TWI475016B - A group of compounds that increase kinase activity and applications thereof - Google Patents

A group of compounds that increase kinase activity and applications thereof Download PDF

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TWI475016B
TWI475016B TW101117004A TW101117004A TWI475016B TW I475016 B TWI475016 B TW I475016B TW 101117004 A TW101117004 A TW 101117004A TW 101117004 A TW101117004 A TW 101117004A TW I475016 B TWI475016 B TW I475016B
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一組提高激酶活性的化合物及其應用A group of compounds that increase kinase activity and applications thereof

本發明有關一組提高葡萄糖激酶活性的化合物及其在醫藥領域中的應用。The present invention relates to a group of compounds which increase glucokinase activity and their use in the field of medicine.

葡萄糖激酶(Glucokinase，GK)是一種哺乳動物己糖激酶(己糖激酶IV)。己糖激酶是葡萄糖轉化成6-磷酸葡萄糖的糖代謝和催化反應的第一階段的酶。表達過程中，葡萄糖激酶限存於肝臟和胰腺β細胞中，並控制這些細胞中葡萄糖代謝的限速步驟(關鍵步驟)。因此葡萄糖激酶在糖代謝過程中有著重要作用。肝臟和胰腺β細胞中的葡萄糖激酶在N端15個氨基酸序列不同，但是酶性質相同。除葡萄糖激酶外其他三種己糖激酶(I、II、III)在葡萄糖濃度為1mM時酶活性達到飽和，而只有葡萄糖激酶在Km時對應的葡萄糖濃度為8mM，接近生理血糖水準。因此，葡萄糖激酶調節的細胞內糖代謝系統能夠對葡萄糖水平的改變作出快速回應，如對葡萄糖水平從正常水準(5mM)增加到餐後水準(10~15mM)作出快速回應。Glucokinase (GK) is a mammalian hexokinase (hexose kinase IV). Hexokinase is the first stage enzyme of glucose metabolism and catalytic reaction of glucose to 6-phosphate glucose. During expression, glucokinase is restricted to liver and pancreatic beta cells and controls the rate-limiting step (critical step) of glucose metabolism in these cells. Therefore, glucokinase plays an important role in the process of glucose metabolism. The glucokinase in the liver and pancreatic beta cells differs in the N-terminal 15 amino acid sequence, but the enzyme properties are the same. In addition to glucokinase, the other three hexokinases (I, II, III) saturate at a glucose concentration of 1 mM, while only the glucose kinase at Km corresponds to a glucose concentration of 8 mM, which is close to physiological blood glucose levels. Thus, the glucokinase-regulated intracellular sugar metabolism system is able to respond quickly to changes in glucose levels, such as a rapid response to an increase in glucose levels from a normal level (5 mM) to a post-prandial level (10-15 mM).

早在十年前，葡萄糖激酶作為肝臟和胰腺β細胞中的葡萄糖的感應蛋白這一理論就已經被提出(見Garfinkel D.等，Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells.American Journal of Physiology,1984年，247卷，第527~536頁)。近期的小鼠葡萄糖激酶基因控制研究表明：葡萄糖激酶對維持體內葡萄糖平衡有著重要作用。葡萄糖激酶基因被擾亂的小鼠在出生後不久即死亡，而葡萄糖激酶基因被過量表達的正常小鼠或患糖尿病的小鼠則具有較低的血糖水準。儘管它們的反應原理不同，但隨著葡萄糖濃度的增加，胰腺β細胞和肝臟細胞均作出 減少血糖水準的反應。胰腺β細胞分泌出較多的胰島素；而肝臟將葡萄糖轉化成糖元儲存起來，同時減少肝糖元的分解和葡萄糖的釋放。As early as ten years ago, the theory that glucokinase is a protein of glucose in liver and pancreatic beta cells has been proposed (see Garfinkel D. et al., Computer modeling identified glucokinase as glucose sensor of pancreatic beta-cells. American Journal of Physiology, 1984, vol. 247, pp. 527-536). Recent studies on mouse glucokinase gene control have shown that glucokinase plays an important role in maintaining glucose balance in the body. Mice that are disrupted by the glucokinase gene die shortly after birth, while normal or diabetic mice with glucokinase gene overexpression have lower blood glucose levels. Although their reaction principles are different, with the increase in glucose concentration, both pancreatic beta cells and liver cells are made. Reduce blood sugar levels in response. Pancreatic beta cells secrete more insulin; the liver converts glucose into glycogen stores, while reducing glycogen breakdown and glucose release.

因此，改變葡萄糖激酶酶活性，通過胰腺β細胞和肝臟的作用機理，將對哺乳動物的體內葡萄糖平衡起著重要作用。在青少年發病的成年型糖尿病(MODY2)患者中已經發現了葡萄糖激酶基因的突變，而且葡萄糖激酶活性的降低引起血糖水準的增加(例如，見Vionnet N.等人，Nonsense mutation in the glucokinase gene causes early-onset non-indulin-dependent diabetes mellitus,Nature Genetics,1992,356卷，第721-722頁)。另一方面，發現增加了葡萄糖激酶活性的基因突變家族，這些家族的後代表現出低血糖水準綜合症。Therefore, changes in glucokinase activity, through the action mechanism of pancreatic beta cells and liver, will play an important role in the glucose balance in mammals. Mutations in the glucokinase gene have been found in adolescent-onset adult diabetic (MODY2) patients, and a decrease in glucokinase activity causes an increase in blood glucose levels (see, for example, Vionnet N. et al., Nonsense mutation in the glucokinase gene by -onset non-indulin-dependent diabetes mellitus, Nature Genetics, 1992, 356, pp. 721-722). On the other hand, a family of gene mutations having increased glucokinase activity was found, and the progeny of these families exhibited a hypoglycemic level syndrome.

綜上所述，葡萄糖激酶作為葡萄糖感應蛋白，在人體內的葡萄糖平衡調節方面有著重要作用；同時，在II型糖尿病病人中應該可以利用調節葡萄糖激酶的活性來相應控制血糖水準。葡萄糖激酶活化劑在胰腺β細胞中能夠促進胰島素的分泌，在肝臟中能夠促進葡萄糖的吸收，同時抑制肝糖元的分解和葡萄糖的釋放。因此，葡萄糖激酶活化劑可用於治療II型糖尿病。In summary, glucokinase acts as a glucose-sensing protein and plays an important role in the regulation of glucose homeostasis in the human body. At the same time, in patients with type 2 diabetes, the activity of glucokinase should be adjusted to control blood glucose levels accordingly. Glucose kinase activators promote insulin secretion in pancreatic beta cells, promote glucose uptake in the liver, and inhibit hepatic glycogen breakdown and glucose release. Therefore, glucokinase activators are useful in the treatment of type 2 diabetes.

近年來還發現，胰腺β細胞型葡萄糖激酶也限制性地在大鼠的大腦中表達，特別是腹內側下丘腦(VMH)處。腹內側下丘腦中約有20%的神經細胞是葡萄糖敏感神經元，因此，認為葡萄糖激酶在控制體重方面起著重要作用。當大鼠的大腦中葡萄糖濃度增加時，將減少攝食量。當通過控制大腦內的葡萄糖胺(一種葡萄糖的類似物)來阻礙葡萄糖進入腦部代謝時，將引起攝食過多。It has also been found in recent years that pancreatic β-cell type glucokinase is also restrictedly expressed in the brain of rats, particularly at the ventromedial hypothalamus (VMH). About 20% of the nerve cells in the ventromedial hypothalamus are glucose-sensitive neurons. Therefore, glucokinase is considered to play an important role in controlling body weight. When the glucose concentration in the brain of the rat increases, the food intake will be reduced. When glucose is introduced into the brain by controlling glucosamine, an analog of glucose, in the brain, it will cause too much food intake.

從一個電生理學實驗可以看出：生理葡萄糖濃度的改變(5~20mM)可調控葡萄糖敏感神經元的活性；當腦部中葡萄糖的代謝被葡糖胺或其類似物抑 制時，它們(葡萄糖敏感神經元)的活性也被減緩。現在認為，腹內側下丘腦(VMH)中的葡萄糖濃度調控系統中，葡萄糖激酶調控機理可能與胰腺β細胞中胰島素分泌的機理類似。因此，腹內側下丘腦(VHM)、肝臟和胰腺β細胞中的葡萄糖激酶活化劑不僅對控制合適的血糖水準是有效的，而且對解決肥胖問題也可能是有效的，而很多II型糖尿病人恰恰同時存在肥胖問題。It can be seen from an electrophysiological experiment that changes in physiological glucose concentration (5-20 mM) can regulate the activity of glucose-sensitive neurons; when glucose metabolism in the brain is inhibited by glucosamine or its analogues Their activity (glucose-sensitive neurons) is also slowed down. It is now believed that the mechanism of glucose kinase regulation in the glucose concentration regulation system in the ventromedial hypothalamus (VMH) may be similar to the mechanism of insulin secretion in pancreatic beta cells. Therefore, glucokinase activators in the ventral medial hypothalamic (VHM), liver, and pancreatic beta cells are not only effective in controlling proper blood glucose levels, but may also be effective in addressing obesity, and many type 2 diabetics are just There is also a problem of obesity.

因此，一種具有激發葡萄糖激酶活性效力的化合物可以應用於治療及/或預防糖尿病，或者治療及/或預防糖尿病引起的慢性併發症如視網膜病變、腎病、神經官能症、缺血性心臟病、動脈硬化等，並可同時達到治療及/或預防肥胖的效果。Thus, a compound having potency for stimulating glucokinase activity can be used for the treatment and/or prevention of diabetes, or for the treatment and/or prevention of chronic complications caused by diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteries. Hardening, etc., and at the same time achieve the effect of treating and / or preventing obesity.

本發明的目的是提供一種提高葡萄糖激酶活性的化合物及其在醫藥領域中的應用。It is an object of the present invention to provide a compound which increases glucokinase activity and its use in the field of medicine.

本發明首先提供了結構式(I)表示的化合物，所述化合物包括結構式(I)表示的至少任意一種化合物，及所述化合物藥學上可接受的鹽、溶劑化物、螯合物、非共價複合物或其前驅藥物、或上述所有形式的任意混合物。The present invention first provides a compound represented by the formula (I), which comprises at least any one of the compounds represented by the formula (I), and a pharmaceutically acceptable salt, solvate, chelate, non-common of the compound A valence complex or a precursor thereof, or any mixture of all of the above.

其中，W和Y分別獨立地選自N或C； X選自O或S；Z選自C、N、O或S；R1 選自：氫、烷基、含取代基的烷基、烯基、含取代基的烯基、炔基、含取代基的炔基、烷氧基、含取代基的烷氧基、C(=O)R5 、SR5 、SO2 R5 或鹵代烴基；所述R5 選自：低級烷基、含取代基的低級烷基、烷氧基、含取代基的烷氧基或NR6 R7 ；所述R6 和R7 分別獨立地選自：氫、低級烷基、含取代基的低級烷基，或者R6 和R7 連在一起形成一個3~6元環或含取代基的3~6元環；R2 選自：氫、烷基、含取代基的烷基、鹵素或鹵代烴基；R3 選自：含取代基的烷基、烯基、含取代基的烯基、炔基、含取代基的炔基、環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基；R4 選自：雜環芳基或含取代基的雜環芳基，其中與結構式(I)中的NH直接相連的原子的雜環芳烴鄰位上至少有一邊是N。在本發明的一個較佳技術方案中，所述W為C。Wherein, W and Y are each independently selected from N or C; X is selected from O or S; Z is selected from C, N, O or S; and R 1 is selected from the group consisting of hydrogen, alkyl, alkyl having a substituent, and alkene a base group, a substituent-containing alkenyl group, an alkynyl group, a substituent-containing alkynyl group, an alkoxy group, a substituent-containing alkoxy group, C(=O)R 5 , SR 5 , SO 2 R 5 or a halogenated hydrocarbon group The R 5 is selected from the group consisting of: a lower alkyl group, a lower alkyl group having a substituent, an alkoxy group, a substituted alkoxy group or NR 6 R 7 ; and the R 6 and R 7 are each independently selected from: a hydrogen, a lower alkyl group, a lower alkyl group having a substituent, or a combination of R 6 and R 7 to form a 3 to 6 membered ring or a 3 to 6 membered ring having a substituent; and R 2 is selected from the group consisting of hydrogen and alkyl. a substituent-containing alkyl group, a halogen or a halogenated hydrocarbon group; and R 3 is selected from the group consisting of a substituent-containing alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituent-containing cycloalkyl group, a heterocyclic hydrocarbon group or a substituted heterocyclic hydrocarbon group; R 4 is selected from a heterocyclic aryl group or a substituted heterocyclic aryl group, which is directly bonded to NH in the formula (I) The heterocyclic aromatic hydrocarbon of the attached atom has at least one side adjacent to N. In a preferred embodiment of the present invention, the W is C.

在本發明的一個特佳實施例中，所述W為C，所述Y為C。在較佳實施例中，所述W為C，所述Y為C，所述X為O。在更較佳實施例中，所述W為C，所述Y為C，所述X為O，所述Z為C。In a particularly preferred embodiment of the invention, said W is C and said Y is C. In a preferred embodiment, said W is C, said Y is C, and said X is O. In a more preferred embodiment, said W is C, said Y is C, said X is O, and said Z is C.

在本發明的另一個特佳實施例中，所述W為C，所述Y為N。在較佳實施例中，所述W為C，所述Y為N，所述X為O。在更較佳實施例中，所述W為C，所述Y為N，所述X為O，所述Z為C。在本發明的一個較佳技術方案中，所述W為N。In another particularly preferred embodiment of the invention, said W is C and said Y is N. In a preferred embodiment, said W is C, said Y is N, and said X is O. In a more preferred embodiment, said W is C, said Y is N, said X is O, and said Z is C. In a preferred embodiment of the present invention, the W is N.

在本發明的一個特佳實施例中，所述W為N，所述Y為C。在較佳實施例中，所述W為N，所述Y為C，所述X為O。在更較佳實施例中，所述W為N，所述Y為C，所述X為O，所述Z為C。In a particularly preferred embodiment of the invention, said W is N and said Y is C. In a preferred embodiment, said W is N, said Y is C, and said X is O. In a more preferred embodiment, said W is N, said Y is C, said X is O, and said Z is C.

在本發明的另一個特佳實施例中，所述W為N，所述Y為N。在較佳實施例 中，所述W為N，所述Y為N，所述X為O。在更較佳實施例中，所述W為N，所述Y為N，所述X為O，所述Z為C。在本發明的一個較佳技術方案中，所述X為O。In another particularly preferred embodiment of the invention, said W is N and said Y is N. Preferred embodiment Wherein W is N, Y is N, and X is O. In a more preferred embodiment, said W is N, said Y is N, said X is O, and said Z is C. In a preferred embodiment of the present invention, the X is O.

在本發明的一個較佳技術方案中，所述Y為C。In a preferred embodiment of the present invention, the Y is C.

在本發明的一個較佳技術方案中，所述Y為N。In a preferred embodiment of the present invention, the Y is N.

在本發明的一個較佳技術方案中，所述Z為N。在本發明的一個較佳技術方案中，所述R1 選自：氫、低級烷基、含取代基的低級烷基、低級烯基、含取代基的低級烯基、低級炔基、含取代基的低級炔基、C1-6 烷氧基或含取代基的C1-6 烷氧基。在本發明的一個特佳實施例中，所述R1 選自：氫、低級烷基、含取代基的低級烷基、低級烯基、含取代基的低級烯基、低級炔基、含取代基的低級炔基、C1-6 烷氧基或含取代基的C1-6 烷氧基；所述R2 為氫；所述R3 選自環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基；所述R4 所選自5元環或6元環的雜環芳基。在本發明的一個較佳實施例中，所述R3 選自以下任意一個基團： In a preferred embodiment of the present invention, the Z is N. In a preferred embodiment of the present invention, the R 1 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl containing a substituent, lower alkenyl group, lower alkenyl group having a substituent, lower alkynyl group, and containing a substituent a lower alkynyl group, C 1-6 alkoxy or a substituted C 1-6 alkoxy group. In a particularly preferred embodiment of the invention, the R 1 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl containing a substituent, lower alkenyl, lower alkenyl having a substituent, lower alkynyl, containing a substituent a lower alkynyl group, a C 1-6 alkoxy group or a substituted C 1-6 alkoxy group; the R 2 is hydrogen; and the R 3 is selected from a cycloalkyl group, a cycloalkyl group having a substituent a heterocyclic hydrocarbon group or a heterocyclic hydrocarbon group having a substituent; wherein R 4 is selected from a 5-membered or 6-membered heterocyclic aryl group. In a preferred embodiment of the invention, the R 3 is selected from any one of the following groups:

在本發明的另一個較佳技術方案中，所述R1 選自以下任意一個基團：氫、C1-3 烷基、含取代基的C1-3 烷基、C1-3 烷氧基或含取代基的C1-3 烷氧基。In another preferred embodiment of the present invention, the R 1 is selected from any one of the following groups: hydrogen, C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 alkoxy Or a C 1-3 alkoxy group having a substituent.

在本發明的又一個較佳技術方案中，所述R1 為氫。In still another preferred embodiment of the present invention, the R 1 is hydrogen.

在本發明的再一個較佳技術方案中，所述R1 選自：C(=O)R5 、SR5 、SO2 R5 或鹵代烴基，其中所述R5 選自：C1-3 烷基、含取代基的C1-3 烷基、C1-6 烷氧基、含取代基的C1-6 烷氧基或NR6 R7 。在本發明的一個特佳實施例中，R1 選自C(=O)R5 、SR5 、SO2 R5 或鹵代烴基，其中所述R5 選自C1-3 烷基、含取代基的C1-3 烷基、C1-6 烷氧基、含取代基的C1-6 烷氧基或NR6 R7 ，其中，所述R6 和R7 分別獨立地選自：氫、低級 烷基、含取代基的低級烷基，或者R6 和R7 能連在一起形成一個3~6元環或含取代基的3~6元環；所述R2 為氫；所述R3 選自：環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基；所述R4 所選自：5元環或6元環的雜環芳基。在本發明的一個較佳實施例中，所述R3 選自： In still another preferred embodiment of the present invention, the R 1 is selected from: C(=O)R 5 , SR 5 , SO 2 R 5 or a halogenated hydrocarbon group, wherein the R 5 is selected from the group consisting of: C 1- A 3- alkyl group, a C 1-3 alkyl group having a substituent, a C 1-6 alkoxy group, a C 1-6 alkoxy group having a substituent or NR 6 R 7 . In a particularly preferred embodiment of the invention, R 1 is selected from C(=O)R 5 , SR 5 , SO 2 R 5 or a halogenated hydrocarbon group, wherein said R 5 is selected from C 1-3 alkyl groups, substituted C 1-3 alkyl group, C 1-6 alkoxy, C substituent group containing 1-6 alkoxy or NR 6 R 7, wherein R 6 and R 7 are each independently selected from: a hydrogen, a lower alkyl group, a lower alkyl group having a substituent, or R 6 and R 7 may be bonded together to form a 3 to 6 membered ring or a 3 to 6 membered ring having a substituent; the R 2 is hydrogen; R 3 is selected from the group consisting of a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic hydrocarbon group or a substituted heterocyclic hydrocarbon group; and the R 4 is selected from a 5-membered or 6-membered heterocyclic aryl group. . In a preferred embodiment of the invention, the R 3 is selected from the group consisting of

在本發明的一個更佳實施例中，所述R1 選自C(=O)R5 ；所述R5 選自NR6 R7 ，其中，所述R6 和R7 分別獨立地選自：氫、低級烷基、含取代基的低級烷基，或者R6 和R7 能連在一起形成一個3~6元環或含取代基的3~6元環。在本發明的另一個更佳技術方案中，所述R1 選自，其中所述R5 選自C1-3 烷基。In a more preferred embodiment of the invention, the R 1 is selected from C(=O)R 5 ; the R 5 is selected from NR 6 R 7 , wherein the R 6 and R 7 are each independently selected from : hydrogen, lower alkyl, lower alkyl containing a substituent, or R 6 and R 7 may be bonded together to form a 3 to 6 membered ring or a 3 to 6 membered ring having a substituent. In another more preferred embodiment of the present invention, the R 1 is selected from the group consisting of, wherein the R 5 is selected from a C 1-3 alkyl group.

在本發明的再一個更佳實施例中，所述R1 選自：C(=O)R5 、SR5 、SO2 R5 或鹵代烴基，其中，所述R5 選自：C1-3 烷基、含取代基的C1-3 烷基、C1-6 烷氧基、含取代基的C1-6 烷氧基或NR6 R7 ，其中，所述R6 和R7 分別獨立地選自：氫、C1-4 烷基或含取代基的C1-4 烷基。In still another more preferred embodiment of the present invention, the R 1 is selected from the group consisting of C(=O)R 5 , SR 5 , SO 2 R 5 or a halogenated hydrocarbon group, wherein the R 5 is selected from the group consisting of: C 1 a -3 alkyl group, a substituted C 1-3 alkyl group, a C 1-6 alkoxy group, a substituted C 1-6 alkoxy group or NR 6 R 7 , wherein said R 6 and R 7 They are each independently selected from the group consisting of hydrogen, C 1-4 alkyl or a substituted C 1-4 alkyl group.

在本發明的再一個更佳實施例中，所述R1 選自：C(=O)R5 、SR5 、SO2 R5 或鹵代烴基，其中，所述R5 選自：C1-3 烷基、含取代基的C1-3 烷基、C1-6 烷氧基、含取代基的C1-6 烷氧基或NR6 R7 ，其中，所述R6 和R7 分別獨立地選自：R6 和R7 能連在一起形成一個3~6元環或含取代基的3~6元環。較佳地，所述3~6元環或含取代基的3~6元環為雜環，其中雜原子選自O或S。In still another more preferred embodiment of the present invention, the R 1 is selected from the group consisting of C(=O)R 5 , SR 5 , SO 2 R 5 or a halogenated hydrocarbon group, wherein the R 5 is selected from the group consisting of: C 1 a -3 alkyl group, a substituted C 1-3 alkyl group, a C 1-6 alkoxy group, a substituted C 1-6 alkoxy group or NR 6 R 7 , wherein said R 6 and R 7 They are independently selected from the group consisting of: R 6 and R 7 can be joined together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring. Preferably, the 3-6-membered ring or the 3- to 6-membered ring containing a substituent is a heterocyclic ring wherein the hetero atom is selected from O or S.

在本發明的又一個較佳技術方案中，所述R2 為氫。In still another preferred embodiment of the present invention, the R 2 is hydrogen.

在本發明的另一個較佳技術方案中，所述R2 選自：低級烷基或含取代基的低級烷基。In another preferred embodiment of the present invention, the R 2 is selected from the group consisting of a lower alkyl group or a lower alkyl group having a substituent.

在本發明的另一個較佳技術方案中，所述R2 為鹵代烴基，特佳鹵代甲基、 鹵代乙基或鹵代丙基。In another preferred embodiment of the present invention, the R 2 is a halogenated hydrocarbon group, particularly preferably a halogenated methyl group, a halogenated ethyl group or a halogenated propyl group.

在本發明的另一個較佳技術方案中，所述R3 選自：含取代基的低級烷基、低級烯基、含取代基的低級烯基、低級炔基或含取代基的低級炔基。特佳地，所述R3 選自含取代基的C1-3 烷基、C2-4 烯基、含取代基的C2-4 烯基。In another preferred embodiment of the present invention, the R 3 is selected from the group consisting of a lower alkyl group having a substituent, a lower alkenyl group, a lower alkenyl group having a substituent, a lower alkynyl group or a lower alkynyl group having a substituent. . Particularly preferred, the R 3 group is selected from a substituted C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkenyl-containing substituent.

在本發明的另一個較佳技術方案中，所述R3 選自：環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基。In another preferred embodiment of the present invention, the R 3 is selected from the group consisting of a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic hydrocarbon group or a substituted heterocyclic hydrocarbon group.

在本發明的另一個較佳技術方案中，所述R3 選自： In another preferred embodiment of the present invention, the R 3 is selected from the group consisting of:

在本發明的另一個較佳技術方案中，所述R4 選自5元環或6元環的雜環芳基。In another preferred embodiment of the present invention, the R 4 is selected from a 5-membered or 6-membered heterocyclic aryl group.

更具體地，本發明的最佳化合物選自：1)2-甲基磺醯基-5-((2-(2-吡咯烷酮基)甲基)-(4-(2-吡啶基)氨基))苯氧基吡啶；2)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；3)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡啶；4)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；5)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；6)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶 基)氨基))苯氧基吡啶；7)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；8)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；9)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；10)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；11)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(4-1H-咪唑基)氨基))苯氧基吡啶；12)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲氧基-2-吡啶基)氨基))苯氧基吡啶；13)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；14)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡啶基)氨基))苯氧基吡啶；15)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；16)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡啶；17)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶； 18)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；19)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶基)氨基))苯氧基吡啶；20)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；21)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；22)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；23)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；24)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(1H-4-咪唑基)氨基))苯氧基吡啶；25)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；26)2-嗎啉磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；27)2-(N-乙基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲氧基-2-吡啶基)氨基))苯氧基吡啶；28)2-甲基-3-氯-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氯-2-吡啶基)氨基))苯氧基吡啶；29)6-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)煙 酸乙酯；30)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)噻唑；31)2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡嗪；32)3-甲基-5-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)1,2,4-噻二唑；33)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)咪唑；34)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡啶；35)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-2-吡啶基胺；36)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-(N’-乙基甲醯胺)-2-吡啶基)胺；37)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-苯基-2-吡啶基)胺；38)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-三氟甲基-2-吡啶基)胺；39)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-氰基-2-吡啶基)胺；40)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-羧基-2-吡啶基)胺； 41)6-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)煙酸乙酯；42)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡啶；43)2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡嗪；44)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑；45)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)咪唑；46)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；47)6-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)煙酸乙酯；48)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡啶；49)2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡嗪；50)5-甲基-3-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)1,2,4-噻二唑；51)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)咪唑；52)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基) 甲基)苯胺基)噻唑；53)2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)吡啶；54)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)吡啶；55)4-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)嘧啶；56)5-甲基-2-(4-(4-(甲基磺醯基)苯硫基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑；57)1H-4-(4-(4-(甲基磺醯基)苯硫基)-3-(4-2H-四氫吡喃氧基)苯胺基)咪唑；58)5-甲基-2-(4-(4-(甲基磺醯基)苯硫基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；59)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)煙酸乙酯；60)5-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)噻唑；61)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡嗪；62)3-甲基-5-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)1,2,4-噻二唑；63)1H-4-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)咪唑； 64)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡啶；65)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；66)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；67)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡啶；68)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；69)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；70)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶基)氨基))苯氧基吡啶；71)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；72)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；73)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；74)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；75)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲 基))-(4-(4-1H-咪唑基)氨基))苯氧基吡啶；76)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；77)2-(6-(4-(6-(N,N-二甲基甲醯胺基)-3-吡啶氧基)-3-(2-(2-氧代吡咯烷-1-甲基))苯氨基)-3-吡啶基)乙酸；78)3-(6-(4-(6-(N,N-二甲基甲醯胺基)-3-吡啶氧基)-3-(2-(2-氧代吡咯烷-1-甲基))苯氨基)-3-吡啶基)丙酸；79)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲氧基-2-吡啶基)氨基))苯氧基吡啶；80)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-2-吡啶基胺；81)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-(N’-乙基甲醯胺)-2-吡啶基)胺；82)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-苯基-2-吡啶基)胺；83)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-三氟甲基-2-吡啶基)胺；84)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-氰基-2-吡啶基)胺；85)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-羧基-2-吡啶基)胺；86)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)煙酸； 87)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡啶；88)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡嗪；89)3-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑；90)1H-4-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)咪唑；91)5-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；92)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)煙酸；93)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡啶；94)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡嗪；95)2-(6-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶氨基)-3-吡啶基)乙酸；96)3-(6-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶氨基)-3-吡啶基)丙酸；97)2-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯氨基)-3-吡啶基)乙酸；98)3-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基) 甲基)苯氨基)-3-吡啶基)丙酸；99)2-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯氨基)-3-吡啶基)乙酸；100)3-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯氨基)-3-吡啶基)丙酸101)2-(6-(4-(6-(甲基磺醯基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)乙酸；102)3-(6-(4-(6-(甲基磺醯基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)丙酸；103)2-(6-(4-(6-(甲氧基甲基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)乙酸；104)3-(6-(4-(6-(甲氧基甲基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)丙酸。More specifically, the most preferred compound of the invention is selected from the group consisting of: 1) 2-methylsulfonyl-5-((2-(2-pyrrolidino)methyl)-(4-(2-pyridyl)amino) Phenoxypyridine; 2) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-(N-ethylformamidine) Amino)-2-pyridyl)amino))phenoxypyridine; 3) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4) -(5-phenyl-2-pyridyl)amino))phenoxypyridine; 4) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine-1-methyl)) -(4-(5-trifluoromethyl-2-pyridyl)amino))phenoxypyridine; 5) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine-1) -methyl))-(4-(5-cyano-2-pyridyl)amino))phenoxypyridine; 6) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine) Alkan-1-methyl))-(4-(5-carboxy-2-pyridine) Amino))phenoxypyridine; 7) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-carboxylic acid ethyl ester) Benzyl-2-pyridyl)amino))phenoxypyridine; 8) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-( 5-methyl-2-pyridyl)amino))phenoxypyridine; 9) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-( 4-(2-pyrazinyl)amino))phenoxypyridine; 10) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4) -(3-methyl-5-(1,2,4-thiadiazolyl)amino)))phenoxypyridine; 11) 2-methylsulfonyl-5-((2-(2-oxygen) Depyrrolidine-1-methyl))-(4-(4-1H-imidazolyl)amino))phenoxypyridine; 12) 2-methylsulfonyl-5-((2-(2-oxygen) Depyrrolidine-1-methyl))-(4-(5-methoxy-2-pyridyl)amino))phenoxypyridine; 13) 2-methylsulfonyl-5-((2- (2-oxopyrrolidin-1-methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxypyridine; 14) 2-methoxymethyl-5-( (2-(2-oxopyrrolidin-1-methyl))-(4-(2-pyridyl)amino))phenoxypyridine; 15) 2-methoxymethyl-5-(2 -(2-oxopyrrolidin-1-methyl))-(4-(5-(N-ethylcarbamimidino)-2-pyridyl)amino))benzene Pyridyl; 16) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-phenyl-2-pyridyl)amino) Phenoxypyridine; 17) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-trifluoromethyl-2-) Pyridyl)amino))phenoxypyridine; 18) 2-Methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-cyano-2-pyridyl)amino))phenoxy Pyridine; 19) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-carboxy-2-pyridyl)amino)) Phenoxypyridine; 20) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-carboxylic acid ethyl ester-2-pyridine) Amino))phenoxypyridine; 21) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methyl-) 2-pyridyl)amino))phenoxypyridine; 22) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2- Pyrazinyl)amino))phenoxypyridine; 23) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(3-A) 5-(1,2,4-thiadiazolyl)amino)))phenoxypyridine; 24) 2-methoxymethyl-5-((2-(2-oxopyrrolidine-1) -methyl))-(4-(1H-4-imidazolyl)amino))phenoxypyridine; 25) 2-methoxymethyl-5-((2-(2-oxopyrrolidine-1) -methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxypyridine; 26) 2-morpholinsulfonyl-5-((2-(2-oxopyrrolidine) Alken-1-methyl))-(4-(5-trifluoromethyl-2-pyridyl)amino))phenoxypyridine; 27) 2-(N-ethyl A醯Amino)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-trifluoromethoxy-2-pyridyl)amino))phenoxypyridine ;28) 2-methyl-3-chloro-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-chloro-2-pyridyl)amino))benzene Oxypyridine; 29) 6-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino) Ethyl acetate; 30) 5-methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)thiazole ;31) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)pyrazine; 32)3-methyl -5-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)1,2,4-thiadiazole; 33 1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)imidazole; 34) 5-trifluoromethyl Benzyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)pyridine; 35) N-(6-( 4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-2-pyridylamine; 36) N-(6-(4) -(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-(N'-ethylcarbamidine)-2- Pyridyl)amine; 37) N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5 -phenyl-2-pyridyl)amine; 38) N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl )-N-(5-trifluoromethyl-2-pyridyl)amine; 39) N-(6-(4-(methylsulfonyl)phenoxy)-5-(3-4- Furyl)methyl)-3-pyridyl)-N-(5-cyano-2-pyridyl)amine; 40) N-(6-(4-(methylsulfonyl)phenoxy)- 5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-carboxy-2-pyridyl)amine; 41) 6-(4-(4-(Methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilinyl)ethyl nicotinate; 42)5 -trifluoromethyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)pyridine; 43) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)pyrazine; 44) 5-methyl- 2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)1,2,4-thiadiazole; 45) 1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)imidazole; 46) 5- Methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 47) 6-( 4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)ethyl nicotinate; 48) 5-trifluoro Methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)pyridine; 49)2 -(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)pyrazine; 50) 5-methyl -3-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)1,2, 4-thiadiazole; 51) 1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)aniline Imidazole; 52) 5-methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl) Methyl)anilino)thiazole; 53) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)anilino)pyridine ;54) 5-Trifluoromethyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)anilino)pyridine 55) 4-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)anilino)pyrimidine; 56)5-methyl -2-(4-(4-(methylsulfonyl)phenylthio)-3-((4-2H-tetrahydropyranyl)methyl)anilino)1,2,4-thiadiazole ;57)1H-4-(4-(4-(methylsulfonyl)phenylthio)-3-(4-2H-tetrahydropyranyloxy)anilino)imidazole; 58)5-methyl -2-(4-(4-(methylsulfonyl)phenylthio)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 59)6-(4- (4-(N,N-Dimethylcarbamoylamino)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)ethyl nicotinate; 60) 5-methyl -2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)thiazole; 61)2 -(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)pyrazine; 62)3- Methyl-5-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl) Amino) 1,2,4-thiadiazole; 63) 1H-4-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxygen) Cyclopentyl)methyl)anilino)imidazole; 64) 5-Trifluoromethyl-2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl) Aniline)pyridine; 65) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2- Pyrazinyl)amino))phenoxypyridine; 66) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1-methyl)) -(4-(5-(N-ethylcarbamimidino)-2-pyridyl)amino))phenoxypyridine; 67) 2-(N,N-dimethylformamido)-5 -((2-(2-oxopyrrolidin-1-methyl))-(4-(5-phenyl-2-pyridyl)amino))phenoxypyridine; 68) 2-(N, N - dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-trifluoromethyl-2-pyridyl)amino)) Phenoxypyridine; 69) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5- Cyano-2-pyridyl)amino))phenoxypyridine; 70) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1-) Methyl))-(4-(5-carboxy-2-pyridyl)amino))phenoxypyridine; 71) 2-(N,N-dimethylformamido)-5-((2- (2-oxopyrrolidin-1-methyl))-(4-(5-carboxylic acid ethyl ester-2-pyridyl)amino))phenoxypyridine; 72) 2-(N,N-dimethyl Base armor 5-(-(2-(2-oxopyrrolidine-1-methyl))-(4-(5-methyl-2-pyridyl)amino))phenoxypyridine; 73)2- (N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2-pyrazinyl)amino))phenoxy Pyridine; 74) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(3-methyl) -5-(1,2,4-thiadiazolyl)amino)))phenoxypyridine; 75) 2-(N,N-dimethylformamido)-5-((2-(2) -oxopyrrolidine-1-methyl ()-(4-(4-1H-imidazolyl)amino))phenoxypyridine; 76) 2-(N,N-dimethylformamido)-5-((2-(2- Oxopyrrolidin-1-methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxypyridine; 77) 2-(6-(4-(6-(N, N-dimethylformamido)-3-pyridyloxy)-3-(2-(2-oxopyrrolidine-1-methyl))phenylamino)-3-pyridyl)acetic acid; 78) 3-(6-(4-(6-(N,N-dimethylformamido)-3-pyridyloxy)-3-(2-(2-oxopyrrolidine-1-methyl)) Phenylamino)-3-pyridyl)propionic acid; 79) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1-methyl)) )-(4-(5-methoxy-2-pyridyl)amino))phenoxypyridine; 80) N-(6-(4-(N,N-dimethylformamido)phenoxy 5-(4-(4-tetrahydrofuryl)methyl)-3-pyridyl)-N-2-pyridylamine; 81)N-(6-(4-(N,N-dimethylformamidine) Amino)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-(N'-ethylformamide)-2-pyridyl)amine; 82) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-( 5-phenyl-2-pyridyl)amine; 83) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl) A Base)-3-pyridine -N-(5-trifluoromethyl-2-pyridyl)amine; 84) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5- ((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-cyano-2-pyridyl)amine; 85) N-(6-(4-(N,N-dimethyl) Methionido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-carboxy-2-pyridyl)amine; 86)6-(4- (4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)nicotinic acid; 87) 5-Trifluoromethyl-2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl) A Benzyl)pyridine; 88) 2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl) A (anilino)pyrazine;89)3-methyl-2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-four) Hydropyranyl)methyl)anilino) 1,2,4-thiadiazole; 90) 1H-4-(4-(4-(N,N-dimethylformamido)phenoxy) -3-((4-2H-tetrahydropyranyl)methyl)anilino)imidazole; 91)5-methyl-2-(4-(4-(N,N-dimethylformamido) Phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 92) 6-(4-(4-(N,N-dimethylformamido) Phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)nicotinic acid; 93)5-trifluoromethyl-2-(4-(4-(N) , N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)pyridine; 94) 2-(4-(4- (N,N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)pyrazine; 95)2-(6- (6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridylamino)-3-pyridyl)acetic acid; 96) 3-(6-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridinyl)-3- Pyridyl)propionic acid; 97) 2-(6-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl) )methyl)phenylamino)-3-pyridyl)acetic acid; 98) 3-(6-(4-(4-(N,N-dimethylformamido)phenoxy)-3-(( 4-2H-tetrahydropyranyl) Methyl)phenylamino)-3-pyridyl)propionic acid; 99) 2-(6-(4-(4-(N,N-dimethylformamido)phenoxy)-3-(( 1-(Ethyl-2-pyrrolidinyl)methyl)phenylamino)-3-pyridyl)acetic acid; 100)3-(6-(4-(4-(N,N-dimethylformamide) Phenyloxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)phenylamino)-3-pyridyl)propionic acid 101)2-(6-(4-(6-) (methylsulfonyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino)-3-pyridyl)acetic acid; 102)3-(6-(4-(6) -(methylsulfonyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino)-3-pyridyl)propionic acid; 103) 2-(6-(4- (6-(Methoxymethyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino)-3-pyridyl)acetic acid; 104)3-(6-(4) -(6-(Methoxymethyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino)-3-pyridyl)propanoic acid.

更具體地，本發明的最佳化合物選自：實施例1至實施例104所述的化合物。More specifically, the most preferred compounds of the invention are selected from the compounds described in Examples 1 to 104.

發明人發現，至少任意一種本發明的化合物對葡萄糖激酶的活性EC50 值在葡萄糖濃度是5mM時是50μM或50μM以下。較佳地，所述化合物對葡萄糖激酶的活性EC50 值在葡萄糖濃度是10mM時是5μM或5μM以下。The inventors have found that, at least any one of the compounds of the present invention glucokinase activity EC 50 value when glucose concentration is 5mM 50μM or 50μM or less. Preferably, the compound 50 values glucokinase activity EC 10mM glucose concentration is 5μM or less when a 5μM.

本發明還進一步提供一種對治療物件施用治療有效量的上述至少任意一種結構式(I)所示化合物，以調節動物或人體內葡萄糖激酶水準或活性的方法。The invention still further provides a method of administering a therapeutically effective amount of at least any one of the compounds of formula (I) above to a therapeutic article to modulate glucokinase levels or activity in an animal or human.

本發明還進一步提供一種對治療物件施用治療有效量的上述至少任意一種結構式(I)所示化合物，以治療及/或預防II型糖尿病或其相關疾病的方 法。本發明還進一步提供了一種對治療物件施用治療有效量的上述至少任意一種結構式(I)所示化合物，以治療或預防I型糖尿病或其相關疾病的方法。The invention still further provides a method of administering a therapeutically effective amount of at least any one of the compounds of formula (I) above to a therapeutic article for the treatment and/or prevention of type 2 diabetes or a related disease thereof. law. The invention still further provides a method of administering a therapeutically effective amount of at least any one of the compounds of formula (I) above to a therapeutic article for the treatment or prevention of type 1 diabetes or a related disorder thereof.

本發明還進一步提供一種對治療物件施用治療有效量的上述至少任意一種結構式(I)所示化合物，以治療或預防肥胖症或其相關疾病的方法。The invention still further provides a method of administering a therapeutically effective amount of at least any one of the compounds of formula (I) above to a therapeutic article for the treatment or prevention of obesity or a related disorder thereof.

本發明還提供上述至少任意一種結構式(I)所示化合物在製藥中的應用。The present invention also provides the use of at least any one of the above compounds of the formula (I) in pharmaceuticals.

本發明還進一步提供上述至少任意一種結構式(I)所示化合物，在製備調節動物或人體內葡萄糖激酶水準或活性的藥物中的用途。The invention still further provides the use of at least one of the compounds of formula (I) above for the manufacture of a medicament for modulating the level or activity of glucokinase in an animal or human.

本發明又進一步提供上述至少任意一種結構式(I)所示化合物，在製備治療或預防II型糖尿病或其相關疾病的藥物中的用途。The present invention still further provides the use of at least any one of the above compounds of the formula (I) for the preparation of a medicament for the treatment or prevention of type 2 diabetes or a related disease thereof.

本發明又進一步提供上述至少任意一種結構式(I)所示化合物，在製備治療或預防I型糖尿病或其相關疾病的藥物中的用途。The present invention still further provides the use of at least any one of the compounds of the above formula (I) for the preparation of a medicament for treating or preventing type I diabetes or a related disease thereof.

本發明又進一步提供結構式(I)所示化合物，在製備治療或預防肥胖症或其相關疾病的藥物中的用途。The present invention still further provides the use of a compound of the formula (I) for the preparation of a medicament for the treatment or prevention of obesity or a related disease thereof.

本發明再進一步提供一種藥物組合物，所述藥物組合物包含有效治療劑量的本發明的至少任意一種結構式(I)所示化合物和至少一種可藥用的賦形劑。The invention still further provides a pharmaceutical composition comprising a therapeutically effective amount of at least any one of the compounds of formula (I) of the invention and at least one pharmaceutically acceptable excipient.

本發明還進一步提供所述藥物組合物在製藥中的應用。The invention still further provides the use of the pharmaceutical composition in pharmaceuticals.

本發明還進一步提供所述藥物組合物在製備調節動物或人體內葡萄糖激酶水準或活性的藥物中的用途。The invention still further provides the use of the pharmaceutical composition for the manufacture of a medicament for modulating the level or activity of glucokinase in an animal or human.

本發明又進一步提供所述藥物組合物在製備治療或預防II型糖尿病或其相關疾病的藥物中的用途。The invention still further provides the use of the pharmaceutical composition for the manufacture of a medicament for the treatment or prevention of type 2 diabetes or a related disease thereof.

本發明又進一步提供所述藥物組合物在製備治療或預防I型糖尿病或其相關疾病的藥物中的用途。The present invention still further provides the use of the pharmaceutical composition for the preparation of a medicament for treating or preventing type I diabetes or a related disease thereof.

另外，本發明又進一步提供一種調節動物或人體內葡萄糖激酶水準或活性的方法，該方法是對治療物件施用有效治療劑量的上述藥物組合物。Further, the present invention still further provides a method of modulating the level or activity of glucokinase in an animal or human by administering a therapeutically effective amount of the above pharmaceutical composition to the therapeutic article.

本發明又進一步提供一種治療或預防II型糖尿病或其相關疾病的方法，該方法是對治療物件施用有效治療劑量的上述藥物組合物。The present invention still further provides a method of treating or preventing Type II diabetes or a related disease thereof, which comprises administering a therapeutically effective amount of the above pharmaceutical composition to a therapeutic article.

另外，本發明又進一步提供一種治療或預防I型糖尿病或其相關疾病的方法，該方法是對治療物件施用有效治療劑量的上述藥物組合物。Further, the present invention still further provides a method of treating or preventing type I diabetes or a related disease thereof, which comprises administering a therapeutically effective amount of the above pharmaceutical composition to a therapeutic article.

另外，本發明又進一步提供一種治療或預防肥胖症或其相關疾病的方法，該方法是對治療物件施用有效治療劑量的上述藥物組合物。Further, the present invention still further provides a method of treating or preventing obesity or a related disease thereof, which comprises administering a therapeutically effective amount of the above pharmaceutical composition to a therapeutic article.

本發明所述術語含義如下：The meanings of the terms of the invention are as follows:

「Cm-n 」(其中，m和n都是整數)是指一個包含數量從m到n個碳原子的原子團。是指例如，C1-3 是指包含1、2或3個碳原子的原子團。"C mn " (where m and n are integers) means an atomic group containing a number of carbon atoms from m to n. It means, for example, that C 1-3 means an atomic group containing 1, 2 or 3 carbon atoms.

「n元」或「n-元」(其中，n是整數)是指在一個環中的原子的數量。例如，吡啶基是一個6-元芳基。"n-ary" or "n-ary" (where n is an integer) refers to the number of atoms in a ring. For example, a pyridyl group is a 6-membered aryl group.

術語「烷基」是指從一個母體烷烴、烯烴或炔烴分子的一個碳上去掉一個氫原子所形成的飽和或不飽和的、支鏈或直鏈的單價碳氫化合物基團。根據其飽和度的特殊水準，分別採用術語「烷基」、「烯基」、「炔基」。具有代表性的烷基基團包括，但不限於，甲基、乙基、乙烯基、乙炔基、丙基，例如：1-丙基、2-丙基、丁基，例如：1-丁基、2-丁基、2-甲基-1-丙基、2-甲基-2-丙基、叔丁基等類似基團。在一些實施例中，烷基基團由1到20個碳原子組成。本發明所述術語低級烷基是指包含1-6個碳原子的烷基基團。有代表性的低級烷基基團包括，但不限於，甲基、乙基、丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、戊基、新戊基或己基。The term "alkyl" refers to a saturated or unsaturated, branched or straight chain monovalent hydrocarbon radical formed by the removal of one hydrogen atom from a carbon of a parent alkane, alkene or alkyne molecule. The terms "alkyl", "alkenyl" and "alkynyl" are used depending on the particular level of saturation. Representative alkyl groups include, but are not limited to, methyl, ethyl, vinyl, ethynyl, propyl, for example: 1-propyl, 2-propyl, butyl, for example: 1-butyl , a similar group such as 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, tert-butyl or the like. In some embodiments, the alkyl group consists of from 1 to 20 carbon atoms. The term lower alkyl as used in the present invention refers to an alkyl group containing from 1 to 6 carbon atoms. Representative lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl Or hexyl.

術語「烷氧基」是指-OR，其中R是烷基。有代表性的烷氧基基團包括，但並不僅限於，甲氧基、乙氧基、丙氧基、丁氧基、環己氧基等類似基團。本發明所述術語「低級烷氧基」是指包含1-6個碳原子的烷氧基基團。The term "alkoxy" refers to -OR wherein R is alkyl. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. The term "lower alkoxy" as used in the present invention means an alkoxy group having 1 to 6 carbon atoms.

「芳基」是指從一個母體芳環系統的一個碳原子上移走一個氫原子所形成的單價的芳烴基團。芳基包括含5-和6-元碳環的芳香環，如：苯；至少有一個環是碳環或芳香環的雙環系統，如：萘、二氫化茚和四氫萘；和至少一個環是碳環或芳環的三環系統，如：芴。例如，芳基包括5-和6-元的碳環的芳香環稠合包含至少一個選自N、O或S的雜原子的5-到7-元雜環烴基。具體的，芳基基團可以包含6到10個碳原子。"Aryl" means a monovalent aromatic hydrocarbon radical formed by the removal of one hydrogen atom from a carbon atom of a parent aromatic ring system. The aryl group includes an aromatic ring having a 5- and 6-membered carbocyclic ring such as benzene; a bicyclic ring system in which at least one ring is a carbocyclic or aromatic ring, such as naphthalene, indane and tetrahydronaphthalene; and at least one ring It is a three-ring system of carbon or aromatic rings, such as: 芴. For example, an aryl group includes a 5- and 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered heterocycloalkyl group containing at least one hetero atom selected from N, O or S. Specifically, the aryl group may contain 6 to 10 carbon atoms.

雜環芳基是指，從一個母體雜環系統的一個碳原子上移走一個氫原子所形成的單價的雜原子基團。雜環芳基包括：5-到7-元芳香、單環，包括至少一個選自N，O和S的雜原子，例如，1到4個、或較佳1到3個，環上的其他原子為碳；多雜環烴基環包括至少一個選自N，O和S的雜原子，例如，1到4個、或較佳1到3個，環上的其他原子為碳，且其中至少一個雜原子在芳環上。特佳的雜環芳基基團是C3-10 的雜環芳基，包括但不限於，吡咯基、呋喃基、噻吩基、吡啶基、吡喃基、吡唑基、嘧啶基、咪唑基、噻唑基、惡唑基、吲哚基、苯並呋喃基、苯並噻唑基、咔唑基、喹啉基、異喹啉基、嘌呤基等類似基團。Heterocyclic aryl refers to a monovalent heteroatom group formed by the removal of one hydrogen atom from a carbon atom of a parent heterocyclic ring system. The heterocyclic aryl group includes a 5- to 7-membered aromatic, monocyclic ring including at least one hetero atom selected from N, O and S, for example, 1 to 4, or preferably 1 to 3, other on the ring. The atom is carbon; the polyheterocycloalkyl ring includes at least one hetero atom selected from N, O and S, for example, 1 to 4, or preferably 1 to 3, and the other atoms on the ring are carbon, and at least one of them The hetero atom is on the aromatic ring. Particularly preferred heterocyclic aryl groups are C 3-10 heterocyclic aryl groups including, but not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, imidazolyl A similar group such as thiazolyl, oxazolyl, fluorenyl, benzofuranyl, benzothiazolyl, oxazolyl, quinolyl, isoquinolyl, indolyl and the like.

但是，在任何情況下，雜環芳基和芳基都不會彼此交叉或相互包含。因此，根據以上定義，如果至少一個全碳芳香環與一個雜環芳基相稠合，得到的是雜環芳基，而不是芳基。However, in any case, the heterocyclic aryl group and the aryl group do not cross each other or contain each other. Thus, according to the above definition, if at least one all-carbon aromatic ring is fused to a heterocyclic aryl group, a heterocyclic aryl group is obtained instead of an aryl group.

「環烷基」指飽和的或不飽和的但非芳香族的環烷基基團。根據其飽和度的特殊水準，分別採用術語「環烷基」、「環烯基」、「環炔基」。有代表性的環烷基基團包括，但不限於，環丙烷、環丁烷、環戊烷、環己烷或環己烯等 類似基團。具體的，環烷基基團可以是C3-10 的環烷基，如：C3-6 環烷基。"Cycloalkyl" means a saturated or unsaturated but non-aromatic cycloalkyl group. The terms "cycloalkyl", "cycloalkenyl", and "cycloalkynyl" are used depending on the particular level of saturation. Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane or cyclohexene, and the like. Specifically, the cycloalkyl group may be a C 3-10 cycloalkyl group such as a C 3-6 cycloalkyl group.

「雜環烴基」是指飽和的或不飽和的，但非芳香族的，環烴基基團，而且其中一個或多個碳原子(以及所連接的氫原子)分別被相同的或不同的雜原子和相應所連接的氫原子所取代。有代表性的取代碳原子的雜原子包括，但不限於，N、P、O、S和Si。當需要描述特定的飽和度時，分別採用術語「雜環烷基」或「雜環烯基」等。具有代表性的雜環烴基基團包括，但不限於，環氧化合物、咪唑烷、嗎啉、呱嗪、呱啶、吡唑烷、吡咯烷、奎寧環、四氫呋喃或四氫吡喃等類似基團。含取代基的雜環烴基也包含被至少一個含氧的(=O)或氧化物(-O-)取代基取代的環系統，如：呱啶-氮-氧化物、嗎啉基-氮-氧化物、1-氧代-1-硫嗎啉基和1-二氧-1-硫嗎啉基。"Heterocycloalkyl" means a saturated or unsaturated, but non-aromatic, cycloalkyl group, and wherein one or more of the carbon atoms (and the attached hydrogen atom) are respectively the same or different heteroatoms And replaced by the corresponding connected hydrogen atom. Representative heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. When it is necessary to describe a specific saturation, the terms "heterocycloalkyl" or "heterocyclenyl" are used, respectively. Representative heterocycloalkyl groups include, but are not limited to, epoxy compounds, imidazolidines, morpholines, pyridazines, acridines, pyrazolidines, pyrrolidines, quinuclidine rings, tetrahydrofuran or tetrahydropyran, and the like. Group. The substituted heterocyclic hydrocarbon group also includes a ring system substituted with at least one oxygen-containing (=O) or oxide (-O-) substituent such as acridine-nitrogen-oxide, morpholinyl-nitrogen- Oxide, 1-oxo-1-thiomorpholinyl and 1-dioxy-1-thiomorpholinyl.

但是，在任何情況下，雜環烴基和環烷基都不會彼此交叉或相互包含。因此，根據上述定義，如果至少一個全碳環與一個雜環烴基稠合形成一個二-、多-或螺-環，將仍然定義為雜環烴基。However, in any case, the heterocyclic hydrocarbon group and the cycloalkyl group do not cross each other or contain each other. Thus, according to the above definition, if at least one percarbocyclic ring is fused to a heterocycloalkyl group to form a di-, poly- or spiro-ring, it will still be defined as a heterocycloalkyl group.

「鹵素」是指氟(F)、氯(Cl)、溴(Br)或碘(I)原子。"Halogen" means a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

「鹵代基」是指氟代、氯代、溴代或碘代基團。"Halo" means a fluoro, chloro, bromo or iodo group.

「含取代基的」是指一個基團中的一個或多個氫原子分別被相同的或不同的取代基所取代。具有代表性的取代基包括，但不限於，X、C3-20 環烷基、-OR13 、SR13 、=O、=S、-C(O)R13 、-C(S)R13 、=NR13 、-C(O)OR13 、-C(S)OR13 、-NR13 R14 、-C(O)NR13 R14 、氰基、硝基、-S(O)2 R13 、-OS(O2 )OR13 、-OS(O)2 R13 、-OP(O)(OR13 )(OR14 )；其中任一個X是一個獨立的鹵素(F、Cl、Br或I)，R13 和R14 獨立地選自氫、低級烷基或低級鹵代烴基。較佳的取代基是：-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、叔丁氧基、-SCH3 、-SC2 H5 、甲醛基、-C(OCH3 )、氰基、硝基、CF3 、-OCF3 、 氨基、二甲胺基、甲硫基、磺醯基或乙醯基。特佳的取代基是-F、-Cl或-Br。"Substituent-containing" means that one or more hydrogen atoms in a group are each substituted with the same or different substituents. Representative substituents include, but are not limited to, X, C 3-20 cycloalkyl, -OR 13 , SR 13 , =O, =S, -C(O)R 13 , -C(S)R 13 , =NR 13 , -C(O)OR 13 , -C(S)OR 13 , -NR 13 R 14 , -C(O)NR 13 R 14 , cyano, nitro, -S(O) 2 R 13 , -OS(O 2 )OR 13 , -OS(O) 2 R 13 , -OP(O)(OR 13 )(OR 14 ); any one of X is an independent halogen (F, Cl, Br or I), R 13 and R1 4 are independently selected from hydrogen, lower alkyl or lower halogenated hydrocarbon. Preferred substituents are: -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methylthio, Sulfonyl or ethyl fluorenyl. Particularly preferred substituents are -F, -Cl or -Br.

本發明所述「化合物」包括結構式為(I)的化合物，及其所有藥學上可接受的形式。這些化合物的藥學上可接受的形式包括鹽、溶劑化物、非共價複合物、螯合物或其前驅藥物、或上述所有形式的任意混合物。The "compound" of the present invention includes a compound of the formula (I), and all pharmaceutically acceptable forms thereof. The pharmaceutically acceptable forms of these compounds include salts, solvates, non-covalent complexes, chelates or precursor drugs thereof, or any mixture of all of the above.

所述「藥學上可接受的」是指公知用於動物，特別是用於人體。"Pharmaceutically acceptable" means that it is well known for use in animals, particularly in humans.

治療有效量是指一個化合物施用於治療主體時治療並且預防及/或抑制一種疾病、病情、症狀、適應症及/或不適的至少一種臨床症狀時，足以對這種疾病、病情、適應症、不適或症狀的治療產生一定效果的劑量。具體的「有效治療劑量」可以根據化合物，用藥途徑，患者年齡，患者體重，所治療的疾病或不適的類型、症狀和嚴重程度等的不同而變化。在任意可能的情況下，一個合適的劑量對那些在本領域的專業人員可以是顯而易見的，也可以是用常規實驗方法確定的。A therapeutically effective amount is one in which a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical condition of a disease, condition, symptom, indication, and/or discomfort, sufficient for the disease, condition, indication, Treatment of discomfort or symptoms produces a dose that is effective. The specific "effective therapeutic dose" may vary depending on the compound, the route of administration, the age of the patient, the weight of the patient, the type of the disease or condition being treated, the symptoms and severity, and the like. Wherever practicable, a suitable dosage will be apparent to those skilled in the art and may be determined by routine experimentation.

本發明有關一種能調節動物或人體內葡萄糖激酶水準或活性的化合物，和採用這些化合物製備治療或預防與體內葡萄糖激酶水準或活性相關病症的藥物。所述化合物具有結構簡單、製備方法簡便、作為活性成分其治療效果好的特點。所述化合物作為一種即將上市的藥物，具有成本低，服用方便的特點，更有利於這些藥物的廣泛應用，能更有效地幫助病人克服病痛，提高生活品質。The present invention relates to a compound which modulates the level or activity of glucokinase in an animal or human, and the use of these compounds for the preparation of a medicament for the treatment or prevention of a condition associated with glucokinase levels or activity in vivo. The compound has the characteristics of simple structure, simple preparation method and good therapeutic effect as an active ingredient. As a kind of medicine to be marketed, the compound has the characteristics of low cost and convenient taking, and is more conducive to the wide application of these drugs, and can more effectively help patients overcome the pain and improve the quality of life.

本發明使用包括但並不僅限於以下實施例來進一步闡述本發明所述的結構式I的化合物的製備。The present invention uses, but is not limited to, the following examples to further illustrate the preparation of the compounds of structural formula I described herein.

本發明使用包括但並不僅限於以下實施例來進一步闡述本發明所述的結構式(I)的化合物的製備。The present invention uses, but is not limited to, the following examples to further illustrate the preparation of the compounds of formula (I) described herein.

下述實施例僅用於說明本發明的具體實施方式，以使本領域的技術人員能夠實施本發明，但不用於限制本發明的保護範圍。本發明的具體實施方式中，未作特別說明的技術手段或方法等為本技術領域的常規技術手段或方法等。本發明中的化合物可以用但並不限於用以下一個或多個通用反應途徑來合成：The following examples are only intended to illustrate the specific embodiments of the present invention to enable those skilled in the art to practice the invention, but not to limit the scope of the invention. In the specific embodiments of the present invention, the technical means or methods, etc., which are not specifically described, are conventional technical means or methods and the like in the technical field. The compounds of the invention may be synthesized, but are not limited to, by one or more of the following general reaction pathways:

通用途徑I：General Approach I:

通用途徑：General approach:

實施例1Example 1

2-甲基磺醯基-5-((2-(2-吡咯烷酮基)甲基)-(4-(2-吡啶基)氨基))苯氧基吡啶的合成：Synthesis of 2-methylsulfonyl-5-((2-(2-pyrrolidino)methyl)-(4-(2-pyridyl)amino))phenoxypyridine:

氮氣保護下，500ml反應瓶中，加入20g(144mmol，1eq.)對硝基苯酚(化合物1 )，加入200ml二硫化碳溶解。加入20g無水AlCl3 (144mmol，1eq.)，加熱回流。緩慢滴加19.2g(144mmol，1eq.)N-氯甲基環丁醯胺。繼續反應約2小時，反應完畢，將反應液倒入到碎冰中，攪拌，過濾。管柱色譜分離得到12.1g白色固體2 ，產率45%。Under a nitrogen atmosphere, 20 g (144 mmol, 1 eq.) of p-nitrophenol (Compound 1 ) was added to a 500 ml reaction flask, and 200 ml of carbon disulfide was added thereto to dissolve. 20 g of anhydrous AlCl 3 (144 mmol, 1 eq.) was added and heated to reflux. 19.2 g (144 mmol, 1 eq.) of N-chloromethylcyclobutylamine was slowly added dropwise. The reaction was continued for about 2 hours. After completion of the reaction, the reaction solution was poured into crushed ice, stirred, and filtered. Column chromatography yielded 12.1 g of a white solid 2 with a yield of 45%.

反應瓶中加入236mg(1.0 mmol，1eq.)2 ，加入DMF20ml，緩慢加入71mg70%KH(1.2mmol，1.2eq.)，攪拌，常溫反應1小時後，加入273mg(1.2mmol，1.2eq.)5-氯-2-甲磺醯基吡啶，攪拌，反應過夜。TLC檢測反 應完畢。緩慢加入10ml50%乙醇淬冷反應。減壓蒸出溶劑。用管柱色譜分離得到180mg的3 ，產率50%。236 mg (1.0 mmol, 1 eq.) 2 was added to the reaction flask, 20 ml of DMF was added, 71 mg of 70% KH (1.2 mmol, 1.2 eq.) was slowly added, stirred, and reacted at room temperature for 1 hour, then 273 mg (1.2 mmol, 1.2 eq.) was added. -Chloro-2-methanesulfonylpyridine, stirred and allowed to react overnight. The reaction was completed by TLC. The reaction was quenched by slowly adding 10 ml of 50% ethanol. The solvent was distilled off under reduced pressure. Separation by column chromatography gave 180 mg of 3 in 50% yield.

100ml氫化儀中，加入400mg(1.02mmol，1eq.)3 ，加入乙醇40ml，加入70mg雷尼鎳，攪拌，氮氣置換兩次，氫氣置換1次，氫氣壓力保持在4atm，50℃反應直至不再吸氫，過濾除去催化劑，減壓除去溶劑。快速色譜法純化得到221mg 4，產率60%。In a 100 ml hydrogenation apparatus, 400 mg (1.02 mmol, 1 eq.) 3 was added, 40 ml of ethanol was added, 70 mg of Raney nickel was added, stirred, replaced with nitrogen twice, hydrogen was replaced once, hydrogen pressure was maintained at 4 atm, and reaction at 50 ° C was stopped. Hydrogen was absorbed, the catalyst was removed by filtration, and the solvent was removed under reduced pressure. Purification by flash chromatography gave 221 mg of 4, yield 60%.

反應瓶中加入361mg(1.0mmol，1eq.)4 ，加入DMF 20ml，緩慢加入43mg70%NaH(1.2mmol，1.2eq.)，攪拌，常溫反應1小時後，加入136mg(1.2mmmol，1.2eq.)2-氯吡啶，攪拌，反應過夜。TLC檢測反應完畢，緩慢加入10ml水淬冷反應。減壓蒸出溶劑。用管柱色譜純化得到180mg的終產物5，產率40%，LC-MS[M+H]-m/z為439。361 mg (1.0 mmol, 1 eq.) 4 was added to the reaction flask, 20 ml of DMF was added, 43 mg of 70% NaH (1.2 mmol, 1.2 eq.) was slowly added, stirred, and reacted at room temperature for 1 hour, then 136 mg (1.2 mmmol, 1.2 eq.) was added. 2-Chloropyridine, stirred and allowed to react overnight. The reaction was completed by TLC, and 10 ml of water was slowly added to quench the reaction. The solvent was distilled off under reduced pressure. Purification by column chromatography gave 180 mg of EtOAc (yield: 40%).

實施例35Example 35

N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-2-吡啶基胺的合成：Synthesis of N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-2-pyridylamine:

反應瓶中加入344mg(2.0 mmol，1eq.)3-甲基-5-硝基-2-羥基-吡啶，加入DMF20ml，緩慢加入86mg70%NaH(2.4mmol，1.2eq.)，攪拌，升高溫度至90℃。反應1小時後，加入254mg(2.4mmol，1.2eq.)3-氯四氫呋喃，90℃條件下，攪拌，反應過夜。TLC檢測反應完畢。緩慢加入10ml 50%乙醇溶液淬冷反應。減壓蒸出溶劑。快速色譜純化得到158mg的1 ，產率33%。Add 344 mg (2.0 mmol, 1 eq.) of 3-methyl-5-nitro-2-hydroxy-pyridine to the reaction flask, add 20 ml of DMF, slowly add 86 mg of 70% NaH (2.4 mmol, 1.2 eq.), stir, raise the temperature. To 90 ° C. After reacting for 1 hour, 254 mg (2.4 mmol, 1.2 eq.) of 3-chlorotetrahydrofuran was added, and the mixture was stirred at 90 ° C overnight. The reaction was completed by TLC. The reaction was quenched by slowly adding 10 ml of 50% ethanol solution. The solvent was distilled off under reduced pressure. Purification by flash chromatography gave 158 mg of 1 in 33% yield.

反應瓶中，氮氣保護下，加入1.9g(11mmol，1.1eq)對-甲磺醯基苯酚、2.24g(10mmol，1eq.)1 、2.6g(31.5mmol，3eq.)NaHCO3 和50ml乙醇，攪拌，回流過夜。TLC檢測反應完畢。減壓蒸乾溶劑。用二氯甲烷溶解，過濾除去不溶物，減壓蒸去二氯甲烷，過液相色譜純化得到1.3g淡黃色固體2，產率34%。In a reaction flask, 1.9 g (11 mmol, 1.1 eq) of p-methanesulfonyl phenol, 2.24 g (10 mmol, 1 eq.) 1 , 2.6 g (31.5 mmol, 3 eq.) NaHCO 3 and 50 ml of ethanol were added under a nitrogen atmosphere. Stir and reflux overnight. The reaction was completed by TLC. The solvent was evaporated to dryness under reduced pressure. The mixture was dissolved in dichloromethane, and the insoluble material was filtered, and dichloromethane was evaporated under reduced pressure, and purified by liquid chromatography to give 1.3 g of pale yellow solid (yield: 34%).

100ml氫化儀中，加入400mg(1.06mmol，1eq.)2，加入無水乙醇40ml和70mg雷尼鎳，攪拌，氮氣置換兩次，氫氣置換1次，氫氣壓力保持在4atm，50℃反應直至不再吸氫，過濾除去催化劑，減壓蒸餾除去溶劑。快速色譜純化得到273mg3 ，產率74%。In a 100 ml hydrogenation apparatus, 400 mg (1.06 mmol, 1 eq.) 2 was added, 40 ml of absolute ethanol and 70 mg of Raney nickel were added, stirred, replaced with nitrogen twice, hydrogen was replaced once, hydrogen pressure was maintained at 4 atm, and reaction was continued at 50 ° C until no longer. Hydrogen absorption, removal of the catalyst by filtration, and distillation of the solvent under reduced pressure. Purification by flash chromatography to give 273mg 3, yield 74%.

反應瓶中加入348mg(1.0mmol，1eq.)3 ，加入DMF20ml，緩慢加入43mg70%NaH(1.2mmol，1.2eq.)，攪拌，常溫反應1小時後，加入136mg(1.2mmol，1.2eq.)2-氯吡啶，攪拌，反應過夜。TLC檢測反應完畢。緩慢加入10ml水淬冷反應。減壓蒸出溶劑。快速色譜分離得到182mg的4 ，產率43%，LC-MS[M+H]-m/z為427。348 mg (1.0 mmol, 1 eq.) 3 was added to the reaction flask, 20 ml of DMF was added, 43 mg of 70% NaH (1.2 mmol, 1.2 eq.) was slowly added, stirred, and reacted at room temperature for 1 hour, then 136 mg (1.2 mmol, 1.2 eq.) was added. -Chloropyridine, stirred, and allowed to react overnight. The reaction was completed by TLC. The reaction was quenched by slowly adding 10 ml of water. The solvent was distilled off under reduced pressure. Flash chromatography gave 182 mg of 4 , yield 43%, LC-MS [M+H]-m/z 427.

實施例53Example 53

2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H -四氫吡喃基)氨基)苯胺基)吡啶2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2 H -tetrahydropyranyl)amino)anilino)pyridine

反應瓶中加4-(甲基磺醯基)苯酚2g(11.6mmol，1.1eq.)，1-氯-2,4-二硝基苯2.1g(10.5mmol，1eq.)和碳酸氫鈉2.6g(31.5mmol，3eq.)，加入乙醇，所得混合物攪拌回流過夜。反應完全後，濾去溶劑，加入二氯甲烷洗滌，再用管柱色譜純化，得到1.7g的1，產率50%。To the reaction flask was added 2 g of 4-(methylsulfonyl)phenol (11.6 mmol, 1.1 eq.), 1-chloro-2,4-dinitrobenzene 2.1 g (10.5 mmol, 1 eq.) and sodium hydrogencarbonate 2.6. g (31.5 mmol, 3 eq.), ethanol was added and the mixture was stirred and refluxed overnight. After completion of the reaction, the solvent was filtered, washed with dichloromethane, and then purified by column chromatography to yield 1.7 g of y.

1(1g，2.9mmol，1eq.)先溶解在乙醇中，加入Na2 S(253mg，3.2mmol，1.1eq.)，然後在室溫下攪拌4小時。反應完成後，真空抽去溶劑，用管柱色譜純化得到455mg的2 ，產率50%。1 (1 g, 2.9 mmol, 1 eq.) was dissolved in ethanol, and Na 2 S (253 mg, 3.2 mmol, 1.1 eq.) was added, and then stirred at room temperature for 4 hours. After completion of the reaction, the solvent was stripped off in vacuo to afford 455mg of 2, 50% yield purified by column chromatography.

2 (455mg，1.4mmol，1eq.)先溶解在DMF中，加入NaH(70mg，1.76mmol，1.1eq.)，然後在室溫下攪拌1小時，再加入4-氯-2H-四氫吡喃(211mg，1.76mmol，1.1eq.)，攪拌過夜。反應完全後，加水，濾去所有溶劑，所得產物再用管柱色譜純化，得到942mg的3 ，產率60%。 2 (455 mg, 1.4 mmol, 1 eq.) was dissolved in DMF, then NaH (70 mg, 1.76 mmol, 1.1 eq.), then stirred at room temperature for 1 hour, then 4-chloro-2H-tetrahydropyran (211 mg, 1.76 mmol, 1.1 eq.), stirred overnight. After completion of the reaction, water was added, and all the solvent was filtered off, and the obtained product was purified by column chromatography to yield 942 g of 3 , yield 60%.

3 (500mg，1.2mmol，1eq.)先溶解在乙醇中，加入Zn(151mg，2.4mmol，2eq.)和CaCl2 (133mg，1.2mmol，1eq.)，然後在室溫下攪拌4小時。減壓蒸出溶劑，用管柱色譜分離得到230mg的4 ，產率50%。 3 (500 mg, 1.2 mmol, 1 eq.) was dissolved in ethanol, and Zn (151 mg, 2.4 mmol, 2 eq.) and CaCl 2 (133 mg, 1.2 mmol, 1 eq.) were added, and then stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and then purified by column chromatography to yield 230 mg of 4 , yield 50%.

4 (200mg，1.8mmol，1eq.)先溶解在DMF中，加入NaH(80mg，1.98mmol， 1.1eq.)，然後在室溫下攪拌1小時，再加入2-氯-2H-四氫吡喃(223mg，1.98mmol，1.1eq.)，攪拌過夜。反應完全後，加水，濾去所有溶劑，所得產物再用管柱色譜純化，得到100mg的終產品5 ，產率40%，LC-MS[M+H]-m/z為441。 4 (200 mg, 1.8 mmol, 1 eq.) was dissolved in DMF, then NaH (80 mg, 1.98 mmol, 1.1 eq.) was added, then stirred at room temperature for 1 hour, then 2-chloro-2H-tetrahydropyran was added. (223 mg, 1.98 mmol, 1.1 eq.), stirred overnight. After completion of the reaction, water was added, and all the solvent was filtered, and the obtained product was purified by column chromatography to give 100 mg of the final product 5 of 40% yield of LC-MS[M+H]-m/z 441.

實施例56Example 56

5-甲基-2-(4-(4-(甲基磺醯基)苯硫基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑的合成：5-methyl-2-(4-(4-(methylsulfonyl)phenylthio)-3-((4-2H-tetrahydropyranyl)methyl)anilino)1,2,4 - Synthesis of thiadiazole:

2-氯-5-硝基苯酚(2g，11.5mmol，1eq.)先溶解在DMF中，加入NaH(440mg，12.7mmol，1.1eq.)，然後在室溫下攪拌1小時，再加入4-氯-2H-四氫吡喃(1.5g，12.7mmol，1.1eq)，攪拌過夜。反應完全後，加水，濾去所有溶劑，所得產物再用管柱色譜純化，得到1.7g的1，產率70%。2-Chloro-5-nitrophenol (2 g, 11.5 mmol, 1 eq.) was first dissolved in DMF, NaH (440 mg, 12.7 mmol, 1.1 eq.) was added, then stirred at room temperature for 1 hour, then 4- Chloro-2H-tetrahydropyran (1.5 g, 12.7 mmol, 1.1 eq) was stirred overnight. After completion of the reaction, water was added, and all the solvent was filtered, and the obtained product was purified by column chromatography to yield 1.7 g of y.

4-(甲基磺醯基)苯酚(1g，3.9mmol，1.1eq.)，1 (900mg，3.5mmol，1eq.)和碳酸氫鈉(882mg，10.5mmol，3eq.)，加入乙醇，所得混合物攪拌回流過夜。反應完全後，濾去溶劑，加入二氯甲烷洗滌過濾，再用管柱色譜純化，得到477mg的2 ，產率30%。4-(methylsulfonyl)phenol (1 g, 3.9 mmol, 1.1 eq.), 1 (900 mg, 3.5 mmol, 1 eq.) and sodium hydrogencarbonate (882 mg, 10.5 mmol, 3 eq.). Stir and reflux overnight. After completion of the reaction, the solvent was filtered off, washed with dichloromethane, and then purified by column chromatography to yield 477 g of 2

2 (300mg，0.733mmol，1eq.)先溶解在乙醇中，加入Zn(93mg，1.466mmol，2eq.)和CaCl2 (81mg，0.733mmol，1eq.)，然後在室溫下攪拌4小時。減壓蒸出溶劑。用管柱色譜純化得到110mg的3 ，產率40%。 2 (300 mg, 0.733 mmol, 1 eq.) was dissolved in ethanol, and Zn (93 mg, 1.466 mmol, 2 eq.) and CaCl 2 (81 mg, 0.733 mmol, 1 eq.) were added, followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure. Purification by column chromatography gave 110 mg of 3 in 40% yield.

3 (100mg，0.26mmol，1eq.)先溶解在DMF中，加入NaH(12mg，0.29mmmol，1.1eq.)，然後在室溫下攪拌1小時，再加入3-氯-5-甲基-1,2,4-1,2,4-噻二唑(36mg，0.29mmol，1.1eq)，攪拌過夜。反應完全後，加水，過濾除去溶劑，所得產物再用管柱色譜純化，得到75mg的終產品4 ，產率60%，LC-MS[M+H]-m/z為479。 3 (100 mg, 0.26 mmol, 1 eq.) was dissolved in DMF, then NaH (12 mg, 0.29mmmol, 1.1 eq.) was added, then stirred at room temperature for 1 hour, then added 3-chloro-5-methyl-1 2,4-1,2,4-thiadiazole (36 mg, 0.29 mmol, 1.1 eq), stirred overnight. After the reaction was completed, water was added, and the solvent was evaporated, and the product obtained was purified by column chromatography to give 75 mg of the final product 4 , yield 60%, LC-MS[M+H]-m/z 479.

實施例65Example 65

2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶的合成：2-(N,N-Dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2-pyrazinyl)amino)) Synthesis of phenoxypyridine:

2.2g化合物1 溶於40ml DMF，0℃以下加入0.59g(70%油液分散體)NaH，攪拌15分鐘。0℃下加入2.45g 2-氯-5-硝基苯甲醛，室溫攪拌30分鐘。將反應液投入冰水中，用乙酸乙酯萃取，得到的有機相用鹽水洗，無水硫酸鈉乾燥，脫除溶劑，所得產物再用管柱色譜純化，得3.80g化合物2 ，產率91%。2.2 g of Compound 1 was dissolved in 40 ml of DMF, and 0.59 g (70% of an oil dispersion) of NaH was added below 0 ° C, and stirred for 15 minutes. 2.45 g of 2-chloro-5-nitrobenzaldehyde was added at 0 ° C and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate, the resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, solvent was removed, the resulting product was then purified by column chromatography to give compound 2 3.80g, 91% yield.

3.80g化合物2 ，溶於200ml甲醇中，室溫下加入0.50gNaBH4 ，攪拌30分鐘。3.80 g of compound 2 was dissolved in 200 ml of methanol, and 0.50 g of NaBH 4 was added at room temperature and stirred for 30 minutes.

蒸乾甲醇，加水和加乙酸乙酯萃取，有機相鹽水洗，無水硫酸鈉乾燥，脫除溶劑得2.64g化合物3 。產率69%。Methanol was evaporated to dryness, added water and the extracted with ethyl acetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, and the solvent removed to give 2.64g of compound 3. The yield was 69%.

0.44g化合物3 溶於20mlTHF中，加入0.46g三乙胺，滴加0.23ml甲基 磺醯氯，滴加完畢，攪拌30分鐘。加乙酸乙酯萃取，有機相鹽水洗，無水硫酸鈉乾燥，過濾後，脫除溶劑得0.60g化合物4 。0.44 g of Compound 3 was dissolved in 20 ml of THF, 0.46 g of triethylamine was added, and 0.23 ml of methylsulfonium chloride was added dropwise, and the addition was completed, followed by stirring for 30 minutes. Extracted with ethylacetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed to give Compound 4 0.60g.

620mg吡咯烷酮溶於15mlDMF，加入143mg(70%油液分散體)氫化鈉，室溫攪拌30分鐘。620 mg of pyrrolidone was dissolved in 15 ml of DMF, and 143 mg (70% of an oil dispersion) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes.

將該溶液冷卻至0℃以下，加入0.60g化合物4 。室溫攪拌30分鐘。加水和加乙酸乙酯萃取，有機相鹽水洗，無水硫酸鈉乾燥，脫除溶劑，所得產物再用管柱色譜純化，得0.39g化合物5 。The solution was cooled to below 0 ° C and 0.60 g of compound 4 was added. Stir at room temperature for 30 minutes. Was added water and the extracted with ethyl acetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, solvent was removed, the resulting product was then purified by column chromatography to give 0.39g of compound 5.

0.39g化合物5 ，分散於0.88g氯化銨的40ml水溶液中，升溫到90℃，加入0.56g鐵粉，攪拌30分鐘。降至室溫，加碳酸鉀和乙酸乙酯萃取，無水硫酸鈉乾燥，脫除溶劑，所得產物再用管柱色譜純化，得0.28g化合物6 ，產率78%。0.39 g of the compound 5 was dispersed in a 40 ml aqueous solution of 0.88 g of ammonium chloride, and the temperature was raised to 90 ° C, 0.56 g of iron powder was added, and the mixture was stirred for 30 minutes. Cooled to room temperature, was added potassium carbonate and extracted with ethyl acetate, dried over anhydrous sodium sulfate, solvent was removed, the resulting product was then purified by column chromatography to give compound 6 0.28g, 78% yield.

210mg化合物6 ，130mg 2-溴吡啶，14mg Pd2 (dba)3 ，21mgBINAP，147mg叔丁醇鉀和2ml二氧六環，於氮氣下80℃反應過夜。反應液蒸乾溶劑，經管柱色譜純化得到51mg的終產品7 ，LC-MS[M+H]-m/z為432，產率20%。210 mg of compound 6 , 130 mg of 2-bromopyridine, 14 mg of Pd 2 (dba) 3 , 21 mg of BINAP, 147 mg of potassium t-butoxide and 2 ml of dioxane were reacted overnight at 80 ° C under nitrogen. The reaction solvent was evaporated to dryness, to give 51mg of 7 final product was purified by column chromatography, LC-MS [M + H ] -m / z 432, 20% yield.

以下表I中的化合物的製備，應用以上實施例所列舉的製備過程： For the preparation of the compounds in Table I below, the preparation procedures exemplified in the above examples were applied:

實施例A：葡糖激酶活性試驗Example A: Glucokinase Activity Test

本試驗最終試驗體積為200uL，所使用最終緩衝條件如下：25mM羥乙基呱嗪乙硫磺酸(HEPES)、5mM葡萄糖、1mM ATP、2mM MgCl2、1mM NAD、1mM DTT、8.5U/mL G6PDH、100nM葡糖激酶和25mM KCl。緩衝區的PH值為7.1。首次製得的混合物A是包括KCl、MgCl2、DTT和葡萄糖的HEPES緩衝區。The final test volume of this test was 200 uL, and the final buffer conditions used were as follows: 25 mM hydroxyethylpyridazine ethanesulfuric acid (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 has a pH of 7.1. The first prepared mixture A was a HEPES buffer including KCl, MgCl2, DTT and glucose.

其次製得的混合物B包括NAD和ATP。The second prepared mixture B includes NAD and ATP.

待測化合物的DMSO溶液、混合物A、混合物B和G6PDH在96-井板上首次混合。然後，加入葡糖激酶以開始反應，並同時在340nm處，每隔5分鐘測一次吸亮度。繪製340nm處吸亮度-時間點變化曲線，並計算其斜率值，由此得到葡萄糖六磷酸的產率。從而測得葡糖激酶的活性。本試驗中採用的本發明所述的化合物，測得的EC50值均小於50μM。化合物較佳的EC50值範圍是10nM~10μM，更較佳的範圍是10nM~1μM，本發明一些實施例的活性試驗結果如表II所示。The DMSO solution of the test compound, Mixture A, Mixture B, and G6PDH were first mixed on a 96-well plate. Then, glucokinase was added to start the reaction, and at the same time, the absorbance was measured every 5 minutes at 340 nm. A luminance-time point change curve at 340 nm was plotted, and the slope value thereof was calculated, thereby obtaining a yield of glucose hexaphosphate. Thus, the activity of glucokinase was measured. The compounds of the invention employed in this assay have EC50 values of less than 50 [mu]M. The preferred EC50 values for the compounds range from 10 nM to 10 [mu]M, more preferably from 10 nM to 1 [mu]M. The results of the activity assays of some embodiments of the invention are shown in Table II.

實施例B：葡萄糖耐量試驗Example B: Glucose tolerance test

先按餵食葡萄糖的水準將小鼠分組，然後給小鼠口服30mg/kg的待測化合物。1小時後，測量血糖水準，按2g/kg劑量給葡萄糖，在30分鐘、60分鐘、120分鐘時檢測小鼠的血糖水準。繪製血糖水準-時間點曲線，得到小鼠的葡萄糖耐量能力。本發明的一些實例的實驗結果如圖1所示。The mice were first grouped according to the level of glucose fed, and then the mice were orally administered with 30 mg/kg of the test compound. After 1 hour, the blood glucose level was measured, glucose was administered at a dose of 2 g/kg, and the blood glucose level of the mice was measured at 30 minutes, 60 minutes, and 120 minutes. The blood glucose level-time point curve was plotted to obtain the glucose tolerance capacity of the mice. Experimental results of some examples of the invention are shown in FIG.

上述實施例僅為充分說明本發明而列舉的具體實施例，本發明的保護範圍以申請專利範圍的內容為準，而不限於上述具體實施例。說明書中公開包括摘要和附圖在內的所有必要技術特徵，及所有方法和過程的步驟，這些特徵及/或步驟互除去至少有一個不相交的組合，都可以任意組合。說明書中公開的包括摘要和附圖在內的每一個技 術特徵，除特別規定外，都可以被功能相同、目的相同或類似的技術特徵替換。因此，除非有明確定義，每個技術特徵公開的僅是通常系列的等同或類似的技術特徵的一個實例。本領域的技術人員在本發明基礎上所作的不脫離本發明實質內容的等同替代或變換，亦均在本發明的保護範圍之內。而這樣的修改亦均在本發明的保護範圍之內。本申請引用的每個參考文獻在此均引用其全文。The above embodiments are merely illustrative of the specific embodiments of the present invention. The scope of the present invention is defined by the scope of the claims, and is not limited to the specific embodiments described above. All necessary technical features, including the abstract and the drawings, and the steps of all methods and processes are disclosed in the specification, and the features and/or steps are removed from each other at least one disjoint combination. Each of the techniques disclosed in the specification, including abstracts and drawings Technical features, unless otherwise specified, may be replaced by technical features that are identical in function, have the same purpose, or are similar. Therefore, unless expressly defined otherwise, each technical feature discloses only one example of the equivalent or similar technical features of the ordinary series. It is also within the scope of the present invention to make equivalent substitutions or alterations of the present invention without departing from the scope of the invention. Such modifications are also within the scope of the present invention. Each of the references cited in this application is hereby incorporated by reference in its entirety.

圖一係表示本發明實施例1、實施例6、實施例13、實施例70、實施例74和實施例101所述的化合物對小鼠糖負荷後絕對血糖值的影響。圖中，橫坐標為時間，縱坐標為血糖濃度。-1小時的點為給化合物的時間點，0小時的點為給葡萄糖的時間點，然後檢測2小時。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the effects of the compounds described in Inventive Example 1, Example 6, Example 13, Example 70, Example 74 and Example 101 on absolute blood glucose levels after glucose load in mice. In the figure, the abscissa is time and the ordinate is blood glucose concentration. The -1 hour point is the time point for the compound, the 0 hour point is the time point for glucose administration, and then 2 hours is detected.

Claims (54)

一種如結構式(I)所示的化合物，及其藥學上可接受的鹽， 其中，W和Y分別獨立地選自N或C；X選自O或S；Z選自C、N、O或S；R1選自：氫、烷基、含取代基的烷基、烯基、含取代基的烯基、炔基、含取代基的炔基、烷氧基、含取代基的烷氧基、C(=O)R5、SR5、SO2 R5或鹵代基；所述R5選自：C1-6 烷基、含取代基的C1-6 烷基、烷氧基、含取代基的烷氧基或NR6R7；所述R6和R7分別獨立地選自：氫、C1-6 烷基、含取代基的C1-6 烷基或者R6和R7連在一起形成一個3~6元環或含取代基的3~6元環；R2選自：氫、烷基、含取代基的烷基、鹵素或鹵代基；R3選自：含取代基的烷基、烯基、含取代基的烯基、炔基、含取代基的炔基、環烷基、含取代基的環烷基、雜環烷基、或含取代基的雜環烷基；R4選自：雜環芳基或含取代基的雜環芳基，且與結構式 (I)中的NH直接相連的原子的雜環芳烴鄰位至少有一邊是N。a compound of the formula (I), and a pharmaceutically acceptable salt thereof, Wherein, W and Y are each independently selected from N or C; X is selected from O or S; Z is selected from C, N, O or S; and R1 is selected from the group consisting of hydrogen, alkyl, substituent-containing alkyl, alkenyl a substituent-containing alkenyl group, an alkynyl group, a substituent-containing alkynyl group, an alkoxy group, a substituent-containing alkoxy group, C(=O)R5, SR5, SO 2 R5 or a halogenated group; said R5 Selected from: C 1-6 alkyl, substituted C 1-6 alkyl, alkoxy, substituent-containing alkoxy or NR 6 R 7 ; said R 6 and R 7 are each independently selected from: hydrogen, C 1 a -6 alkyl group, a C 1-6 alkyl group having a substituent or a combination of R 6 and R 7 to form a 3 to 6 membered ring or a 3 to 6 membered ring having a substituent; and R 2 is selected from the group consisting of hydrogen, alkyl, and An alkyl group, a halogen or a halogen group of a substituent; R3 is selected from the group consisting of a substituent-containing alkyl group, an alkenyl group, a substituent-containing alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, and a substituent-containing group. a cycloalkyl, heterocycloalkyl or a heterocyclic alkyl group having a substituent; R4 is selected from a heterocyclic aryl group or a heterocyclic aryl group having a substituent, and is directly bonded to NH in the formula (I) The heterocyclic aromatic hydrocarbon of the atom has at least one side being N. 根據請求項1所述的化合物，其中，該W為C。 The compound according to claim 1, wherein the W is C. 根據請求項2所述的化合物，其中，該Y為C。 The compound according to claim 2, wherein Y is C. 根據請求項3所述的化合物，其中，該X為O。 The compound according to claim 3, wherein the X is O. 根據請求項4所述的化合物，其中，該Z為C。 The compound according to claim 4, wherein the Z is C. 根據請求項2所述的化合物，其中，該Y為N。 The compound according to claim 2, wherein Y is N. 根據請求項6所述的化合物，其中，該X為O。 The compound according to claim 6, wherein the X is O. 根據請求項7所述的化合物，其中，該Z為C。 The compound according to claim 7, wherein the Z is C. 根據請求項1所述的化合物，其中，該W為N。 The compound according to claim 1, wherein the W is N. 根據請求項9所述的化合物，其中，該Y為C。 The compound according to claim 9, wherein Y is C. 根據請求項10所述的化合物，其中，該X為O。 The compound according to claim 10, wherein the X is O. 根據請求項11所述的化合物，其中，該Z為C。 The compound according to claim 11, wherein the Z is C. 根據請求項9所述的化合物，其中，該Y為N。 The compound according to claim 9, wherein Y is N. 根據請求項13所述的化合物，其中，該X為O。 The compound according to claim 13, wherein the X is O. 根據請求項14所述的化合物，其中，該Z為C。 The compound according to claim 14, wherein the Z is C. 根據請求項1所述的化合物，其中，該X為O。 The compound according to claim 1, wherein the X is O. 根據請求項1所述的化合物，其中，該Y為C。 The compound according to claim 1, wherein the Y is C. 根據請求項1所述的化合物，其中，該Y為N。 The compound according to claim 1, wherein Y is N. 根據請求項1所述的化合物，其中，該Z為C。 The compound according to claim 1, wherein the Z is C. 根據請求項1~19任一項所述的化合物，其中，該R1選自：氫、C1-6 烷基、含取代基的C1-6 烷基、C1-6 烯基、含取代基的C1-6 烯基、C1-6 炔基、含取代基的C1-6 炔基、C1-6烷氧基或含取代基的C1-6烷氧基。19 1 requested item according to any one of the compound, wherein the R1 is selected from: hydrogen, C 1-6 alkyl, substituted group containing C 1-6 alkyl, C 1-6 alkenyl group, a substituted A C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 alkynyl group having a substituent, a C 1-6 alkoxy group or a C1-6 alkoxy group having a substituent. 根據請求項20所述的化合物，其中，該R2為氫；該R3選自：環烷基、含取代基的環烷基、雜環烷基、或含取代基的雜環烷基；該R4選自：5元環或6元環的雜環芳基。 The compound according to claim 20, wherein the R 2 is hydrogen; the R 3 is selected from the group consisting of a cycloalkyl group, a cycloalkyl group having a substituent, a heterocycloalkyl group, or a heterocycloalkyl group having a substituent; It is selected from a 5-membered ring or a 6-membered ring heterocyclic aryl group. 根據請求項21所述化合物，其中，該R3選自： The compound according to claim 21, wherein the R3 is selected from the group consisting of: 根據請求項1~19任一項所述的化合物，其中，該R1選自；氫、C1-3烷基、含取代基的C1-3烷基、C1-3烷氧基或含取代基的C1-3烷氧基。 The compound according to any one of claims 1 to 19, wherein the R1 is selected from the group consisting of hydrogen, a C1-3 alkyl group, a C1-3 alkyl group having a substituent, a C1-3 alkoxy group or a substituent-containing group. C1-3 alkoxy group. 根據請求項1~19任一項所述的化合物，其中，該R1為氫。 The compound according to any one of claims 1 to 19, wherein the R1 is hydrogen. 根據請求項1~19任一項所述的化合物，其中，該R1選自：C(=O)R5、SR5、SO2R5或鹵代烷基；該R5選自：C1-3烷基、含取代基的C1-3烷基、NR6R7、C1-6烷氧基或含取代基的C1-6烷氧基。 The compound according to any one of claims 1 to 19, wherein the R1 is selected from the group consisting of: C(=O)R5, SR5, SO2R5 or a halogenated alkyl group; the R5 is selected from the group consisting of: a C1-3 alkyl group, a substituent-containing group C1-3 alkyl group, NR6R7, C1-6 alkoxy group or a substituted C1-6 alkoxy group. 根據請求項25所述的化合物，其中，該R2為氫；該R3選自：環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基；該R4選自：5元環或6元環的雜環芳基。 The compound according to claim 25, wherein the R 2 is hydrogen; and the R 3 is selected from the group consisting of a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic hydrocarbon group or a substituted heterocyclic hydrocarbon group; and the R 4 is selected from the group consisting of: 5-membered or 6-membered heterocyclic aryl. 根據請求項26所述化合物，其中，該R3選自： The compound according to claim 26, wherein the R3 is selected from the group consisting of: 根據請求項27所述化合物，其中，該R1選自C(=O)R5；該R5選自NR6R7。 The compound according to claim 27, wherein the R1 is selected from the group consisting of C(=O)R5; and the R5 is selected from the group consisting of NR6R7. 根據請求項27所述化合物，其中，該R1選自SO2R5；該 R5選自C1-3烷基。 The compound according to claim 27, wherein the R1 is selected from the group consisting of SO2R5; R5 is selected from C1-3 alkyl. 根據請求項25所述的化合物，其中，該R6和R7分別獨立地選自：氫、C1-4烷基或含取代基的C1-4烷基。 The compound according to claim 25, wherein the R6 and R7 are each independently selected from the group consisting of hydrogen, a C1-4 alkyl group or a C1-4 alkyl group having a substituent. 根據請求項25所述的化合物，其中，該R6和R7選自：R6和R7連在一起形成一個3~6元環或含取代基的3~6元環。 The compound according to claim 25, wherein the R6 and R7 are selected from the group consisting of: R6 and R7 are joined together to form a 3-6-membered ring or a 3- to 6-membered ring containing a substituent. 根據請求項31所述的化合物，其中，該3~6元環或含取代基的3~6元環為雜環，其中雜原子選自O或S。 The compound according to claim 31, wherein the 3- to 6-membered ring or the 3- to 6-membered ring containing a substituent is a heterocyclic ring, wherein the hetero atom is selected from O or S. 根據請求項1~19任一項所述的化合物，其中，該R2為氫。 The compound according to any one of claims 1 to 19, wherein the R2 is hydrogen. 根據請求項1~19任一項所述的化合物，其中，該R2選自：C1-6 烷基或含取代基的C1-6 烷基。Requested item according to any one of claims 1 to 19. A compound according to, wherein the R2 is selected from: C 1-6 alkyl or an optionally substituted C 1-6 alkyl. 根據請求項1~19任一項所述的化合物，其中，該鹵代基為鹵代甲基、鹵代乙基或鹵代丙基。 The compound according to any one of claims 1 to 19, wherein the halogenated group is a halogenated methyl group, a halogenated ethyl group or a halogenated propyl group. 根據請求項1~19任一項所述的化合物，其中，該R3選自：C1-6 烷基、含取代基的C1-6 烷基、C1-6 烯基、含取代基的C1-6 烯基、C1-6 炔基或含取代基的C1-6 炔基。Compound according to any one of claims 1 to 19 according to the requested item, wherein the R3 is selected from: C 1-6 alkyl group, a substituted group containing C 1-6 alkyl, C 1-6 alkenyl group, a substituent containing C 1-6 alkenyl, C 1-6 alkynyl or a substituted C 1-6 alkynyl group. 根據請求項36所述的化合物，其中，該R3選自：C1-3烷基、含取代基的C1-3烷基、C2-4烯基或含取代基的C2-4烯基。 The compound according to claim 36, wherein the R3 is selected from the group consisting of a C1-3 alkyl group, a C1-3 alkyl group having a substituent, a C2-4 alkenyl group or a C2-4 alkenyl group having a substituent. 根據請求項1~19任一項所述的化合物，其中，該R3選自：環烷基、含取代基的環烷基、雜環烴基或含取代基的雜環烴基。 The compound according to any one of claims 1 to 19, wherein the R3 is selected from the group consisting of a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic hydrocarbon group or a substituted heterocyclic hydrocarbon group. 根據請求項1~19任一項所述的化合物，其中，該R3選 自： The compound according to any one of claims 1 to 19, wherein the R3 is selected from the group consisting of: 根據請求項1~19任一項所述的化合物，其中，該R4為選自5元環或6元環的雜環芳基。 The compound according to any one of claims 1 to 19, wherein the R4 is a heterocyclic aryl group selected from a 5-membered ring or a 6-membered ring. 根據請求項1所述化合物，其中該化合物選自：1)2-甲基磺醯基-5-((2-(2-吡咯烷酮基)甲基)-(4-(2-吡啶基)氨基))苯氧基吡啶；2)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；3)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡啶；4)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；5)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；6)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶基)氨基))苯氧基吡啶；7)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲 基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；8)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；9)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；10)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；11)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(4-1H-咪唑基)氨基))苯氧基吡啶；12)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲氧基-2-吡啶基)氨基))苯氧基吡啶；13)2-甲基磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；14)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡啶基)氨基))苯氧基吡啶；15)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；16)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲 基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡啶；17)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；18)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；19)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶基)氨基))苯氧基吡啶；20)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；21)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；22)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；23)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；24)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(1H-4-咪唑基)氨基))苯氧基吡啶； 25)2-甲氧基甲基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；26)2-嗎啉磺醯基-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；27)2-(N-乙基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲氧基-2-吡啶基)氨基))苯氧基吡啶；28)2-甲基-3-氯-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氯-2-吡啶基)氨基))苯氧基吡啶；29)6-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)煙酸乙酯；30)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)噻唑；31)2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡嗪；32)3-甲基-5-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)1,2,4-噻二唑；33)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)咪唑；34)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡啶；35)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃 基)甲基)-3-吡啶基)-N-2-吡啶基胺；36)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-(N’-乙基甲醯胺)-2-吡啶基)胺；37)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-苯基-2-吡啶基)胺；38)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-三氟甲基-2-吡啶基)胺；39)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-氰基-2-吡啶基)胺；40)N-(6-(4-(甲基磺醯基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-羧基-2-吡啶基)胺；41)6-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)煙酸乙酯；42)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡啶；43)2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡嗪；44)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑； 45)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)咪唑；46)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；47)6-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)煙酸乙酯；48)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡啶；49)2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡嗪；50)5-甲基-3-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)1,2,4-噻二唑；51)1H-4-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)咪唑；52)5-甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)噻唑；53)2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)吡啶；54)5-三氟甲基-2-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)吡啶；55)4-(4-(4-(甲基磺醯基)苯氧基)-3-((4-2H-四氫吡喃基)氨基)苯胺基)嘧啶；56)5-甲基-2-(4-(4-(甲基磺醯基)苯硫基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑； 57)1H-4-(4-(4-(甲基磺醯基)苯硫基)-3-(4-2H-四氫吡喃氧基)苯胺基)咪唑；58)5-甲基-2-(4-(4-(甲基磺醯基)苯硫基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；59)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)煙酸乙酯；60)5-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)噻唑；61)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡嗪；62)3-甲基-5-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)1,2,4-噻二唑；63)1H-4-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)咪唑；64)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((3-氧代環戊基)甲基)苯胺基)吡啶；65)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；66)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-(N-乙基甲醯胺基)-2-吡啶基)氨基))苯氧基吡啶；67)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-苯基-2-吡啶基)氨基))苯氧基吡 啶；68)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-三氟甲基-2-吡啶基)氨基))苯氧基吡啶；69)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-氰基-2-吡啶基)氨基))苯氧基吡啶；70)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-羧基-2-吡啶基)氨基))苯氧基吡啶；71)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲酸乙酯基-2-吡啶基)氨基))苯氧基吡啶；72)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲基-2-吡啶基)氨基))苯氧基吡啶；73)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(2-吡嗪基)氨基))苯氧基吡啶；74)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(3-甲基-5-(1,2,4-噻二唑基)氨基)))苯氧基吡啶；75)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(4-1H-咪唑基)氨基))苯氧基吡啶；76)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1- 甲基))-(4-(5-甲基-2-噻唑基)氨基))苯氧基吡啶；77)2-(6-(4-(6-(N,N-二甲基甲醯胺基)-3-吡啶氧基)-3-(2-(2-氧代吡咯烷-1-甲基))苯氨基)-3-吡啶基)乙酸；78)3-(6-(4-(6-(N,N-二甲基甲醯胺基)-3-吡啶氧基)-3-(2-(2-氧代吡咯烷-1-甲基))苯氨基)-3-吡啶基)丙酸；79)2-(N,N-二甲基甲醯胺基)-5-((2-(2-氧代吡咯烷-1-甲基))-(4-(5-甲氧基-2-吡啶基)氨基))苯氧基吡啶；80)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-2-吡啶基胺；81)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-(N’-乙基甲醯胺)-2-吡啶基)胺；82)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-苯基-2-吡啶基)胺；83)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-三氟甲基-2-吡啶基)胺；84)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-氰基-2-吡啶 基)胺；85)N-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶基)-N-(5-羧基-2-吡啶基)胺；86)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)煙酸；87)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡啶；88)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)吡嗪；89)3-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)1,2,4-噻二唑；90)1H-4-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)咪唑；91)5-甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯胺基)噻唑；92)6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)煙酸；93)5-三氟甲基-2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡啶；94)2-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯胺基)吡嗪； 95)2-(6-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶氨基)-3-吡啶基)乙酸；96)3-(6-(6-(4-(N,N-二甲基甲醯胺基)苯氧基)-5-((3-四氫呋喃基)甲基)-3-吡啶氨基)-3-吡啶基)丙酸；97)2-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯氨基)-3-吡啶基)乙酸；98)3-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((4-2H-四氫吡喃基)甲基)苯氨基)-3-吡啶基)丙酸；99)2-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯氨基)-3-吡啶基)乙酸；100)3-(6-(4-(4-(N,N-二甲基甲醯胺基)苯氧基)-3-((1-乙醯基-2-吡咯烷基)甲基)苯氨基)-3-吡啶基)丙酸101)2-(6-(4-(6-(甲基磺醯基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)乙酸；102)3-(6-(4-(6-(甲基磺醯基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)丙酸；103)2-(6-(4-(6-(甲氧基甲基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)乙酸；及104)3-(6-(4-(6-(甲氧基甲基)-3-吡啶氧基)-3-((2-吡咯烷酮基)甲基)苯氨基)-3-吡啶基)丙酸。 The compound according to claim 1, wherein the compound is selected from the group consisting of: 1) 2-methylsulfonyl-5-((2-(2-pyrrolidino)methyl)-(4-(2-pyridyl)amino) )) phenoxypyridine; 2) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-(N-ethyl) Amidino)-2-pyridyl)amino))phenoxypyridine; 3) 2-methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-( 4-(5-phenyl-2-pyridyl)amino))phenoxypyridine; 4) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine-1-methyl)) )-(4-(5-trifluoromethyl-2-pyridyl)amino))phenoxypyridine; 5) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine)- 1-methyl))-(4-(5-cyano-2-pyridyl)amino))phenoxypyridine; 6) 2-methylsulfonyl-5-((2-(2-oxo) Pyrrolidine-1-methyl))-(4-(5-carboxy-2-pyridyl)amino))phenoxypyridine; 7) 2-methylsulfonyl-5-((2-(2-) Oxopyrrolidine-1-methyl Base))-(4-(5-carboxylic acid ethyl ester-2-pyridyl)amino))phenoxypyridine; 8) 2-methylsulfonyl-5-((2-(2-oxopyrrolidine) Alkan-1-methyl))-(4-(5-methyl-2-pyridyl)amino))phenoxypyridine; 9) 2-methylsulfonyl-5-((2-(2-) Oxopyrrolidin-1-methyl))-(4-(2-pyrazinyl)amino))phenoxypyridine; 10) 2-methylsulfonyl-5-((2-(2-oxygen) Depyrrolidine-1-methyl))-(4-(3-methyl-5-(1,2,4-thiadiazolyl)amino)))phenoxypyridine; 11) 2-methylsulfonate Mercapto-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(4-1H-imidazolyl)amino))phenoxypyridine; 12) 2-methylsulfonate Mercapto-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methoxy-2-pyridyl)amino))phenoxypyridine; 13) 2 -methylsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxypyridine; 14) 2-Methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2-pyridyl)amino))phenoxypyridine; 15) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-(N-ethylcarbamoyl)-2-pyridyl) Amino))phenoxypyridine; 16) 2-methoxymethyl-5-((2-(2-oxopyrrolidine-1-) ()-(4-(5-phenyl-2-pyridyl)amino))phenoxypyridine; 17) 2-methoxymethyl-5-((2-(2-oxopyrrolidine)- 1-methyl))-(4-(5-trifluoromethyl-2-pyridyl)amino))phenoxypyridine; 18) 2-methoxymethyl-5-((2-(2-) Oxopyrrolidin-1-methyl))-(4-(5-cyano-2-pyridyl)amino))phenoxypyridine; 19) 2-methoxymethyl-5-((2- (2-oxopyrrolidin-1-methyl))-(4-(5-carboxy-2-pyridyl)amino))phenoxypyridine; 20) 2-methoxymethyl-5-(( 2-(2-oxopyrrolidin-1-methyl))-(4-(5-carboxylic acid ethyl ester-2-pyridyl)amino))phenoxypyridine; 21) 2-methoxymethyl -5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methyl-2-pyridyl)amino))phenoxypyridine; 22) 2-methoxy Methyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(2-pyrazinyl)amino))phenoxypyridine; 23) 2-methoxy Methyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(3-methyl-5-(1,2,4-thiadiazolyl)amino)) Phenoxypyridine; 24) 2-methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(1H-4-imidazolyl)amino) Phenoxypyridine; 25) 2-Methoxymethyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxy Pyridine; 26) 2-morpholinsulfonyl-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-trifluoromethyl-2-pyridyl) Amino))phenoxypyridine; 27) 2-(N-ethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5- Trifluoromethoxy-2-pyridyl)amino))phenoxypyridine; 28) 2-methyl-3-chloro-5-((2-(2-oxopyrrolidine-1-methyl)) -(4-(5-chloro-2-pyridyl)amino))phenoxypyridine; 29) 6-(4-(4-(methylsulfonyl)phenoxy)-3-((3- Oxocyclopentyl)methyl)anilino)ethyl nicotinate; 30) 5-methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((3- Oxocyclopentyl)methyl)anilino)thiazole; 31) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl Aniline)pyrazine; 32) 3-methyl-5-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl)aniline 1,1,2,4-thiadiazole; 33)1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl Anilino)imidazole; 34) 5-trifluoromethyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((3-oxocyclopentyl)methyl ) Anilino) pyridine; 35) N- (6- (4- (meth sulfo acyl) phenoxy) -5 - ((3-tetrahydrofuryl Methyl)-3-pyridyl)-N-2-pyridylamine; 36) N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuranyl) )methyl)-3-pyridyl)-N-(5-(N'-ethylformamide)-2-pyridyl)amine; 37) N-(6-(4-(methylsulfonyl) Phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-phenyl-2-pyridyl)amine; 38) N-(6-(4- (methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-trifluoromethyl-2-pyridyl)amine; 39) N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-cyano-2-pyridine Amine; 40) N-(6-(4-(methylsulfonyl)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5- Carboxy-2-pyridyl)amine; 41) 6-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)phenylamino Ethyl nicotinate; 42) 5-trifluoromethyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl) A Benzyl)pyridine; 43) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)pyridinium Tetrazine; 44) 5-methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)benzene Amino) 1,2,4-thiadiazole; 45) 1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)imidazole; 46) 5- Methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 47) 6-( 4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)ethyl nicotinate; 48) 5-trifluoro Methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)pyridine; 49)2 -(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindolyl-2-pyrrolidinyl)methyl)anilino)pyrazine; 50) 5-methyl -3-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)1,2,4-thiazide Diazole; 51) 1H-4-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)imidazole ;52) 5-methyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino) Thiazole; 53) 2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)anilino)pyridine; 54) 5-three Fluoromethyl-2-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)benzene Pyridine; 55) 4-(4-(4-(methylsulfonyl)phenoxy)-3-((4-2H-tetrahydropyranyl)amino)anilino)pyrimidine; 56)5 -methyl-2-(4-(4-(methylsulfonyl)phenylthio)-3-((4-2H-tetrahydropyranyl)methyl)anilino)1,2,4- Thiadiazole 57) 1H-4-(4-(4-(methylsulfonyl)phenylthio)-3-(4-2H-tetrahydropyranyloxy)anilino)imidazole; 58) 5-methyl- 2-(4-(4-(methylsulfonyl)phenylthio)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 59) 6-(4-( 4-(N,N-Dimethylcarbamoylamino)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)ethyl nicotinate; 60) 5-methyl- 2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)thiazole; 61)2- (4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)pyrazine; 62)3-A 5-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl)anilino)1,2, 4-thiadiazole; 63) 1H-4-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxocyclopentyl)methyl Aniline)imidazole; 64)5-trifluoromethyl-2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((3-oxo ring) Pentyl)methyl)anilino)pyridine; 65) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1-methyl))- (4-(2-pyrazinyl)amino))phenoxypyridine; 66) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine)- 1-methyl))- (4-(5-(N-ethylformamido)-2-pyridyl)amino))phenoxypyridine; 67) 2-(N,N-dimethylformamido)-5- ((2-(2-oxopyrrolidin-1-methyl))-(4-(5-phenyl-2-pyridyl)amino))phenoxypyr Acridine; 68) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-trifluoromethyl) Benzyl-2-pyridyl)amino))phenoxypyridine; 69) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1-) ()-(4-(5-Cyano-2-pyridyl)amino))phenoxypyridine; 70) 2-(N,N-dimethylformamido)-5-((2- (2-oxopyrrolidin-1-methyl))-(4-(5-carboxy-2-pyridyl)amino))phenoxypyridine; 71) 2-(N,N-dimethylformamidine Amino)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-carboxylic acid ethyl ester-2-pyridyl)amino))phenoxypyridine; 72 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5-methyl-2-pyridine) Amino))phenoxypyridine; 73) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-yl))-( 4-(2-pyrazinyl)amino))phenoxypyridine; 74) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidine-1) -methyl))-(4-(3-methyl-5-(1,2,4-thiadiazolyl)amino)))phenoxypyridine; 75) 2-(N,N-dimethyl Methionido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(4-1H-imidazolyl)amino))phenoxypyridine; 76)2- (N,N-dimethyl A Amino) -5 - ((2- (2-oxo-pyrrolidin-1 Methyl))-(4-(5-methyl-2-thiazolyl)amino))phenoxypyridine; 77) 2-(6-(4-(6-(N,N-dimethylformamidine) Amino)-3-pyridyloxy)-3-(2-(2-oxopyrrolidine-1-methyl))phenylamino)-3-pyridyl)acetic acid; 78)3-(6-(4) -(6-(N,N-dimethylformamido)-3-pyridyloxy)-3-(2-(2-oxopyrrolidin-1-methyl))phenylamino)-3- Pyridyl)propionic acid; 79) 2-(N,N-dimethylformamido)-5-((2-(2-oxopyrrolidin-1-methyl))-(4-(5 -Methoxy-2-pyridyl)amino))phenoxypyridine; 80) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-(( 3-tetrahydrofuranyl)methyl)-3-pyridyl)-N-2-pyridylamine; 81) N-(6-(4-(N,N-dimethylformamido)phenoxy) -5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-(N'-ethylcarbamidine)-2-pyridyl)amine; 82) N-(6- (4-(N,N-Dimethylcarbamamino)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl)-N-(5-phenyl-2- Pyridyl)amine; 83) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl -N-(5-trifluoromethyl-2-pyridyl)amine; 84) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-( (3-tetrahydrofuranyl )methyl)-3-pyridyl)-N-(5-cyano-2-pyridine Amine; 85) N-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridyl) -N-(5-carboxy-2-pyridyl)amine; 86) 6-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H) -tetrahydropyranyl)methyl)anilino)nicotinic acid; 87)5-trifluoromethyl-2-(4-(4-(N,N-dimethylformamido)phenoxy) -3-((4-2H-tetrahydropyranyl)methyl)anilino)pyridine; 88) 2-(4-(4-(N,N-dimethylformamido)phenoxy) -3-((4-2H-tetrahydropyranyl)methyl)anilino)pyrazine; 89)3-methyl-2-(4-(4-(N,N-dimethylformamide) Phenyloxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)1,2,4-thiadiazole; 90)1H-4-(4-(4-( N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)imidazole; 91)5-methyl-2-(4 -(4-(N,N-dimethylformamido)phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)anilino)thiazole; 92) 6-(4 -(4-(N,N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilino)nicotinic acid; 93)5 -trifluoromethyl-2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl Anilino)pyr ;94) 2-(4-(4-(N,N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)anilinyl Pyrazine; 95) 2-(6-(6-(4-(N,N-Dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl)-3-pyridinylamino)- 3-pyridyl)acetic acid; 96) 3-(6-(6-(4-(N,N-dimethylformamido)phenoxy)-5-((3-tetrahydrofuryl)methyl) -3-pyridylamino)-3-pyridyl)propionic acid; 97) 2-(6-(4-(4-(N,N-dimethylformamido)phenoxy)-3-(( 4-2H-tetrahydropyranyl)methyl)phenylamino)-3-pyridyl)acetic acid; 98)3-(6-(4-(4-(N,N-dimethylformamido)) Phenoxy)-3-((4-2H-tetrahydropyranyl)methyl)phenylamino)-3-pyridyl)propanoic acid; 99)2-(6-(4-(4-(N, N-dimethylformamido)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)phenylamino)-3-pyridyl)acetic acid; 100)3-( 6-(4-(4-(N,N-Dimethylcarbamamino)phenoxy)-3-((1-ethylindol-2-pyrrolidinyl)methyl)phenylamino)-3 -pyridyl)propionic acid 101) 2-(6-(4-(6-(methylsulfonyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino)- 3-pyridyl)acetic acid; 102) 3-(6-(4-(6-(methylsulfonyl)-3-pyridyloxy)-3-((2-pyrrolidino)methyl)phenylamino) -3-pyridyl)propionic acid; 103) 2-(6-(4-(6-(methoxymethyl)-3-pyridyloxy)-3-((2-pyrrolidone) )methyl)phenylamino)-3-pyridyl)acetic acid; and 104)3-(6-(4-(6-(methoxymethyl)-3-pyridyloxy)-3-((2- Pyrrolidinyl)methyl)phenylamino)-3-pyridyl)propanoic acid. 根據請求項1~19任一項所述的化合物，其中，該化合物及其藥學上可接受的鹽對葡萄糖激酶的活性EC50值在葡萄糖濃度是5mM時是50μM或50μM以下。 The compound according to any one of claims 1 to 19, wherein the EC50 value of the activity of the compound and the pharmaceutically acceptable salt thereof to glucokinase is 50 μM or less at a glucose concentration of 5 mM. 根據請求項42所述的化合物，其中，該化合物及其藥學上可接受的鹽對葡萄糖激酶的活性EC50值在葡萄糖濃度是5mM時是5μM或5μM以下。 The compound according to claim 42, wherein the EC50 value of the activity of the compound and the pharmaceutically acceptable salt thereof against glucokinase is 5 μM or less at a glucose concentration of 5 mM. 一種如請求項1~43任一項所述的化合物在製藥中的應用。 A compound according to any one of claims 1 to 43 for use in pharmaceuticals. 根據請求項44所述的應用，其中，該化合物在製備調節動物或人體內葡萄糖激酶水準或活性的藥物中的用途。 The use according to claim 44, wherein the compound is for use in the manufacture of a medicament for modulating the level or activity of glucokinase in an animal or human. 根據請求項44所述的應用，其中，該化合物在製備治療II型糖尿病或其相關疾病的藥物中的用途。 The use according to claim 44, wherein the compound is for use in the manufacture of a medicament for the treatment of type 2 diabetes or a related disease thereof. 根據請求項44所述的應用，其中，該化合物在製備治療I型糖尿病或其相關疾病的藥物中的用途。 The use according to claim 44, wherein the compound is for use in the manufacture of a medicament for the treatment of type 1 diabetes or a related disease thereof. 根據請求項44所述的應用，其中，該化合物在製備治療肥胖症或其相關疾病的藥物中的用途。 The use according to claim 44, wherein the compound is for use in the manufacture of a medicament for the treatment of obesity or a related disease thereof. 一種藥物組合物，其特徵在於，包括治療有效量的至少一種請求項1-43任一項所述的化合物和至少一種可藥用的賦形劑。 A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-43 and at least one pharmaceutically acceptable excipient. 一種如請求項49所述藥物組合物在製藥中的應用。 A pharmaceutical composition according to claim 49 for use in medicine. 根據請求項50所述的應用，其中，該藥物組合物在製備調節動物或人體內葡萄糖激酶水準或活性的藥物中的用途。 The use according to claim 50, wherein the pharmaceutical composition is for use in the manufacture of a medicament for modulating the level or activity of glucokinase in an animal or human. 根據請求項50所述的應用，其中，該藥物組合物在製備治療II型糖尿病或其相關疾病的藥物中的用途。 The use according to claim 50, wherein the pharmaceutical composition is for use in the manufacture of a medicament for the treatment of type 2 diabetes or a related disease thereof. 根據請求項50所述的應用，其中，該藥物組合物在製備治療I型糖尿病或其相關疾病的藥物中的用途。 The use according to claim 50, wherein the pharmaceutical composition is for use in the manufacture of a medicament for the treatment of type 1 diabetes or a related disease thereof. 根據請求項50所述的應用，其中，該藥物組合物在製備治療肥胖症或其相關疾病的藥物中的用途。 The use according to claim 50, wherein the pharmaceutical composition is used in the manufacture of a medicament for treating obesity or a related disease thereof.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147557A2 (en) * 2007-05-22 2008-12-04 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles and their use as antiviral agents
JP2009091324A (en) * 2007-10-11 2009-04-30 Banyu Pharmaceut Co Ltd Method for producing pyridin-2-yl-benzimidazole derivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008147557A2 (en) * 2007-05-22 2008-12-04 Achillion Pharmaceuticals, Inc. Heteroaryl substituted thiazoles and their use as antiviral agents
JP2009091324A (en) * 2007-10-11 2009-04-30 Banyu Pharmaceut Co Ltd Method for producing pyridin-2-yl-benzimidazole derivative

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