CN101218230A

CN101218230A - Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes

Info

Publication number: CN101218230A
Application number: CNA2006800248890A
Authority: CN
Inventors: D·麦克克雷彻; K·G·皮克; M·J·沃林
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-07-09
Filing date: 2006-07-03
Publication date: 2008-07-09
Also published as: GB0514174D0

Abstract

Compounds of formula (I) wherein R<1>, R<2>, R<3>, and HET-1 are as described in the specification, and their salts, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.

Description

In treating diabetes, be used as the heteroaryl benzamide derivatives of GLK activator

The present invention relates to one group of benzoyl-amido heterogeneous ring compound, disease or medical conditions that it is useful on treatment or prevents to be mediated by glucokinase (GLK or GK) cause the reduction of the threshold glucose value of insulin secretion.In addition, estimate that these compounds can absorb and lowering blood glucose by increasing hepatic glucose.Such compound can have treatment diabetes B and fat practicality.The present invention also relates to comprise the pharmaceutical composition of described compound, and relate to the method for using the disease that described compounds for treating GLK mediated.

In pancreas beta cell and hepatic parenchymal cells, main cytoplasmic membrane glucose transporter is GLUT2.Under the physiology glucose concn, the speed that GLUT2 transhipment glucose passes cytolemma is not the restricted speed of the total speed of glucose uptake in these cells.The speed that glucose uptake speed is subjected to glucokinase (GLK) [1] catalysis glucose phosphate to turn to G-6-P (G-6-P) limits.GLK has high (6-10mM) Km to glucose, and not suppressed by the physiological concentration [1] of G-6-P.GLK expresses tissue and the cell type that is limited to minority, and the most noticeable is pancreas beta cell and liver cell (liver cell) (liver cell (hepatocyte)) [1].The GLK activity is the restricted speed of glucose utilization in these cells, thereby regulates the scope of inducing insulin secretion and liver glycogen synthetic glucose.These processes are very crucial in the glucose running balance in keeping whole body, and in diabetes both unusual [2].

In a kind of diabetes hypotype, i.e. 2 type maturity onset diabetes of the young (MODY-2), these diabetes are [3,4] that the GLK disappearance by function mutation causes.MODY-2 patient's hyperglycemia causes [5] by glucose utilization defective in pancreas and the liver.The threshold value that the glucose utilization defective causes being stimulated insulin secretion by glucose in MODY-2 patient's pancreas raises.On the contrary, the rare activated mutant of GLK reduces this threshold value, thereby causes familial Hyperinsulinism [6,6a, 7].Except that observe the active reduction of GLK in the MODY-2 diabetic subject, the kinase whose activity of hepatic glucose also reduces [8] in the diabetes B patient.Importantly, in the diet and two kinds of models of heredity of this disease, the overall or liver selectivity of GLK is crossed and is expressed the development [9-12] that prevents or reversed the diabetes phenotypes.In addition, with fructose the acute treatment of diabetes B has been improved glucose tolerance [13] by stimulating the hepatic glucose utilization.It is believed that this result is by following mechanism, by active the increasing of kytoplasm GLK in the fructose inducing hepatocyte [13] of mediation.

Liver GLK activity suppresses by the association with GLK adjusting protein (GLKRP).The GLK/GLKRP mixture is stablized with combining of GLKRP by fructose-6-phosphate (F6P), and makes the displacement of this sugar phosphorylation and instability by fructose-1-phosphate (FlP).By the meals fructose phosphorylation of fructokinase mediation, produce FlP.Subsequently, regulate GLK/GLKRP mixture globality and liver GLK activity in nutrition dependent form mode, in described mode, F6P preponderates in postabsorptive state, and F1P preponderates in the state after food.Opposite with liver cell, the pancreas beta cell is expressed GLK under the GLKRP disappearance.Therefore, beta cell GLK activity is subjected to the adjusting of the utilizability of its substrate glucose widely.Small molecules can be directly or by making the unstable GLK that activates of GLK/GLKRP mixture.The former type of expected compound can stimulate the glucose utilization in liver and the pancreas, and the latter estimates that the energy selectively acting is in liver.Yet the compound with two specific characters is estimated effectively to treat diabetes B, because the defective that is characterized as glucose utilization in two kinds of tissues of this disease.

GLK, GLKRP and K _ATPPassage is expressed in hypothalamus neurons, and hypothalamus is the important area [14-18] that brain is regulated energy balance and control ingestion of food.These neurones have shown to express and have improved a poor appetite and the neuropeptide [15,19,20] of apocleisis, and are assumed to the glucose-Sensory neurone in the hypothalamus, and it can be suppressed or stimulate [17,19,21,22] with the variation of glucose concn on every side.The ability that these neurone sensation glucose levels change is defective [23-28] in the multiple heredity of obesity with testing in the inductive model.The Intraventricular of glucalogue (icv) perfusion (competitive inhibitor of glucokinase) stimulates the ingestion of food [29,30] of thin rat.On the contrary, the icv of glucose perfusion suppresses to ingest [31].Therefore, the small molecules activator of GLK can reduce ingestion of food and weight increase by the centre effect to GLK.Therefore, except that diabetes, the GLK activator also is used for the treatment of eating disorder remediably, comprises obesity.In the treatment for diabetes B, in the effect that makes glucose running balance normalizing, the hypothalamus effect plays a part to add up or is collaborative to the same compound that acts on liver and/or pancreas.Therefore, the GLK/GLKRP system can be described to potential " obese diabetes (Diabesity) " target (useful in two kinds of diabetes and obesity).

GLK also expresses in the specificity enteroendocrine cell, it is believed that it can control incretin peptide GIP (glucose-dependent-insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) the glucose-sensitive secretion (32 from intestines K-cell and L-cell respectively, 33,34).Therefore, as stimulating GIP and GLP-1 from these enteroendocrine cell excretory result, the small molecules activator of GLK has other beneficial effect to insulin secretion, b-cell function and survival rate and body weight.

In WO00/58293 and WO01/44216 (Roche), a series of benzyl carbamino compounds as glucokinase activators have been described.By detect these compounds GLK is active measure with the NADH generic connection in the direct effect of (generation of NADH detects with optical means again, sees external test hereinafter described for details), assessed the mechanism that these compounds activate GLK.Compound of the present invention can directly activate GLK maybe can activate GLK by the interaction that suppresses GLKRP and GLK.

At the WO03/095438 (phenyl-acetamides of replacement; Roche), WO03/055482 (carboxylic acid amides and sulfone amide derivative; Novo Nordisk), WO2004/002481 (aryl carbonyl derivatives; Novo Nordisk) and WO03/080585 (the amino benzoyl-amido heterocycle that replaces has been described other GLK activator in Banyu).

Our international application no: described one group of benzoyl-amido pyridyl carboxylic acid among the WO03/000267, it is the activator of enzymatic glucose kinases (GLK).

Our international application no: the compound of having described formula (A) among the WO03/015774:

R wherein ³Be the substituted heterocycle except the pyridyl of carboxylic acid-substituted.

The compound of the subgroup that is generally compound described in the WO03/015774 has been described, wherein R for example in the International Application No. WO 2004/076420 (Banyu) ¹Be (replacement) alkyl oxide, R ²Be (replacement) phenoxy group.

We surprisingly find group's compound, be generally the subgroup that is selected from the described compound of WO03/015774, it has good potentiality to the GLK enzyme usually, and has how useful physical properties, comprises for example higher water-soluble, higher perviousness and/or lower plasma protein binding ratio.Therefore, such compound has these characteristics of isostatic, in (when for example by oral glucose tolerance test (0GTTs) determination of activity) behind the oral dosage, expectedly demonstrates higher plasma free levels of drugs, and has good usefulness in vivo.Therefore this group compound can provide good oral absorption (oral exposure) at lower dosage expectancy, thereby is particularly suitable for treating or prevents disease or medical condition by the GLK mediation.Compare with those GLK activator described in other GLK activator known in the art and the WO 03/015774, The compounds of this invention also has good potentiality and/or useful physical properties (as mentioned above) and/or favourable toxicity characteristic and/or favourable metabolic characteristic.

Therefore, according to a first aspect of the invention, provide the compound or its salt of formula (I):

Wherein:

R ¹Be selected from fluorine methoxymethyl, difluoro-methoxy methyl and trifluoromethoxy methyl;

R ²Be selected from-C (O) NR ⁴R ⁵,-SO ₂NR ⁴R ⁵,-S (O) _PR ⁴And HET-2;

HET-1 be comprise 2-position nitrogen-atoms and optional 1 or 2 other ring hetero atom that independently is selected from O, N and S pass through the 5-that C-is connected or the heteroaryl ring of 6-unit; Described ring is chosen wantonly at available carbon atom or on theheterocyclic nitrogen atom and independently is selected from R by 1 or 2 ⁶Substituting group replace, condition is that this nitrogen-atoms can not be therefore and by quaternized;

HET-2 comprises 1,2,3 or 4 heteroatomic 4-, the 5-that is connected by C-or N-that independently is selected from O, N and S or the heterocycle of 6-unit, wherein-and CH ₂-group can be chosen wantonly by-C (O)-displacement, and wherein the sulphur atom on the heterocycle can be chosen wantonly and is oxidized to S (O) or S (O) ₂Group, described ring is chosen wantonly on available carbon atom or nitrogen-atoms and independently is selected from R by 1 or 2 ⁷Substituting group replace;

R ³Be selected from halogen;

R ⁴Be selected from hydrogen, (1-4C) alkyl [optional by 1 or 2 independently be selected from HET-2 ,-OR ⁵,-SO ₂R ⁵, (3-6C) cycloalkyl (optional is selected from R by 1 ⁷Group replace) and-C (O) NR ⁵R ⁵Substituting group replace], (3-6C) cycloalkyl (optionally is selected from R by 1 ⁷Group replace) and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

Or R ⁴And R ⁵Can form defined heterocycle ring system with the nitrogen-atoms that connects them as HET-3;

R ⁶Independently be selected from (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (1-4C) alkyl S (O) p (1-4C) alkyl, amino (1-4C) alkyl, (1-4C) alkylamino (1-4C) alkyl, two (1-4C) alkylamino (1-4C) alkyl and/or (for R ⁶Be the substituting group on the carbon) halogen;

R ⁷Be selected from (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl ,-S (O) pR ⁵And/or (for R ⁷Be the substituting group on the carbon) hydroxyl and (1-4C) alkoxyl group;

HET-3 is 4 to 6 yuan of saturated or undersaturated heterocycles of part that connect by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that the N atom that is connected) that independently is selected from O, N and S, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and wherein the sulphur atom on the ring can be chosen wantonly and is oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon atom and independently is selected from R by 1 or 2 ⁸Substituting group replace; And/or quilt is selected from R on available nitrogen-atoms ⁹Substituting group replace; Or

HET-3 is 7 yuan of saturated or undersaturated heterocycles of part that connect by N-, chooses wantonly to comprise 1 other heteroatoms (except that the N atom that is connected) that independently is selected from O, S and N, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and wherein the sulphur atom on the ring can be chosen wantonly and is oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon atom and independently is selected from R by 1 or 2 ⁸Substituting group replace; And/or quilt is selected from R on available nitrogen-atoms ⁹Substituting group replace; Or

HET-3 is the undersaturated heterocycle of saturated or part of 6 to 10 yuan of dicyclos, optional other 1 nitrogen-atoms (except that the N atom that connects) that comprises, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement; Described ring is chosen wantonly on available carbon atom and is selected from hydroxyl and R by 1 ³Substituting group or on available nitrogen-atoms by methyl substituted;

R ⁸Be selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) pR ⁵

R ⁹Be selected from (1-4C) alkyl ,-C (0) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) pR ⁵

P is (when at every turn occurring independently) 0,1 or 2;

N is 0,1 or 2.

Should be appreciated that and work as R ⁴For-C (O) NR ⁵R ⁵During (1-4C) alkyl of replacing, each R ⁵Independently be selected from hydrogen and (1-4C) alkyl, therefore, R ⁴This definition include, but is not limited to by-CONH ₂,-CONHMe ,-CONMe ₂Or-(1-4C) alkyl that CONMeEt replaces.

Should be appreciated that they can be identical or different when formula (I) compound comprises the HET-2 ring that surpasses 1.

Should be appreciated that when formula (I) compound comprises and surpass 1 R ⁴During group, they can be identical or different.

Should be appreciated that when formula (I) compound comprises and surpass 1 R ⁵During group, they can be identical or different.

Should be appreciated that when formula (I) compound comprises and surpass 1 R ⁸During group, they can be identical or different.

Should be appreciated that when formula (I) compound comprises and surpass 1 R ³During group, they can be identical or different.

All other group and substituting groups on formula (I) compound of similarly arranging to can be used for defining as mentioned.

Formula (I) compound can form salt within the scope of the present invention.Pharmaceutically acceptable salt is preferred, though other salt can be used for for example isolated or purified compound.

On the other hand, the present invention relates to formula (I) compound that defines as mentioned or relate to pharmaceutically acceptable salt.

On the other hand, the present invention relates to formula (I) compound or its prodrug that define as mentioned.The suitable example of formula (I) compound prodrug is the interior hydrolyzable ester of the body of formula (I) compound.Therefore on the other hand, hydrolyzable ester in the formula that the present invention relates to define as mentioned (I) compound or its body.

In this specification sheets, generic term " alkyl " comprises straight chain and branched alkyl group.But only specific when mentioning indivedual alkyl groups as " propyl group " is linear form, and only specific when mentioning the indivedual branched-chain alkyls such as the tertiary butyl is the side chain form.For example " (1-4C) alkyl " comprises methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.Similarly agreement is used for other generic term.

For fear of query, when mentioning group HET-1 and comprise nitrogen, be meant that the amide nitrogen atom that connects with respect to this group is the 2-position in the 2-position.For example, the definition of formula (I) includes, but is not limited to following structure:

HET-1 be definition as mentioned pass through 5-that C-connects or 6-unit hetero-aromatic ring the time, its suitable example comprises thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base,  di azoly and triazolyl.

Should be appreciated that HET-2 can be saturated or partially or completely undersaturated ring.

The suitable example of HET-2 comprises azetidinyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base, the  di azoly, morpholino, morpholinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrryl, pyrrolidyl, pyrrolidone-base, 2,5-dioxo pyrrolidyl, 1,1-dioxo tetrahydro-thienyl, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, 2-oxo-1,3,4-(4-triazoline base (triazolinyl)), 2- oxazolidone base, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo thiomorpholine generation (dioxothiomorpholino), 1, the 3-dioxolanyl, 1,2, the 4-triazolyl, 1,2, the 3-triazolyl, pyranyl and 4-pyriconyl.

Should be appreciated that HET-2 can connect by any suitable available C or N atom, therefore, for example, comprise 1-, 2-, 4-and 5-imidazolyl for the HET-2 of " imidazolyl ".

The suitable example of the HET-3 of or part unsaturated heterocycle saturated as 4-6 unit is morpholino, piperidyl, piperazinyl, pyrrolidyl and azetidinyl.

The suitable example of the HET-3 of or part unsaturated heterocycle saturated as 7-unit is that high piperazinyl, height-morpholino, height-thiomorpholine generation, (and wherein sulphur was oxidized to SO or S (O) ₂The form of group) and height-piperidyl.

As the suitable example of the HET-3 of 6-10 unit bicyclic heterocycle for the dicyclo that for example shows structure institute example down saturated or part unsaturated heterocycle (wherein dotted line represent the point that is connected with the molecule other parts and wherein R represent optional substituting group on above defined carbon or the nitrogen):

Especially, HET-3 is [2,2,1] system, as

(7-azabicyclo [2.2.1] heptan-7-yl).

In another embodiment, HET-3 is [2,1,1] system, as

(2-azabicyclo [2.1.1] oneself-2-yl).

Should be appreciated that, when the definition of the heterocyclic group of HET-1 to HET-3 comprises wherein on nitrogen-atoms can substituted heteroaryl or during heterocycle, this replacement can not produce charged quaternary nitrogen atom or unstable structure (as the N-halogen compounds).The definition that should be appreciated that HET-1 to HET-3 does not plan to comprise any O-O, O-S or S-S key.The definition that should be appreciated that HET-1 to HET-3 does not plan to comprise unsettled structure.

(1-4C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl; (1-4C) example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy and tert.-butoxy; (3-6C) example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The example of halogen comprises fluorine, chlorine, bromine and iodine; The example of hydroxyl (1-4C) alkyl comprises methylol, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyl sec.-propyl and 4-hydroxybutyl; (1-4C) example of alkoxyl group (1-4C) alkyl comprises methoxymethyl, ethoxyl methyl, tert.-butoxy methyl, 2-methoxy ethyl, 2-ethoxyethyl group, methoxy-propyl, 2-methoxy-propyl and methoxyl group butyl; (1-4C) example of alkyl S (O) p (1-4C) alkyl comprises methylsulfinyl methyl, ethyl sulfinyl methyl, ethyl sulfinyl ethyl, methylsulfinyl propyl group, methylsulfinyl butyl, sulfonyloxy methyl ylmethyl, ethylsulfonyl methyl, ethylsulfonyl ethyl, methyl sulphonyl propyl group, methyl sulphonyl butyl, methylthiomethyl, ethylenebis dithiocarbamate methyl, ethylenebis dithiocarbamate ethyl, methyl sulfo-propyl group and methyl sulfo-butyl; The example of amino (1-4C) alkyl comprises amino methyl, amino-ethyl, 2-aminopropyl, 3-aminopropyl, the amino sec.-propyl of 1-and the amino butyl of 4-; (1-4C) example of alkylamino (1-4C) alkyl comprises (N-methyl) amino methyl, (N-ethyl) amino methyl, 1-((N-methyl) amino) ethyl, 2-((N-methyl) amino) ethyl, (N-ethyl) amino-ethyl, (N-methyl) aminopropyl and 4-((N-methyl) amino) butyl; The example of two (1-4C) alkylamino (1-4C) alkyl comprises dimethylaminomethyl, methyl (ethyl) amino methyl, methyl (ethyl) amino-ethyl, (N, the N-diethyl) amino-ethyl, (N, the N-dimethyl) aminopropyl and (N, N-dimethyl) amino butyl; (1-4C) example of alkylamino comprises methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino and tertiary butyl amino; The example of two (1-4C) alkylamino comprises dimethylamino, methyl (ethyl) amino, diethylamino, dipropyl amino, two-sec.-propyl amino and dibutylamino;-C (O) (1-4C) example of alkyl comprises methyl carbonyl, ethyl carbonyl, propyl group carbonyl and tertiary butyl carbonyl.

Should be appreciated that in the scope of formula (I) compound because one or more unsymmetrical carbons in some above-mentioned definition, can exist for optical activity or racemization form, the present invention comprises any such optical activity or raceme form with direct stimulation GLK or inhibition GLK/GLKRP interactive property in its definition.Can carry out the synthetic of optical activity form by vitochemical standard technique well-known in the art, for example synthesize or synthesize by splitting the racemization form by optically active starting raw material.Should also be clear that some changes house thing and can have tautomeric form, the present invention also relates to activate the tautomeric form of any He all The compounds of this invention of GLK.

Should also be clear that some formula (I) compound and salt thereof can exist solvate and non-solvent compound (unsolvated) form, for example hydrate forms.Should be appreciated that and the present invention includes all such solvates that activate GLK.

The compound of formula (I) is provided in one embodiment of the invention, the pharmaceutically acceptable salt of formula (I) compound is provided in the embodiment of an alternative, hydrolyzable ester in the body of formula (I) compound is provided in the embodiment of another alternative, the pharmaceutically acceptable salt of hydrolyzable ester in the body of formula (I) compound is provided in the embodiment of another alternative.

The preferred value of each variable group is as follows.Such value can suitably be used for value, definition, claim, aspect or the embodiment of any contextual definition.Especially, each value can be used as indivedual restrictions of the formula (I) of extensive definition.In addition, each following value can combine the extensive definition that is used for restraint-type (I) with one or more other following values.

(1) R ¹Be fluorine methoxymethyl, difluoro-methoxy methyl

(2) R ¹For fluorine methoxymethyl and configuration are preferably (S), its side chain is:

(3) R ¹For difluoro-methoxy methyl and configuration are preferably (S), its side chain is:

(4) R ²For-C (O) NR ⁴R ⁵

(5) R ²For-SO ₂NR ⁴R ⁵

(6) R ²For-S (O) _PR ⁴

(7) R ²Be HET-2

(8) R ²In contraposition with respect to ehter bond

(9) n is O or 1

(10) n is O

(11) n is 1, R ²At the contraposition with respect to ehter bond, R ³At ortho position with respect to ehter bond

(12) n is 1, R ²At the contraposition with respect to ehter bond, R ³Position between with respect to ehter bond

(13) n is 1

(14) n is 2

(15) n is 2 and two R ³It all is halogen

(16) n is 2 and each R ³Independent is fluorine or chlorine

(17) n is 2, R ²At contraposition and each R with respect to ehter bond ³At ortho position with respect to ehter bond

(18) n is 2, two R ³All be halogen, R ²At contraposition and each R with respect to ehter bond ³At ortho position with respect to ehter bond

(19) n is 2, two R ³All be halogen, R ²At contraposition and R with respect to ehter bond ³At ortho position with respect to ehter bond, another R ³Position between with respect to ehter bond

(20) R ³Be chlorine or fluorine

(21) R ³Be fluorine

(22) R ³Be chlorine

(24) n is 2 and two R ³It all is fluorine

(25) n is 2 and R ³Be fluorine, another R ³Be chlorine

(26) p is 0

(27) p is 1

(28) p is 2

(29) HET-1 is 5 yuan of hetero-aromatic rings

(30) HET-1 is 6 yuan of hetero-aromatic rings

(31) HET-1 is for independently to be selected from R by 1 or 2 ⁶Substituting group replace

(32) HET-1 is for to be selected from R by 1 ⁶Substituting group replace

(33) HET-1 is unsubstituted

(34) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base,  di azoly and triazolyl

(35) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl,  azoles base, different  azoles base,  di azoly

(36) HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidyl

(37) HET-1 is a pyrazolyl, for example N-methylpyrazole base

(38) HET-1 is pyridyl or pyrazinyl

(39) HET-1 is a pyrazinyl

(40) HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl group and pyrazinyl

(41) HET-1 is pyrazolyl (optional by ethyl, sec.-propyl or 1 or 2 methyl substituted), thiazolyl (optional by methyl substituted), pyrazinyl (optional by methyl substituted), pyridyl (choose wantonly and replaced by fluorine), different  azoles base (optional by methyl substituted) and thiadiazolyl group (optional by methyl substituted)

(42) HET-1 elect as pyrazolyl (optional by ethyl, sec.-propyl or, difluoromethyl, 1 or 2 methyl substituted), thiazolyl (optional), pyrazinyl (optional), pyridyl (optional replaced), different  azoles base (optional) and thiadiazolyl group (choosing wantonly) by methyl substituted by methyl substituted by fluorine by methyl substituted by methyl substituted

(43) to be selected from pyrazinyl (optional by methyl substituted), pyrazolyl (choosing wantonly on carbon by methyl substituted), methyl thiazolium di azoly (especially be 1 to HET-1,2,4-thiadiazoles-5-base, more in particular be the 3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl), thiazolyl (optional), pyridyl (optional replaced) and different  azoles base by fluorine by methyl substituted

(44) R ⁶Be selected from (1-4C) alkyl, halogen, hydroxyl (1-4C) alkyl, two (1-4C) alkylamino (1-4C) alkyl

(45) R ⁶Be selected from methyl, ethyl, chlorine, fluorine, methylol, methoxymethyl, amino methyl, N-methylamino methyl, dimethylaminomethyl

(46) R ⁶Be selected from methyl, ethyl, chlorine, fluorine, methylol and methoxymethyl

(47) R ⁶Be selected from methyl and ethyl

(48) R ⁶Be methyl

(49) R ⁶Be selected from (1-4C) alkyl and (1-4C) alkoxyl group (1-4C) alkyl

(50) R ⁶Be selected from methyl, ethyl, sec.-propyl and methoxymethyl

(51) when there being 2 substituent R ⁶The time, both are selected from methyl, ethyl, bromine, chlorine, fluorine; Preferably both are methyl and at least one is on available nitrogen-atoms

(52) R ⁴Be hydrogen

(53) R ⁴For (1-4C) alkyl [optional by 1 or 2 independently be selected from HET-2 ,-OR ⁵,-SO ₂R ⁵, (3-6C) cycloalkyl (optional is selected from R by 1 ⁷Group replace) and-C (O) NR ⁵R ⁵Substituting group replace]

(54) R ⁴For (1-4C) alkyl [optional by 1 be selected from HET-2 ,-OR ⁵,-SO ₂R ⁵, (3-6C) cycloalkyl and-C (O) NR ⁵R ⁵Substituting group replace]

(55) R ⁴Be (1-4C) alkyl

(56) R ⁴Be quilt-OR ⁵(1-4C) alkyl that replaces

(57) R ⁴Be (1-4C) alkyl that is replaced by HET-2

(58) R ⁴Being (3-6C) cycloalkyl, especially is cyclopropyl or cyclobutyl

(59) R ⁴For being selected from R ⁷(3-6C) cycloalkyl of replacing of group

(60) R ⁴For being selected from-OR ⁵(1-4C) (3-6C) cycloalkyl of the group of alkyl replacement

(61) R ⁴Be selected from (1-4C) alkyl and (3-6C) cycloalkyl

(62) R ⁴Be selected from methyl, ethyl, cyclopropyl and cyclobutyl

(63) R ⁴Be HET-2

(64) R ⁴Be selected from hydrogen, (1-4C) alkyl and quilt-OR ⁵(1-4C) alkyl that replaces

(65) HET-2 is unsubstituted

(66) HET-2 independently is selected from (1-4C) alkyl, hydroxyl and (1-4C) the substituting group replacement of alkoxyl group by 1 or 2

(67) HET-2 is complete saturated ring system

(68) HET-2 is complete undersaturated ring system

(69) HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidyl, piperazinyl, 3-oxo piperazinyl, thio-morpholinyl, pyrrolidyl, pyrrolidone-base, 2,5-dioxo pyrrolidyl, 1,1-dioxo tetrahydro-thienyl, 2- oxazolidone base, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo thiomorpholine generation, 1,3-dioxolanyl, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, pyranyl and 4-pyriconyl

(70) HET-2 is selected from azetidinyl, morpholino, morpholinyl, piperidyl, piperazinyl, pyrrolidyl, thio-morpholinyl, tetrahydrofuran base and THP trtrahydropyranyl

(71) HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base,  di azoly, pyrryl, 1,2,4-triazolyl and 1,2,3-triazoles base

(72) HET-2 is selected from furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base,  di azoly, piperidyl, piperazinyl, 3-oxo piperazinyl, pyrrolidyl, pyrrolidone-base, 2- oxazolidone, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo tetrahydro-thienyl and 2-oxo-imidazole alkyl

(73) HET-2 is selected from morpholino, furyl, imidazolyl,  azoles base,  azoles base,  di azoly, piperidyl, piperazinyl, 3-oxo piperazinyl, pyrrolidyl, 2-Pyrrolidone base, 2- oxazolidone base, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo tetrahydro-thienyl and 2-oxo-imidazole alkyl

(74) HET-2 is selected from morpholino, furyl, imidazolyl,  azoles base,  di azoly, piperidyl, piperazinyl, 3-oxo piperazinyl, pyrrolidyl, 2-Pyrrolidone base, THP trtrahydropyranyl, 1,1-dioxo tetrahydro-thienyl and 2-oxo-imidazole alkyl

(75) HET-2 is  di azoly or pyrazolyl

(76) R ⁵Be hydrogen

(77) R ⁵Be (1-4) alkyl, preferable methyl

(78) R ⁵Be hydrogen or methyl

(79) R ⁷For the substituting group on the carbon and be selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkyl ,-C (0) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl and hydroxyl (1-4C) alkyl

(80) R ⁷For the substituting group on the carbon and be selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkyl ,-C (0) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, and hydroxyl (1-4C) alkyl

(81) R ⁷For the substituting group on the carbon and be selected from hydroxyl, methoxyl group ,-COMe ,-CONH ₂,-CONHMe ,-CONMe ₂, and hydroxymethyl

(82) R ⁷For the substituting group on the carbon and be selected from (1-4C) alkyl, hydroxyl and (1-4C) alkoxyl group

(83) R ⁷For the substituting group on the carbon and be selected from methyl, ethyl, methoxyl group and hydroxyl

(84) R ⁷For the substituting group on the nitrogen and be selected from (1-4C) alkyl ,-C (0) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl and hydroxyl (1-4C) alkyl

(85) R ⁷For the substituting group on the nitrogen and be selected from (1-4C) alkyl, hydroxyl and (1-4C) alkoxyl group

(86) R ⁷Be methyl

(87) R ⁸Be selected from methyl, hydroxyl, methoxyl group ,-CONH ₂,-CONHMe ,-CONMe ₂, methylol, hydroxyethyl ,-NHMe and-NMe ₂

(88) R ⁸Be selected from methyl ,-CONH ₂, hydroxyethyl and hydroxyl

(89) R ⁸Be selected from (1-4C) alkyl and (1-4C) alkoxyl group

(90) R ⁸Be selected from methyl, methoxyl group and isopropoxy

(91) R ⁸Be methyl

(92) R ⁹Be selected from methyl, hydroxyl, methoxyl group ,-CONH ₂,-CONHMe ,-CONMe ₂, methylol, hydroxyethyl ,-NHMe and-NMe ₂

(93) R ⁹Be methyl

(94) HET-3 is complete saturated ring

(95) HET-3 is selected from morpholino, piperidyl, piperazinyl, pyrrolidyl and azetidinyl

(96) R ⁴And R ⁵Form defined ring with the nitrogen-atoms that connects them as HET-3

(97) HET-3 is selected from pyrrolidyl and azetidinyl

(98) HET-3 is an azetidinyl

(99) HET-3 is 4 to 6 yuan of saturated or undersaturated heterocycles of part that define as mentioned

(100) HET-3 is 7 yuan of saturated or undersaturated heterocycles of part that define as mentioned

(101) HET-3 is the undersaturated heterocycle of saturated or part of 6 to 10 yuan of dicyclos of definition as mentioned

(102) HET-3 be 7-azabicyclo [2.2.1] heptan-7-base or 2-azabicyclo [2.1.1] oneself-the 2-base

(103) HET-3 is selected from morpholino, piperidyl, piperazinyl, pyrrolidyl and azetidinyl

(104) HET-3 is unsubstituted

(105) HET-3 is replaced by methyl, methoxyl group or isopropoxy

(106) R ²Be selected from-C (O) NR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

(107) R ²Be azetidinyl carbonyl or azetidinyl alkylsulfonyl

(108) R ²Be azetidinyl carbonyl or methyl sulphonyl

(109) R ²Be azetidinyl carbonyl or azetidinyl alkylsulfonyl or (1-4C) alkyl sulphonyl

(110) R ²Be azetidinyl carbonyl or azetidinyl alkylsulfonyl or methyl sulphonyl

According to further aspect of the present invention, provide the The compounds of this invention of following preferred group:

In one aspect of the invention, provide formula (I) compound or its salt of definition as mentioned, wherein:

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

R ²Be selected from-C (O) NR ⁴R ⁵,-SO ₂NR ⁴R ⁵, and-S (O) _PR ⁴

HET-1 is the heteroaryl ring that comprises 2-position nitrogen-atoms and optional 1 or 2 other ring hetero atom that independently is selected from O, N and S by the 5-of C-connection or 6-unit; Described ring is chosen wantonly at available carbon atom or on theheterocyclic nitrogen atom and independently is selected from R by 1 or 2 ⁶Substituting group replace, condition is that this nitrogen-atoms can not be therefore and by quaternized;

R ³Be selected from halogen;

R ⁴Be selected from hydrogen and (1-4C) alkyl;

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁶Independently be selected from (1-4C) alkyl and (1-4C) alkoxyl group (1-4C) alkyl and/or (for R ⁶Be the substituting group on the carbon) halogen;

HET-3 is 4 to 6 yuan of saturated or undersaturated heterocycles of part that connect by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that the N atom that is connected) that independently is selected from O, N and S, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and wherein the sulphur atom on the ring can be chosen wantonly and is oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon atom and independently is selected from R by 1 or 2 ⁸Substituting group replace; And/or quilt is selected from R on available nitrogen-atoms ⁹Substituting group replace;

R ⁸Be selected from hydroxyl, (1-4C) alkoxyl group and (1-4C) alkyl;

R ⁹Be (1-4C) alkyl;

P is (when at every turn occurring independently) 0,1 or 2;

N is 0,1 or 2.

In another aspect of the present invention, formula (I) compound or its salt of definition as mentioned is provided, wherein:

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

R ²Be selected from-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵

R ³Be selected from halogen;

R ⁴Be selected from hydrogen and (1-4C) alkyl;

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁸Be selected from hydroxyl, (1-4C) alkoxyl group and (1-4C) alkyl;

R ⁹Be (1-4C) alkyl;

P is (when at every turn occurring independently) 0,1 or 2;

N is 0,1 or 2.

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

R ²Be selected from-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵

R ³Be selected from halogen;

R ⁴And R ⁵Can form defined heterocycle ring system with the nitrogen-atoms that connects them as HET-3;

R ⁸Be selected from hydroxyl, (1-4C) alkoxyl group and (1-4C) alkyl;

R ⁹Be (1-4C) alkyl;

P is (when at every turn occurring independently) 0,1 or 2;

N is 0,1 or 2.

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl group and pyrazinyl; R wherein ¹Optional by methyl or ethyl replacement;

R ²For-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵, R wherein ⁴And R ⁵Form the ring of azetidinyl, piperidyl, morpholino or (optional N-replaces) piperidino-(1-position only) with the nitrogen-atoms that connects them;

R ³Be chlorine or fluorine;

N is 0 or 1.

R ¹Be the difluoro-methoxy methyl;

HET-1 is a N-methylpyrazole base;

R ²For-C (O) NR ⁴R ⁵, R wherein ⁴And R ⁵Form the azetidine basic ring with the nitrogen-atoms that connects them;

R ³Be chlorine;

N is 0 or 1.

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl group and pyrazinyl; Wherein HET-1 is optional is replaced by methyl or ethyl;

R ²For-SO ₂R ⁴, R wherein ⁴Be (1-4C) alkyl;

R ³Be chlorine or fluorine;

N is 0 or 1.

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

R ²For-C (O) NR ⁴R ⁵Or-SO ₂NR ⁴R ⁵, R wherein ⁴And R ⁵Form the ring of azetidinyl, piperidyl, morpholino or (optional N-replaces) piperidino-(1-position only) with the nitrogen-atoms that connects them; Or

R ²For-SO ₂R ⁴, R wherein ⁴Be (1-4C) alkyl;

R ³Be chlorine or fluorine;

N is 0 or 1.

R ¹Be selected from fluorine methoxymethyl and difluoro-methoxy methyl;

HET-1 is a N-methylpyrazole base;

R ²For-C (O) NR ⁴R ⁵Or-SO ₂NR ⁴R ⁵, R wherein ⁴And R ⁵Form azetidinyl, piperidyl, morpholino or (optional N-replaces) piperidino-(1-position only) ring with the nitrogen-atoms that connects them; Or

R ²For-SO ₂R ⁴, R wherein ⁴Be (1-4C) alkyl;

R ³Be chlorine or fluorine;

N is 0 or 1.

The further preferred compound of the present invention is each compound of embodiment, and they provide the present invention further independent aspects separately.Further, the present invention also comprises any two or more compounds of embodiment.

Specilization compound of the present invention comprises following any one or more a plurality of compound and salt thereof: 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide; And 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide; And/or 3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{[4-(sulfonyloxy methyl) phenyl] the oxygen base } benzamide.

Compound of the present invention can the prodrug forms administration.Prodrug is that bioprecursor or pharmacy can be accepted compound (as hydrolyzable ester in the ester and the acid amides, particularly body of The compounds of this invention), and it is degradable generation The compounds of this invention in vivo.The prodrug of various ways is as known in the art.The example of these prodrug derivants, referring to:

A) Design of Prodrugs, H.Bundgaard compiles, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, the 309-396 page or leaf, K.Widder waits volume (Academic Press, 1985);

B) Textbook of Drug Design and Development, Krogsgaard-Larsen compiles;

C) H.Bundgaard, Chapter 5 ＂ Design and Application of Prodrugs ＂, H.Bundgaard, 113-191 page or leaf (1991);

d)H.Bundgaard，Advanced?Drag?Delivery?Reviews， 8，1-38(1992)；

E) H.Bundgaard, etc., Journal of Pharmaceutical Sciences, 77, 285 (1988); With

F) N.Kakeya, etc., Chem Pharm Bull, 32, 692 (1984).

The content of above-mentioned citing document is hereby incorporated by.

The example of prodrug is as follows.The interior hydrolyzable ester of body that comprises the The compounds of this invention of carboxyl and oh group is that for example, hydrolysis produces the pharmacy acceptable ester of parent acid or alcohol in human or animal body.Suitable carboxyl pharmacy acceptable ester comprises C ₁-C ₆The alkoxy methyl ester, as methoxymethyl ester, C ₁-C ₆Alkyloyl oxygen ylmethyl ester such as valeryl oxygen ylmethyl, phthalidyl ester, C ₃-C ₈Cyclo alkoxy carbonyl oxygen base C ₁-C ₆Alkyl ester such as 1-cyclohexyl-carbonyl oxygen base ethyl; 1,3-dioxole-2-ketone group methyl ester (1,3-dioxolen-2-onylmethyl esters), as the 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl; And C ₁-C ₆The alkoxy-carbonyl oxy ethyl ester.

The interior hydrolyzable ester of body that comprises the The compounds of this invention of hydroxyl comprises inorganic ester such as phosphoric acid ester (comprising phosphoramidic acid cyclic ester (phosphoramidic cyclic esters)) and alpha-acyloxy alkyl oxide and related compound, they are because hydrolysis in the body of ester fracture obtains the parent hydroxy group.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The selection of the ester of hydrolyzable hydroxyl formation group comprises benzoyl and phenyl acetyl, alkoxy carbonyl (obtaining alkyl carbonate), dialkyl amino formyl radical and N-(dialkyl amido ethyl)-N-alkylcarbamoyl group (obtaining carbamate), dialkyl amido ethanoyl and the carboxyl ethanoyl of alkyloyl, benzoyl, phenylacetyl and replacement in the body.

The suitable pharmaceutically acceptable salt of The compounds of this invention is, for example, acid salt with The compounds of this invention of enough alkalescence, for example inorganic or organic acid acid salt, described sour example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid/citric acid or toxilic acid.Should be appreciated that and can form acid salt with any enough basic groups, described basic group for example can be HET-1 or can be substituent R ²In addition, the suitable pharmaceutically acceptable salt with enough tart benzoxazine ketone derivatives of the present invention is an alkali metal salt (as sodium or sylvite), alkaline earth salt (as calcium or magnesium salts), ammonium salt or can accepts cationic salt (for example salt that forms with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine) with the physiology that provides that organic bases forms.

Another feature of the present invention is a pharmaceutical composition, and it comprises formula (I) compound or its pharmacologically acceptable salts and the pharmacy acceptable diluent or the carrier of above-mentioned definition.

According to a further aspect in the invention, provide compound or its pharmacologically acceptable salts of the formula (I) of above-mentioned definition, as medicine.

According to a further aspect in the invention, provide compound or its pharmacologically acceptable salts of the formula (I) of above-mentioned definition, as the disease of treatment by the GLK mediation especially medicine of diabetes B.

Also according to the present invention, provide the compound of formula (I) or its pharmacologically acceptable salts purposes in the medicine of the disease of preparation treatment by the GLK mediation especially diabetes B.

Compound suitably is formulated as pharmaceutical composition, is used for this mode.

According to a further aspect in the invention, the disease that treatment GLK mediation is provided is the method for diabetes especially, and it is by giving formula (I) compound or its pharmacologically acceptable salts of the administration significant quantity that needs this treatment.

The disease specific of available The compounds of this invention or combination treatment comprises: (and effective to the treatment type 1 diabetes), blood ester are unusual, obesity, insulin resistant, metabolism syndrome X, glucose tolerance reduce not have the blood sugar of severe hypoglycemia risk to reduce in diabetes B.

As mentioned above, thus the GLK/GLKRP system can be described to potential " obese diabetes (Diabesity) " target (useful in two kinds of diabetes and obesity).Therefore, according to a further aspect in the invention, provide formula (I) compound or its pharmacologically acceptable salts to be used for the purposes of the medicine of combination therapy or prevention (especially treatment) diabetes and obesity in preparation.

According to a further aspect in the invention, provide formula (I) compound or its pharmacologically acceptable salts preparation be used for the treatment of or the medicine of obesity prevention in purposes.

According to another aspect of the invention, provide the method for combination therapy or prevent diabetes and obesity, it is by giving formula (I) compound or its pharmacologically acceptable salts of the administration significant quantity that needs this treatment.

According to a further aspect in the invention, provide compound or its pharmacologically acceptable salts of the formula (I) of above-mentioned definition, as the purposes in the medicine of treatment or prevention (especially treatment) obesity.

According to another aspect of the invention, provide the method for treatment of obesity, it is by giving formula (I) compound or its pharmacologically acceptable salts of the administration significant quantity that needs this treatment.

The compounds of this invention can be particularly suitable for as medicine, for example because its favourable physics and/or pharmacokinetics character and/or toxic characteristic.

Composition of the present invention can be suitable oral form (as tablet, lozenge, hard or soft capsule, water-based or oil-based suspension, emulsion, powder (dispersible powders) or granule, syrup or elixir), the topical application form is (as ointment, ointment, gelifying agent or water-based or oily solution agent or suspensoid), or the form (as meticulous pulvis (finely divided powder) or liquid aerosol) by inhalation, (as be used for intravenous injection by the form (as meticulous pulvis) or the parenteral admin form of insufflation administration, subcutaneous injection, the sterile aqueous of intramuscularly or intramuscular administration or oily solution or be used for the suppository of rectal administration).Be suitable for oral formulation for preferred.

Can use conventional pharmaceutical excipient and obtain the present composition by ordinary method well known in the art.Therefore, being intended to be used for oral composition can comprise, for example one or more tinting materials, sweeting agent, correctives and/or sanitas.

Suitable pharmaceutical acceptable excipient comprises to be used for tablet formulation, as inert diluent such as lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulation and disintegrating agent such as W-Gum or Lalgine (algenicacid); Tackiness agent such as starch; Lubricant such as Magnesium Stearate, stearic acid or talcum; Sanitas such as P-hydroxybenzoic acid second or propyl ester, and antioxidant such as xitix.That tablet formulation can be dressing not or dressing, with modify its disintegration and subsequently activeconstituents or improve its stability and/or outward appearance in gastrointestinal absorption, in these two kinds of situations, can use conventional Drug coating well known in the art and method and carry out dressing.

Be used for oral composition and can be form of hard gelatin capsules, wherein activeconstituents and inert solid diluent are (for example, lime carbonate, calcium phosphate or kaolin) mixed, or be the soft capsule form, wherein activeconstituents and water or oil (as peanut oil, whiteruss or sweet oil) are mixed.

Aqueous suspension comprises activeconstituents and one or more suspension agents of fine powder form usually, as Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; The condenses (as polyoxyethylene stearic acid ester (polyoxethylene stearate)) of dispersion or wetting agent such as Yelkin TTS or alkylene oxide and lipid acid, or the condenses of oxyethane and long chain aliphatic such as heptadecaethylene oxycetanol (heptadecaethyleneoxycetanol), or oxyethane and derive from lipid acid and the condenses of the partial ester of hexitol such as octadecanoic acid ester of polyethylene glycol, or the condenses of oxyethane and long chain aliphatic such as heptadecaethylene oxycetanol, or oxyethane and derive from lipid acid and the condenses of the partial ester of hexitol such as octadecanoic acid ester of polyethylene glycol, or oxyethane and derive from lipid acid and the condenses of the partial ester of hexitan such as the polyethylene sorbitol monooleate that anhydrates.Aqueous suspension also can comprise one or more sanitass (as P-hydroxybenzoic acid second or propyl ester), antioxidant (as xitix), tinting material, correctives and/or sweeting agent (as sucrose, asccharin or aspartame).

The oiliness suspensoid can make by activeconstituents being suspended in vegetables oil (as flower t4-oil generation, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (as whiteruss).The oiliness suspensoid also can comprise thickening material such as beeswax, solid paraffin or hexadecanol.Can add aforesaid sweeting agent and correctives so that good to eat oral preparations to be provided.Can preserve these compositions by adding antioxidant such as xitix.

Be suitable for comprising activeconstituents and dispersion or wetting agent, suspension agent and one or more sanitass usually by adding powder and the granule that entry prepares aqueous suspension.By above narration, for example understood suitable dispersion or wetting agent and suspension agent.Also can there be other vehicle such as sweeting agent, correctives and tinting material.

Pharmaceutical composition of the present invention also can be oil-in-water emulsion form.Oil phase can be the mixture of vegetables oil (as sweet oil or peanut oil) or mineral oil (as whiteruss) or any of these.Suitable emulsifying agent can be as naturally occurring natural gum such as gum arabic or tragacanth gum, naturally occurring phosphatide such as soybean lecithin, the ester that derives from lipid acid and hexitan or partial ester (as the sorbitol monooleate that anhydrates) and as described in the condenses such as the Tween 80 of partial ester and oxyethane.Emulsion also can comprise sweeting agent, seasonings and sanitas.

Syrup and elixir can also can comprise negative catalyst, sanitas, correctives and/or tinting material with sweeting agent (as glycerine, propylene glycol, sorbyl alcohol, aspartame or sucrose) preparation.

Pharmaceutical composition also can be the form of sterile injectable water-based or oil-based suspension, and one or more suitable dispersions that it has been described above can using or wetting agent and suspension agent make according to currently known methods.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or the aseptic parenteral solution or the suspension of solvent, for example solution in the 1,3 butylene glycol.

Can be the form of conventional pressurised aerosol by the composition of inhalation, wherein activeconstituents is separated into and comprises fine solid aerosol or small droplets.Can use conventional aerosol propellant such as volatility hydrofluoric ether or hydrocarbon polymer and available aerosol device, the activeconstituents that measures easily.

As for the further information in preparation aspect, the reader can be with reference to Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), the 5th of Pergamon Press1990 the volume the 25.2nd chapter.

Based on the particular approach of host who is treated and administration, can adjust the amount of activeconstituents necessarily, the amount of this activeconstituents combines to produce single formulation with one or more vehicle.For example, the preparation that is intended to be used for the human oral administration for example comprises the activeconstituents with the 0.5mg to 2g of the mixed with excipients of suitable and suitable amount usually, the amount of described vehicle its can about 98% variation at about 5-of total composition weight percentage ratio.Dosage unit form comprises the activeconstituents of the about 500mg of about 1mg-usually.As for the further information of route of administration and dosage regimen, the reader can be with reference to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board), the 5th of Pergamon Press 1990 the volume the 25.3rd chapter.

According to character and seriousness, animal or patient's age and the sex and the route of administration of illness,, be used for the treatment of or prevent the dosage size nature of formula (I) compound of purpose to change to some extent according to well-known medicine principle.

When use formula (I) compound was used for the treatment of or prevents purpose, the administration per daily dose that it gives usually existed, in the 0.5mg-75mg/kg weight range, if the words that need give with broken dose.When using the parenteral admin approach, give lower dosage usually.Therefore, for example, for intravenous injection, the dosage range of common application examples such as 0.5mg-30mg/kg body weight.Similarly, for inhalation, the dosage range of common application examples such as 0.5mg-5mg/kg body weight.But oral administration is preferred.

The active raising of GLK described herein can be used as independent treatment or makes up with one or more other materials and/or therapeutics, is used for the indication of needs treatment.By simultaneously, in succession or the mode of each therapeutic component of separate administration can realize this combination therapy.The tablet that treatment simultaneously can be single tablet or separates.For example, when the treatment diabetes, chemotherapy can comprise the treatment of following main type:

1) Regular Insulin and insulin analog;

2) Drugs Promoting Insulin Secretion comprises sulfonylurea (as Glyburide, Glipizide), meals glucose conditioning agent (as repaglinide, nateglinide);

3) improve the medicine (as inhibitors of dipeptidyl IV and GLP-1 agonist) that incretin (incretin) acts on;

4) euglycemic agent comprises peroxidase vegetation activated receptor γ (PPARgamma) agonist (for example pioglitazone and rosiglitazone) and has the medicine of PPAR α and gamma activity simultaneously;

5) regulate hepatic glucose equilibrated medicine (as N1,N1-Dimethylbiguanide, fructose 1,6 diphosphatase inhibitor, glycogen phosphorylase (glycogen phopsphorylase) inhibitor, glycogen synthase kinase inhibitor);

6) have a mind to reduce the medicine (as acarbose) of glucose from intestinal absorption;

7) stop kidney heavily to absorb the medicine (SGLT inhibitor) of glucose;

8) have a mind to treat the medicine (as aldose reductase inhibitor) of long-term hyperglycemia complication;

9) anti-obesity medicine (as sibutramine and orlistat);

10) anti-lipid unusual medicine is as HMG-CoA reductase inhibitor (as statins); PPAR alfa agonists (chlorine Bei Te is as gemfibrozil); Bile acid multivalent chelator (Colestyramine); Cholesterol absorption inhibitor (plant sterol (plant stanol), synthetic inhibitor); Bile acide absorption inhibitor (IBATi) and nicotinic acid and analogue thereof (niacin usp (niacin) and sustained release preparation);

11) antihypertensive drug such as beta-blocker (as atenolol USP 23, propranolol); ACE inhibitor (as lisinopril); Calcium antagonist (as nifedipine); Angiotensin receptor antagonist (as Candesartan); Alpha-2 antagonists and diuretic(s) (as Furosemide, benzthiazide);

12) hemostasis conditioning agent such as antithrombotic, fibrinolytic activator and anti-platelet agents; The zymoplasm antagonist; The Xa factor inhibitor; The VIIa factor inhibitors; Anti-platelet agents (as acetylsalicylic acid, clopidogrel); Anti-coagulant (heparin and lower molecular weight analogue thereof, r-hirudin) and warfarin;

13) medicine of antagonism hyperglycemic-glycogenolytic factor effect; With

14) antiphlogiston such as NSAID (non-steroidal anti-inflammatory drug) (as acetylsalicylic acid) and steroidal anti-inflammatory medicine (as cortisone).

According to a further aspect in the invention, provide individuation compound and the salt of producing as end product among the following embodiment thereof.

By being used to prepare any currently known methods of such compound or structurally associated compound, can prepare The compounds of this invention or its salt.Can use ordinary method protects and deprotection functional group.For example blocking group is as the example of amino and carboxylic acid protective group (and formation method and final deprotection method), referring to T.W.Greene and P.G.M. Wuts, " Protective Groups inOrganic Synthesis ", second edition, John Wiley﹠amp; Sons, New York, 1991.

As further aspect of the present invention, provide the synthetic method of formula (I) compound.Therefore, the further aspect according to the present invention provides the preparation method of formula (I) compound, comprising method a)-e) (wherein except as otherwise noted, the variable of formula (I) compound defines as mentioned):

(a) with the acid of formula (III) or the compound reaction of its activatory derivative and formula (IV), wherein R ¹Define or for its precursor suc as formula (I);

Or

(b) with the compound of formula V and the compound reaction of formula (VI),

X wherein ¹Be leavings group and X ²Be oh group, or X ¹Be oh group and X ²Be leavings group and R wherein ¹Define or for its precursor suc as formula (I);

The also available wherein P of method (b) ¹Intermediate ester for the formula (VII) of the blocking group of following zhang description is used in other local finishing by ester hydrolysis and amidation with the well-known method of those skilled in the art of describing then;

Or

(c) with the compound of formula (VIII) and the compound reaction of formula (IX)

X wherein ³Be leavings group or organometallic reagent and X ⁴Be oh group, or X ³Be oh group and X ⁴Be leavings group or organometallic reagent and R wherein ¹Define or for its precursor suc as formula (I);

The intermediate ester of the also available formula of method (c) (X) is used in other local finishing by ester hydrolysis and amidation with the well-known method of those skilled in the art of describing then;

Or

(d) with the compound of formula (XI) and the compound reaction of formula (XII)

X wherein ⁵Be leavings group and R wherein ¹Define or for its precursor suc as formula (I); Or

E) formula (XIII) compound

R wherein ^2aBe R ²(as-CONR ⁴R ⁵Or-SO ₂R ⁴R ⁵) precursor, for example carboxylic acid, ester or acid anhydride are (for R ²=-CONR ⁴R ⁵) or the sulfonic acid equivalent (for R ²=-SO ₂R ⁴R ⁵);

With formula NR ⁴R ⁵Amine reaction;

Then, if desired:

I) formula (I) compound is converted into other compound of formula (I);

Ii) with R ¹Precursor conversion be R ¹

Iii) remove any blocking group; And/or

Iv) form its salt.

Usability methods b)-d) leavings group X ¹-X ⁵Any leavings group that is used for these reaction types that is known in the art is as halogen, alkoxyl group, trifluoromethyl sulfonyl oxygen base, methyl sulphonyl oxygen base or p-toluenesulfonyl oxygen base; Or can be converted into the group (as oh group) of leavings group (as oxygen base triphenyl phosphorus  group (oxytriphenylphosphonium group)) in position

R ¹The precursor that is fit to comprises the oh group of oh group or protection, any suitable hydroxy-protective group as known in the art, and for example simple ether such as methyl ether, or silyl ether is as-OSi[(1-4C) alkyl] ₃(wherein each (1-4C) alkyl group independently is selected from methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl).The example of these trialkylsilyl group is trimethyl silyl, triethylsilyl, triisopropyl silyl and t-butyldimethylsilyl.Suitable in addition silyl ether comprises the phenyl of phenyl and replacement, as-Si (PhMe ₂) and-Si (TolMe ₂)-(be T01=toluene wherein).Hereinafter provided the further desired value of hydroxy-protective group.R that then can generation itself ¹, it is by removing hydroxy-protective group (if exist), then in the presence of cupric iodide (I) by reacting with for example 2-(fluorine sulphonyl) difluoroacetic acid, obtain wherein R ¹Compound for the difluoro-methoxy methyl.In scheme 1 illustrated should the reaction.Can be similarly or by method well-known in the art, produce R ¹Other value, for example referring to Bull.Chem.Soc.Japan, 73 (2000), 471-484,471-484; International Patent Application WO 2002/050003 and Bioorganicand Medicinal Chemistry Letters, (2001), 11,407.

The compound of formula (III)-(XII) is commercial arriving, or is as known in the art, maybe can make by the method as shown in appended embodiment known in the art.As for the further information of method of this compounds of preparation, with reference to our PCT announcement WO 03/000267, WO03/015774, WO 03/000262, WO 2004/076420, WO 2005/054200, WO2005/054233, WO 2005/044801 and WO 2005/056530 and reference wherein.In a word, should be appreciated that to choose wantonly and in the presence of suitable alkali, pass through nucleophilic substitution or metal catalytic method, can form any aryl-O or alkyl-O key.

The compound of formula (XIII) can make by those methods shown in a)-d) of method for example or those methods by above-mentioned formula (III)-(XII) compound.

React by precursor and the formula V compound or derivatives thereof that is fit to, can make formula (III), (IX), (X), (XI) and compound (XIII), this depends on R ¹The character of group or its precursor is for example by leavings group X in the nucleophilic displacement formula V compound ¹The formula V compound is generally commercial and arrives, maybe can be by carrying out simple functional group to compound and exchange or make by literature method commercial.When the formula V compound contains R ¹Precursor the time, the reaction of application examples such as following scheme 1 illustrated can suitably produce R in formula (III), (IX), (X), (XI) or compound (XIII) ¹Group.In the following scheme and/or embodiment subsequently shown the illustrative example.

[PG is a blocking group].

Scheme 1

It is that those skilled in the art are well-known that formula (I) compound is converted into other examples for compounds of formula (I), comprise functional group's change (as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction), and/or other functionalization of coupled reaction or affine replacement(metathesis)reaction by standard reaction such as acid amides or metal catalytic.An example can be removed R ³=chlorine substituent, for example by under barometric point or the elevated pressure in suitable solvent such as THF/ methyl alcohol or ethanol with the reaction of hydrogen.

Should be appreciated that substituent R ², R ³And/or R ⁶Can in composition sequence, introduce in any suitable site in molecule, or may reside in the parent material.The precursor of one of these substituting groups can be present in the molecule during aforesaid method step a)-e), is translated into the substituting group of expection then as final step, forms the compound of formula (I), if desired subsequently

I) formula (I) compound is converted into other compound of formula (I);

Ii) with R ¹Precursor conversion be R ¹

Iii) remove any blocking group; And/or

Iv) form its salt.

The specific reaction conditions of reacting above is as follows, wherein works as P ¹During for blocking group, P ¹Be preferably (1-4C) alkyl, as methyl or ethyl:

Method a)-coupled reaction that amino and carboxylic acid form acid amides is well known in the art.For example,

(i) use suitable coupled reaction, as at room temperature, in the presence of dimethyl aminopyridine (DMAP), in suitable solvent such as methylene dichloride (DCM), chloroform or dimethyl formamide (DMF), carry out the carbodiimide coupled reaction with EDAC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride); Or

(ii) the carboxylic group activation is the reaction of acyl chlorides, it is by reacting with oxalyl chloride in the presence of suitable solvent such as DCM.Described acyl chlorides then can with formula (IV) compound in the presence of alkali (as triethylamine or pyridine), in suitable solvent (as chloroform or DCM), between 0 ℃-80 ℃, react.

Method b)-can with formula V and (VI) compound in suitable solvent such as DMF or tetrahydrofuran (THF) (THF) with alkali such as sodium hydride or potassium tert.-butoxide 0 ℃-200 ℃ next react, optional with microwave heating or metal catalytic such as acid chloride (II), palladium/carbon, venus crystals (II) or cupric iodide (I); Alternative ground can be with formula V and compound (VI) in suitable solvent such as THF or DCM, reacts with suitable phosphine such as triphenylphosphine and azo two acid esters such as diethylazodicarboxylate one; Method b) also can use precursor such as the aryl nitrile or the trifluoromethyl derivative of formula (VII) ester, react, be translated into carboxylic acid then as previously mentioned and form acid amides;

Method c)-can be in suitable solvent such as DMF or THF with formula (VIII) and compound (IX), next reacts optional microwave heating or metal catalytic such as acid chloride (II), palladium/carbon, venus crystals (II) or the cupric iodide (I) of adopting 0 ℃-200 ℃ temperature with suitable alkali such as sodium hydride or potassium tert.-butoxide; Process c) also can use precursor such as the aryl nitrile or the trifluoromethyl derivative of formula (X) ester, react, be translated into carboxylic acid then as previously mentioned and form acid amides;

Method d)-reaction of Shi (XI) compound and formula (XII) compound can be in polar solvent such as DMF or non-polar solvent such as THF carries out optional microwave heating or metal catalytic such as acid chloride (II), palladium/carbon, venus crystals (II) or the cupric iodide (I) of adopting with highly basic such as sodium hydride or potassium tert.-butoxide under 0 ℃-200 ℃ temperature;

Method e)-coupled reaction that amino and carboxylic acid or sulfonic acid form acid amides is that those skilled in the art are well-known, and be described in above method a) in.

It is novel that formula (III), (VI), (VII), (IX) and/or some intermediate (XI) are considered to, and comprise independent aspects of the present invention.

R wherein ¹It is novel that formula as defined herein (III), (IX) and/or some intermediate (XI) are considered to, and comprise independent aspects of the present invention.

It is novel that some intermediate of formula (XIII) is considered to, and comprise independent aspects of the present invention.

In the preparation method, it is useful that intramolecular functional group is used blocking group.Can by describe in the document or the known any method easily that is fit to remove the blocking group of being touched upon of chemical technology personnel, remove blocking group, select in such method to disturb minimum blocking group to remove method to other group in the molecule.

For convenience, provided the specific examples of blocking group below, wherein the used group of " rudimentary " expression preferably has 1-4 carbon atom.Should be appreciated that these examples are not exhaustive.The specific examples of removing the blocking group method given below equally neither exhaustive.The use of the blocking group of specifically not mentioning and the method for deprotection are certainly also within the scope of the invention.

Carboxy protective group can be the residue of the fatty alcohol that forms ester or aryl fatty alcohol (araliphatic alcohol) or is the residue (described alcohol or silanol preferably comprise 1-20 carbon atom) of the silanol that forms ester.The example of carboxy protective group comprises straight or branched (1-12C) alkyl group (as sec.-propyl, the tertiary butyl); Lower alkoxy low alkyl group (as methoxymethyl, ethoxyl methyl, isobutoxy methyl); Lower aliphatic acyloxy low-grade alkyl group (as acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl, valeryl oxygen ylmethyl); Elementary alkoxy carbonyl oxygen base low-grade alkyl group (as 1-methoxycarbonyl oxygen base ethyl, 1-ethoxy carbonyl oxygen base ethyl); Aromatic yl elementary alkyl group (as to methoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl-group (as trimethyl silyl and t-butyldimethylsilyl); Three (low alkyl group) silyl low-grade alkyl group (as the trimethyl silyl ethyl); (2-6C) kiki alkenyl group (as allyl group and vinyl ethyl).

The method that is particularly suitable for removing carboxy protective group comprise as acid-, metal-or enzyme-catalytic hydrolysis.

The example of hydroxy-protective group comprises methyl, the tertiary butyl, low-grade alkenyl group (as allyl group); Low-grade alkane acidyl group (as ethanoyl); Elementary alkoxy carbonyl group (as tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl group (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl group (as benzoyl oxygen base carbonyl, to methoxyl group benzyloxy base carbonyl, adjacent nitro benzyloxycarbonyl, to the nitro benzyloxycarbonyl); Three lower alkyl/aryl groups silyl-group (as trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); Tetrahydropyrans-2-base; Aromatic yl elementary alkyl group (as benzyl) group; With triaryl low alkyl group (as trityl group).

The example of amido protecting group comprises formyl radical, aromatic alkyl group (as the benzyl of benzyl and replacement as to methoxy-benzyl, nitrobenzyl and 2,4-dimethoxy-benzyl, and trityl group); The two pairs of anisyl methyl and furyl methyl group; Elementary alkoxy carbonyl (as tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl group (as benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, adjacent nitro benzyloxycarbonyl, to the nitro benzyloxycarbonyl); Trialkylsilkl (as trimethyl silyl and t-butyldimethylsilyl); Alkylidene group (as methylene radical); Benzylidene and replacement benzylidene group.

The usability methods of removing hydroxyl and amido protecting group comprises as nucleophilic displacement, acid-, alkali-, metal-or enzyme-catalytic hydrolysis reaction, to the catalytic hydrogenolysis/hydrogenation or the photodissociation of group (as adjacent nitro benzyloxycarbonyl), to the silyl-group fluoride ion.For example, can remove the methyl ether blocking group of oh group by trimethyl silyl iodine.Can remove the tertbutyl ether blocking group of oh group by hydrolysis, for example use hydrochloric acid and in methyl alcohol, be hydrolyzed.

The example of amide group blocking group comprises aralkoxy methyl (as the benzyl oxygen ylmethyl of benzyl oxygen ylmethyl and replacement); Alkoxy methyl (as methoxymethyl and trimethylsilylethoxymethyl); Trialkyl/aryl silyl (as trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); Trialkyl/aryl silyl oxygen ylmethyl (as t-butyldimethylsilyl oxygen ylmethyl, t-butyldiphenylsilyl oxygen ylmethyl); 4-alkoxyl phenyl (as the 4-p-methoxy-phenyl); 2,4-(alkoxyl group) phenyl (as 2, the 4-Dimethoxyphenyl); 4-alkoxybenzyl (as the 4-methoxy-benzyl); 2,4-two (alkoxyl group) benzyl (as 2,4-two (methoxyl group) benzyl); And chain-1-thiazolinyl (as allyl group, but-1-ene base and substituted ethylene base such as 2-phenyl vinyl).

Can be by with amide group and the reaction of suitable aralkoxy Methochloride and the aralkoxy methyl group is incorporated into amide group, available catalytic hydrogenation is removed.By with acid amides and suitable muriate reaction, can introduce alkoxy methyl, trialkyl/aryl silyl and trialkyl/silyl oxygen ylmethyl group, can remove by acid; Or, use fluoride ion comprising under the situation of silyl-group.By reacting or alkylated reaction with suitable halid arylation, can introduce alkoxyl phenyl and alkoxybenzyl group easily, can be by removing with the oxygenizement of ceric ammonium nitrate.At last, by with acid amides and suitable aldehyde reaction, can introduce chain-1-alkenyl group, usable acid is removed.

In above-mentioned other the feature of pharmaceutical composition, process, method, purposes and medication preparation, also use The compounds of this invention as herein described alternative and preferred aspect and embodiment.

The following examples are illustrative purposes for example, rather than are intended to limit the application's scope.The compound of each example is represented specific and independent aspects of the present invention.Unless otherwise stated, in the following non-limiting Examples:

(i) evaporation is undertaken by rotary evaporation in the vacuum, is carrying out working routine by after removing by filter residual solids such as siccative;

Be under 18-25 ℃ (ii), under rare gas element such as argon gas or nitrogen atmosphere, operate in room temperature;

(iii) giving the rate of output only is to illustrate for example and needn't be decided to be maximum available productive rate;

(iv) unless otherwise stated, the structure of formula (I) final product is 300MHz (using Varian Gemini 2000 usually) or 400MHz (using BrukerAvanceDPX400 usually) nuclear (being generally proton) mr and mass-spectrometric technique conclusive evidence by intensity of field (to proton); Measure the chemical displacement value of proton resonance on the δ scale, the peak multiplicity is as follows: S, and unimodal; D, doublet; T, triplet; M, multiplet; Br, broad peak; Q, quartet, quin, quintet;

(v) intermediate does not all provide its feature usually, and its purity is measured by tlc (TLC), high performance liquid chromatography (HPLC), infrared spectra (IR) or NMR method of inspection;

(vi) unless otherwise stated, typically refer to flash column chromatography on the silica gel through chromatography purification.Column chromatography uses the silica gel tube of packing in advance (being up to 400g from 4g) as Redisep usually ^TM(can get, as from Presearch Ltd, Hitchin, Herts, UK) or Biotage (Biotage UK Ltd, Hertford, Herts, UK), wash-out uses pump and fraction collector system;

(vii) mass spectrum (MS) data produce in the LCMS system, and wherein the HPLC assembly comprises Agilent 1100 or waters Alliance HT (2790﹠amp usually; 2795) equipment, and at PhemonenexGemini C 185 μ m, 50 * 2mm post (or similarly) is gone up operation, (as using gradient is water/acetonitrile of 0-95% and 50: 50 water that contain 1% formic acid of 5%: the mixture of acetonitrile (v/v) with acid elutriant; Or use the solvent systems that the methyl alcohol be equal to replaces acetonitrile), or alkaline eluant (as application gradient being arranged is the mixture of the acetonitrile solution that contains 0.1% 880 ammonia of O-95% water/acetonitrile and 5%) wash-out; The MS assembly comprises Waters ZQ spectrograph usually.Produce the color atlas of positive and negative base peak intensity of electrospray (ESI) and the UV of 220-300nm and always absorbed color atlas, and provided the m/z value; Unless otherwise stated, only write down the ion of expression parent quality usually, described value is (M-H) ^-

(viii) suitable microwave reactor comprises " Smith Creator ", " CEM Explorer ", " Biotage Initiator sixty " and " Biotage Initiator eight ".

Abbreviation

The DCM methylene dichloride;

The DEAD diethylazodicarboxylate;

DIAD azoformic acid diisopropyl ester;

DIPEA N, the N-diisopropylethylamine;

The DMA N,N-DIMETHYLACETAMIDE;

The DMSO methyl-sulphoxide;

The DMF dimethyl formamide;

EDAC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride;

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea  six

Fluorophosphate

The HPLC high pressure lipuid chromatography (HPLC):

The HPMC Vltra tears;

LCMS liquid phase chromatography/mass spectroscopy;

NMP N-N-methyl-2-2-pyrrolidone N-;

The NMR nuclear magnetic resonance spectroscopy(NMR spectroscopy);

The RT room temperature;

The THF tetrahydrofuran (THF):

The TFA trifluoroacetic acid;

CDCl ₃Deuterochloroform;

The title of all compounds adopts ACD NAME computer package to obtain.

Embodiment 1:3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] oxygen Base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3 Base) benzamide

In ' Biotage initiator Microwave '; under 160 ℃; with 3-({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide (70mg; 0.21mmol), 1-(3-chloro-4-fluoro benzoyl) azetidine (44mg; 0.21mmol) and salt of wormwood (57mg, mixture 0.41mmol) stirred 3 hours in acetonitrile (5mL).Remove in a vacuum and desolvate, in residuum, add ethyl acetate (50mL).With mixture water (20mL), salt solution (50mL) washing, dry (MgSO ₄), filter, remove in a vacuum then and desolvate, obtain yellow oil, in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, use the gradient elution of the isohexane solution of 50-100% ethyl acetate, obtain expected compound (35mg).

¹H NMR δ (CDCl ₃): 1.37 (d, 3H), 2.40 (quintet, 2H), 3.82 (s, 3H), 3.98 (m, 2H), 4.20-4.45 (m, 4H), 4.57 (m, 1H), 6.10-6.45 (t, 1H), 6 78 (d, 2H), 7.04 (m, 1H), 7.22 (s, 1H), 7.28 (m, 2H), 7.54 (d, 1H), 7.81 (s, H), 8.50 (s, 1H).m/z?535(M+H) ⁺。

1-(3-chloro-4-fluoro benzoyl) azetidine

To 3-chloro-4-fluorobenzoic acid (1.74g, add in DCM 10.0mmol) (50mL) solution oxalyl chloride (1.05mL, 12.0mmol) and DMF (1).At ambient temperature, mixture was stirred 16 hours, evaporate DCM and excessive oxalyl chloride in a vacuum.(1.12g, 12mmol), (4.18mL 30mmol), stirred it 2 hours at ambient temperature to add triethylamine in this mixture to absorb remaining acyl chlorides and azetidine hydrochloride with DCM (25mL).Evaporate DCM in a vacuum, residuum is allocated between ethyl acetate (100mL) and the 1N hydrochloric acid (50mL).Ethyl acetate layer is used saturated sodium bicarbonate aqueous solution and salt water washing continuously, dry (MgSO ₄), evaporation.Residuum obtains title compound (1.64g) with ethyl acetate/isohexane crystallization.

¹H?NMRδ(CDCl ₃)：2.4(m，2H)，4.2-4.4(m，4H)，7.2(m，1H)，7.55(m，1H)，7.7(m，1H)。

3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the hydrogen base)-5-hydroxy-n-(1-methyl -1H-pyrazoles-3 base) benzamide

With 3-({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3 base)-5-[(phenyl methyl) the oxygen base] benzamide (0.1g, 0.23mmol) be dissolved in ethanol (3mL) THF and (3mL) in, flask is evacuated, and with purification for argon (3 times).Add 10% palladium/carbon (0.01g), further flask is evacuated and uses hydrogen cleaning.In room temperature the reaction mixture stirring was finished until reaction in 20 hours.Reaction mixture is evacuated, and with nitrogen purge (3 times).By the diatomite filtration catalizer, concentrated filtrate obtains expected compound (70mg) in a vacuum. ¹H NMR δ (CDCl ₃): 1.28 (d, 3H), 3.71 (s, 3H), 3.80-3.95 (m, 2H), 4.51 (sextet, 1H), 5.96-6.36 (t, 1H), 6.53 (s, 1H), 6.73 (s, 1H), 6.91 (s, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 8.83 (s, 1H).m/z?342(M+H) ⁺。

3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles -3 bases)-and the 5-[(phenyl methyl) the oxygen base] benzamide

To the 3-in DMF (3mL) ({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] phenylformic acid (0.1g, 0.28mmol), 3 amino-1-methylpyrazole (39mg, 0.4mmol) and H ATU (0.227g, 0.6mmol) mixture in, add DIPEA (0.198mL, 1.14mmol), then stirring at room 20 hours.Add ethyl acetate (30mL), with mixture water (30mL), salt solution (30mL) washing, dry (MgSO ₄), filter, concentrate in a vacuum then, obtain yellow oil, in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, use the gradient elution of the isohexane solution of 0-100% ethyl acetate, obtain expected compound (0.1g). ¹H NMR δ (CDCl ₃): 1.36 (d, 3H), 3.68 (s, 3H), 3.82-3.95 (m, 2H), 4.48 (sextet, 1H), 5.00 (s, 2H), 6.19 (t, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 6.93 (s, 1H), 7.03 (s, 1H), 7.28 (m, 1H), 7.35 (m, 5H), 8.59 (s, 1H).m/z?432(M+H) ⁺。

3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] Phenylformic acid

To the 3-in THF (4mL) ({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] methyl benzoate (0.11g, 0.3mmol) in, be added in the lithium hydroxide monohydrate (19mg in the water (2mL), 0.45mmol), with mixture stirring at room 20 hours.Remove THF in a vacuum, water layer is adjusted to pH3 with citric acid, use ethyl acetate (ethyl actetate) (2 * 30mL) extractions then.With organism water (30mL), salt solution (30mL) washing, dry (MgSO ₄), filter, remove in a vacuum then and desolvate, obtain expected compound (0.1g).

¹H NMR δ (d ₆-DMSO): 1.27 (d, 3H), 4.00 (m, 2H), 4.75 (sextet, 1H), 5.15 (s, 2H), 6.72 (t, 1H), 7.08 (t, 1H), 7.16 (t, 1H), 7.41 (m, 5H), 12.95 (s, 1H).m/z?351(M+H) ⁺。

3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] Methyl benzoate

3-after the degassing ((1S)-and 2-hydroxyl-1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] methyl benzoate (0.73g, 2.31mmol) and cupric iodide (I) (88mg, 0.46mmol) acetonitrile (10mL) mixture in, 45 ℃, drip in the stirring 2-(fluorine sulphonyl) difluoroacetic acid (0.239mL, 2.31mmol).To react stirring 24 hours at 45 ℃.Remove in a vacuum and desolvate, add ethyl acetate (30mL).With organism water (30mL), salt solution (30mL) washing, dry (MgSO ₄), filter, remove in a vacuum then and desolvate, obtain yellow oil, at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel, use the gradient elution of the isohexane solution of 0-30% ethyl acetate, obtain expected compound (0.11g).

¹H NMR δ (CDCl ₃): 1.37 (d, 3H), 3.93 (s, 3H), 4.00 (m, 2H), 4.63 (sextet, 1H), 5.10 (s, 2H), 6.28 (t, 1H), 6.77 (t, 1H), 7.28 (t, 1H), 7.41 (m, 6H).m/z?367(M+H) ⁺。

3-((1S)-and 2-hydroxyl-1-methylethyl } the oxygen base)-the 5-[(phenyl methyl) the oxygen base] methyl benzoate

To the 3-hydroxyl in DMF (16mL)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] methyl benzoate (1.55g, 6.86mmol) and salt of wormwood (1.89g, 0.014mol) in the mixture, adding bromotoluene (1.89g, 7.20mmol), will react and at room temperature stir 20 hours.Add ethyl acetate (40mL), mixture water (40mL), saturated sodium hydrogen carbonate solution (40mL), salt solution (40mL) are washed dry (MgSO ₄), filter, remove in a vacuum then and desolvate, obtain reddish oil, at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel, use the gradient elution of the isohexane solution of 0-100% ethyl acetate, obtain expected compound (1.7g).

¹H?NMRδ(CDCl ₃)：1.30(d，3H)，1.95(m，1H)，3.76(m，2H)，3.92(s，3H)，4.53(m，1H)，5.11(s，2H)，6.78(t，1H)，7.25(m，1H)，7.32(m，1H)，7.45(m，5H)。m/z?317(M+H) ⁺。

The 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy] methyl benzoate

To 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base] (38.01g, in acetonitrile 0.158mol) (500mL) solution, (115mL 0.79mol), and stirred 24 hours methyl benzoate to add the iodate trimethyl silyl.Add methyl alcohol (300mL), and will react and stir 10 minutes.In this mixture, add the aqueous solution (100mL) of 10%w/v Sodium Thiosulfate Pentahydrate, and stirred 20 minutes.With saturated sodium bicarbonate aqueous solution reaction mixture is neutralized, remove organic solvent in a vacuum, with the ethyl acetate (resultant of 4 * 100mL) extraction gained.With the organic layer drying (MgSO after merging ₄), filter, and remove in a vacuum and desolvate.With crude material ethyl acetate crystallization, obtain title mixture (16.80g).

¹H NMR δ (d ₆-DMSO): 1.18 (d, 3H), 3.40-3.55 (m, 2H), 3.80 (s, 3H), 4.35 (sextet, 1H), 4.80 (t, 1H), 6.57 (m, 1H), 6.90 (m, 2H), 9.75 (s, 1H); M/z 225 (M-H) ⁺

The 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base] methyl benzoate

With 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } methyl benzoate (50.0g 0.152mmol) is dissolved in THF: in the alcoholic acid mixture (600mL), flask is evacuated, and with nitrogen purge (3 times).Add 10% palladium/carbon (5.0g), further flask is evacuated, and uses hydrogen cleaning at last.In envrionment temperature the reaction mixture stirring was finished until reaction in 20 hours.Reaction mixture is evacuated, and with nitrogen purge (3 times).Filtration catalizer, concentrated filtrate obtains expected compound (36.7g) in a vacuum. ¹H?NMRδ(d ₆-DMSO)：1.2(d，3H)，3.25(s，3H)，3.44(m，2H)，3.82(s，3H)，4.55(m，1H)，6.6(s，1H)，6.9(s，1H)，6.95(s，1H)，9.8(s，1H)。

3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } methyl benzoate

3-hydroxyl-5-{[phenyl methyl] the oxygen base in the THF solution of methyl benzoate (77.4mmol), add polymkeric substance prop up the triphenylphosphine that carries (51.7g (every gram is loaded with 3mmol), 155mmol) and (R)-(-)-1-methoxyl group-2-propyl alcohol (102mmol).Cover the solution of stirring with argon gas, and in ice bath, cool off.In 10 minutes, drip DIAD (116mmol) solution by syringe.With solution stirring 20 minutes, filter, with THF (500mL) washing residuum.Filtrate and washings are merged, and evaporation obtains expected compound, is not further purified and uses.

¹H?NMRδ(d ₆-DMSO)：3.26(s，3H)，3.44(m，2H)，3.82(s，3H)，4.63(m，1H)5?5.14(s，2H)，6.85(s，1H)，7.05(s，1H)，7.11(s，1H)，7.30-7.47(m，5H)。Should ¹H NMR spectrum also comprises a small amount of two (1-methylethyl) hydrazine-1,2-dicarboxylic ester.

3-hydroxyl-5-{[phenyl methyl] the oxygen base } methyl benzoate

With 3 of stirring, in DMF (6L) solution of 5-methyl dihydroxy benzoate (5.95mol), add salt of wormwood (9mol) suspension is stirred under ambient temperature argon gas.,, reaction mixture stirred at ambient temperature spend the night slowly to wherein adding bromotoluene (8.42mol) through 1 hour with slight exotherm.Use modestly ammonium chloride solution (5L) subsequently water will react (35L) and quench.With DCM (1 * 3L and 2 * 5L) extraction water suspensions.With extraction liquid water (10L) washing after merging, dry (MgSO ₄) spend the night.Solution is evaporated in a vacuum, crude product divide 3 batches of usefulness carry out chromatogram (quick post, 3 * 2kg silica gel, with the hexane that comprises 10%DCM to pure DCM to the DCM gradient elution that comprises 50% ethyl acetate) to remove starting raw material.Thick eluate further carries out chromatography (Amicon HPLC, the 5kg purification on normal-phase silica gel is with the isohexane wash-out that comprises the 20%v/v ethyl acetate) with the batch of 175g and obtains expected compound (21% productive rate);

¹H?NMRδ(d ₆-DMSO)：3.8(s，3H)，5.1(s，2H)，6.65(m，1H)，7.0(m，1H)，7.05(m，1H)，7.3-7.5(m，5H)，9.85(br?s，1H)。

Embodiment 2:3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-((1S)-the 2-[(difluoro Methyl) oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide (35mg, 0.07mmol) and triethylamine (0.028mL, 0.2mmol) mixture be dissolved in ethanol (3mL) and (3mL) in, flask is evacuated, and with purification for argon (3 times).Add 10% palladium/carbon (4mg), further flask is evacuated, use hydrogen cleaning at last.In room temperature the reaction mixture stirring was finished until reaction in 20 hours.Reaction mixture is evacuated, and with nitrogen purge (3 times).By the diatomite filtration catalizer, concentrated filtrate obtains water white oil in a vacuum, at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel, uses the gradient elution of the ethyl acetate solution of 0-5% methyl alcohol, obtains expected compound (19mg). ¹H NMR δ (CDCl ₃): 1.30 (d, 3H), 2.30 (quintet, 2H), 3.72 (s, 3H), 3.80 (m, 2H), 4.10-4.35 (m, 4H), 4.57 (m, 1H), 6.00-6.38 (t, 1H), 6.70 (m, 2H), 6.96 (d, 2H), 7.01 (m, 1H), 7.17 (m, 1H), 7.21 (m, 1H), 7.58 (d, 2H), 8.23 (s, 1H).m/z?501(M+H) ⁺。

Embodiment 1 has described 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-preparation of N-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide.

Embodiment 3:

3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3- Base)-and 5-{[4-(sulfonyloxy methyl) phenyl] the oxygen base } benzamide

In ' Biotage imtiator Microwave ', under 160 ℃, with 3-({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide (220mg, 0.64mmol), 4-fluorophenyl methyl sulfone (113mg, 0.64mmol) and salt of wormwood (178mg, mixture 1.29mmol) stirred 4 hours at acetonitrile (5mL).Remove in a vacuum and desolvate, in residuum, add ethyl acetate (50mL).With organism water (20mL), salt solution (50mL) washing, dry (MgSO ₄), filter, remove in a vacuum then and desolvate, obtain yellow oil.Residuum at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel, is used the gradient elution of the isohexane solution of 50-100% ethyl acetate, obtain expected compound (174mg).

¹H?NMRδ(CDCl ₃)：1.38(d，3H)，3.10(s，3H)，3.77(s，3H)，4.00(m，2H)，4.64(m，1H)，6.28(t，1H)，6.82(m，2H)，7.15(m，3H)，7.31(m，2H)，7.94(d，2H)，8.92(s，1H)；m/z?496(M+H) ⁺。

Embodiment 1 has described 3-({ (1S)-2-[(difluoromethyl) oxygen base]-the 1-methylethyl } the oxygen base)-preparation of 5-hydroxy-n-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide.

Biology

Test

Can check the biological effect of formula (I) compound in the following method:

(1) enzymic activity

By hatching GLK, ATP and glucose, can measure the enzymic activity of recombinant human pancreas GLK.By with the mensuration that combines of G-6-P desaturase, NADP/NADPH system, and increase in 340nm measuring light density linearity in time, can determine the speed (Matschinsky etc. 1993) that product forms.Available this measuring method GLKRP exist or disappearance under assessing compound to the activation of GLK, (Diabetes 2004,53, and is 535-541) described as Brocklehurst etc.

The generation of reorganization GLK and GLKRP:

Use Sambrook J, Fritsch EF﹠amp; Maniatis T, the technology of setting up described in 1989 respectively from people's pancreas and liver mRNA, obtains people GLK and GLKRPcDNA by PCR.According to Tanizawa etc. 1991 and Bonthron, D.T. etc. 1994 (proofreaied and correct in Warner J.P.1995) GLK shown in and GLKRP cDNA sequence, design PCR primer afterwards.

In Bluescript II carrier, clone

Use pBluescript II (Short etc. 1998), clone GLK and GLKRP cDNA in intestinal bacteria (E.coli), this pBluescript II is the recombinant cloning vector system that a kind of Yanisch-Perron of being similar to C etc. (1985) uses, comprise the replicon based on colEI, this replicon has the polylinker dna fragmentation (flank is phage T3 and T7 promoter sequence) that comprises a plurality of unique restriction enzyme sites; Filobactivirus replication initiation starting point and Ampicillin Trihydrate drug resistance marker's gene.

Transform

Usually carry out the intestinal bacteria conversion by electroporation.With the culture of 400mL bacterial strain DH5a or BL21 (DE3) in L-meat soup (broth), cultivate to OD 600 be 0.5,2, the centrifugal results of 000g.With ice-cold deionized water wash twice, resuspending is preserved at-70 ℃ of following minute equal portions in 1mL 10% glycerine with these cells.To connect mixture (Ligation mix) Millipore V series ^TMFilm ((0.0025mm) aperture) removes freshen.In 0.2cm electroporation container, the 40ml cell is connected mixture or plasmid DNA hatched on ice 10 minutes with 1mL, use Gene Pulser then ^TMInstrument (BioRad) is at 0.5kVcm ^-1, pulse under the 250mF.On the L-agar that is supplemented with 10mg/mL tsiklomitsin or 100mg/mL Ampicillin Trihydrate, select transformant.

Express

By the pTB375NBSE vector expression GLK in the E.coli BL21 cell, produce the recombinant protein that comprises next-door neighbour N-end methionine(Met) 6-His mark.Alternative ground, another suitable carriers is pET21 (+) DNA, Novagen, catalog number (Cat.No.) (Cat number) 697703.The 6-His mark is used to be equipped with available from purification of recombinant proteins matter on the pillar of Qiagen (cat no 30250) nickel-nitrilotriacetic acid(NTA) agarose.

By the pFLAG CTC in the E.coli BL21 cell (IBI Kodak) vector expression GLKRP, produce the recombinant protein that comprises C-end FLAG mark.This protein is used the DEAESepharose ion-exchange purification at first, then utilize FLAG be marked at available from the M2 of Sigma-Aldrich (catno.A1205) anti--carry out last purifying on the FLAG immunoaffinity post.

(2) oral glucose tolerance test (OGTT)

Carry out oral glucose tolerance test with the fat fa/fa rat of clear-headed Zucker (age 12-13 week or bigger), feed at least before the experiment and raise high fat diet (45%kcal fat) two weeks.Test is used preceding with animal fasting two hours.At the glucose solution of Orally administered 2g/kg body weight dosage preceding 120 minutes, orally give test-compound or solvent.Before glucose administration and different time points afterwards (time-histories 60 minutes) gather the afterbody blood sample, with Accucheck blood sugar detection instrument measurement of glucose levels, obtain the time curve of glucose level, calculate 120 minutes area under curve (AUC) (time of glucose administration is the zero-time).The AUC that uses the solvent control group determines the percentage reduction number of glucose fluctuation as percent 0 reduction number.

Compound of the present invention activates glucokinase usually, has the EC less than about 500nM ₅₀For example, embodiment 1 has the EC of 40nM ₅₀

Reference

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Claims

1. the compound or its salt of formula (I):

Wherein:

HET-2 comprises 1,2,3 or 4 heteroatomic 4-, the 5-that is connected by C-or N-that independently is selected from O, N and S or the heterocycle of 6-unit, wherein-and CH ₂-group can be chosen wantonly by-C (O)-displacement, and wherein the sulphur atom on the heterocycle can be chosen wantonly and is oxidized to S (0) or S (O) ₂Group, described ring is chosen wantonly on available carbon atom or nitrogen-atoms and independently is selected from R by 1 or 2 ⁷Substituting group replace;

R ³Be selected from halogen;

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁷Be selected from (1-4C) alkyl ,-C (0) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl ,-S (O) pR ⁵And/or (for R ⁷Be the substituting group on the carbon) hydroxyl and (1-4C) alkoxyl group;

P is (when at every turn occurring independently) 0,1 or 2;

N is 0,1 or 2.

2. the compound or its salt of formula as claimed in claim 1 (I), wherein R ¹Be fluorine methoxymethyl or difluoro-methoxy methyl.

3. as the compound or its salt of claim 1 or the described formula of claim 2 (I), R wherein ¹Has (S) configuration.

4. as the compound or its salt of the described formula of claim 1, claim 2 or claim 3 (I), wherein HET-1 is 5 yuan of rings.

5. as the compound or its salt of any one described formula (I) of claim 1-4, R wherein ²Be selected from-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵, and R ⁴And R ⁵Form defined heterocycle ring system with the nitrogen-atoms that connects them as HET-3.

6. as the compound or its salt of any one described formula (I) of claim 1-5, wherein HET-3 is 4 to 6 yuan a ring.

7. as the compound or its salt of any one described formula (I) of claim 1-5, R wherein ⁴And R ⁵Form the azetidine basic ring with the nitrogen-atoms that connects them;

8. as the compound or its salt of any one described formula (I) of claim 1-4, R wherein ²Be selected from azetidinyl carbonyl, azetidinyl alkylsulfonyl and (1-4C) alkyl sulphonyl.

9. the compound of formula as claimed in claim 1 (I), it is following any one or a plurality of compound or its salt:

3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazoles-3 base) benzamide; And 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide; And/or 3-((1S)-and the 2-[(difluoromethyl) the oxygen base]-the 1-methylethyl } the oxygen base)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{[4-(sulfonyloxy methyl) phenyl] the oxygen base } benzamide.

10. pharmaceutical composition, it comprises according to the compound of any one of claim 1-9 or its pharmacologically acceptable salts and pharmacy acceptable diluent or carrier.

11. according to any one compound or its pharmacologically acceptable salts of claim 1-9, as medicine.

12. according to claim 1-9 any one compound or its pharmacologically acceptable salts in preparation treatment by the purposes in the medicine of the disease of GLK mediation.

13. any one compound or the purposes of its pharmacologically acceptable salts in the medicine of preparation treatment diabetes B according to claim 1-9.

14. the method for the disease of treatment GLK mediation, it is by giving any one described formula (I) compound or its pharmacologically acceptable salts as claim 1-9 of the administration significant quantity that needs this treatment.

15. the method for claim 14, wherein the disease of GLK mediation is a diabetes B.

16. according to any one compound or its pharmacologically acceptable salts of claim 1-9, as the medicine of treatment by the disease of GLK mediation.

17. according to the compound of claim 16, wherein the disease of GLK mediation is a diabetes B.

18. as the preparation method of any one described formula (I) compound of claim 1-9, comprising method a)-e) (definition of variable wherein such as claim 1 Chinese style (I) compound except as otherwise noted):

Or

(b) with the compound of formula V and the compound reaction of formula (VI),

The also available wherein P of method (b) ¹For the intermediate ester of the formula (VII) of blocking group, finish by ester hydrolysis and amidation then;

Or

Or

E) formula (XIII) compound

With formula NR ⁴R ⁵Amine reaction;

Then, if desired:

I) formula (I) compound is converted into other compound of formula (I);

Ii) with R ¹Precursor conversion be R ¹

Iii) remove any blocking group; And/or

Iv) form its salt.