonyl]phenyl}oxy)-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
N-(1-ethyl-1H-pyrazol-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-chloro-4-{3-{[(1-ethyl-1H-pyrazol-3-yl)amino]carbonyl}-5-[(1S)-2-hydroxy-1-methylethoxy]phenoxy}-N,N-dimethylbenzamide;
3-{4-[(dimethylamino)carbonyl]phenoxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-fluoro-4-[(3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]-N,N-dimethylbenzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-isopropyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-[2-chloro-4-(ethylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-[4-(ethylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-{4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[5-chloro-2-fluoro-4-(methylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2,5-difluoro-4-(methylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
2-chloro-5-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
2,5-difluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
3-[(3,5-difluorophenyl)oxy]-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-(3-fluoro-4-methoxyphenoxy)-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and
3-(3,4-dimethoxyphenoxy)-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
or a salt, pro-drug, or solvate thereof.
20 . A compound of Formula (I), as claimed in claim 19 , which is selected from:
3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-chloro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
N-(1-ethyl-1H-pyrazol-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-chloro-4-{3-{[(1-ethyl-1H-pyrazol-3-yl)amino]carbonyl}-5-[(1S)-2-hydroxy-1-methylethoxy]phenoxy}-N,N-dimethylbenzamide;
3-{4-[(dimethylamino)carbonyl]phenoxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-fluoro-4-[(3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]-N,N-dimethylbenzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-chloro-4-(ethylsulfinyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-isopropyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide;
3-[2-chloro-4-(ethylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-[4-(ethylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-{4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[5-chloro-2-fluoro-4-(methylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2,5-difluoro-4-(methylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
2-chloro-5-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
2,5-difluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)-N,N-dimethylbenzamide;
3-[(3,5-difluorophenyl)oxy]-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-(3-fluoro-4-methoxyphenoxy)-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and
3-(3,4-dimethoxyphenoxy)-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
or a salt, pro-drug, or solvate thereof.
21 . A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
wherein:
R 1 is hydroxymethyl;
R 2 is selected from —C(O)—HET-3 and —SO 2 -HET-3;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R 6 ;
HET-2 is a 4-, 5- or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O) 2 group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 7 ;
R 3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
R 4 is selected from hydrogen; (1-4C)alkyl optionally substituted with 1 or 2 substituents independently selected from HET-2, —OR 5 , —SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ), and —C(O)NR 5 R 5 ; (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ); and HET-2;
R 5 is hydrogen or (1-4C)alkyl;
or R 4 and R 5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;
R 6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O) p (1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
R 7 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-3 is an N-linked, 4-, 5- or 6-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an N-linked, 7-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom independently selected from O, S, and N, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom wherein a —CH 2 — group can optionally be replaced by a —C(O)—; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R 3 ;
R 8 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
p is independently at each occurrence 0, 1, or 2;
m is 1;
n is 0, 1, or 2.
22 . A compound of Formula (I) as claimed in claim 21 , or a salt, pro-drug, or solvate thereof, wherein HET-3 is a 4- to 6-membered ring.
23 . A compound of Formula (I) as claimed in claim 21 , which is selected from:
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{[4-(azetidin-1-ylcarbonyl)-2-fluorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide;
3-{[4-(azetidin-1-ylcarbonyl)-2-fluorophenyl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
N-(1-ethyl-1H-pyrazol-3-yl)-3-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-[2-chloro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1S)-2-hydroxy-1-methylethoxy]benzamide;
3-{[4-(azetidin-1-ylcarbonyl)phenyl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzamide;
3-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-1H-pyrazol-3-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1,3-thiazol-2-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-[4-(methoxymethyl)-1,3-thiazol-2-yl]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(piperidin-1-ylcarbonyl)phenoxy]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(morpholin-4-ylcarbonyl)phenoxy]benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-{4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-fluoro-4-(piperidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[2-fluoro-4-(morpholin-4-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{2-fluoro-4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{2-fluoro-4-[(2-methylazetidin-1-yl)carbonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{2-fluoro-4-[(3-methoxyazetidin-1-yl)carbonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-{2-fluoro-4-[(3-isopropoxyazetidin-1-yl)carbonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-{4-[(2-methylazetidin-1-yl)carbonyl]phenoxy}-N-(5-methylpyrazin-2-yl)benzamide;
3-[(1S)-2-hydroxy-1-methylethoxy]-5-{4-[(3-methoxyazetidin-1-yl)carbonyl]phenoxy}-N-(5-methylpyrazin-2-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;
3-[4-(azetidin-1-ylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-1H-pyrazol-3-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)-2,5-difluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-5-chloro-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-1,3-thiazol-2-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-1,3-thiazol-2-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-pyrazin-2-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-pyrazin-2-ylbenzamide;
3-[4-(azetidin-1-ylcarbonyl)-3-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and
3-[4-(2-azabicyclo[2.1.1]hex-2-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
or a salt, pro-drug, or solvate thereof.
24 . A compound of Formula (I) as claimed in claim 21 , which is selected from:
3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and
3-{[4-(azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
or a salt, pro-drug, or solvate thereof.
25 . A compound of Formula (I), or a salt, pro-drug or solvate thereof:
wherein:
R 1 is hydroxymethyl;
R 2 is selected from —C(O)NR 41 R 51 , —SO 2 NR 41 R 51 and —S(O) p R 41 ;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R 6 ;
HET-2 is a 4-, 5-, or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O) 2 group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 7 ;
R 3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
R 41 is selected from (1-4C)alkyl substituted with 1 or 2 substituents independently selected from HET-2, —OR 5 , —SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ), and —C(O)NR 5 R 5 ; (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ); and HET-2;
R 51 is hydrogen or (1-4C)alkyl;
R 4 is selected from (1-4C)alkyl optionally substituted with 1 or 2 substituents independently selected from HET-2, —OR 5 , —SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ), and —C(O)NR 5 R 5 ; (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ); and HET-2;
R 5 is hydrogen or (1-4C)alkyl;
or R 4 and R 5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;
R 6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O) p (1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
R 7 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-3 is an N-linked, 4-, 5-, or 6-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an N-linked, 7-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom independently selected from O, S, and N, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom wherein a —CH 2 — group can optionally be replaced by a —C(O)—; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R 3 ;
R 8 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
p is independently at each occurrence 0, 1, or 2;
m is 1;
n is 0, 1, or 2.
26 . A compound of Formula (I) as claimed in claim 25 , which is selected from:
3-{4-[(cyclopropylamino)carbonyl]phenoxy}-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
N-cyclopropyl-3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzamide;
3-[4-(cyclobutylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
3-[4-(cyclopropylsulfonyl)phenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
or a salt, pro-drug, or solvate thereof.
27 . A compound of Formula (I), or a salt, pro-drug, or solvate thereof:
wherein:
R 1 is hydroxymethyl;
R 2 is HET-2;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S; which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R 6 ;
HET-2 is a 4-, 5-, or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(O) 2 group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 7 ;
R 3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
R 4 is selected from hydrogen; (1-4C)alkyl optionally substituted with 1 or 2 substituents independently selected from HET-2, —OR 5 , —SO 2 R 5 , (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ), and —C(O)NR 5 R 5 ; (3-6C)cycloalkyl (optionally substituted with 1 group selected from R 7 ); and HET-2;
R 5 is hydrogen or (1-4C)alkyl;
or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl ring system as defined by HET-3;
R 6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O) p (1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
R 7 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-3 is an N-linked, 4-, 5-, or 6-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms independently selected from O, N, and S, wherein a —CH 2 — group can optionally be replaced by a —C(O)— and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an N-linked, 7-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom independently selected from O, S, and N, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O) 2 group; which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R 8 ; or
HET-3 is an 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom, wherein a —CH 2 — group can optionally be replaced by a —C(O)—; which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R 3 ;
R 8 is selected from —OR 5 , (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR 4 R 5 , (1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O) p R 5 ;
HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
p is independently at each occurrence 0, 1, or 2;
m is 1;
n is 0, 1, or 2.
28 . A compound of Formula (I), as claimed in claim 27 , which is selected from:
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1,2,4-oxadiazol-3-yl)phenoxy]benzamide; and
3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1H-pyrazol-3-yl)phenoxy]benzamide;
or a salt, pro-drug, or solvate thereof.
29 . A compound of Formula (I) as claimed in claim 18 , claim 21 , claim 25 , or claim 27 or a salt, pro-drug, or solvate thereof wherein R 1 has the (S) configuration.
30 . A compound of Formula (I) as claimed in claim 18 , claim 21 , claim 25 , or claim 27 or a salt, pro-drug, or solvate thereof, wherein HET-1 is a 5-membered ring.
31 . A pharmaceutical composition comprising a compound as claimed in claim 18 , claim 21 , claim 25 , or claim 27 , or a salt, pro-drug, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.
32 . A method of treating GLK mediated diseases comprising administering an effective amount of a compound of Formula (I) as claimed in claim 18 , claim 21 , claim 25 , or claim 27 or a salt, pro-drug, or solvate thereof, to a mammal in need of such treatment.
33 . The method of claim 32 , wherein the GLK mediated disease is type 2 diabetes.
34 . A process for the preparation of a compound of Formula (I), or a salt, pro-drug, or solvate thereof as claimed in claim 18 , claim 21 , claim 25 , or claim 27 , comprising:
(a) reacting an acid of Formula (III) or activated derivative thereof with a compound of Formula (IV),
or
(b) reacting a compound of Formula (V) with a compound of Formula (VI),
wherein X 1 is a leaving group and X 2 is a hydroxyl group; or X 1 is a hydroxyl group and X 2 is a leaving group;
or
reacting a compound of Formula (V) with the intermediate ester of Formula (VII), wherein P 1 is a protecting group followed by ester hydrolysis and amide formation;
or
(c) reacting a compound of Formula (VIII) with a compound of Formula (IX)
wherein X 3 is a leaving group or an organometallic reagent and X 4 is a hydroxyl group; or
X 3 is a hydroxyl group and X 4 is a leaving group or an organometallic reagent;
or
reacting a compound of Formula (VIII) with the intermediate ester of Formula (X), followed by ester hydrolysis and amide formation;
or
(d) reacting a compound of Formula (XI) with a compound of Formula (XII),
wherein X 5 is a leaving group;
or
e) when R 2 is of the Formula —C(O)NR 4 R 5 , reacting a compound of Formula:
with a compound of the Formula HNR 4 R 5 ;
and thereafter, if necessary:
i) converting a compound of Formula (I) into another compound of Formula (I);
ii) removing any protecting groups; and or
iii) forming a salt, pro-drug or solvate.
35 . The compound 3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide.Cited by (0)
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