Heteroaryloxy quinazoline derivatives   

Abstract: R2 represents a lower alkyl group, etc.; r indicates an integer of from 0 to 3; k indicates an integer of from 0 to 4). (wherein R11 and R12 each independently represent a hydrogen atom, etc.; m indicates an integer of from 2 to 6), etc.; (wherein ring A represents a pyrazolyl group optionally having a lower alkyl group, etc.; ring B represents a heteroaryl group; R represents a lower alkyl group, etc.; R1 represents a group of a formula: Disclosed are compounds of the following formula and their pharmaceutically-acceptable salts, which have an effect of glucokinase activation and are useful in the field of medicines for treatment for diabetes, obesity, etc.

FIELD OF THE INVENTION

The present invention relates to glucokinase activators containing heteroaryloxy quinazoline derivatives as active ingredients. The present invention further relates to novel heteroaryloxy quinazoline derivatives.

BACKGROUND OF THE INVENTION

Glucokinase (GK) (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) is one of four mammalian hexokinases (hexokinase IV). Hexokinases are enzymes in the first step of the glycolytic pathway and catalyze the reaction from glucose to glucose-6-phosphate. Glucokinase is expressed principally in the liver and pancreatic beta cells and plays an important role in whole-body glucose metabolism by controlling the rate-determining step in glucose metabolism in these cells. The glucokinases expressed in the liver and pancreatic beta cells differ in the sequence of the 15 N-terminal amino acids due to a difference in splicing, respectively, whereas their enzymatic characteristics are identical. The enzyme activities of the three hexokinases (I, II, and III) other than the glucokinase become saturated at a glucose concentration of 1 mM or lower, whereas the Km of glucokinase to glucose is 8 mM, which is close to the physiological blood glucose level. Accordingly, glucokinase-mediated intracellular glucose metabolism is accelerated in response to blood glucose level changes by postprandial glucose level increase (10-15 mM) from normal glucose (5 mM).

It has been hypothesized for around 10 years that glucokinase serves as a glucose sensor for pancreatic beta cells and the liver (for example, see non-patent document 1). Recent results in glucokinase gene-manipulated mice have confirmed that glucokinase does in fact play an important role in systemic glucose homeostasis. Mice lacking a functional glucokinase gene die shortly after birth (for example, see non-patent document 2), while healthy and diabetic mice overexpressing glucokinase have lower blood glucose levels (for example, see non-patent document 3). With glucose level increase, the reactions of pancreatic beta- and liver cells, while differing, both act toward lowering blood glucose. Pancreatic beta cells secrete more insulin, while the liver takes up glucose and stores it as glycogen while also reducing glucose release.

Such variation in glucokinase enzyme activity is important for liver and pancreatic beta cell-mediated glucose homeostasis in mammals. A glucokinase gene mutation has been found in a case of diabetes which occurs in youth, referred to as MODY2 (maturity-onset diabetes of the young), and the reduced glucokinase activity has been shown to be responsible for blood glucose increase (for example, see non-patent document 4). In contrast, families having a mutation increasing the glucokinase activity has been found, and such individuals exhibit hypoglycemia (for example, see non-patent document 5).

These suggest that in humans as well, glucokinase functions as a glucose sensor and thus plays an important role in glucose homeostasis. Glucose regulation utilizing a glucokinase sensor system is likely to be possible to achieve in most patients with type II diabetes mellitus. Since glucokinase activators should have effects of accelerating insulin secretion by pancreatic beta cells and of promoting glucose uptake and inhibiting glucose release by the liver, they are likely to be useful as therapeutic agents for patients with type II diabetes mellitus.

In recent years, it has been found that pancreatic beta cell glucokinase is expressed locally in rat brain, particularly in the ventromedial hypothalamus (VMH). Around 20% of VMH neurons are referred to as “glucose-responsive neurons”, and these have long been considered to play an important role in body weight control. Administration of glucose into rat brain reduces feeding consumption, whereas inhibition of glucose metabolism by intracerebral administration of glucose analog glucosamine produces hyperphagia. Electrophysiological experiments have indicated that glucose-responsive neurons are activated in response to physiological glucose level changes (5-20 mM) but that their activation is inhibited with glucose metabolism inhibition by, e.g., glucosamine. The glucose level-detecting system in the VMH is intended to be based on a glucokinase-mediated mechanism similar to that for insulin secretion by pancreatic beta cells. Accordingly, substances which activate glucokinase in the VMH in addition to the liver and pancreatic beta cells not only exhibit a glucose rectifying effect but can also potentially rectify obesity, which is a problem for most patients with type II diabetes mellitus.

The above description indicates that compounds having glucokinase-activating effects are useful as therapeutic and/or prophylactic agents for diabetes mellitus, as therapeutic and/or prophylactic agents for chronic complications of diabetes mellitus, such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis, and further as therapeutic and/or prophylactic agents for obesity.

As a compound associated with a heteroaryloxy quinazoline derivative according to the present invention, for example, a compound represented by the following formula (A):

is disclosed in patent document 1.

Although there is a commonality of having GK activity between the compound represented by the formula (A) and a compound according to the present invention, the compound represented by the formula (A) has no dimethylaminoethoxy group as an essential substituent on a pyridine ring. patent document 1: WO2005/090332 non-patent document 1: Garfinkel D. et al., Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells, American Journal Physiology, vol. 247 (3Pt2) 1984, pp. 527-536 non-patent document 2: Grupe A. et al., Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis, Cell, vol. 83, 1995, pp. 69-78 non-patent document 3: Ferre T. et al., Correction of diabetic alterations by glucokinase, Proceedings of the National Academy of Sciences of the U.S.A, vol. 93, 1996, pp. 7225-7230 non-patent document 4: Vionnet N. et al., Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus, Nature Genetics, vol. 356, 1992, pp. 721-722 non-patent document 5: Glaser B. et al., Familial hyperinsulinism caused by an activating glucokinase mutation, New England Journal Medicine, vol. 338, 1998, pp. 226-230

SUMMARY

It is desirable to provide therapeutic and/or prophylactic agents for diabetes mellitus that bind to glucokinase to increase glucokinase activity; and to provide anti-obesity agents that stimulate and act on satiety center by activating glucokinase. The present invention also provides compounds having drug efficacy and/or more excellent properties as medicaments. Further provided are glucokinase activators comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. Also provided are treatments and/or therapeutic agents for diabetes mellitus comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. Also provided are pharmaceutical compositions comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. In addition, the present invention also provides pharmaceutical compositions comprising: compounds according to the present invention used for treating, preventing and/or delaying onset of type 2 diabetes mellitus; other drugs; and pharmaceutically acceptable carriers.

The present inventors undertook thorough research to find that introduction of a dimethylaminoethoxy group or the like as a substituent on a quinazoline ring into quinazoline compounds having GK activation action in related art results in great improvement in drug efficacy and/or properties such as solubility compared to quinazoline compounds in related art, and the invention was thus accomplished.

Specifically, the present invention relates to:

(1) a compound represented by a formula (I):

[wherein the A ring represents a 5- or 6-membered heteroaryl ring that is selected from the group consisting of pyrazolyl, pyrazinyl, thiadiazolyl, thiazolyl, pyridinyl, thiatriazolyl, triazolyl, tetrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl and isoxazolyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups, or represents a ring in which the 5- or 6-membered heteroaryl ring and a benzene or pyridine ring are condensed; the B ring represents a 5- or 6-membered heteroaryl group having 1-3 identical or different hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms; R represents a group selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups; k represents an integer of from 0 to 4; R1 denotes a group represented by a formula (II-1)

(wherein R11 and R12 each independently represent hydrogen, lower alkyl or C3-7 cycloalkyl, or R11 and R12, together with the nitrogen atom to which they are bound, constitute 4- to 7-membered nitrogen-containing aliphatic rings (which may be substituted with 1-3 identical or different halogen atoms), or any carbon atom of (CH2)m, together with R11 or R12, may constitute 4- to 7-membered nitrogen-containing aliphatic rings; any carbon atom in (CH2)m may be substituted with a lower alkyl group; the nitrogen atom to which R11 and R12 are bound may form N-oxide; and m represents an integer of from 2 to 6), a group represented by a formula (II-2)

—O—(CH2)n—R13  (II-2)

(wherein R13 represents lower alkoxy, hydroxy or carboxyl; n represents an integer of from 1 to 6; upon R13 being lower alkoxy, the lower alkoxy, together with any carbon atom of (CH2)n, may form 5- to 7-membered aliphatic rings; and any carbon atom in (CH2)n may be substituted with a lower alkyl group), a group represented by a formula (II-3)

(wherein R14 and R15 are synonymous with the above R11 and R12; p represents an integer of from 2 to 6; and R3 represents a hydrogen atom or a lower alkyl group), or a group represented by a formula (II-4)

(wherein R16 and R17 are synonymous with the above R11 and R12; q represents an integer of from 2 to 6; and R4 represents a hydrogen atom or a lower alkyl group), and the substituent which the B ring has; R2 is a group selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, carboxyl, alkoxycarbonyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, lower alkylsulfonyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms, hydroxy groups, cyano groups, carboxyl groups, alkoxycarbonyl groups, N-alkylcarbamoyl groups, N,N-dialkylcarbamoyl groups or lower alkylsulfonyl groups, and the substituent which the B ring may have; and r represents an integer of from 0 to 3] or a pharmaceutically acceptable salt thereof;

(2) the compound according to the above (1), wherein the B ring is a group selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, imidazolyl and isoxazolyl groups, or a pharmaceutically acceptable salt thereof;

(3) the compound according to the above (1), wherein the A ring is a 5- or 6-membered heteroaryl group that is selected from the group consisting of pyrazolyl, pyrazinyl, thiadiazolyl, pyridinyl, triazolyl and isoxazolyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups; and the B ring is a group selected from the group consisting of pyridinyl and pyrimidinyl groups,

or a pharmaceutically acceptable salt thereof;

(4) the compound according to any one of the above (1) to (3), wherein R1 is a group represented by the formula (II-1) or (II-2), or a pharmaceutically acceptable salt thereof;

(5) the compound according to any one of the above (1) to (3), wherein R1 is a group represented by the formula (II-1), or a pharmaceutically acceptable salt thereof;

(6) the compound according to any one of the above (1) to (3), wherein R1 is a group represented by the formula (II-2), or a pharmaceutically acceptable salt thereof;

(7) the compound according to any one of the above (1) to (3), wherein R1 is a group represented by the formula (II-3), or a pharmaceutically acceptable salt thereof;

(8) the compound according to any one of the above (1) to (3), wherein R1 is a group represented by the formula (II-4), or a pharmaceutically acceptable salt thereof;

(9) the compound according to the above (5), wherein one of R11 and R12 is a hydrogen atom; and the other is a lower alkyl or C3-7 cycloalkyl group, or a pharmaceutically acceptable salt thereof;

(10) the compound according to the above (5), wherein R11 and R12 each independently are lower alkyl or C3-7 cycloalkyl groups, or a pharmaceutically acceptable salt thereof;

(11) the compound according to the above (5), wherein R11 and R12 represent 4- to 7-membered nitrogen-containing aliphatic rings constituted by R11 and R12 together with the nitrogen atom to which they are bound, (the nitrogen atom to which R11 and R12 are bound may form N-oxide; and the 4- to 7-membered nitrogen-containing aliphatic rings may be substituted with 1-3 identical or different halogen atoms), or a pharmaceutically acceptable salt thereof;

(12) the compound according to the above (5), wherein R11 and R12 represent a 4- to 7-membered nitrogen-containing aliphatic rings formed by either R11 or R12 together with any carbon atom of (CH2)m (any carbon atom in (CH2)m may be substituted with a lower alkyl group), or a pharmaceutically acceptable salt thereof;

(13) the compound according to the above (1), wherein the compound represented by the formula (I) is 6-({3-chloro-5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({2-chloro-5-[2-(dimethylamino)ethoxy]pyridin-3-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({6-[2-(dimethylamino)ethoxy]pyridin-3-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({5-[3-(dimethylamino)propoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({5-[2-(isopropylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({5-[(1-methylazetidin-3-yl)oxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({2-[2-(dimethylamino)ethoxy]pyrimidin-5-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({5-[2-(dimethylamino)ethoxy]pyrimidin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, N-(1-methyl-1H-pyrazol-3-yl)-6-{[-5-(2-piperidin-1-yl)ethoxy)pyridin-2-yl]oxy}quinazolin-4-amine, 6-[(5-{2-[ethyl(methyl)amino]ethoxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({5-[2-(diethylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-[(5-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-[(5-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethoxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-{2-[(2R)-2-methylpyrrolidin-1-yl]ethoxy}pyridin-2-yl)oxy]quinazolin-4-amine hydrochloride, N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-{2-[(2S)-2-methylpyrrolidin-1-yl]ethoxy}pyridin-2-yl)oxy]quinazolin-4-amine hydrochloride, 6-({5-[2-(cyclobutylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({5-[2-(cyclopentylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[2-(ethylamino)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({5-[2-(ethylamino)ethoxy]-3-fluoropyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[3-(ethylamino)propoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[3-(isopropylamino)propoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[3-(methylamino)propoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-{[-5-(azetidin-3-yloxy)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({5-[(1-isopropylazetidine-3-yl)oxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-({5-[(1-ethylazetidin-3-yl)oxy]-3-fluoropyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, 6-[(5-{[(2S)-2-(methylamino)propyl]oxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-[(5-{[(2R)-2-(methylamino)propyl]oxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 6-({5-[(1-methylazetidin-3-yl)methoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine hydrochloride, N-(1-methyl-1H-pyrazol-3-yl)-6-{[5-(2-pyrrolidin-2-ylethoxy)pyridin-2-yl]oxy}quinazolin-4-amine, N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[2-(1-methylpyrrolidin-2-yl)ethoxy]pyridin-2-yl}oxy)quinazolin-4-amine hydrochloride, 6-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, 6-({3-chloro-5-[2-(methylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-{[3-fluoro-5-(2-pyrrolidin-1-ylethoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, 6-({5-[2-(dimethylamino)ethoxy]-3-methylpyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, 6-({5-[2-(ethylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, 6-({5-[2-(isopropylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, N-(5-methylpyrazin-2-yl)-6-{[5-(2-pyrrolidin-1-ylethoxy)pyridin-2-yl]oxy}quinazolin-4-amine, 6-({3-fluoro-5-([2-(methylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-({3-fluoro-5-[2-(isopropylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-({3-methyl-5-[2-(methylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-{[5-(2-azetidin-1-ylethoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, 6-{[3-chloro-5-(3-pyrrolidin-1-ylpropoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazolin-4-amine hydrochloride, 6-({3-chloro-5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-pyrazin-2-ylquinazolin-4-amine, 6-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-pyrazin-2-ylquinazolin-4-amine, 6-({3-chloro-5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)quinazolin-4-amine, 6-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}oxy)-N-(3-methyl)-1,2,4-thiadiazol-5-yl)quinazolin-4-amine, 6-({5-[2-(ethylamino)ethoxy]pyridin-2-yl}oxy)-N-(3-methyl)-1,2,4-thiadiazol-5-yl)quinazolin-4-amine, 2-{[5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, 6-{[3-chloro-5-(2-methoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine, 2-{[6-chloro-5-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, 2-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, 3-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-1-ol, 2-{[5-fluoro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, (2R)-2-{[5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-1-ol, (2R)-1-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-2-ol, (2S)-1-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-2-ol, 2-{[5-chloro-6-({4-[(5-methylpyrazin-2-yl)-amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, 2-[(5-chloro-6-{[4-(pyrazin-2-ylamino)quinazolin-6-yl]oxy}pyridin-3-yl)oxy]ethanol, 2-{[5-fluoro-6-({4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, 3-{[5-chloro-6-({4-[(5-methylpyrazin-2-yl)-amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-1-ol, {[5-chloro-6-({4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}acetic acid, 5-chloro-N-[2-(dimethylamino)ethyl]-N-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-sulfonamide, 5-chloro-N-[3-(dimethylamino)propyl]-N-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-sulfonamide, 5-chloro-N-[2-(dimethylamino)ethyl]-N-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)nicotinamide, 5-chloro-N-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)-N-(2-pyrrolidin-1-ylethyl)nicotinamide, 3-chloro-N-[2-(dimethylamino)ethyl]-N-methyl-2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)isonicotinamide, 5-chloro-N-[3-(dimethylamino)propyl]-N-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)nicotinamide, N,N-dimethyl-2-{[5-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanamine hydrochloride, N-methyl-2-{[5-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanamine hydrochloride, N-ethyl-2-{[5-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanamine hydrochloride, N-(2-{[5-methyl-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, N-{2-[(6-{[4-(pyridin-2-ylamino]quinazolin-6-yl]oxy}pyridin-3-yl)oxy]ethyl}propan-2-amine hydrochloride, N-(2-{[6-({4-[(5-methylpyridin-2-yl)amino)quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, 6-{[5-(2-aminoethoxy)-3-chloropyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazolin-4-amine, N-(2-{[6-({4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, N-ethyl-2-({6-[(4-{[2-(propan-2-yl)-2H-1,2,3-triazol-4-yl]amino}quinazolin-6-yl)oxy]pyridin-3-yl}oxy)ethanamine hydrochloride, N-[2-({6-[(4-{[2-(propan-2-yl)-2H-1,2,3-triazol-4-yl]amino}quinazolin-6-yl)oxy]pyridin-3-yl}oxy)ethyl]cyclopropane amine hydrochloride, N-(2-{[6-({4-[(2-ethyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, N-methyl-2-({6-[(4-{[2-(propan-2-yl)-2H-1,2,3-triazol-4-yl]amino}quinazolin-6-yl)oxy]pyridin-3-yl}oxy)ethanamine hydrochloride, N-(2-{[5-methyl-6-({4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, N-(2-{[6-({4-[(2-cyclopropyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)propan-2-amine hydrochloride, (3R)-3-fluoro-1-(2-{[5-methyl-6-({4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)pyrrolidine hydrochloride or 2-{[5-methyl-6-({4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethanol, or a pharmaceutically acceptable salt thereof;

(14) a pharmaceutical composition comprising (1) to (3), described below, used for treating, preventing and/or delaying the onset of type 2 diabetes mellitus:

(1) the compound according to the above (1) represented by the formula (I):

[wherein each symbol has the same definition specified above]; (2) one or more compounds selected from the group consisting of (a) to (i) described below: (a) other glucokinase activators; (b) biguanides; (c) PPAR agonists; (d) insulin; (e) somatostatins; (f) α-glucosidase inhibitors; (g) insulin secretagogues; (h) DPP-IV inhibitors (dipeptidyl peptidase inhibitors); and (i) glucose uptake facilitators; and (3) pharmacologically acceptable carriers;

(15) a glucokinase activator comprising the compound according to any one of the above (1) to (13) or the pharmaceutically acceptable salt thereof as an active ingredient;

(16) a treatment and/or a therapeutic agent for diabetes mellitus comprising the compound according to any one of the above (1) to (13) or the pharmaceutically acceptable salt thereof as an active ingredient; and

(17) a pharmaceutical composition comprising the compound according to any one of the above (1) to (13) or the pharmaceutically acceptable salt thereof.

Heteroaryloxy quinazoline derivatives according to the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof have potent glucokinase-activating effects and are thus useful for treatment and/or prevention of diabetes mellitus, complications of diabetes mellitus, or obesity. The heteroaryloxy quinazoline derivatives according to the present invention are also greatly improved in properties, such as solubility, and/or drug efficacy, compared to 2-pyridinecarboxamide derivatives in related art, and thus more excellent as medicaments.

Compounds according to the present invention are adaptable for both types of diabetes mellitus, insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM).

As used herein, a diabetes mellitus complication refer to a disease accompanying due to the onset of diabetes mellitus. Specifically, examples of diabetes mellitus complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and diabetic arteriosclerosis.

DETAILED DESCRIPTION

The meanings of terms as used herein are described below, and a compound according to the present invention is described in further detail. The term “lower alkyl” refers to linear or branched C1-6 alkyl and encompasses, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl and 1-ethyl-2-methylpropyl.

The term “lower alkoxy” refers to a group, in which a hydrogen atom of hydroxy is substituted with the above-mentioned lower alkyl, and encompasses, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy.

The term “halogen atom” encompasses, for example, fluorine, chlorine, bromine and iodine atoms.

The term “C3-7 cycloalkyl” refers to a cycloalkyl group having 3 to 7 carbon atoms, specifically, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In order to further specifically disclose a compound represented by the formula (I) in accordance with the present invention

[wherein each symbol has the same definition specified above] each symbol used in the formula (I) is described referring to specific examples.

The A ring means a 5- or 6-membered heteroaryl group that is selected from the group consisting of pyrazolyl, pyrazinyl, thiadiazolyl, thiazolyl, pyridinyl, thiatriazolyl, triazolyl, tetrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl and isoxazolyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups, or means a ring in which the 5- or 6-membered heteroaryl ring and a benzene or pyridine ring are condensed.

Specifically, the A ring means: a 5- or 6-membered heteroaryl group selected from the group consisting of unsubstituted pyrazolyl, pyrazinyl, thiadiazolyl, thiazolyl, pyridinyl, thiatriazolyl, triazolyl, tetrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl and isoxazolyl groups, or a ring in which the 5- or 6-membered heteroaryl ring and a benzene or pyridine ring are condensed; or a 5- or 6-membered heteroaryl group that is selected from the group consisting of pyrazolyl, pyrazinyl, thiadiazolyl, thiazolyl, pyridinyl, thiatriazolyl, triazolyl, tetrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl and isoxazolyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups.

A lower alkyl group that is a substituent of the A ring encompasses the same groups as the above-defined lower alkyl groups.

A lower alkoxy group that is a substituent of the A ring encompasses the same groups as the above-defined lower alkoxy groups.

A halogen atom that is a substituent of the A ring encompasses the same groups as the above-defined halogen atoms.

A cycloalkyl group that is a substituent of the A ring encompasses the same groups as the above-defined cycloalkyl groups.

A lower alkyl group having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups that is a substituent of the A ring encompasses the same groups as the above-defined group having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups

The A ring encompasses pyrazolyl, pyrazinyl, thiadiazolyl, pyridinyl, triazolyl and thiazolopyridinyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups, more specifically, e.g., pyrazolyl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-isopropyl-1H-pyrazol-3-yl, 1-propyl-1H-pyrazol-3-yl, pyrazinyl, 5-methylpyrazin-2-yl, 5-ethylpyrazin-2-yl, 5-isopropylpyrazin-2-yl, 5-propylpyrazin-2-yl, [1,3]thiazolo[5,4-b]pyridin-2-yl, 5-methoxy-[1,3]thiazolo[5,4-b]pyridin-2-yl, 5-methyl-[1,3]thiazolo[5,4-b]pyridin-2-yl, pyridin-2-yl, 5-methylpyridin-2-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 2-(propan-2-yl)-2H-1,2,3-triazol-4-yl, 2-ethyl-2H-1,2,3-triazol-4-yl and 2-cyclopropyl-2H-1,2,3-triazol-4-yl groups.

The B ring means a 5- or 6-membered heteroaryl group having 1-3 identical or different hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms.

The B ring encompasses pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, imidazolyl and isoxazolyl groups, among which the pyridinyl, pyrimidinyl and pyrazinyl groups are preferred.

R denotes a group selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups.

The symbol k denotes an integer of from 0 to 4.

R1 denotes a group represented by the formula (II-1)

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