# Patent

## Title
Compound for increasing kinase active and application thereof

## Abstract

The compound of Formula (I), pharmaceutically acceptable salts thereof, solvates thereof, chelates thereof, non-covalent complexes thereof or produgs of compounds mentioned above or the mixture of any form above mentioned are provided. The use of the compounds in manufacturing a medicament for the treatment and/or prevention of diabetes, obesity and related disorders.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. National Phase Application of PCT International Application PCT/CN2011/082004, filed Nov. 9, 2011, which claims priority to Chinese Application No. 201010535640.4, filed Nov. 9, 2010, the contents of each of which are incorporated herein by reference in their entireties for all purposes.
FIELD OF THE INVENTION
The present invention relates to compounds for increasing glucokinase activities and their use in manufacturing a medicament.
BACKGROUND OF THE INVENTION
Glucokinase (GK) is one (hexokinase IV) of four mammal hexokinases. Hexokinases is a first-stage enzyme in glycolysis and catalyzes a reaction from glucose to glucose hexaphosphate. In its expression, glucokinase is limited essentially in liver and pancreas beta cells, and it controls the rate limiting step of glucose metabolism in these cells. Thereby playing an important role in systemic saccharometabolism. Glucokinase in liver and that in pancreas beta cells differ from each other in point of the N-terminal 15-amino acid sequence owing to the difference in splicing there between, but they are the same in point of the enzymatic property. The enzymatic activity of the other three hexokinases (I, II, III) than glucokinase is saturated at a glucose concentration of at most 1 mM, but Km glucokinase to glucose is 8 mM and near to a physiological blood-glucose level. Thereof, in accordance with the blood-glucose level change from a normal blood-glucose level (5 nM) to an increased blood-glucose level after meals (10 to 15 mM), intracellular glucose metabolism is accelerated via glucokinase.
Since ten years ago, a hypothesis that glucokinase may act as a glucose sensor in pancreas beta cells and liver has been proposed [for example, see D. et al's “Computer modeling identified glucokinase as glucose sensor of pancreatic beta-cells”, American Journal Physiology, V247 (3Pt2), 1984, p 527 ̃536]. A result of recent glucokinase gene-manipulated mice has clarified that glucokinase actually plays an important role in systemic glucose homeostasis. Mice in which the glucokinase gene was disrupted die soon after their birth, but on the other hand, normal or diabetic mice in which glucokinase wad excessively expressed have a lowered blood-glucose level. With the increase in glucose concentration therein, the reacting of pancreas beta cells and that of liver cells are both toward the reduction in a blood-glucose level, though differing from each other. Pancreas beta cells come to secrete more insulin, and liver takes up sugar to store it as glycogen therein and simultaneously reduces sugar release.
To that effect, the change in the enzymatic activity of gulcokinase plays an important role in mammal glucose homeostasis via liver and pancreas beta cells. In a juvenile diabetic case that case is referred to as MODY2, mutation of a glucokinase gene has been found, and the glucokinase activity reduction causes the blood-glucose level increase [for example, see Vionnet N. et al's “Nonsense mutation in the glucokinase gene causes early-onset non-indulin-dependent diabetes mellitus”, Nature Genetics, Vol, 356, 1992, pp. 721-722]. On the other hand, a pedigree having mutation of increasing glucokinase activity has been found, and those of the family line show low blood-glucose level symptoms.
Form these, glucokinase acts as a glucose sensor and plays an important role in glucose homeostasis also in humans. On the other hand, blood-glucose level control by utilizing a glucokinase sensor system may be possible in many type-II diabetes patients. A glucokinase-activating substance may be expected to have an insulin secretion promoting effect in pancreas beta cells and have a sugar take-up accelerating and sugar release inhibiting activity in liver, And therefore it may be useful as a remedy for type-II diabetes patients.
Recently, it has become clarified that pancreas beta cell-type gulcokinase is limitedly expressed locally in rat brains, especially in ventromedial hypothalamus (VMH) thereof. About 20% neurocytes in VMH are referred to as glucose-resonsive neurons, and heretofore it has been considered they may play an important role in body weight control. When glucose is administered to a rat brain, then it reduces the amount of ingestion; but when glucose metabolism is retarded through intracerebral administration of glucosamine, a glucose analogue, then it cause hyperphagia.
From an electrophysiological experiment, it is admitted that glucose-responsive neurons are activated in accordance with a physiological glucose concentration change (5-20 mM), but when glucose metabolisns is inhibited by glucosamine or the like, and then their activity is retarted. In the glucose concentration-sensitive system in VMH, a glucose-mediated mechanism is anticipated like the insulin secretion in pancreas beta cells. Accordingly, there may be a possibility that a substance for glucokinase activation in VMH, in addition to liver and pancreas beta cells, may be effective not only for blood-glucose level correction but also for solution of obedity that is problematic in many type-II diabetes patients.
From the above description, a compound having a glucokinase activation effect is useful for remedies and/or preventives for diabetes, or for remedies and/or preventives for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic cardiopathy, arterisclerosis, and further for remedies and/or preventives for obesity.
SUMMARY OF THE INVENTION
The present invention provides compounds for increasing glucokinase activities and their use in manufacturing a medicament.
The present invention provides a compound of the following Formula (I). The compound includes compounds of Formula (I), pharmaceutically acceptable salts thereof, solvates thereof, chelates thereof, non-covalent complexes thereof or, produgs of the compounds mentioned above, or the mixture of any form above mentioned,




wherein
W and Y are independently selected from N or C;
X is selected from O or S;
Z is selected from C, N, O or S;
R1 is selected from the group consisting of —H, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, C(═O)R5, SR5, SO2R5, or haloalkyl; R5 is selected from the group consisting of: lower alkanyl, substituted lower alkanyl, alkoxy, substituted alkoxy or NR6R7; R6 and R7 are independently selected from the group consisting of: —H, lower alkanyl, substituted lower alkanyl, or R6 and R7 can join together to from a 3 to 6 membered ring or a substituted 3 to 6 membered ring;
R2 is selected from the group consisting of —H, alkanyl, substituted alkanyl, halogen or haloalkyl;
R3 is selected from the group consisting of substituted alkanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl;
R4 is selected from the group consisting of heteroaryl or substituted heteroaryl, wherein at least one ortho atom of the heteroaryl connected with NH fragment in Formula (I) is N.
In a preferred embodiment of the present invention, W is C.
In a particularly preferred embodiment of the present invention, W is C and Y is C. In a more preferred embodiment of the present invention, W is C, Y is C and X is O. In an even more preferred embodiment of the present invention, W is C, Y is C, X is O and Z is C.
In another particularly preferred embodiment of the present invention, W is C and Y is N. In a more preferred embodiment of the present invention, W is C, Y is N and X is O. In an even more preferred embodiment of the invention, W is C, Y is N, X is O and Z is C.
In a preferred embodiment of the present invention, W is N.
In a particularly preferred embodiment of the present invention, W is N and Y is C. In a more preferred embodiment of the present invention, W is N, Y is C and X is O. In an even more preferred embodiment of the present invention, W is N, Y is C, X is O and Z is C.
In another particularly preferred embodiment of the present invention, W is N and Y is N. In a more preferred embodiment of the present invention, W is N, Y is N and X is O. In an even more preferred embodiment of the present invention, W is N, Y is N, X is O and Z is C.
In a preferred embodiment of the present invention, X is O.
In a preferred embodiment of the present invention, Y is C.
In a preferred embodiment of the present invention, Y is N.
In a preferred embodiment of the present invention, Z is N.
In a more preferred embodiment of the present invention, R1 is selected from —H, lower alkanyl, substituted lower alkanyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, C1-6alkoxy or substituted C1-6alkoxy. In a particularly preferred embodiment of the present invention, R1 is selected from —H, lower alkanyl, substituted lower alkanyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, C1-6 alkoxy or substituted C1-6alkoxy; R2 is —H; R3 is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl; and R4 is a 5- or 6-membered heteroarkyl. In a more preferred embodiment of the present invention, R1 is selected from:




In a more preferred embodiment of the present invention, R3 is selected from —H, C1-3alkanyl, substituted C1-3alkanyl, C1-3alkoxyl or substituted C1-3alkoxyl.
In yet another more preferred embodiment of the present invention, R1 is —H.
In yet another more preferred embodiment of the present invention, R1 is selected from C(═O)R5, SR5, SO2R5 or haloalkyl, wherein R5 is selected from C1-3alkanyl, substituted C1-3alkanyl, C1-6alkoxy, substituted C1-6alkoxy or NR6R7. In a particularly preferred embodiment of the present invention, R1 is selected from C(═O)R5, SR5, SO2R5 or haloalkyl; R5 is selected from C1-3alkanyl, substituted C1-3alkanyl, C1-6alkoxy, substituted C1-6alkoxy or, wherein R6 and R7 are indepented selected from —H, lower alkanyl, substituted lower alkanyl, or R6 and R7 can join together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring; R2 is —H; R3 is selected from cycloalkanyl, substituted cycloalkanyl, heterocycloalkyl, substituted heterocycloalkyl; and R4 is a 5- or 6-membered heteroaryl. In a more preferred embodiment of the present invention, R3 is selected from:




In an even more preferred embodiment of the present invention, R1 is C(═O)R5, and R5 is NR6R7, wherein R6 and R7 are independently selected from —H, lower alkanyl, substituted lower alkanyl, or R6 and R7 can join together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring. In another even more preferred embodiment of the invention, R1 is C(═O)R5, and R5 is C1-3alkanyl.
In another more preferred embodiment of the present invention, R1 is selected from C(═O)R5, SR5, SO2R5 or haloalkyl, wherein R5 is selected from C1-3alkanyl, substituted C1-3alkanyl, C1-6alkoxy, substituted C1-6alkoxy or NR6R7, and R6 and R7 are independently selected from —H, C1-4alkanyl or substituted C1-4alkanyl.
In yet another even more preferred embodiment of the present invention, R1 is selected from C(═O)R5, SR5, SO2R5 or haloalkyl, wherein R5 is selected from C1-3alkanyl, substituted C1-3alkanyl, C1-6alkoxy, substituted C1-6alkoxy or NR6R7, and R6 and R7 can join together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring. Preferably, the 3 to 6 membered ring or substituted 3 to 6 membered ring is a hetero ring which contains heteroatoms selected from O or S.
In a more preferred embodiment of the present invention, R2 is —H.
In a more preferred embodiment of the present invention, R2 is selected from lower alkanyl or substituted lower alkanyl.
In a more preferred embodiment of the present invention, R2 is haloalkyl, with more preferably halomethyl, haloethyl or halopropyl.
In a more preferred embodiment of the present invention, R3 is selected from substituted lower alkanyl, lower alkenyl, substituted lower alkenyl, lower alkynyl or substituted lower alkynyl. With preferably, R3 is selected from substituted C1-3alkanyl, C2-4alkenyl, or substituted C2-4alkenyl.
In a more preferred embodiment of the invention, R3 is selected from cycloalkanyl, substituted cycloalkanyl, heterocycloalkyl or substituted heterocycloalkyl.
In a more preferred embodiment of the present invention, R3 is selected from:




In another more preferred embodiment of the present invention, R4 is a 5- or 6-membered heteroaryl.
Most preferably, the compound of the present invention is selected from:

    1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(pyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    N-ethyl-6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinamide;
    1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(5-phenylpyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinonitrile;
    6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinic acid;
    ethyl 6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinate;
    1-(5-(5-methylpyridin-2-ylamino)-2-(6-(methylsulfonyl)pyridin-3-yloxy)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(pyrazin-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(5-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(6-(methylsulfonyl)pyridin-3-yloxy)benzyl)pyrrolidin-2-one;
    1-(5-(1H-imidazol-4-ylamino)-2-(6-(methylsulfonyl)pyridin-3-yloxy)benzyl)pyrrolidin-2-one;
    1-(5-(5-methoxypyridin-2-ylamino)-2-(6-(methylsulfonyl)pyridin-3-yloxy)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(5-methylthiazol-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(pyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    N-ethyl-6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinamide;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(5-phenylpyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinonitrile;
    6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinic acid;
    ethyl 6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinate;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(5-methylpyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(pyrazin-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(3-methyl-1,2,4-thiadiazol-5-ylamino)benzyl)pyrrolidin-2-one;
    1-(5-(1H-imidazol-4-ylamino)-2-(6-(methoxymethyl)pyridin-3-yloxy)benzyl)pyrrolidin-2-one;
    1-(2-(6-(methoxymethyl)pyridin-3-yloxy)-5-(5-methylthiazol-2-ylamino)benzyl)pyrrolidin-2-one;
    1-(2-(6-(morpholinosulfonyl)pyridin-3-yloxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    N-ethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(5-(trifluoromethoxy)pyridin-2-ylamino)phenoxy)picolinamide;
    1-(2-(5-chloro-6-methylpyridin-3-yloxy)-5-(5-chloropyridin-2-ylamino)benzyl)pyrrolidin-2-one;
    ethyl 6-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)phenylamino)nicotinate;
    3-(2-(4-(methylsulfonyl)phenoxy)-5-(5-methylthiazol-2-ylamino)benzyl)cyclopentanone;
    3-(2-(4-(methylsulfonyl)phenoxy)-5-(pyrazin-2-ylamino)benzyl)cyclopentanone;
    3-(5-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(4-(methylsulfonyl)phenoxy)benzyl)cyclopentan one;
    3-(5-(1H-imidazol-4-ylamino)-2-(4-(methylsulfonyl)phenoxy)benzyl)cyclopentanone;
    3-(2-(4-(methylsulfonyl)phenoxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)cyclopentanone;
    N-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-yl)pyridin-2-amine;
    N-ethyl-6-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino) nicotinamide;
    N-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-yl)-5-phenylpyridin-2-amine;
    N-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-yl)-5-(trifluoromethyl)pyridin-2-amine;
    6-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)nicotinonitrile;
    6-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)nicotinic acid;
    ethyl 6-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)nicotinate;
    N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-amine;
    N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)pyrazin-2-amine;
    3-methyl-N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1,2,4-thiadiazol-5-amine;
    N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1H-imidazol-4-amine;
    5-methyl-N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)thiazol-2-amine;
    ethyl 6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(methylsulfonyl)phenoxy)phenylamino)nicotinate;
    1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)pyrrolidin-1-yl)ethanone;
    1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(pyrazin-2-ylamino)benzyl)pyrrolidin-1-yl)ethanone;
    1-(2-(5-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(4-(methylsulfonyl)phenoxy)benzyl)pyrrolidin-1-yl)ethanone; 1-(2-(5-(1H-imidazol-4-ylamino)-2-(4-(methylsulfonyl)phenoxy)benzyl)pyrrolidin-1-yl)ethanone;
    1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(5-methylthiazol-2-ylamino)benzyl)pyrrolidin-1-yl)ethanone;
    4-(4-(methylsulfonyl)phenoxy)-N1-(pyridin-2-yl)-N3-(tetrahydro-2H-pyran-4-yl)benzene-1,3-diamine;
    4-(4-(methylsulfonyl)phenoxy)-N3-(tetrahydro-2H-pyran-4-yl)-N1-(5-(trifluoromethyl)pyridin-2-yl)benzene-1,3-diamine;
    4-(4-(methylsulfonyl)phenoxy)-N1-(pyrimidin-4-yl)-N3-(tetrahydro-2H-pyran-4-yl)benzene-1,3-diamine;
    3-methyl-N-(4-(4-(methylsulfonyl)phenylthio)-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,2,4-thiadiazol-5-amine;
    N-(4-(4-(methylsulfonyl)phenylthio)-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-imidazol-4-amine;
    5-methyl-N-(4-(4-(methylsulfonyl)phenylthio)-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)thiazol-2-amine;
    ethyl 6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((3-oxocyclopentyl)methyl)phenylamino)nicotinate;
    N,N-dimethyl-4-(4-(5-methylthiazol-2-ylamino)-2-((3-oxocyclopentyl)methyl)phenoxy)benzamide;
    N,N-dimethyl-4-(2-((3-oxocyclopentyl)methyl)-4-(pyrazin-2-ylamino)phenoxy)benzamide;
    N,N-dimethyl-4-(4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(3-oxocyclopentyl)methyl)phenoxy)benzamide;
    4-(4-(1H-imidazol-4-ylamino)-2-(3-oxocyclopentyl)methyl)phenoxy)-N,N-dimethylbenzamide;
    N,N-dimethyl-4-(2-((3-oxocyclopentyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)benzamide;
    N,N-dimethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(pyridin-2-ylamino)phenoxy)picolinamide;
    5-(4-(5-(ethylcarbamoyl)pyridin-2-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)-N,N-dimethylpicolinamide;
    N,N-dimethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(5-phenylpyridin-2-ylamino)phenoxy)picolinamide;
    N,N-dimethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)picolinamide;
    5-(4-(5-cyanopyridin-2-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)-N,N-dimethylpicolinamide;
    6-(4-(6-(dimethylcarbamoyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinic acid;
    ethyl 6-(4-(6-(dimethylcarbamoyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)nicotinate;
    N,N-dimethyl-5-(4-(5-methylpyridin-2-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)picolinamide;
    N,N-dimethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(pyrazin-2-ylamino)phenoxy)picolinamide;
    N,N-dimethyl-5-(4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)picolinamide;
    5-(4-(1H-imidazol-4-ylamino)-2-(2-oxopyrrolidin-1-yl)methyl)phenoxy)-N,N-dimethylpicolinamide;
    N,N-dimethyl-5-(4-(5-methylthiazol-2-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)picolinamide;
    2-(6-(4-(6-(dimethylcarbamoyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)acetic acid;
    3-(6-(4-(6-(dimethylcarbamoyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)propanoic acid;
    5-(4-(5-methoxypyridin-2-ylamino)-2-((2-oxopyrrolidin-1-yl)methyl)phenoxy)-N,N-dimethylpicolinamide;
    N,N-dimethyl-4-(5-(pyridin-2-ylamino)-3-((tetrahydrofuran-3-yl)methyl)pyridin-2-yloxy)benzamide;
    6-(6-(4-(dimethylcarbamoyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)-N-ethylnicotinamide;
    N,N-dimethyl-4-(5-(5-phenylpyridin-2-ylamino)-3-((tetrahydrofuran-3-yl)methyl)pyridin-2-yl oxy)benzamide;
    N,N-dimethyl-4-(3-((tetrahydrofuran-3-yl)methyl)-5-(5-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yloxy)benzamide;
    4-(5-(5-cyanopyridin-2-ylamino)-3-((tetrahydrofuran-3-yl)methyl)pyridin-2-yloxy)-N,N-dimethylbenzamide;
    6-(6-(4-(dimethylcarbamoyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)nicotinic acid;
    6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)nicotinic acid;
    N,N-dimethyl-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)benzamide;
    N,N-dimethyl-4-(4-(pyrazin-2-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)benzamide;
    N,N-dimethyl-4-(4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)benzamide;
    4-(4-(1H-imidazol-4-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)-N,N-dimethylbenzamide;
    N,N-dimethyl-4-(4-(5-methylthiazol-2-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)benzamide;
    6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbamoyl)phenoxy)phenylamino)nicotinic acid;
    4-(2-((1-acetylpyrrolidin-2-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)-N,N-dimethylbenzamide;
    4-(2-((1-acetylpyrrolidin-2-yl)methyl)-4-(pyrazin-2-ylamino)phenoxy)-N,N-dimethylbenzamide;
    2-(6-(6-(4-(dimethylcarbamoyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)pyridin-3-yl)acetic acid;
    3-(6-(6-(4-(dimethylcarbamoyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-ylamino)pyridin-3-yl)propanoic acid;
    2-(6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)pyridin-3-yl)acetic acid;
    3-(6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)pyridin-3-yl)propanoic acid;
    2-(6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbamoyl)phenoxy)phenylamino)pyridin-3-yl)acetic acid;
    3-(6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbamoyl)phenoxy)phenylamino)pyridin-3-yl)propanoic acid;
    2-(6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)acetic acid;
    3-(6-(4-(6-(methylsulfonyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)propanoic acid;
    2-(6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)acetic acid; or
    3-(6-(4-(6-(methoxymethyl)pyridin-3-yloxy)-3-((2-oxopyrrolidin-1-yl)methyl)phenylamino)pyridin-3-yl)propanoic acid.


We found any one of compound of the present invention has a glucokinase activation EC50 value of 50 μM or less in the presence of 5 mM glucose. With particularly, the compounds of the present invention has a glucokinase activation EC50 value of 5 μM or less in the presence of 5 mM glucose.
The present invention also provides a method of modulating glucokinase levels or activities in animals or humans by administering to the subject at least one compound of Formula (I).
The present invention further provides a method for treating and/or preventing type II diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of Formula (I). The present invention further provides a method for treating and/or preventing type I diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of Formula (I).
The present invention further provides a method for treating and/or preventing obesity or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of Formula (I).
The present invention also provides the use of the compound of Formula (I) of the present invention in manufacturing a medicament. Particularly, the present invention provides the use of the compounds of Formula (I) in manufacturing a medicament for modulating glucokinase levels or activities in animals or humans.
The present invention further provides the use of the compound of Formula (I) in manufacturing a medicament for the treatment and/or prevention of type II diabetes or related disease thereof.
The present invention further provides the use of the compound in manufacturing a medicament for the treatment and/or prevention of type I diabetes or related disease thereof.
The present invention further provides the use of the compound in manufacturing a medicament for the treatment and/or prevention of obesity or related disease thereof. The present invention also further provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of compounds of Formula (I), and at least one pharmaceutically acceptable excipient, adjuvant or carrier.
The present invention further provides the use of the pharmaceutical composition in manufacturing a medicament. Particularly, the present invention further provides the use of the pharmaceutical composition in manufacturing a medicament for modulating glucokinase levels or activities in animals or humans.
The present invention further provides the use of the pharmaceutical composition in manufacturing a medicament for the treatment or prevention of type II diabetes and/or related disease thereof.
The present invention further provides the use of the pharmaceutical composition in manufacturing a medicament for the treatment or prevention of type I diabetes and/or related disease thereof.
The present invention further provides the use of the pharmaceutical composition in manufacturing a medicament for the treatment and/or prevention of obesity or related disease thereof.
In addition, the present invention also further provides a method of modulating glucokinase levels or activities in animals or humans by administering to the subject a therapeutically effective amount of the pharmaceutical composition of the present invention.
The present invention also provides a method for the treatment and/or prevention of type II diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the pharmaceutical composition of the present invention.
The invention also provides a method for the treatment and/or prevention of type I diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the pharmaceutical composition of the present invention.
The present invention also provides a method for the treatment and/or prevention of obesity or related disease thereof, by administering to the subject a therapeutically effective amount of the pharmaceutical composition of the present invention.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the glucose levels in some examples.



DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following underlined terms are intended to have the following meanings:
“Cm-n” (where m and n are integers) refers to a radical inclusively containing from m number of carbon atoms to n number of carbon atoms. For example, C1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
“n membered” or “n-membered” (where n are integers) refers to the atom numbers in a ring. For example, pyridyl is a 6-membered aryl.
The term “alkyl” refers to a saturated or unsaturated, branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Where a specific level of saturation is intended, the nomenclature “alkanyl”, “alkenyl” or “alkynyl” is used. Typical alkyl groups include, but are not limited to, methyl, ethyl, ethenyl, ethynyl, propyls such as propan-1-yl, and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises from 1 to 20 carbon atoms. As used herein the term “lower alkyl” refers to an alkyl group comprising from 1 to 6 carbon atoms. Typical lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, s-butyl, pentyl, neopentyl or hexyl.
“Alkoxy” refers to —OR in which R is an alkyl. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butyloxy, cyclohexyloxy and the like. As used herein the term “lower alkoxy” refers to an alkoxy group comprising from 1 to 6 carbon atoms.
“Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O, and S. In certain embodiments, an aryl group can comprise from 6 to 10 carbon atoms.
“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and polycyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring. Particularly preferred heteroaryl groups are C3-C10 heteroaryl, include but are not limited to, pyrrolyl, furanyl, thienyl, pyridinyl, pyranyl, pyrazolyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, indolyl, benzofuranyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.
But, in any case, the heteroaryl and the aryl do not cross or include each other. Thereby, according to as defined above, if one or more full carbon aromatic ring fused with a heteroaryl is a heteroaryl, but not an aryl.
“Cycloalkyl” refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl”, “cycloalkenyl” or “cycloalkynyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene, and the like. In certain embodiments, the cycloalkyl group can be C3-10 cycloalkyl, such as, for example, C3-6 cycloalkyl.
“Heterocycloalkyl” refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom and its associated hydrogen atoms, where appropriate. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, and Si. Where a specific level of saturation is intended, the nomenclature “heterocycloalkanyl” or “heterocycloalkenyl” is used. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran and the like. Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (═O) or oxide (—O—) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
But, in any case, the heterocycloalkyl and the cycloalkyl do not cross or include each other. Thereby, according to as defined above, if one or more full carbon hydrocarbon ring fused with a hererocycloalkyl to form a bi- or multi- or spiro-cyclic ring, is still defined as a hererocycloalkyl.
“Halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.
“Halo” refers to a fluoro, chloro, bromo, or iodo group.
“Substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, X, C3-20 cycloalkyl, —OR13, SR13, ═O, ═S, —C(O)R13, —C(S)R13, —C(O)OR13, —C(S)OR13, —NR13R14, —C(O)NR13R14, cyano, nitro, —S(O)2R13, —OS(O2)OR13, —OS(O)2R13, —OP(O)(OR13)(OR14); wherein each X is independently a halogen (F, Cl, Br or I), and R13 and R14 is independently selected from —H, lower alkyl, lower haloalkyl. In some embodiments, the substituent(s) is independently selected from the group consisting of —F, —Cl, —Br, —I, —OH, trifluoromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, —SCH3, —SC2H5, formaldehyde group, —C(OCH3), cyano, nitro, CF3, —OCF3, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent(s) is —F, —Cl or —Br.
As used herein, the “compound” of the present invention includes the compounds of Formula (I), and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms of the compounds include salts, solvates, non-covalent complexes, chelates, or produgs thereof, or the mixture of any form mentioned above.
As used herein, “pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.
“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.
The present invention provides compounds regulating the glucokinase level or activity in animal(s) or a human, and using these compounds to manufacture medicaments for the treatment and/or prevention of diseases associated with glucokinase level or activity. These compounds are characteristic of relatively simple structures, convenient preparation and outstanding therapeutic effect. As a potential drug with low cost and convenient administration, it can be more widely applied, be more of help to patients for treating diseases and improving life quality.
EXAMPLES
The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds of Formula (I) of the present invention.
The following examples are only used to disclose the preferred embodiments of the present invention, to help technicians in the art understand well, but are not used to limit the spirit and scope of the present invention. In the examples of the present invention, the approach or methods or the like is conventional in the art without specification. The compounds of the present invention can be prepared through, but not limited to, one or more of the following general reaction scheme:








Example 1
Synthesis of 1-(2-(6-(methylsulfonyl)pyridin-3-yloxy)-5-(pyridin-2-ylamino)benzyl)pyrrolidin-2-one




Under nitrogen gas, 20 g (144 mmol, 1 eq.) of p-nitrophenol was added into a 500 mL reaction flask, and dissolved in 200 mL of carbon disulfide, and then 20 g (144 mmol, 1 eq.) of anhydrous AlCl3 was added. The mixture was refluxed and 19.2 g (144 mmol, 1 eq.) of N-chloromethyl cyclobutyramide was slowly added in drops. After about 2 hr. till reaction was complete, the reaction mixture was poured into crushed ice, stirred and filtered. The filtrate was run through column chromatography to obtain 12.1 g of white solid 2, with a yield of 45%.
236 mg (1.0 mmol, 1 eq.) of 2 and 20 mL of DMF were added into a reaction flask, and then 71 mg of 70% of KH (1.2 mmol, 1.2 eq.) was slowly added in, and stirred for 1 hr at rt. (room temperature). 273 mg (1.2 mmol, 1.2 eq.) 5-chloro-2-methylsulfonylpyridine was then added and stirred overnight till reaction completion verified by TLC, 10 mL of 50% ethanol was slowly added into the reaction mixture to quench the reaction. The solvent was removed by vacuum distillation, and the product was purified by column chromatography, to obtain 180 mg of 3, with a yield of 50%.
400 mg (1.02 mmol, 1 eq.) of 3, 40 mL of ethanol and 70 mg of raney nickel were added into a 100 mL hydrogen addition apparatus. The mixture was stirred, and subjected to nitrogen gas replacement twice, followed by hydrogen gas replacement once with the hydrogen pressure maintained at 4 atm. The reaction mixture was maintained at 50° C. until the hydrogen gas was no longer absorbed in the system. After removing catalyst by filtration and solvent by vacuum distillation, the product was purified by a flash chromatography to obtain 221 mg of 4, with a yield of 60%.
361 mg (1.0 mmol, 1 eq.) of 4 and 20 mL of DMF were added into a reaction flask, and then 43 mg of 70% NaH (1.2 mmol, 1.2 eq.) was slowly added and stirred for 1 hr. at rt. The reaction mixture was then added 136 mg (1.2 mmol, 1.2 eq.) of 2-chloropyridine, and stirred overnight till reaction completion verified by TLC. 10 mL of water was slowly added to quench the reaction. The solvent was removed by vacuum distillation, and the product was purified by column chromatography, to obtain 180 mg of final product 5, with a yield of 40%, and a LC-MS [M+H]-m/z of 439.
Example 35
Synthesis of N-(6-(4-(methylsulfonyl)phenoxy)-5-((tetrahydrofuran-3-yl)methyl)pyridin-3-yl)pyridin-2-amine




344 mg (2.0 mmol, 1 eq.) of 3-methyl-5-nitro-2-chloro-pyridine and 20 mL of DMF were added into a reaction flask, and then 86 mg of 70% NaH (2.4 mmol, 1.2 eq.) was slowly added. The mixture was stirred and heated to the temperature of 90° C. After 1 hr of reaction, 254 mg (2.4 mmol, 1.2 eq.) of 3-chloro-tetrahydrofuran was added and stirred overnight at 90° C., till reaction completion verified by TLC. 10 mL of 50% ethanol was then slowly added to quench the reaction. The solvent was removed by vacuum distillation, and the product was purified by a flash chromatography, to obtain 158 mg of 1, with a 33% yield.
Under nitrogen gas, 1.9 g (11 mmol, 1.1 eq) of o-methylsulfonyl phenol, 2.24 g (10 mmol, 1 eq.) of 1, 2.6 g (31.5 mmol, 3 eq.) of NaHCO3 and 50 mL of ethanol were added into a reaction flask, and stirred and refluxed overnight, till reaction completion verified by TLC. The solvent was removed by vacuum distillation, and the residue was dissolved with dichloromethane, filtered to remove insoluble material(s), distilled in vacuum to remove solvent, and further purified by liquid chromatography, to obtain a 1.3 g of yellow solid 2, yielding 34%.
400 mg (1.06 mmol, 1 eq.) of 2, 40 mL of anhydrous ethanol and 70 mg of raney nickel were added into a 100 mL hydrogen addition apparatus. The mixture was stirred and subjected to nitrogen gas replacement twice, followed by hydrogen gas replacement once with the hydrogen pressure maintained at 4 atm. The reaction mixture was maintained at 50° C. until the hydrogen gas was no longer absorbed in the system. After removing catalyst by filtration and solvent by vacuum distillation, the product was purified by a flash chromatography to obtain 273 mg of 3, yielding 74%.
348 mg (1.0 mmol, 1 eq.) of 3 and 20 mL of DMF were added into a reaction flask, and then 43 mg of 70% NaH (1.2 mmol, 1.2 eq.) was slowly added, and stirred for 1 hr. at rt. The reaction mixture was then added 136 mg (1.2 mmol, 1.2 eq.) of 2-chloropyridine, and stirred overnight till reaction completion verified by TLC. 10 mL of water was slowly added to quench the reaction. The solvent was removed by vacuum distillation, and the product was purified by a flash chromatography to obtain 182 mg of 4, with a 43% yield. LC-MS [M+H]-m/z is 427.
Example 53
Synthesis of 4-(4-(methylsulfonyl)phenoxy)-N1-(pyridin-2-yl)-N3-(tetrahydro-2H-pyran-4-yl)benzene-1,3-diamine







2 g (11.6 mmol, 1.1 eq.) of 4-(methyl-sulfonyl) phenol, 2.1 g (10.5 mmol, 1 eq.) of 1-chloro-2,4-dinitrobenzene, 2.6 g (31.5 mmol, 3 eq.) of NaHCO3 and ethanol were added into a reaction flask, stirred and refluxed overnight. After the reaction was complete, the reaction mixture was filtered to remove the solvent, and washed by methylene chloride and purified by column chromatography to obtain 1.7 g of 1, with a yield of 50%.
253 mg (3.2 mmol, 1.1 eq.) of Na2S was added into the solution of 1 g (2.9 mmol, 1 eq.) of 1 in ethanol, and stirred for 4 hr at rt. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was purified by column chromatography to obtain 455 mg of 2, with a yield of 50%.
70 mg (1.76 mmol, 1.1 eq.) of NaH was added into the solution of 455 mg (1.4 mmol, 1 eq.) 2 in DMF, and stirred for 1 hr at rt. 211 mg (1.76 mmol, 1.1 eq.) of 4-chloro-2H-tetrahydropyran was then added and stirred overnight. After the reaction was complete, water was added, and then all the solvent was removed by filtration and the product was purified by column chromatography to obtain 942 mg of 3, with a yield of 60%.
151 mg (2.4 mmol, 2 eq.) of Zn and 133 mg (1.2 mmol, 1 eq.) of CaCl2 were added into the solution of 500 mg (1.2 mmol, 1 eq.) of 3 in ethanol, and then stirred for 4 hr at rt. The solvent was removed by vacuum distillation, and the product was purified by column chromatography to obtain 230 mg of 4, yield 50%.
80 mg (1.98 mmol, 1.1 eq.) of NaH was added into the solution of 200 mg (1.8 mmol, 1 eq.) 4 in DMF, and stirred for 1 hr at rt. And then, 223 mg (1.98 mmol, 1.1 eq.) of 2-chloro-2H-tetrahydropyran was added and stirred overnight. After the reaction was complete, water was added and filtered to remove solvent. The product was purified by column chromatography to obtain 100 mg of 5, with a yield of 40%. and a LC-MS [M+H]-m/z of 441.
Example 56
Synthesis of 3-methyl-N-(4-(4-(methylsulfonyl)phenylthio)-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,2,4-thiadiazol-5-amine







440 mg (12.7 mmol, 1.1 eq.) of NaH was added into the solution of 2 g (11.5 mmol, 1 eq.) 2-chloro-5-nitrophenol in DMF, and stirred for 1 hr at rt. And then, 1.5 g (12.7 mmol, 1.1 eq) of 4-chloro-2H-tetrahydropyran was added and stirred overnight. After the reaction was complete, water was added and filtered to remove solvent. The product was purified by column chromatography to obtain 1.7 g of 1, with a yield of 70%.
1 g (3.9 mmol, 1.1 eq.) of 4-(methylsulfonyl) phenol, 900 mg (10.5 mmol, 1 eq.) of 1-chloro 0.3-dinitrobenzene, 882 mg (10.5 mmol, 3 eq.) of NaHCO3 and ethanol were added into a reaction flask, stirred and refluxed overnight. After the reaction was complete, the reaction mixture was filtered to remove the solvent, and the resulted solid was washed by methylene chloride twice and purified by column chromatography to obtain 477 mg of 2, with a yield of 30%.
93 mg (1.466 mmol, 2 eq.) of Zn and 81 mg (0.733 mmol, 1 eq.) of CaCl2 were added into the solution of 300 mg (0.733 mmol, 1 eq.) of 2 in ethanol, and then stirred for 4 hr at rt. The solvent was removed by vacuum distillation, and the product was purified by column chromatography to obtain 110 mg of 3, with a yield of 40%.
12 mg (0.29 mmol, 1.1 eq.) of NaH was added into the solution of 100 mg (0.26 mmol, 1 eq.) 3 in DMF, and stirred for 1 hr at rt. And then, 267 mg (1.98 mmol, 1.1 eq.) of 3-chloro-2H-tetrahydropyran was added and stirred overnight. After the reaction was complete, water was added and filtered to remove solvent. The product was purified by column chromatography to obtain 75 mg of 4, with a yield of 60%, and LC-MS [M+H]-m/z of 479.
Example 65
Synthesis of N,N-dimethyl-5-(2-((2-oxopyrrolidin-1-yl)methyl)-4-(pyridin-2-ylamino)phenoxy)picolinamide







At 0° C., 0.59 g (70% oil dispersion) of NaH was added into 2.2 g of compound 1 in 40 mL of DMF, and stirred for 15 min. 2.45 g of 2-chloro-5-nitrobenzaldehyde was added into the mixture maintained at 0° C., and stirred for 30 min. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the obtained organic layer was washed with saline water. After dried by anhydrous sodium sulfate and filtered, the solvent was removed, and the product was purified by column chromatography to obtain 3.80 g of 2, with a yield of 91%.
At rt., 0.50 g of NaBH4 was added into the solution of 3.80 g 2 in 200 mL methanol, and stirred for 30 min.
After the solvent methanol was removed, water was added, then extracted with ethyl acetate, and the organic layer was washed with saline water. After dried by anhydrous sodium sulfate and filtered, the solvent was removed to obtain 2.64 g of 3, with a yield of 69%.
0.46 g of triethylamine was added into the solution of 0.44 g of 3 in 20 mL THF, followed by 0.23 mL of methyl sulfonyl chloride added in drops, and stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saline water, and dried by anhydrous sodium sulfate. After filtration, the solvent was removed to obtain 0.60 g of 4.
143 mg of (70% oil dispersion) of NaH was added into the solution of 620 mg pyrrolidone in 15 mL DMF, and stirred for 30 min at rt.
The mixture solution was cooled to below 0° C., and then 0.60 g of 4 was add, and stirred for 30 min at rt. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saline water. After dried by anhydrous sodium sulfate and filtered, the solvent was removed, and the product was purified by column chromatography to obtain 0.39 g of 5, with a two-step yield of 74%.
0.39 g of 5 was suspended in the solution of 0.88 g ammonium chloride in 40 mL water, and then heated to 90° C., 0.56 g of Fe powder was added and stirred for 30 min. The reaction mixture was cool down to rt., and K2CO3 was add, then extracted with ethyl acetate. After dried by anhydrous sodium sulfate and filtered, the solvent was removed, and the product was purified by column chromatography to obtain 0.28 g of 6, with a yield of 78%.
210 mg of 6,130 mg of 2-bromopyridine, 14 mg of Pd2(dba)3, 3.21 mg of BINAP, 147 mg of potassium tert-butanol and 2 mL of dioxane was mixed, and reacted overnight at 80° C. under nitrogen gas. The solvent was removed by distillation, and the product was purified by column chromatography to obtain 51 mg of final product 7, with a LC-MS[M+H]-m/z of 432, and a yield of 20%.
The following compounds listed in Table I can be prepared through similar procedures to those of the above examples:












TABLE I










LC-MS







[M + 




Molecular
Molecular

H](m/


Example
Structure
Formula
Weight
Molecular Name
z)







 2




C25H27N5O5S
510
N-ethyl-6-(4-(6-(methyl-  sulfonyl)pyridin-3-yloxy)-  3-((2-oxopyrrolidin-  1-yl)methyl)phenylamino)  nicotinamide 
511


 


 3




C28H26N4O4S
515
1-(2-(6-(methylsulfonyl)  pyridin-3-yloxy)-5-(5-  phenylpyridin-2-ylamino)  benzyl)pyrrolidin-2-  one 
516


 


 4




C23H21F3N4O4S
506
1-(2-(6-(methylsulfonyl)  pyridin-3-yloxy)-5-(5-  (trifluoromethyl)pyridin-  2-ylamino)benzyl)  pyrrolidin-2-one 
507


 


 5




C23H21N5O4S
464
6-(4-(6-(methylsulfonyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl) phenylamino)  nicotinonitrile 
465


 


 6




C23H22N4O6S
483
6-(4-(6-(methylsulfonyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl) phenylamino)  nicotinic acid 
484


 


 7




C25H26N4O6S
511
ethyl  6-(4-(6-(methylsulfonyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl)  phenylamino)  nicotinate 
512


 


 8




C23H24N4O4S
453
1-(5-(5-methylpyridin-  2-ylamino)-2-(6- (methylsulfonyl) pyridin-3-yloxy)  benzyl)pyrrolidin-  2-one 
454


 


 9




C21H21N5O4S
439
1-(2-(6-(methylsulfonyl)  pyridin-3-yloxy)-5-  (pyrazin-2-ylamino)benzyl)  pyrrolidin-2-one 
440


 


 10




C20H21N5O4S2
460
1-(5-(3-methyl-1,2,4-  thiadiazol-5-ylamino)-2-  (6-(methylsulfonyl) pyridin-3-yloxy)benzyl)  pyrrolidin-2-one 
461


 


 11




C20H21N5O4S
427
1-(5-(1H-imidazol-4-  ylamino)-2-(6-  (methylsulfonyl) pyridin-3-yloxy) benzyl)pyrrolidin-2-one  
428


 


 12




C23H24N4O5S
469
1-(5-(5-methoxypyridin-  2-ylamino)-2-(6-  (methylsulfonyl) pyridin-3- yloxy)benzyl)pyrrolidin-  2-one 
470


 


 13




C21H22N4O4S2
459
1-(2-(6-(methylsulfonyl)  pyridin-3-yloxy)-5-(5-  methylthiazol-2-ylamino) benzyl)pyrrolidin-2-  one 
460


 


 14




C23H24N4O3
404
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-  (pyridin-2-ylamino)benzyl)  pyrrolidin-2-one 
405


 


 15




C26H29N5O4
476
N-ethyl-6-(4-(6-  (methoxymethyl) pyridin-3-yloxy)-  3-((2-oxopyrrolidin- 1-yl)methyl)phenylamino)  nicotinamide 
477


 


 16




C29H28N4O3
481
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-(5-  phenylpyridin-2-ylamino)  benzyl)pyrrolidin-2-  one 
482


 


 17




C24H23F3N4O3
472
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-(5-  (trifluoromethyl)pyridin-  2-ylamino)benzyl)  pyrrolidin-2-one 
473


 


 18




C24H23N5O3
429
6-(4-(6-(methoxymethyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl) phenylamino)  nicotinonitrile 
430


 


 19




C24H24N4O5
448
6-(4-(6-(methoxymethyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl) phenylamino)  nicotinic acid 
449


 


 20




C26H28N4O5
477
ethyl  6-(4-(6-(methoxymethyl)  pyridin-3-yloxy)-3-((2-  oxopyrrolidin-1-yl)methyl)  phenylamino)  nicotinate 
478


 


 21




C24H26N4O3
418
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-(5-  methylpyridin-2-ylamino)  benzyl)pyrrolidin-2-  one 
419


 


 22




C22H23N5O3
405
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5- (pyrazin-2-ylamino)benzyl) pyrrolidin-2-one 
406


 


 23




C21H23N5O3S
426
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-(3-  methyl-1,2,4-thiadiazol- 5-ylamino)benzyl)  pyrrolidin-2-one 
427


 


 24




C21H23N5O3
393
1-(5-(1H-imidazol-4- ylamino)-2-(6-(methoxy- methyl)pyridin-3-yloxy) benzyl)pyrrolidin-2-one 
394


 


 25




C22H24N4O3S
425
1-(2-(6-(methoxymethyl)  pyridin-3-yloxy)-5-(5-  methylthiazol-2-ylamino) benzyl)pyrrolidin-2-  one 
426


 


 26




C26H26F3N5O5S
425
1-(2-(6- (morpholinosulfonyl)  pyridin-3-yloxy)-  5-(5-(trifluoromethyl)  pyridin-2-ylamino)benzyl)  pyrrolidin-2-one 
426


 


 27




C25H24F3N5O4 
515
N-ethyl-5-(2-((2- oxopyrrolidin-  1-yl)methyl)-4-  (5-(trifluoromethoxy)  pyridin-2-ylamino)  phenoxy)picolinamide 
516


 


 28




C22H20Cl2N4O2
443
1-(2-(5-chloro-6- methylpyridin-  3-yloxy)-5-(5-  chloropyridin-2-ylamino) benzyl)pyrrolidin-2-  one 
444


 


 29




C27H28N2O6S
509
ethyl  6-(4-(4-(methylsulfonyl)  phenoxy)-3-((3- oxocyclopentyl) methyl)  phenylamino)nicotinate 
510


 


 30




C23H24N2O4S2
457
3-(2-(4-(methylsulfonyl)  phenoxy)-5-(5- methylthiazol- 2-ylamino)benzyl)  cyclopentanone 
458


 


 31




C23H23N3O4S
438
3-(2-(4-(methylsulfonyl)  phenoxy)-5-(pyrazin-2-  ylamino)benzyl)  cyclopentanone 
439


 


 32




C22H23N3O4S2
458
3-(5-(3-methyl-1,2,4-  thiadiazol-5-ylamino)-2-  (4-(methylsulfonyl)  phenoxy)benzyl)  cyclopentanone 
459


 


 33




C22H23N3O4S
426
3-(5-(1H-imidazol-4-yl  amino)-2-(4- (methylsulfonyl) phenoxy)benzyl)  cyclopentanone 
427


 


 34




C25H23F3N2O4S
505
3-(2-(4-(methylsulfonyl)  phenoxy)-5-(5-  (trifluoromethyl) pyridin-2-ylamino) benzyl)  cyclopentanone 
506


 


 36




C25H28N4O5S
497
N-ethyl-6-(6-(4- (methylsulfonyl)  phenoxy)-5- ((tetrahydrofuran-3-yl) methyl)pyridin-3-ylamino)  nicotinamide 
498


 


 37




C28H27N3O4S
502
N-(6-(4-(methylsulfonyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl)pyridin- 3-yl)-5-  phenylpyridin-2-amine 
503


 


 38




C23H22F3N3O4S
493
N-(6-(4-(methylsulfonyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl)pyridin-  3-yl)-5-  (trifluoromethyl) pyridin-2-amine  
494


 


 39




C23H22N4O4S
451
6-(6-(4-(methylsulfonyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl)pyridin- 3-ylamino)  nicotinonitrile 
452


 


 40




C23H23N3O6S
407
6-(6-(4-(methylsulfonyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl)pyridin-  3-ylamino)  nicotinic acid 
471


 


 41




C27H30N2O6S
511
ethyl  6-(4-(4-(methylsulfonyl)  phenoxy)-3-((tetrahydro- 2H-pyran-4-yl)methyl)  phenylamino)  nicotinate 
512


 


 42




C25H25F3N2O4S
507
N-(4-(4-(methylsulfonyl)  phenoxy)-3-((tetrahydro-  2H-pyran-4-yl)methyl)  phenyl)-5-  (trifluoromethyl) pyridin-2-amine  
508


 


 43




C23H25N3O4S
440
N-(4-(4-(methylsulfonyl)  phenoxy)-3-((tetrahydro-  2H-pyran-4-yl)methyl) phenyl)pyrazin-2-amine  
441


 


 44




C22H25N3O4S2
460
3-methyl-N-(4-(4-  (methylsulfonyl) phenoxy)-3-  ((tetrahydro-2H-pyran- 4-yl)methyl)phenyl)-1,2,4-  thiadiazol-5-amine 
461


 


 45




C22H25N3O4S
428
N-(4-(4-(methylsulfonyl)  phenoxy)-3-((tetrahydro-  2H-pyran-4-yl)methyl) phenyl)-1H-imidazol-  4-amine 
429


 


 46




C23H26N2O4S2
459
5-methyl-N-(4-(4-  (methylsulfonyl) phenoxy)-3-  ((tetrahydro-2H-pyran- 4-yl)methyl)phenyl)  thiazol-2-amine 
460


 


 47




C28H31N3O6S
538
ethyl  6-(3-((1-acetylpyrrolidin-  2-yl)methyl)-4-(4- (methylsulfonyl)phenoxy)  phenylamino)nicotinate 
539


 


 48




C26H26F3N3O4S
534
1-(2-(2-(4-(methylsulfonyl)  phenoxy)-5-(5-  (trifluoromethyl) pyridin-2-  ylamino)benzyl)pyrrolidin-  1-yl)ethanone 
535


 


 49




C24H26N4O4S
467
1-(2-(2-(4-(methylsulfonyl)  phenoxy)-5-(pyrazin-  2-ylamino)benzyl)  pyrrolidin-1-yl)ethanone 
468


 


 50




C23H26N4O4S2
487
1-(2-(5-(3-methyl-1,2,4-  thiadiazol-5-ylamino)-  2-(4-(methylsulfonyl) phenoxy)benzyl)pyrrolidin-  1-yl)ethanone 
488


 


 51




C23H26N4O4S 
455
1-(2-(5-(1H-imidazol-4-  ylamino)-2-(4-  (methylsulfonyl) phenoxy)benzyl) pyrrolidin-1-yl)ethanone  
456


 


 52




C24H27N3O4S2
486
1-(2-(2-(4-(methylsulfonyl)  phenoxy)-5-(5-  methylthiazol- 2-ylamino)benzyl) pyrrolidin-1-yl)  ethanone 
487


 


 54




C24H24F3N3O4S
508
4-(4-(methylsulfonyl)  phenoxy)-N3-(tetrahydro-  2H-pyran-4-yl)-N1- (5-(trifluoromethyl)pyridin-  2-yl)benzene-1,3-  diamine 
509


 


 55




C22H24N4O4S
441
4-(4-(methylsulfonyl)  phenoxy)-N1-(pyrimidin-  4-yl)-N3-(tetrahydro-2  H-pyran-4-yl)benzene-  1,3-diamine 
442


 


 57




C21H23N3O4S2
446
N-(4-(4-(methylsulfonyl)  phenylthio)-3-(tetrahydro-  2H-pyran-4-yloxy) phenyl)-1H-imidazol-4-  amine 
447


 


 58




C22H24N2O4S3
477
5-methyl-N-(4-(4-  (methylsulfonyl) phenylthio)-  3-(tetrahydro-2H-pyran-  4-yloxy)phenyl)thiazol-  2-amine 
478


 


 59




C29H31N3O5
502
ethyl  6-(4-(4- (dimethylcarbamoyl)  phenoxy)-3-((3- oxocyclopentyl)methyl)  phenylamino)nicotinate 
503


 


 60




C25H27N3O3S
450
N,N-dimethyl-4-(4-(5-  methylthiazol-2-ylamino)-  2-((3-oxocyclopentyl) methyl)phenoxy)  benzamide 
451


 


 61




C25H26N4O3
430
N,N-dimethyl-4-(2-((3-  oxocyclopentyl)methyl)-  4-(pyrazin-2-ylamino)  phenoxy)benzamide 
431


 


 62




C24H26N4O3S
451
N,N-dimethyl-4-(4-(3-  methyl-1,2,4-thiadiazol-  5-ylamino)-2-((3- oxocyclopentyl) methyl)  phenoxy)benzamide 
452


 


 63




C24H26N4O3
418
4-(4-(1H-imidazol-4- ylamino)-2-((3-  oxocyclopentyl) methyl)phenoxy)- N,N-dimethylbenzamide  
419


 


 64




C27H26F3N3O3
498
N,N-dimethyl-4-(2-((3-  oxocyclopentyl)methyl)-  4-(5-(trifluoromethyl) pyridin-2-ylamino)  phenoxy)benzamide 
499


 


 66




C27H30N6O4
503
5-(4-(5-(ethylcarbamoyl) pyridin-2-ylamino)-2- ((2-oxopyrrolidin-1-yl) methyl)phenoxy)-N,N- dimethylpicolinamide
504


 


 67




C30H29N5O3
508
N,N-dimethyl-5-(2-((2-  oxopyrrolidin-1-yl) methyl)-  4-(5-phenylpyridin-  2-ylamino)phenoxy)  picolinamide 
509


 


 68




C25H24F3N5O3
499
N,N-dimethyl-5-(2-((2-  oxopyrrolidin-1-yl) methyl)-  4-(5-(trifluoromethyl) pyridin-2-ylamino)  phenoxy)picolinamide 
500


 


 69




C25H24N6O3
456
5-(4-(5-cyanopyridin-2-  ylamino)-2-((2- oxopyrrolidin-  1-yl)methyl)phenoxy)- N,N-  dimethylpicolinamide 
457


 


 70




C25H25N5O5
475
6-(4-(6- (dimethylcarbamoyl)  pyridin-3-yloxy)-  3-((2-oxopyrrolidin-1- yl)methyl)phenylamino)  nicotinic acid 
476


 


 71




C27H29N5O5
504
ethyl  6-(4-(6- (dimethylcarbamoyl)  pyridin-3-yloxy)-  3-((2-oxopyrrolidin-1-  yl)methyl)phenylamino)  nicotinate 
505


 


 72




C25H27N5O3
446
N,N-dimethyl-5-(4-(5-  methylpyridin-2-ylamino)-  2-((2-oxopyrrolidin- 1-yl)methyl)phenoxy)  picolinamide 
447


 


 73




C23H24N6O3
432
N,N-dimethyl-5-(2-((2-  oxopyrrolidin-1-yl)methyl)-  4-(pyrazin-2-ylamino)  phenoxy)picolinamide  
433


 


 74




C22H24N6O3S
453
N,N-dimethyl-5-(4-(3-  methyl-1,2,4-thiadiazol-  5-ylamino)-2-((2- oxopyrrolidin- 1-yl)methyl)  phenoxy)picolinamide 
454


 


 75




C22H24N6O3
420
5-(4-(1H-imidazol-4-  ylamino)-2-((2- oxopyrrolidin-  1-yl)methyl)phenoxy)-  N,N-  dimethylpicolinamide 
421


 


 76




C23H25N5O3S
452
N,N-dimethyl-5-(4-(5-  methylthiazol-2-ylamino)-  2-((2-oxopyrrolidin-  1-yl)methyl)phenoxy)  picolinamide 
453


 


 77




C26H27N5O5
490
2-(6-(4-(6-  (dimethylcarbamoyl) pyridin-3-yloxy)-  3-((2-oxopyrrolidin-  1-yl)methyl)phenylamino)  pyridin-3-yl)acetic  acid 
491


 


 78




C27H29N5O5
504
3-(6-(4-(6- (dimethylcarbamoyl)  pyridin-3-yloxy)-  3-((2-oxopyrrolidin-  1-yl)methyl)phenylamino)  pyridin-3-yl)  propanoic acid 
505


 


 79




C25H27N5O4
462
5-(4-(5-methoxypyridin-  2-ylamino)-2-((2-  oxopyrrolidin- 1-yl)methyl)phenoxy)-  N,N-  dimethylpicolinamide 
463


 


 80




C24H26N4O3
418
N,N-dimethyl-4-(5- (pyridin-  2-ylamino)-3- ((tetrahydrofuran-  3-yl)methyl) pyridin-2-yloxy)  benzamide 
419


 


 81




C27H31N5O4
490
6-(6-(4- (dimethylcarbamoyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl) pyridin-3-ylamino)-  N-ethylnicotinamide 
491


 


 82




C30H30N4O3
495
N,N-dimethyl-4-(5-(5-  phenylpyridin-2-ylamino)-  3-((tetrahydrofuran-3-  yl)methyl)pyridin-2-  yloxy)benzamide 
496


 


 83




C25H25F3N4O3
486
N,N-dimethyl-4-(3-  ((tetrahydrofuran-3-yl)  methyl)-5-(5- (trifluoromethyl) pyridin-2-ylamino)  pyridin-2-yloxy)  benzamide 
487


 


 84




C25H25N5O3
443
4-(5-(5-cyanopyridin-2-  ylamino)-3- ((tetrahydrofuran-  3-yl)methyl)pyridin-  2-yloxy)-N,N-  dimethylbenzamide 
444


 


 85




C25H26N4O5 
462
6-(6-(4- (dimethylcarbamoyl)  phenoxy)-5- ((tetrahydrofuran-  3-yl)methyl)  pyridin-3-ylamino)  nicotinic acid 
463


 


 86




C27H29N3O5
476
6-(4-(4- (dimethylcarbamoyl)  phenoxy)-3-((tetrahydro-  2H-pyran-4-yl) methyl)phenylamino)  nicotinic acid 
477


 


 87




C27H28F3N3O3
500
N,N-dimethyl-4-(2- ((tetrahydro-2H-pyran-4-yl) methyl)-4-(5- (trifluoromethyl) pyridin-2- ylamino) phenoxy)benzamide
501


 


 88




C25H28N4O3
433
N,N-dimethyl-4-(4- (pyrazin-  2-ylamino)-2-((tetrahydro-  2H-pyran-4-yl)  methyl)phenoxy)  benzamide 
434


 


 89




C24H28N4O3S
453
N,N-dimethyl-4-(4-(3-  methyl-1,2,4-thiadiazol-  5-ylamino)-2-((tetrahydro- 2H-pyran-4-yl)methyl)  phenoxy)benzamide  
454


 


 90




C24H28N4O3
421
4-(4-(1H-imidazol-4-yl  amino)-2-((tetrahydro-  2H-pyran-4-yl)methyl)  phenoxy)-N,N-  dimethylbenzamide 
422


 


 91




C25H29N3O3S
452
N,N-dimethyl-4-(4-(5-  methylthiazol-2-ylamino)-  2-((tetrahydro-2H- pyran-4-yl)methyl)  phenoxy)benzamide 
453


 


 92




C28H30N4O5
503
6-(3-((1-acetylpyrrolidin-  2-yl)methyl)-4-(4-  (dimethylcarbamoyl) phenoxy) phenylamino)  nicotinic acid 
504


 


 93




C28H29F3N4O3
527
4-(2-((1-acetylpyrrolidin-  2-yl)methyl)-4-(5-  (trifluoromethyl)pyridin-2-  ylamino)phenoxy)-N,N-  dimethylbenzamide 
528


 


 94




C26H29N5O3
460
4-(2-((1-acetylpyrrolidin-  2-yl)methyl)-4-(pyrazin-  2-ylamino)phenoxy)-  N,N-dimethylbenzamide  
461


 


 95




C26H28N4O5
477
2-(6-(6-(4- (dimethylcarbamoyl)  phenoxy)-5-  ((tetrahydrofuran-3-yl) methyl)pyridin-3-ylamino)  pyridin-3-yl)acetic acid 
478


 


 96




C27H30N4O5
491
3-(6-(6-(4- (dimethylcarbamoyl)  phenoxy)-5-  ((tetrahydrofuran-3-yl) methyl)pyridin-3-ylamino)  pyridin-3-yl)propanoic  acid 
492


 


 97




C28H31N3O5
490
2-(6-(4-(4- (dimethylcarbamoyl)  phenoxy)-3- ((tetrahydro-2H-pyran-4- yl)methyl)phenylamino)  pyridin-3-yl)acetic  acid 
491


 


 98




C29H33N3O5
504
3-(6-(4-(4- (dimethylcarbamoyl)  phenoxy)-3-  ((tetrahydro-2H-pyran-4-  yl)methyl)phenylamino)  pyridin-3-yl)propanoic  acid 
505


 


 99




C29H32N4O5
517
2-(6-(3-((1- acetylpyrrolidin-  2-yl)methyl)-4-(4-  (dimethylcarbamoyl) phenoxy)phenylamino)  pyridin-3-yl)acetic acid 
518


 


100




C30H34N4O5
531
3-(6-(3-((1- acetylpyrrolidin-  2-yl)methyl)-4-(4-  (dimethylcarbamoyl) phenoxy)phenylamino)  pyridin-3-yl)propanoic  acid 
532


 


101




C24H24N4O6S
497
2-(6-(4-(6-(methylsulfonyl)  pyridin-3-yloxy)-3-  ((2-oxopyrrolidin-1-yl) methyl)phenylamino)  pyridin-3-yl)acetic acid 
498


 


102




C25H26N4O6S
497
3-(6-(4-(6-(methylsulfonyl)  pyridin-3-yloxy)-3-  ((2-oxopyrrolidin-1-yl) methyl)phenylamino)  pyridin-3-yl)propanoic  acid 
498


 


103




C25H26N4O5
462
2-(6-(4-(6- (methoxymethyl)  pyridin-3-yloxy)-3-  ((2-oxopyrrolidin-1-yl) methyl)phenylamino)  pyridin-3-yl)acetic acid 
463


 


104




C26H28N4O5
477
3-(6-(4-(6- (methoxymethyl)  pyridin-3-yloxy)-3-  ((2-oxopyrrolidin-1-yl) methyl)phenylamino)  pyridin-3-yl)propanoic  acid 
478









Example A
Glucokinase Activation Assay
The final assay volume was 200 uL and the final buffer conditions used in this assay were as follows: 25 mM HEPES, 5 mM glucose, 1 mM ATP, 2 mM MgCl2, 1 mM NAD, 1 mM DTT, 8.5 U/mL G6PDH, 100 nM glucokinase, and 25 mM KCl. The buffer pH was 7.1. The mixture A was first made containing KCl, MgCl2, DTT and Glucose in HEPES buffer. The mixture B was made containing NAD and ATP. The test compound in DMSO solution, the mixture A, the mixture B and G6PDH were first mixed in a 96-well plate. Glucokinase was then added to initiate the reaction, and the absorbance at 340 nm was monitored every 5 mins. The activity of glucokinase was represented by the initial generation rate of glucose-6-phosphate, which was calculated by drawing the slope values from the absorbance changing curve at 340 nm vs. the time points. Compounds of this invention have an EC50 value as measured using the assay described herein of less than 50 μM. Compounds preferably have an EC50 in the range of 10 nM to 10 μM, more preferably in the range of 10 nM to 1 μM, The activity test results of some examples of the present invention are shown in Table II.










TABLE II








EC50, Glucokinase



Example
Activation (μM)



















Example 6
2



Example 13
2



Example 65
5



Example 78
1.5










Example B
Glucose Tolerance Test
Mice were grouped based on fasting glucose levels, and then was orally given 30 mg/kg of test compounds. After 1 hr., the blood glucose levels were measured, and then a glucose dose of 2 g/kg was given, and the blood glucose levels were monitored at 30 mins., 60 mins. and 120 mins. The glucose levels vs. the time points were drawn to show the glucose tolerance capabilities. The test results of some examples of the present invention are shown in FIG. 1.
Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the present invention should not be limited to the description of the preferred versions described herein. All features disclosed in the specification, including the abstract and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in the specification, including abstract and drawings, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is herein incorporated by reference in its entirety.

## Claims

1. A compound of Formula (I), or pharmaceutically acceptable salts thereof,



wherein:
W and Y are each C;
X is O;
Z is C;
R1 is selected from the group consisting of —H, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, C(═O)R5, SR5, SO2R5 and haloalkyl; R5 is selected from the group consisting of C1-6 alkanyl, substituted C1-6 alkanyl, alkoxy, substituted alkoxy and NR6R7; R6 and R7 are independently selected from the group consisting of —H, C1-6 alkanyl, and substituted C1-6 alkanyl, or R6 and R7 can join together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring;
R2 is selected from the group consisting of —H, alkanyl, substituted alkanyl, halogen and haloalkyl;
R3 is selected from the group consisting of substituted alkanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl; and
R4 is selected from the group consisting of heteroaryl and substituted heteroaryl, wherein at least one ortho atom of the heteroaryl connected with NH in Formula (I) is N.

2. The compound of claim 1, wherein R1 is selected from the group consisting of C(═O)R5, SRS, SO2R5 and haloalkyl; and wherein R5 is selected the group consisting of C1-3alkanyl, substituted C1-3alkanyl, NR6R7, C1-6alkoxy, and substituted C1-6alkoxy.

3. The compound of claim 1, wherein R2 is —H; wherein R3 is selected from the group consisting of cycloalkanyl, substituted cycloalkanyl, heterocycloalkyl and substituted heterocycloalkyl; and wherein R4 is substituted 5- or 6-membered heteroaryl.

4. The compound of claim 2, wherein R3 is

5. The compound of claim 3, wherein R1 is SO2R5; R5 is C1-3alkanyl.

6. The compound of claim 1, wherein R3 is

7. The compound of claim 1, wherein the compound is selected from the group consisting of:
ethyl 6-(4-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)phenylamino) nicotinate;
3-(2-(4-(methylsulfonyl)phenoxy)-5-(5-methylthiazol-2-ylamino)benzyl)cyclopentanone;
3-(2-(4-(methylsulfonyl)phenoxy)-5-(pyrazin-2-ylamino)benzyl)cyclopentanone;
3-(5-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(4-(methylsulfonyl) phenoxy)benzyl)cyclopentanone;
3-(5-(1H-imidazol-4-ylamino)-2-(4-(methylsulfonyl)phenoxy)benzyl)cyclopentanone;
3-(2-(4-(methylsulfonyl)phenoxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl)cyclopentanone;
ethyl 6-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)nicotinate;
N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-amine;
N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl) pyrazin-2-amine;
3-methyl-N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1,2,4-thiadiazol-5-amine;
N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1H-imidazol-4-amine;
5-methyl-N-(4-(4-(methylsulfonyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)thiazol-2-amine;
ethyl 6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(methylsulfonyl) phenoxy)phenylamino)nicotinate;
1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(5-(trifluoromethyl)pyridin-2-ylamino)benzyl) pyrrolidin-1-yl)ethanone;
1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(pyrazin-2-ylamino)benzyl)pyrrolidin-1-yl) ethanone;
1-(2-(5-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-(4-(methylsulfonyl) phenoxy)benzyl) pyrrolidin-1-yl)ethanone;
1-(2-(5-(1H-imidazol-4-ylamino)-2-(4-(methylsulfonyl) phenoxy)benzyl)pyrrolidin-1-yl)ethanone;
1-(2-(2-(4-(methylsulfonyl)phenoxy)-5-(5-methylthiazol-2-ylamino)benzyl)pyrrolidin-1-yl)ethanone;
ethyl 6-(4-(4-dimethylcarbamoyl)phenoxy)-3-((3-oxocyclopentyl)methyl)phenylamino)nicotinate;
N,N-dimethyl-4-(4-(5-methylthiazol-2-ylamino)-2-((3-oxocyclopentyl)methylphenoxy)benzamide;
N,N-dimethyl-4-(2-((3-oxocyclopentyl)methyl)-4-(pyrazin-2-ylamino) phenoxy)benzamide;
N,N-dimethyl-4-(4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-((3-oxocyclopentyl)methyl)phenoxy)benzamide;
4-(4-(1H-imidazol-4-ylamino)-2-((3-oxocyclopentyl)methyl)phenoxy)-N,N-dimethylbenzamide;
N,N-dimethyl-4-(2-((3-oxocyclopentyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)benzamide;
6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl amino)nicotinic acid;
N,N-dimethyl-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino)phenoxy)benzamide;
N,N-dimethyl-4-(4-(pyrazin-2-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl) phenoxy)benzamide;
N,N-dimethyl-4-(4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)benzamide;
4-(4-(1H-imidazol-4-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl)phenoxy)-N,N-dimethylbenzamide;
N,N-dimethyl-4-(4-(5-methylthiazol-2-ylamino)-2-((tetrahydro-2H-pyran-4-yl)methyl) phenoxy)benzamide;
6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbamoyl) phenoxy)phenyl amino)nicotinic acid;
4-(2-((1-acetylpyrrolidin-2-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-ylamino) phenoxy)-N,N-dimethylbenzamide;
4-(2-((1-acetylpyrrolidin-2-yl)methyl)-4-(pyrazin-2-ylamino)phenoxy)-N,N-dimethylbenzamide;
2-(6-(4-(4-(4-(dimethylcarbamoyl)phenoxy) 3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)pyridin-3-yl)acetic acid;
3-(6-(4-(4-(dimethylcarbamoyl)phenoxy)-3-((tetrahydro-2H-pyran-4-yl)methyl)phenylamino)pyridin-3-yl)propanoic acid;
2-(6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbarnoyl) phenoxy)phenylamino)pyridin-3-yl)acetic acid; or
3-(6-(3-((1-acetylpyrrolidin-2-yl)methyl)-4-(4-(dimethylcarbamoyl)phenoxy)phenylamino)pyridin-3-yl)propanoic acid.

8. A method of modulating glucokinase levels or activities in animals or humans by administering to the subject at least one compound of claim 1.

9. A method for treating and/or preventing type II diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 1.

10. A method for treating and/or preventing type I diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 1.

11. A method for treating and/or preventing obesity or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 1.

12. The compound of claim 5, wherein R4 is substituted 5 or 6 membered heteroaryl, and wherein one substitution is C1-3 carboxylate.

13. The compound of claim 6, wherein R4 is selected from the group consisting of 5-membered heteroaryl, 6-membered heteroaryl, substituted 5-heteroaryl and 6-membered heteroaryl.

14. The compound of claim 13, wherein R4 is selected from the group consisting of

15. The compound of claim 14, wherein R is selected from the group consisting of lower alkanyl, C1-6alkoxy, C(═O)R5 and SO2R5, wherein R5 is selected from the group consisting of lower alkanyl and NR6R7, and wherein R6 and R7 are independently selected from the group consisting of —H and lower alkanyl, or R6 and R7 can join together to form a 3 to 6 membered ring.

16. The compound of claim 15, wherein R2 is —H, or halogen.

17. The compound of claim 16, wherein R3 is




and wherein R4 is selected from the group consisting of

18. The compound of claim 16, wherein R is —H; wherein R1 is C(═O)NR6R7 or SO2R5; and wherein R5 is C1-3alkanyl.

19. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound of claim 1, and at least one pharmaceutically acceptable excipient, adjuvant or carrier.

20. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound of claim 7, and at least one pharmaceutically acceptable excipient, adjuvant or carrier.

21. A method of modulating glucokinase levels or activities in animals or humans by administering to the subject at least one compound of claim 7.

22. A method for treating and/or preventing type II diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 7.

23. A method for treating and/or preventing type I diabetes or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 7.

24. A method for treating and/or preventing obesity or related disease thereof, by administering to the subject a therapeutically effective amount of the compound of claim 7.