CN102558149A - Pyrimidine derivative, preparation method thereof, medicinal composition and application thereof - Google Patents
Pyrimidine derivative, preparation method thereof, medicinal composition and application thereof Download PDFInfo
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- CN102558149A CN102558149A CN2010106126132A CN201010612613A CN102558149A CN 102558149 A CN102558149 A CN 102558149A CN 2010106126132 A CN2010106126132 A CN 2010106126132A CN 201010612613 A CN201010612613 A CN 201010612613A CN 102558149 A CN102558149 A CN 102558149A
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- 0 *NC(c1cc(Cl)nc(Cl)n1)=O Chemical compound *NC(c1cc(Cl)nc(Cl)n1)=O 0.000 description 4
- KJBKGEOCVGGKGB-TVXUUACXSA-N C/C=C(\C=C(/C)\Cl)/Nc1nc(Cl)nc(C(Nc2nc(C)c[s]2)=O)c1 Chemical compound C/C=C(\C=C(/C)\Cl)/Nc1nc(Cl)nc(C(Nc2nc(C)c[s]2)=O)c1 KJBKGEOCVGGKGB-TVXUUACXSA-N 0.000 description 1
- DTZVJTWKJUITRX-XQRVVYSFSA-N C=C(/C=C(/C(Nc1ncc[s]1)=O)\N=C(/N)\Cl)Cl Chemical compound C=C(/C=C(/C(Nc1ncc[s]1)=O)\N=C(/N)\Cl)Cl DTZVJTWKJUITRX-XQRVVYSFSA-N 0.000 description 1
- PSFASKFUHHQBTM-UHFFFAOYSA-N CC(C)OC(c1ccc(NC(c2cc(OCc3ccccc3Cl)nc(OCc(cccc3)c3Cl)n2)=O)nc1)=O Chemical compound CC(C)OC(c1ccc(NC(c2cc(OCc3ccccc3Cl)nc(OCc(cccc3)c3Cl)n2)=O)nc1)=O PSFASKFUHHQBTM-UHFFFAOYSA-N 0.000 description 1
- OKPNAOHZEYZEIN-UHFFFAOYSA-N CC(C)OC(c1ccc(NC(c2cc(Oc(cc3)ccc3Cl)nc(Cl)n2)=O)nc1)=O Chemical compound CC(C)OC(c1ccc(NC(c2cc(Oc(cc3)ccc3Cl)nc(Cl)n2)=O)nc1)=O OKPNAOHZEYZEIN-UHFFFAOYSA-N 0.000 description 1
- CTUFGZQGPTZYDG-UHFFFAOYSA-N CC(C)Oc1nc(Cl)nc(C(Nc(cc2)ncc2C(O)=O)=O)c1 Chemical compound CC(C)Oc1nc(Cl)nc(C(Nc(cc2)ncc2C(O)=O)=O)c1 CTUFGZQGPTZYDG-UHFFFAOYSA-N 0.000 description 1
- AUAWGFDIDWEZNX-UHFFFAOYSA-N Cc1c[s]c(NC(c2cc(OCCc3ccccc3)nc(Cl)n2)=O)n1 Chemical compound Cc1c[s]c(NC(c2cc(OCCc3ccccc3)nc(Cl)n2)=O)n1 AUAWGFDIDWEZNX-UHFFFAOYSA-N 0.000 description 1
- NGZWGQQXJBUWBW-UHFFFAOYSA-N Cc1c[s]c(NC(c2cc(Oc(cc3)ccc3Cl)nc(Oc(cc3)ccc3Cl)n2)=O)n1 Chemical compound Cc1c[s]c(NC(c2cc(Oc(cc3)ccc3Cl)nc(Oc(cc3)ccc3Cl)n2)=O)n1 NGZWGQQXJBUWBW-UHFFFAOYSA-N 0.000 description 1
- NUYJCMGJLNVOML-UHFFFAOYSA-N O=C(c1cc(Cl)nc(Cl)n1)Cl Chemical compound O=C(c1cc(Cl)nc(Cl)n1)Cl NUYJCMGJLNVOML-UHFFFAOYSA-N 0.000 description 1
- PWQBRFUETYGADD-UHFFFAOYSA-N O=C(c1cc(Cl)nc(Cl)n1)Nc1ccccn1 Chemical compound O=C(c1cc(Cl)nc(Cl)n1)Nc1ccccn1 PWQBRFUETYGADD-UHFFFAOYSA-N 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N OC(C(NC(N1)=O)=CC1=O)=O Chemical compound OC(C(NC(N1)=O)=CC1=O)=O PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a novel pyrimidine derivative, a preparation method thereof, a medicinal composition and an application thereof. The invention specifically relates to a pyrimidine derivative show as a general formula I, a medicinal salt thereof, a precursor or a derivative thereof with the same biological function, a preparation method thereof, a compound containing one or more of the compounds, and an application of the compound to treatment of glucokinase-related diseases such as diabetes, obesity, and the like.
Description
Technical field
The present invention relates to the pyrimidine derivatives shown in the general formula I; Its pharmacologically acceptable salt, its hydrate and solvolyte, its polycrystalline and eutectic; The precursor of its same biological function or verivate; And preparation method thereof, contain one or more these compound compositions and this compounds purposes at treatment and gk diseases associated such as aspects such as mellitus, obesity.
Background technology
Sugar is organism important energy and carbon source.The sugar decomposition generate energy can be supplied with the needs of organism vital movement, and glycometabolic intermediate product can be transformed into other carbon compound again, like amino acid, lipid acid, nucleosides etc.Carbohydrate metabolism can be divided into the decomposition of sugar and synthetic two aspects of sugar.Catabolism of carbohydrate comprises glycolysis-, i.e. the common decomposition approach of sugar; And tricarboxylic acid cycle, the i.e. last oxidative pathway of sugar.Glycolysis is that enzyme becomes pyruvic acid with glucose degradation and is accompanied by the process that generates ATP.It is the energy-producing common metabolic approach of breakdown of glucose in animal, plant, the microorganism cells.In the oxygen consumption organism, the pyruvic acid that glycolysis generates gets into plastosome, is become CO through tricarboxylic acid cycle by exhaustive oxidation
2And water; The NADH that glycolysis generates produces ATP and water through the respiratory chain oxidation.So glycolysis is the prelude of oxidative phosphorylation and tricarboxylic acid cycle.Gk (GK) is one of four kinds of HKs finding on one's body Mammals [Cofowick, S.P.The Enzymes, Vol.9 (P.Boyer ' ed.) Academic Press; New York, N bifurcation .1-48 page or leaf, 1973]; It is first key enzyme in the glycolytic pathway; It can become the 6-glucose 1-phosphate1-with glucose phosphorylation under the condition that ATP exists, get into the metabolic process in downstream.Therefore, this step is first rate-limiting step of whole carbohydrate metabolism process, and GK is first rate-limiting enzyme in the carbohydrate metabolism process, plays important biological action.
The cell distribution of GK is limited, is mainly seen in pancreas beta cell and hepatic tissue cell.In addition, GK is playing the part of important role in controlling blood sugar balance and metabolism, regulates on the one hand the glycogen metabolism, and when on an empty stomach or blood sugar when low, GK is active low, and glycogen output increases, to guarantee the energy supply of vitals; After the meal or blood sugar when high, the GK increased activity, thus promote liver starch synthetic, suppress the liver glyconeogenesis, to keep glycaemic homeostasis.Regulate and control secretion of insulin as the susceptor of glucose on the other hand.When blood sugar concentration was higher than normal value in the body, the glucose in the blood got into beta Cell of islet by glucose transporter 2 (GLUT2) transhipment, and phosphorylation generates the 6-glucose 1-phosphate1-under the GK effect.The glycolysis of glucose, oxidative metabolism increase ATP/ADP ratio; The K+ ionic channel is closed, film depolarize, voltage susceptibility Ca2+ channel opener; Stream in the Ca2+; Regular Insulin storage vesica and plasma membrane merge, and make Regular Insulin discharge into blood, and get into the adjusting that liver, fat and muscle cell are participated in blood sugar with blood circulation.Glucose in liver phosphoric acid under the effect of GK turns to-6 glucose 1-phosphate1-s, then synthetic liver starch under insulin action.At fat and muscle cell, Regular Insulin triggers glucose transporter 4 (GLUT4) and in cell, stores picked-up and the metabolism that vesica migrates to plasma membrane promotion glucose.GK discharges and glycogen metabolism double action mechanism lowering blood glucose through regulating Regular Insulin, and [Al-Hasani H plays a significant role in keeping the glycaemic homeostasis process; Tschopl M H.Mol Interv, 2003,3 (7), 367-370].[Chipkin, S.R., Kelly, K.L. and Ruderrnam, N.B. are shown in Joslin ' Diabetes (C.R.Khan and G.C.Wier compile), Lea and Febiger, Philadelphia, PA, 97-115 page or leaf, 1994].
It is to be caused by afunction after the GK transgenation that young type is early sent out mellitus (MODY), shows that GK also plays glucose sensor Liang in human body, Y, Kesavan, P., Wang, people such as L., Biochem.J.309,167-173,1995).Except that MODY, also ubiquity GK is active in one diabetic individual descends.Pathogenesis to diabetes B discovers that further the active reduction of liver GK possibly participated in insulin resistant mechanism, causes blood sugar increasing, and islet function is impaired to be increased the weight of with insulin resistant.Can increase the active medicine of GK to stop or to delay advancing of disease so seek, might open up a new way for early prevention and treatment mellitus.
Recognize in recent years: pancreatic beta type glucokinase is confined to the brain of rat, wherein particularly expresses in the feeding center (ventromedial nucleus of hypothalamus, VMH).The neurocyte of the about twenty percent among the VMH is known as glucose response property neurone (glucose-responsive neutrons), is considered to aspect management of body weight, play a significant role in the past.In the brain of rat, give glucose, then food ration reduces, and if analogue one glycosamine that gives glucose in the brain suppresses glucose metabolism, many foods then take place.The electrophysiology experiment shows: glucose response property neurone and physiological glucose concn change (5-20mM) and are activated accordingly, but through inhibition glucose metabolisms such as glycosamines, then its activity is suppressed.Can infer the glucose concn sensory perceptual system of VHM and the insulin secretion of pancreatic beta cell is the mechanism via glucokinase equally.Therefore, except that liver, pancreatic beta cell, the active material of glucokinase that activates VHM not only has the effect of blood sugar regulation, also possibly regulate the worried obesity of a lot of diabetes B patients.Can know by above-mentioned record; Compound with glucokinase activation can be used as treatment of diabetes medicine and/or prophylactic agent; Perhaps the chronic complicating diseases of mellitus such as retinopathy, ephrosis, neurosis, ischemic heart disease, arteriosclerosis treat and/or prevent medicine, further can be used as the fat medicine that treats and/or prevents.
It has been found that many GK small molecules acvators; Has the various structure characteristic: like substituted phenylacetamides (WO0058293 WO0185706 WO0208209 WO0185707 WO0183465 WO0246173WO2004072066 WO0246173); Substituted hydantoins (WO0183478), substituted azole class (WO2006112549), substituent indole (US0067939 WO031179); The substituted Propionamides of isoindoline (WO0248106); Substituted anthranilamide-based (WO03080585), substituted α phenylacryloyl amine (WO0214312) etc., wherein phenylacetamides is that research is done many one type.Though above-mentioned GK acvator research has been made very big contribution to this area, and is active for improving compound structure and GK acvator, research is still being continued in this area.
Summary of the invention
The technical problem that the present invention will solve provides a kind of new for glucokinase activators, comprises its pharmacologically acceptable salt, the precursor of its same biological function or verivate.
Another technical problem that the present invention will solve provides a kind of method for preparing new pyrimidine derivatives.
Another technical problem that the present invention will solve provides a kind of pharmaceutical composition that contains one or more this compounds.
Another technical problem that the present invention will solve provide a kind of this compounds mellitus, diabetic complication, obesity and with the medicine of GK diseases related in purposes.
In order to accomplish the present invention's purpose, can adopt following technical scheme:
R1 or R2 are selected from hydrogen, halogen, alkoxyl group, alkylamino radical, alkylthio, aryloxy, heteroaryloxy, aryl amine, assorted aryl amine, arylthio, heteroarylthio, alkyl amide, aromatic amide.R1 and R2 can be identical, also can be different, comprise chirality and achirality group.
Wherein, alkyl is for replacing or do not replace the straight or branched alkyl of C1-12, and comprise the C3-6 carbocyclic ring or contain the C3-6 heterolipid ring of 1-3 oxygen, nitrogen, sulfur heteroatom,
Substituting group on the alkyl is selected from halogen, hydroxyl, nitro, itrate group, cyanic acid, amino, C1-8 alkoxyl group, C1-8 alkylamino, C1-8 alkylthio, C1-8 amido, carboxyl, ester group, C1-8 alkanoyloxy, aryl or heteroaryl,
Wherein aryl is for replacing or not substituted phenyl, naphthyl; Heteroaryl is for replacing or not substituted heterocyclic aryl; As furans, thiophene phenol, pyridine, pyrimidine 、 oxazole 、 isoxazole, pyrazoles, imidazoles, pyrrole iron, quinoline, isoquinoline 99.9, indoles, pyrazine, thiazole, benzothiazole, benzoglyoxaline etc.
Substituting group on aryl, the heteroaryl is selected from the alkyl of C1-8, alkoxyl group, halogen, trifluoromethyl, hydroxyl, nitro, itrate group, cyanic acid, amino, C1-8 alkylamino, C1-8 amido, substituted amino azo-group, carboxyl, ester group, C1-8 alkanoyloxy, imidazoles, the substituted imidazoles of C1-8 alkyl, replacement or not substituted heterocycle or aromatic heterocyclic, replacement or not substituted heterocycle or the fragrant Heterocyclylalkyl of C1-8;
R1 or R2 more preferably are chlorine, bromine, alkoxyl group, alkylamino radical, alkylthio, aryloxy, heteroaryloxy, aryl amine, assorted aryl amine, arylthio, heteroarylthio, alkyl amido, aromatic acylamino; Wherein alkyl, heteroaryl and aryl comprise substituted or not substituted, substituent scope such as claim 1.R1 and R2 can be identical, also can be different, comprise chirality and achirality group.
R1 or R2 are more preferably from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, adjacent cyano benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, (1; 2; 4-triazole-3) sulfenyl, phenoxy, 3; 5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, to the adjacent chlorophenoxy of second sulfinyl, to the adjacent fluorophenoxy of piperidine formyl, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, o-methyl-benzene formamido-, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, (5-methyl-isoxazole-3)-methyl, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to fluorobenzene sulfenyl, 2; 2-two fluoro-2-phenyl ethoxies, benzo [D] [1; 3] dioxy cyclopentenes-5-oxygen base, benzothiazole-2-oxygen base, 2-methylsulfonyl pyridine-5-oxygen base, 2-n n dimetylaniline formylpyridine-5-oxygen base; 1; 3,4-triazole-2-sulfenyl, 2-n n dimetylaniline formyl pyrazine-5-oxygen base, pyridine-2-sulfenyl;
R1 or R2 spy are preferably from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, adjacent cyano benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, (1; 2; 4-triazole-3) sulfenyl, phenoxy, 3; 5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, o-methyl-benzene formamido-, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to fluorobenzene sulfenyl, 2,2-two fluoro-2-phenyl ethoxies, pyridine-2-sulfenyl;
R1 or R2 are most preferably from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, phenoxy, 3,5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to the fluorobenzene sulfenyl;
The optional hetero-aromatic ring of doing for oneself and connecting through ring carbon atom of A ring has 1-6 heteroatoms to be selected from nitrogen, oxygen and sulphur in its ring.Said hetero-aromatic ring does not replace for having, single replacement or polysubstituted.
Substituting group is selected from halogen, alkyl, part or perfluor C1-8 alkyl, alkoxyl group, alkyl sulfenyl, amino, alkylamino radical, alkylthio, sulfonamido, carboxyl, ester group, nitro, cyanic acid, perfluoroalkyl group sulfonyl, alkyl sulphinyl, replacement or not substituted aryl or heteroaryl, replacement or not substituted Heterocyclylalkyl or fragrant Heterocyclylalkyl; Wherein the definition of alkyl and aryl and heteroaryl as stated.
The A ring more preferably is the hetero-aromatic ring through 5-10 annular atoms of ring carbon atom connection, has 1-5 heteroatoms to be selected from nitrogen, oxygen and sulphur in its ring, and wherein encircles a nitrogen-atoms and the ring carbon atom adjacent that is connected at least.Said hetero-aromatic ring does not replace for having, single replacement or polysubstituted.
A encircles more preferably thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base; 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base; 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base, pyrazole-3-yl, N-methylpyrazole-3-base, 3-methyl isophthalic acid; 2,4-thiadiazoles-5-base, 3-methoxyl group-1,2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base; Pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base; Pyrimidine-4-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base; 5-methyl-isoxazole-3-base, isoquinolyl-1;
A ring spy is preferably thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base; 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base; 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-carbalkoxyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base, pyrazole-3-yl, N-methylpyrazole-3-base, 3-methyl isophthalic acid; 2,4-thiadiazoles-5-base, 3-methoxyl group-1,2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base; Pyrimidine-4-base, 5-methyl-isoxazole-3-base;
The A ring most preferably is thiazol-2-yl, 4-methylthiazol-2-base; 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl; Pyrazine-2-base, 5-methylpyrazine-2-base, 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-carbalkoxyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base; Pyrazole-3-yl, N-methylpyrazole-3-base, 5-methyl-isoxazole-3-base;
The alkyl of C1-8 is meant the alkyl of the straight or branched with 1-8 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, neo-pentyl, hexyl, octyl group etc.
The C1-8 alkoxyl group is meant the alkoxyl group of the straight or branched with 1-8 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy, octyloxy etc.
The C1-8 alkylthio is meant the alkylthio of the straight or branched with 1-8 carbon atom, for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, uncle's butylthio, secondary butylthio, penta sulfenyl, new penta sulfenyl, own sulfenyl, hot sulfenyl etc.
The C1-8 alkylamino is meant the alkylamino of the straight or branched with 1-8 carbon atom, and for example methylamino-, ethylamino, third amino, isopropylamino, fourth are amino, isobutyl is amino, uncle's fourth amino, Zhong Ding is amino, penta amino, new penta amino, own amino, hot amino etc.
Halogen is meant fluorine, chlorine, bromine or iodine atom, preferred fluorine, chlorine, bromine atoms.
Aryl: comprise the aryl that contains 6 or 10 ring carbon atoms, for example phenyl, naphthyl; Preferred aryl groups is a phenyl;
Aryloxy: comprise replacing or the not substituted aryloxy that contains 6 or 10 ring carbon atoms, for example: phenoxy, naphthyloxy.
Aryl amine: refer to by the substituted amino of aryl, comprise replacing or the not substituted aryl amine that contains 6 or 10 ring carbon atoms, for example: anilino, naphthylamine base etc.
Arylthio: comprise replacing or the not substituted arylthio that contains 6 or 10 ring carbon atoms, for example: thiophenyl, naphthalene sulfenyl.
Heteroaryl: comprise and contain heteroatomic aryl in the aromatic ring; Preferably contain 1-3 the heteroatomic heteroaryl that is selected from N, O or S, for example quinolyl, isoquinolyl, pyrryl, pyridyl, pyrimidyl, furyl, thienyl, imidazolyl 、 isoxazolyl, thiazolyl; More preferably contain 1-3 heteroatomic 5 yuan or the 6 yuan of heteroaryls that is selected from N, O or S, for example pyrryl, pyridyl, pyrimidyl, furyl, thienyl, imidazolyl 、 isoxazolyl, thiazolyl; Most preferred heteroaryl is selected from isoxazolyl, thiazolyl or pyridyl.
The present invention also provides the method for preparing the described compound of general formula I of the present invention:
(i) with the vitamin B13 be raw material, through with PCl
3Or PCl
5Or POCl
3Or SOCl
2Deng chlorination reaction, obtain 2,6 dichloro pyrimidines-4-formyl chloride.Then with assorted arylamine (R
3NH
2) reaction, obtain 2,6 dichloro pyrimidines-4-methane amide.Again with nucleophilic substitution reagent HR
1Or HR
2Reaction obtains 2-R
1-6-chloropyrimide-4-methane amide or 2-chloro-6-R
2Pyrimidine-4-methane amide, then further with nucleophilic substitution reagent HR
1Or HR
2Reaction obtains 2-R
1-6-R
2Pyrimidine-4-methane amide.
(ii) be raw material, can be converted into 2,6 dihydroxy-pyrimidines-4-formyl chloride earlier, again with assorted arylamine (R with the vitamin B13
3NH
2) reaction, or direct and assorted arylamine (R
3NH
2) reaction, obtain 2,6 dihydroxy-pyrimidines-4-methane amide.But and then with the instead reagent XR that has leavings group
3Or XR
5(but X is a leavings group, like the halogen ion, sulphonyl oxonium ion etc.) reaction obtains 2-R
4O-6-hydroxy pyrimidine-4-methane amide or 2-hydroxyl-6-R
5O pyrimidine-4-methane amide.Then further with reagent XR
5Or XR
3Reaction obtains 2-R
4O-6-R
5O pyrimidine-4-methane amide, wherein R
4O is at R
1Within the scope, R
5O is at R
2Within the scope.
In addition, starting raw material and midbody in the above-mentioned reaction obtain easily, and each step reaction can be according to the document of having reported or can is easy to the ordinary method in the organic synthesis synthesize to those skilled in the art.The said pyrimidine derivatives of general formula I can solvolyte or the form of non-solvent compound exist, utilize different solvents to carry out crystallization and possibly obtain different solvolytes.The said pharmacy acceptable salt of general formula I comprises different acid salt, like following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid; Methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid; Tartrate, fumaric acid, Hydrocerol A, lactic acid.The said pharmacy acceptable salt of general formula I also comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt
(calcium, magnesium salts) and ammonium salt and the salt of physiologically acceptable cationic organic bases can be provided, like methylamine, n n dimetylaniline, Trimethylamine 99, piperidines, the salt of morpholine and three (2-hydroxyethyl) amine.All these salt within the scope of the present invention all can adopt the ordinary method preparation.In the preparation process of described 3-substituted salicylamide verivate and solvolyte and its salt, polycrystalline or eutectic possibly appear in different crystallization conditions.
The present invention also provides with the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be through the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, process to be suitable for any formulation of human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration; Route of administration can be enteron aisle or non-enteron aisle, like oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be processed ordinary preparation, also process is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is processed tablet, the various vehicle well known in the art that can be widely used comprises thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, TKK 021, vinyl resin, carbomer, Vinylpyrrolidone polymer, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, sodium starch glycolate, sodium hydrogencarbonate and Citric Acid, polyoxyethylene sorbitol fatty ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
For capsule is processed in the administration unit, can the effective constituent The compounds of this invention be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also can the effective constituent The compounds of this invention be processed particle or micropill with thinner, tamanori, disintegrating agent earlier, place hard capsule or soft capsule again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is processed injection, can water, ethanol, Virahol, Ucar 35 or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be Prist, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, enhancing treatment effect, medicine of the present invention or pharmaceutical composition can be used any known medication administration.
The dosage of The compounds of this invention pharmaceutical composition according to prevent or treat the character and the severity of disease, the individual instances of patient or animal, route of administration and formulation etc. can have large-scale variation.One, the appropriate dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or compsn can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
The compounds of this invention is GK acvator or its precursor; Through promoting Regular Insulin to discharge and glycogen metabolism double action mechanism lowering blood glucose; Can be used for preventing and treat 1 type or 2 types especially diabetes B and relevant complication, or other disease relevant with gk.
Embodiment
Below will combine embodiment that invention is described further, but not limit the scope of the invention.
Determining instrument: NMR spectrum is with Vaariaan Mercury 300 type NMRs.Mass spectrum is with ZAD-2F and VG300 mass spectrograph.
Embodiment 1.6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
2,6-dichloro pyrimidine-4-carboxylic acid:
With vitamin B13 (40g, 0.256mol; 1,2,3,6-tetrahydrochysene-2,6-dioxo pyrimidine-4-carboxylic acid) and N, accelerine (40ml) places 240ml POCl
3In, refluxed 7 hours.Excessive POCl is removed in decompression
3, the purple soup compound that obtains is poured in the 500ml frozen water, stirred 2 hours, with ether (350ml * 5) extraction, anhydrous sodium sulfate drying gets the 32g yellow solid after the solvent evaporated.Yield: 64%.
1H-NMR(DMSO-d
6，300M)δ8.16(s，1H，ArH)。
6-amino-nicotinic acid isopropyl ester:
With 6-amino-nicotinic acid (810mg, 6mmol; 6-EL-970-3-carboxylic acid) is suspended in the Virahol (20ml), splashes into the 1.5ml vitriol oil, reflux 10 hours under stirring.Cooling concentration is to 5ml, in the impouring water.KOH transfers pH to 10, ETHYLE ACETATE (50ml * 3) extraction, and the saturated common salt water washing, anhydrous sodium sulfate drying gets the 660mg white solid after the solvent evaporated.Yield: 63%.
1H-NMR(Acetone-d
6，300M)δ1.28-1.31(d，6H，-CH
3)，5.10-5.14(m，1H，-CH)，6.13(s，1H，-NH2)，6.53-6.56(dd，1H，ArH)，7.86-7.90(dd，1H，ArH)，8.57-8.58(d，1H，ArH)；m/z?181(M+H)
+。
6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester:
With 2, (1.93g 0.01mol) is suspended in the 20ml toluene 6-dichloro pyrimidine-4-carboxylic acid, adds PCl
5(2.19g, 0.0105mol), stirring at room 5 hours becomes golden transparent liquid; Decompression desolventizes, and in resistates, adds the 20ml dry THF, stirs; Get suspension liquid, this suspension liquid is added to 6-amino-nicotinic acid isopropyl ester, and (1.80 restrain, 0.01mol); DMAP (80mg), triethylamine (3ml) is in the solution of 30ml dry THF.Refluxed 12 hours, suction filtration is poured filtrating in the water into, stirs 1 hour, and suction filtration obtains white solid 850mg, yield: 24%.
1H-NMR(Acetone-d
6，300M)δ1.36-1.38(d，6H，-CH
3)，5.21-5.23(m，1H，-CH)，8.28(s，1H，ArH)，8.43(s，2H，ArH)，8.95(s，1H，ArH)，10.28(s，1H，-CONH-)；m/z?355(M+H)
+。
Embodiment 2.6-(2-chloro-6-(4-chlorophenoxy) pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
With anhydrous K
2CO
3(290mg, 2.1mmol) join 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester (355mg in DMSO 1.0mmol) (5ml) solution, stirs after 30 minutes, add para-chlorophenol (129mg, 1.0mmol).The TLC detection reaction finishes, and suction filtration is poured filtrating in the frozen water into, stirs suction filtration after 2 hours, and acetone recrystallization obtains white crystal 236mg, yield: 53%.
1H-NMR(Acetone-d
6，300M)δ1.36-1.38(d，6H，-CH
3)，5.21-5.25(m，1H，-CH)，7.37-7.40(d，2H，ArH)，7.55-7.58(d，2H，ArH)，7.74(s，1H，ArH)，8.43-8.44(d，2H，ArH)，8.94(s，1H，ArH)，10.22(s，1H，-CONH-)；m/z?447(M+H)
+。
Embodiment 3.6-(2,6-diisopropoxy pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
(132mg 0.4mmol) is suspended in adding Virahol 1ml among the DMF (5ml) with 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester; Stir and to add NaH down in batches (86mg 2mmol), stirs in 2 hours impouring water; Ethyl acetate extraction; The saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets white solid 60mg, yield: 38%.
1H-NMR(Acetone-d
6，300M)δ1.36-1.43(m，18H，-CH
3)，5.18-5.26(m，1H，-CH)，5.34-5.48(m，2H，-CH)，7.05-7.09(d，1H，ArH)，8.38-8.45(m，2H，ArH)，8.92(s，1H，ArH)，10.31(s，1H，-CONH-)；m/z?403(M+H)
+。
Embodiment 4.6-(2 chloro-6-isopropoxy pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid
(100mg 0.28mmol) is dissolved among the THF (10ml), adds Virahol (2ml) with 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester; (12mg 0.3mmol) is stirred to raw material and disappears solvent evaporated NaH; Add water 10ml and stir 2N hydrochloric acid accent pH to 3 down, ethyl acetate extraction, saturated common salt water washing; Anhydrous sodium sulfate drying, solvent evaporated get solid 45mg, yield: 48%.
1H-NMR(DMSO-d
6，300M)δ1.31-1.33(d，6H，-CH
3)，5.14-5.23(m，1H，-CH)，6.45(s，1H，ArH)，8.29-8.40(m，2H，ArH)，8.86(s，1H，ArH)，10.23(s，1H，-COOH)；m/z?337(M+H)
+。
Embodiment 5.6-(2-chloro-6-(3-chloroanilino) pyrimidine-4-carboxamide groups) pyridine-3-carboxylic acid isopropyl ester
(360mg 1.01mmol) is dissolved in the ethanol (20ml), and (130mg 1.02mmol), splashes into DIPEA20 and drips, stirred overnight at room temperature to add m-chloro aniline with 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated gets solid 175mg, yield: 39%.m/z?446(M+H)
+。
Embodiment 6.2,6-two chloro-N-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides
(2.19g 0.0105mol) adds to 20ml 2, and (1.93g is in toluene 0.01mol) (Na the is dry) suspension liquid for 6-dichloro pyrimidine-4-carboxylic acid with PCl5; Stirring at room 5 hours becomes golden transparent liquid, and decompression desolventizes, and in resistates, adds the 20ml dry THF; Stir, suspension liquid, with this suspension liquid be added to thiazolamine (1g, 0.01mol); DMAP (80mg), triethylamine (3ml) is in the solution of 30ml dry THF.Refluxed 12 hours, suction filtration is poured filtrating in the water into, stirs 1 hour, and suction filtration obtains yellow solid 550mg, yield: 20%.
1H-NMR(DMSO-d
6，300M)δ6.54-6.55(dd，1H，ArH)，6.87(s，1H，ArH)，6.92-6.93(dd，1H，ArH)；m/z?275(M+H)
+。
Embodiment 7.2,6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
(2.19g 0.0105mol) adds to 20ml 2, and (1.93g is in toluene 0.01mol) (Na the is dry) suspension liquid for 6-dichloro pyrimidine-4-carboxylic acid with PCl5; Stirring at room 5 hours becomes golden transparent liquid, and decompression desolventizes, and in resistates, adds the 20ml dry THF; Stir, suspension liquid, with this suspension liquid be added to 4-methyl-thiazolamine (1.1g, 0.01mol); DMAP (80mg), the 3ml triethylamine is in the solution of 30ml dry THF.Refluxed 12 hours, suction filtration is poured filtrating in the water into, stirs 1 hour, and suction filtration obtains yellow solid 790mg, yield: 27%.
1H-NMR(DMSO-d
6，300M)δ2.31(s，1H，-CH
3)，6.93(s，1H，ArH)，8.27(s，1H，ArH)；m/z?289(M+H)
+。
Embodiment 8.2,6-two (4-chlorophenoxy)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2, and 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides (95mg, 0.33mmol) and anhydrous K
2CO
3(1g 7.2mmol) adds to stirring among the DMSO (10ml), and (80mg 0.62mmol), is heated to 50 ℃ and spends the night to add para-chlorophenol.Suction filtration is poured filtrating in the water into, ethyl acetate extraction, and the saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography after the solvent evaporated obtains the 42mg white solid, yield: 27%.
1H-NMR(Acetone-d
6，300M)δ2.30(s，3H，-CH
3)，6.93(S，1H，ArH)，7.27-7.32(m，4H，ArH)，7.40(S，1H，ArH)，7.45-7.52(m，4H，ArH)，12.00(s，1H，-CONH-)；m/z?473(M+H)
+。
Embodiment 9.2-chloro-6-(4-chlorophenoxy)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2, and 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides (550mg, 1.9mmol) and anhydrous K
2CO
3(552g 4.0mmol) adds to the middle stirring of DMF (10ml) 30 minutes, and the adding para-chlorophenol (260mg, 2.0mmol); After the stirred overnight at room temperature, suction filtration is poured filtrating in the water into; Ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying; Column chromatography after the solvent evaporated obtains the 292mg white solid, yield: 40%.
1H-NMR(Acetone-d
6，300M)δ2.32(s，3H，-CH
3)，6.86(S，1H，ArH)，7.36-7.58(dd，4H，ArH)，7.69(s，1H，ArH)，11.26(s，1H，-CONH-)；m/z?381(M+H)
+。
Embodiment 10.2-chloro-6-(1-methoxy-propyl-2-oxygen base)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
(8mg 0.2mmol) is suspended in and is stirred to no gas in the 1-methoxyl group propan-2-ol (3ml) and overflows, in addition with 2-chloro-6-(4-chlorophenoxy)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides (39mg with NaH; 0.1mmol) be dissolved among the THF (5ml), drip in the pure sodium solution stirred overnight; Concentrating under reduced pressure, in the impouring water, equivalent dichloromethane extraction three times; The saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets the 5mg white solid, yield: 15%.
1H-NMR(Acetone-d6，300M)δ1.36-1.38(d，6H，-CH
3)，2.31(s，3H，-CH
3)，3.33(s，3H，-CH
3)，3.54-3.65(m，2H，-CH
2)，5.52-5.57(m，1H，-CH)，6.84(s，1H，ArH)，7.44(s，1H，ArH)，10.94(s，1H，-CONH-)；m/z?343(M+H)
+。
Embodiment 11.2-chloro-6-benzyloxy-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2, (95mg 0.3mmol) is dissolved among the THF (10ml) 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides, drips 10 phenylcarbinols, and add NaH under stirring (40mg 1mmol) stirred 48 hours in batches.Water gagings such as impouring, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography after the solvent evaporated obtains the 42mg white solid, total recovery: 39%.
1H-NMR(Acetone-d
6，300M)δ2.32(s，3H，-CH
3)，5.68(s，2H，-CH
2)，6.83(s，1H，ArH)，7.21-7.46(m，4H，ArH)，7.55-7.57(d，1H，ArH)，7.83(s，1H，ArH)，11.23(s，1H，-CONH-)；m/z?361(M+H)
+。
Embodiment 12.2,6-two benzyloxies-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2, (95mg 0.3mmol) is dissolved among the THF (10ml) 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides, drips 10 phenylcarbinols, and add NaH under stirring (40mg 1mmol) stirred 48 hours in batches.Water gagings such as impouring, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography after the solvent evaporated obtains the 39mg white solid, total recovery: 30%.
1H-NMR(DMSO-d
6，300M)δ2.32(s，3H，-CH
3)，5.45(s，2H，-CH
2)，5.65(s，2H，-CH
2)，6.93(s，1H，ArH)，7.18(s，1H，ArH)，7.33-7.52(m，10H，ArH)，12.34(s，1H，-CONH-)；m/z?433(M+H)
+。
Embodiment 13.2-chloro-N-(4-methylthiazol-2-yl)-6-benzene oxyethyl group pyrimidine-4-carboxylic acid amides
With 2, (95mg 0.3mmol) is dissolved among the THF (10ml) 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides, drips 10 phenylcarbinols, and add NaH under stirring (40mg 1mmol) stirred 48 hours in batches.Water gagings such as impouring, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography after the solvent evaporated obtains the 52mg white solid, yield: 42%.
1H-NMR(DMSO-d
6，300M)δ2.30(s，3H，-CH
3)，3.05-3.10(t，2H，-CH
2)，4.60-4.65(t，2H，-CH
2)，6.91(S，1H，ArH)，7.22-7.25(m，1H，ArH)，7.31-7.32(d，4H，ArH)，7.45(s，1H，ArH)，12.33(s，1H，-CONH-)；m/z?375(M+H)
+。
Embodiment 14.2,6-two (2-chlorobenzene methoxyl group)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
(110mg 0.8mmol) is dissolved among the THF (10ml), and add NaH under stirring (40mg 1mmol) stirred 10 minutes in batches with adjacent chlorobenzene methanol.Add 2, (95mg 0.3mmol), stirred 48 hours 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides.Water gagings such as impouring, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography after the solvent evaporated obtains the 33mg white solid, yield: 22%.
1H-NMR(Acetone-d
6，300M)δ2.32(s，3H，-CH
3)，5.63(s，2H，-CH
2)，5.75(s，2H，-CH
2)，6.82(s，1H，ArH)，7.29(s，1H，ArH)，7.38-7.41(m，4H，ArH)，7.48-7.50(m，2H，ArH)，7.63-7.66(m，2H，ArH)，11.17(s，1H，-CONH-)；m/z?501(M+H)
+。
Embodiment 15.2,6-two (furans-2-methoxyl group)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With the 2-furfuralcohol (107mg, 1.1mmol) alcohol is dissolved in and adds NaH among the THF (5ml) (41mg 1mmol) stirs solution blackening in 10 minutes, adds 2; (280mg, 1mmol) stirred overnight are added 2-furfuralcohol (50mg, 0.5mmol) NaH (20mg to 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides; 0.5mmol) stirring at room 10 hours, removal of solvent under reduced pressure adds water (30ml); Ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying; Column chromatography after the solvent evaporated obtains the 41mg white solid, yield: 9%.
1H-NMR(Acetone-d
6，300M)δ2.32(s，3H，-CH
3)，5.50(s，2H，-CH
2)，5.63(s，2H，-CH
2)，6.82(s，1H，ArH)，7.29(s，1H，ArH)，7.38-7.41(m，4H，ArH)，7.48-7.50(m，2H，ArH)，7.63-7.66(m，2H，ArH)，11.17(s，1H，-CONH-)；m/z?413(M+H)
+。
Embodiment 16.2-chloro-6-(3-chloroanilino)-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2, (289mg, (130mg, 1mmol) DIPEA20 drips 6-two chloro-N-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid amides, stirred overnight at room temperature 1mmol) to be dissolved in the middle adding of ethanol (20ml) m-chloro aniline.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated gets solid 260g, yield: 68%.
1H-NMR(Acetone-d
6，300M)δ2.32(s，3H，-CH
3)，6.83(S，1H，ArH)，7.19-7.64(dd，1H，ArH)，7.41-7.52(m，2H，ArH)，7.75-7.78(d，1H，ArH)，7.95(s，1H，ArH)，9.76(s，2H，-CONH-)；m/z?381(M+H)
+。
Embodiment 17.2-(2,6-dichloro pyrimidine-4-carboxylic acid amides) thiazole-5-carboxylic acid ethyl ester
(2.19g 0.0105mol) adds to 20ml 2, and (1.93g is in toluene 0.01mol) (Na the is dry) suspension liquid for 6-dichloro pyrimidine-4-carboxylic acid with PCl5; Stirring at room 5 hours becomes golden transparent liquid, removes solvent under reduced pressure, in resistates, adds the 20ml dry THF; Stir, suspension liquid, with this suspension liquid be added to thiazolamine-5-carboxylic acid, ethyl ester (1.7g, 0.01mol); DMAP (80mg), triethylamine (3ml) is in the solution of dry THF (30ml).Refluxed 12 hours, suction filtration is poured filtrating in the water into, stirs 1 hour, and suction filtration obtains yellow solid 562g, yield: 15.4%.
1H-NMR(Acetone-d
6，300M)δ1.33-1.37(T，3H，-CH
3)，4.29-4.35(q，2H，-CH
2)，8.16(s，1H，ArH)，8.29(s，1H，ArH)；m/z?347(M+H)
+。
Embodiment 18.2,6-two chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides
With vitamin B13 (2.35g, 0.015mmol; 1,2,3,6-tetrahydrochysene-2,6-dioxo pyrimidine-4-carboxylic acid) and N, accelerine (2ml) places POCl
3(20ml), backflow 3-4 hour, excessive POCl was removed in decompression
3, the purple soup compound that obtains is poured in the 50ml frozen water, suction filtration, filtrating is washed with ether (50ml * 3) extraction, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, revolve dried solvent after, re-crystallizing in ethyl acetate, 0.581g yellow solid.Yield: 20%.Fusing point: 70-71 ℃ (document
[48]: 115-117 ℃).
1H-NMR(DMSO-d
6，300M)δppm8.14(s，1H，ArH).
With PCl
5(2.186g 0.0105mol) adds to 2,6-dichloro pyrimidine-4-carboxylic acid (1.930g; 0.01mol) toluene (20ml) suspension liquid in, stirring at room 30 minutes removes solvent under reduced pressure; Get the acyl chlorides bullion, add dry THF (30ml), the gained suspension liquid is added to 2-EL-970 (0.941g; 0.01mol), DMAP (80mg) is in THF (50ml) solution of triethylamine (6ml).Stirring at room 2 hours, suction filtration is poured filtrating in the water into, suction filtration, acetone recrystallization obtains yellow solid 808mg, yield 30%.Fusing point: 183-184 ℃.
1H-NMR(Acetone-d
6，300M)δppm?7.22-7.27(m，1H，ArH)，7.89-7.94(m，1H，ArH)，8.25(s，1H，pyrimidine?H)，8.32(d，1H，ArH)，8.40-8.42(m，1H，ArH)，10.02(br，1H，CONH).
Embodiment 19.6-is to toluene sulfenyl-2-chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides
With anhydrous K
2CO
3(290mg 2.1mmol) joins 2,6-two chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides (269mg in DMF 1mmol) (5ml) solution, stirs after 30 minutes, add to the methylbenzene thiophenol (124mg, 1mmol).2-3 hour, the TLC detection reaction finished, and suction filtration is poured filtrating in the frozen water into, suction filtration, and acetone recrystallization obtains white solid 215mg, yield 60%.Fusing point: 165-166 ℃.
1H-NMR(Acetone-d
6，300M)δppm?2.46(s，3H，-CH
3)，7.18-7.22(m，1H，ArH)，7.46(d，2H，ArH)，7.52(s，1H，pyrimidine?H)，7.62(d，2H，ArH)，7.82-7.88(m，1H，ArH)，8.23(d，1H，ArH)，8.36-8.39(m，1H，ArH)，9.95(br，1H，CONH).
Embodiment 20.2, two couples of toluene sulfenyl-N-of 6-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides
With anhydrous K
2CO
3(152mg, 1.1mmol) join 6-to toluene sulfenyl-2-chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides (357mg in DMF 1.0mmol) (5ml) solution, stirs after 30 minutes, add to the methylbenzene thiophenol (124mg, 1.0mmol).After 2-3 hour, the TLC detection reaction finishes, and suction filtration is poured filtrating in the frozen water into, suction filtration, and the bullion column chromatography obtains white crystal 355mg, yield 80%.Fusing point: 218-219 ℃.
1H-NMR(Acetone-d
6，300M)δppm?2.44(s，3H，-CH
3)，2.45(s，3H，-CH
3)，7.13-7.17(m，1H，ArH)，7.22(s，1H，pyrimidine?H)，7.33-7.40(m，4H，ArH)，7.51-7.55(m，4H，ArH)，7.77-7.83(m，1H，ArH)，8.17(d，1H，ArH)，8.3-8.37(m，1H，ArH)，9.63(br，1H，CONH).MS：445(M+1)(100)，911(2M+Na).HRMS：cal.for?C
24H
21N
4OS
2：445.1151，found：445.1151。
Embodiment 21.2, two couples of toluene sulfenyl-N-of 6-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides
With 2,6-two chloro-N-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides 550mg and anhydrous K
2CO
3(552mg 4.0mmol) adds among the DMF (10ml) and stirred 30 minutes, add to the methylbenzene thiophenol (249mg, 2.0mmol); Stirring at room 2 hours, suction filtration is poured filtrating in the water into; Ethyl acetate extraction, saturated NaCl washing, anhydrous sodium sulfate drying; Revolve column chromatography behind the dried solvent, obtain the 292mg white solid, total recovery 6.5%.Fusing point: 160-161 ℃.
1H-NMR(Acetone-d
6，300M)δppm?2.44(s，6H，2-CH
3)，7.20(d，1H，pyrimidine?H)，7.25(dd，1H，ArH)，7.32-7.39(m，4H，ArH)，7.50-7.54(m，5H，ArH)，7.77-7.83(m，1H，ArH).MS?451(M+1).
Embodiment 22.6-(6-is to toluene sulfenyl-2-chloropyrimide-4-carboxylic acid amides) pyridine-3-carboxylic acid ethyl ester
With anhydrous K
2CO
3(290mg, 2.1mmol) join 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid ethyl ester (341mg in DMF 1.0mmol) (5ml) solution, stirs after 30 minutes, add to the methylbenzene thiophenol (124mg, 1mmol).2-3 hour, the TLC detection reaction finished, and suction filtration is poured filtrating in the frozen water into, suction filtration, and acetone recrystallization obtains white crystal 236mg, yield 55%.Fusing point: 160-161 ℃.
1H-NMR(Acetone-d
6，300M)δppm?1.34(t，3H，-CH
3)，4.37(q，2H，-CH
2)，7.45-7.48(m，2H，ArH)，7.53(s，1H，pyrimidine?H)，7.60-7.63(m，2H，ArH)，8.32-8.41(m，2H，ArH)，8.92-8.93(m，1H，ArH)，10.20(br，1H，CONH).
Embodiment 23.6-[2-(2-hydroxyl ethylmercapto group)-6-is to toluene sulfenyl pyrimidine-4-carboxylic acid amides) the pyridine-3-carboxylic acid ethyl ester
With anhydrous Na OAc (90mg, 1.1mmol) join 6-(6-is to toluene sulfenyl-2-chloropyrimide-4-carboxylic acid amides) pyridine-3-carboxylic acid ethyl ester (429mg in DMF 1mmol) (5ml) solution, stirs after 30 minutes, add 2 mercapto ethanol (78mg, 1mmol).After 2-3 hour, the TLC detection reaction finishes, and suction filtration is poured filtrating in the frozen water into, suction filtration, and the bullion column chromatography obtains white crystal 355mg, yield 80%.Fusing point: 115-117 ℃.
1H-NMR(Acetone-d
6，300M)δppm?1.38(t，3H，-CH
3)，2.46(s，3H，-CH
3)，3.16(t，2H，S-CH
2)，3.61(q，2H，O-CH
2)，3.94(t，1H，-OH)，4.37(q，2H，-CH
2)，7.39(d，2H，ArH)，7.58(d，2H，ArH)，7.63(s，1H，pyrimidine?H)，8.33-8.40(m，2H，ArH)，8.91(s，1H，ArH)，9.98(br，1H，CONH).MS：471(M+1)(100)，963(2M+Na).HRMS：cal.for?C
22H
23N
40
48
2：471.1155，found：471.1153.
Embodiment 24.2-(2-hydroxyl ethylmercapto group)-6-is to toluene sulfenyl-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides
With anhydrous Na OAc (90mg, 1.1mmol) join 2-chloro-6-to toluene sulfenyl-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides (357mg in DMF 1mmol) (5ml) solution, stirs after 30 minutes, add 2 mercapto ethanol (78mg, 1mmol).After 2-3 hour, the TLC detection reaction finishes, and suction filtration is poured filtrating in the frozen water into, suction filtration, and the bullion column chromatography obtains white crystal 229mg, yield 57%.Fusing point: 138-139 ℃.
1H-NMR(Acetone-d
6，300M)δppm?2.44(s，3H，-CH
3)，3.15(t，2H，S-CH
2)，3.60(q，2H，O-CH
2)，3.92(t，1H，-OH)，7.16-7.20(m，1H，ArH)，7.38(d，2H，ArH)，7.57(d，2H，ArH)，7.63(s，1H，pyrimidine?H)，7.82-7.87(m，1H，ArH)，8.27(d，1H，ArH)，8.37-8.39(m，1H，ArH)，9.80(br，1H，CONH).MS：399(M+1).HRMS：cal.for?C
19H
19N
4O
2S
2：399.0943，found：399.0948.
Embodiment 25.6-(2-hydroxyl ethylmercapto group)-2-is to toluene sulfenyl-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides
With anhydrous Na OAc (172mg 2.1mmol) joins 2,6-two chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides (269mg in DMF 1mmol) (5ml) solution, stirs after 30 minutes, add 2 mercapto ethanol (78mg, 1mmol).2-3 hour, the TLC detection reaction finished, and suction filtration is poured filtrating in the frozen water into, suction filtration, and acetone recrystallization obtains white solid 170mg, yield 55%.
With anhydrous Na OAc (90mg, 1.1mmol) join 6-(2-hydroxyl ethylmercapto group)-2-chloro-N-(pyridine-2-yl) pyrimidine-4-carboxylic acid amides (310mg in DMF 1.0mmol) (5ml) solution, stirs after 30 minutes, add to the methylbenzene thiophenol (125mg, 1.0mmol).After 2-3 hour, the TLC detection reaction finishes, and suction filtration is poured filtrating in the frozen water into, suction filtration, and the bullion column chromatography obtains white crystal 238mg, yield 60%.Fusing point: 134-135 ℃.
1H-NMR(Acetone-d
6，300M)δppm?2.45(s，3H，-CH
3)，3.15(t，2H，S-CH
2)，3.60(q，2H，O-CH
2)，3.92(t，1H，-OH)，7.16-7.20(m，1H，ArH)，7.38(d，2H，ArH)，7.555-7.59(m，2H，ArH)，7.63(s，1H，pyrimidine?H)，7.82-7.88(m，1H，ArH)，8.26-8.28(m，1H，ArH)，8.37-8.39(m，1H，ArH)，9.80(br，1H，CONH).MS：399(M+1).HRMS：cal.for?C
19H
19N
4O
2S
2：399.0943，found：399.0952.
Embodiment 26.6-(4-chlorophenoxy)-2-chloro-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
With 2, and 6-two chloro-N-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides (275mg, 1mmol) and anhydrous K
2CO
3(552mg 4.0mmol) adds to the middle stirring of DMSO (10ml) 30 minutes, and the adding para-chlorophenol (130mg, 1mmol), after the stirred overnight at room temperature; Suction filtration is poured filtrating in the water into, ethyl acetate extraction, saturated common salt water washing; Anhydrous sodium sulfate drying, solvent evaporated obtains the 215mg white solid
1H-NMR (Acetone-d6,300M), 7.25-7.53 (m, 7H, ArH) .MS m/z 368 (M+H)
+
Embodiment 27.2,6-dimethoxy-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
(100mg 0.27mmol) adds to stirring and dissolving in the anhydrous methanol (10ml), adds Cs with 2-chloro-6-(4-chlorophenoxy)-N-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides
2C0
3(878mg, 2.7mmol), stirring at room 24 hours, suction filtration is poured filtrating in the water into, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated, column chromatography obtains the 25mg white solid, yield: 34%.
1H-NMR(Acetone-d6，300M)，δ4.04(s，3H，-CH
3)，4.12(s，3H，-CH
3)，7.16(s，1H，ArH)，7.28-7.29(d，1H，ArH)，7.54-7.55(d，1H，ArH)；MS?m/z?267(M+H)
+。
Embodiment 28.2,6-oxyethyl group-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
(100mg 0.27mmol) adds to stirring and dissolving in the absolute ethyl alcohol (10ml), adds Cs with 2-chloro-6-(4-chlorophenoxy)-N-(thiazol-2-yl) pyrimidine-4-carboxylic acid amides
2CO
3(878mg, 2.7mmol), stirring at room 24 hours, suction filtration is poured filtrating in the water into, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated, column chromatography obtains the 19mg white solid, yield: 24%.
1H-NMR(Acetone-d6，300M)δ1.38-1.44(m，6H，-CH
3)，4.48-4.57(m，4H，-CH
2)，7.11(s，1H，ArH)，7.28-7.29(d，1H，ArH)，7.54-7.55(d，1H，ArH)，10.78(s，1H，-CONH-)；MS?m/z?295(M+H)
+。
Embodiment 29.6-(2,6-benzyloxy pyrimidine-4-formamido group) isopropyl nicotinate
(324mg 3mmol) is dissolved among the THF (10ml), and add NaH under stirring (120mg 3mmol), stirs and processed sodium alkoxide in 8 hours in batches with phenylcarbinol.(355mg 1mmol) is suspended in THF (10ml) and is added drop-wise in the sodium alkoxide stirred overnight 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets white solid 138mg.
1H-NMR(Acetone-d
6，300M)δ1.36-1.38(d，6H，-CH
3)，5.21-5.25(m，1H，-CH)，5.45(s，2H，-CH
2)，5.60(s，2H，-CH
2)，7.23(s，1H，ArH)，7.35-7.60(m，10H，ArH)，8.41(m，2H，ArH)，8.94(s，1H，ArH)，10.33(s，1H，-CONH-)；m/z?499(M+H)
+。
Embodiment 30.6-(2,6-two (2-chlorine benzyloxy) pyrimidine-4-formamido group) isopropyl nicotinate
(426mg 3mmol) is dissolved among the THF (10ml), and add NaH under stirring (120mg 3mmol), stirs and processed sodium alkoxide in 8 hours in batches with adjacent chlorobenzene methanol.(355mg 1mmol) is suspended in THF (10ml) and is added drop-wise in the sodium alkoxide stirred overnight 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets white solid 219mg.
1H-NMR(Acetone-d
6，300M)δ1.36-1.38(d，6H，-CH
3)，5.18-5.27(m，1H，-CH)，5.56-5.61(d，2H，-CH
2)，5.71-5.73(d，2H，-CH
2)，7.31(s，1H，ArH)，7.38-7.44(m，4H，ArH)，7.49-7.51(m，2H，ArH)，7.63-7.71(m，2H，ArH)，8.38(m，2H，ArH)，8.94(s，1H，ArH)，10.34(s，1H，-CONH-)；m/z?567(M+H)
+。
Embodiment 31.6-(6-chloro-2-(2-fluorine benzyloxy) pyrimidine-4-formamido group) isopropyl nicotinate
(378mg 3mmol) is dissolved among the THF (10ml), and add NaH under stirring (120mg 3mmol), stirs and processed sodium alkoxide in 8 hours in batches with adjacent fluorophenyl methanol.(355mg 1mmol) is suspended in THF (10ml) and is added drop-wise in the sodium alkoxide stirred overnight 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets white solid 67mg.
1H-NMR(Acetone-d
6，300M)δ1.36-1.38(d，6H，-CH
3)，5.18-5.27(m，1H，-CH)，5.61-5.64(d，2H，-CH
2)，7.19-7.29(m，1H，ArH)，7.46-7.49(m，1H，ArH)，7.59(s，1H，ArH)，7.63-7.68(m，1H，ArH)，8.28(s，1H，ArH)，8.43(s，2H，ArH)，8.94(s，1H，ArH)，10.22(s，1H，-CONH-)；m/z?445(M+H)
+。
Embodiment 32.6-(2,6-diisobutyl oxygen yl pyrimidines-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
Isopropylcarbinol (1ml) is dissolved among the THF (10ml), and add NaH under stirring (120mg 3mmol), stirs and processed sodium alkoxide in 8 hours in batches.(355mg 1mmol) is suspended in THF (10ml) and is added drop-wise in the sodium alkoxide stirred overnight 6-(2,6-dichloro pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester.Concentrating under reduced pressure, in the impouring water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated.Column chromatography gets white solid 103mg.
1H-NMR(Acetone-d
6，300M)δ1.03-1.09(m，12H，-CH
3)，1.37-1.39(d，6H，-CH
3)，2.08-2.21(m，2H，-CH)，4.13-4.34(m，4H，-CH
2)，5.20-5.28(m，1H，-CH)，7.16(s，1H，ArH)，8.39-8.45(m，2H，ArH)，8.93-8.96(m，1H，ArH)，10.32(s，1H，-CONH-)；m/z?431(M+H)
+。
Pharmacological evaluation
1. reaction principle:
2. reaction system is formed:
Comprise 5mmol/l ATP in the reaction system, 0.2U/ml G6PDH, 0.2mmol/l NADP, 5mmol/lMgCl
2, 1mmol/l DTT, 25mmol/l KCl, 100mmol/l Tris-HCl, different concns glucose, 1%DMS0, different concns test-compound and recombination human source liver GK protein liquid.
3. operating process:
Preparation reaction mixture (ATP, G6PDH, NADP, MgCl
2, DTT, KCl, glucose Tris-HCl) → add test-compound → addings reorganization GK protein liquid → room temperature measuring 340nm absorbance, and is designated as initial value (0min) → 37 ℃ incubation, every at a distance from 10 minutes 340nm readings once till the 60min → calculation result.
4. method of calculation:
Activate multiple=(OD
t-OD
0)
Sample hose/ (OD
t-OD
0)
Reaction tubes
Annotate: sample hose is to add test-compound in the system, and reaction tubes shines for the reaction pair that does not add test-compound.
Activate multiple＞1.5 and be regarded as the positive.
Part embodiment compound activity result:
Claims (14)
1. the pyrimidine derivatives shown in general formula I comprises its pharmacologically acceptable salt, the precursor of its same biological function or verivate
In the formula
R1 or R2 are selected from hydrogen, halogen, alkoxyl group, alkylamino radical, alkylthio, aryloxy, heteroaryloxy, aryl amine, assorted aryl amine, arylthio, heteroarylthio, alkyl amide, aromatic amide.R1 and R2 can be identical, also can be different, comprise chirality and achirality group.
Wherein, alkyl is for replacing or do not replace the straight or branched alkyl of C1-12, and comprise the C3-6 carbocyclic ring or contain the C3-6 heterolipid ring of 1-3 oxygen, nitrogen, sulfur heteroatom,
Substituting group on the alkyl is selected from halogen, hydroxyl, nitro, itrate group, cyanic acid, amino, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylthio, C1-6 amido, carboxyl, ester group, C1-6 alkanoyloxy, aryl or heteroaryl,
Wherein aryl is for replacing or not substituted phenyl, naphthyl; Heteroaryl is for replacing or not substituted heterocyclic aryl; As furans, thiophene phenol, pyridine, pyrimidine 、 oxazole 、 isoxazole, pyrazoles, imidazoles, pyrrole iron, quinoline, isoquinoline 99.9, indoles, pyrazine, thiazole, benzothiazole, benzoglyoxaline etc.
Substituting group on aryl, the heteroaryl is selected from the alkyl of C1-8, alkoxyl group, halogen, trifluoromethyl, hydroxyl, nitro, itrate group, cyanic acid, amino, C1-8 alkylamino, C1-8 amido, substituted amino azo-group, carboxyl, ester group, C1-8 alkanoyloxy, imidazoles, the substituted imidazoles of C1-8 alkyl, replacement or not substituted heterocycle or aromatic heterocyclic, replacement or not substituted heterocycle or the fragrant Heterocyclylalkyl of C1-8;
The optional hetero-aromatic ring of doing for oneself and connecting through ring carbon atom of A ring has 1-6 heteroatoms to be selected from nitrogen, oxygen and sulphur in its ring.Said hetero-aromatic ring does not replace for having, single replacement or polysubstituted.
Substituting group is selected from halogen, alkyl, part or perfluor C1-6 alkyl, alkoxyl group, alkyl sulfenyl, amino, alkylamino radical, alkylthio, sulfonamido, carboxyl, ester group, nitro, cyanic acid, perfluoroalkyl group sulfonyl, alkyl sulphinyl, replacement or not substituted aryl or heteroaryl, replacement or not substituted Heterocyclylalkyl or fragrant Heterocyclylalkyl; Wherein the definition of alkyl and aryl and heteroaryl as stated.
2. according to the compound of claim 1, it is characterized in that,
R1 or R2 are selected from halogen, alkoxyl group, alkylamino radical, alkylthio, aryloxy, heteroaryloxy, aryl amine, assorted aryl amine, arylthio, heteroarylthio, alkyl amide, aromatic amide; Wherein alkyl, heteroaryl and aryl comprise substituted or not substituted, substituent scope such as claim 1.R1 and R2 can be identical, also can be different, comprise chirality and achirality group.
The A ring is selected from the hetero-aromatic ring of 5-10 the annular atoms that connects through ring carbon atom, has 1-5 heteroatoms to be selected from nitrogen, oxygen and sulphur in its ring, and wherein encircles a nitrogen-atoms and the ring carbon atom adjacent that is connected at least.Said hetero-aromatic ring does not replace for having, single replacement or polysubstituted.
3. according to the compound of claim 2; R1 or R2 can be selected from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, adjacent cyano benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, (1; 2; 4-triazole-3) sulfenyl, phenoxy, 3; 5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, to the adjacent chlorophenoxy of second sulfinyl, to the adjacent fluorophenoxy of piperidine formyl, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, o-methyl-benzene formamido-, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, (5-methyl-isoxazole-3)-methyl, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to fluorobenzene sulfenyl, 2; 2-two fluoro-2-phenyl ethoxies, benzo [D] [1; 3] dioxy cyclopentenes-5-oxygen base, benzothiazole-2-oxygen base, 2-methylsulfonyl pyridine-5-oxygen base, 2-n n dimetylaniline formylpyridine-5-oxygen base; 1,3,4-triazole-2-sulfenyl, 2-n n dimetylaniline formyl pyrazine-5-oxygen base, pyridine-2-sulfenyl;
The A ring can be selected from thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base; 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base; 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base, pyrazole-3-yl, N-methylpyrazole-3-base, 3-methyl isophthalic acid; 2,4-thiadiazoles-5-base, 3-methoxyl group-1,2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base; Pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base; Pyrimidine-4-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base; 5-methyl-isoxazole-3-base, isoquinolyl-1;
4. according to the compound of claim 3; R1 or R2 can be selected from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, adjacent cyano benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, (1; 2; 4-triazole-3) sulfenyl, phenoxy, 3; 5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, o-methyl-benzene formamido-, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to fluorobenzene sulfenyl, 2,2-two fluoro-2-phenyl ethoxies, pyridine-2-sulfenyl;
The A ring can be selected from thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base; 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base; 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-carbalkoxyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base, pyrazole-3-yl, N-methylpyrazole-3-base, 3-methyl isophthalic acid; 2,4-thiadiazoles-5-base, 3-methoxyl group-1,2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base; Pyrimidine-4-base, 5-methyl-isoxazole-3-base;
5. according to the compound of claim 4; R1 or R2 can be selected from chlorine; Methoxyl group, oxyethyl group, isopropoxy, isobutoxy, (Alpha-Methyl) methoxyethoxy, (Alpha-Methyl) difluoro methoxyethoxy, (Alpha-Methyl) (2-hydroxyl) oxyethyl group, (Alpha-Methyl) benzene oxyethyl group, (furans-2) methoxyl group, benzyloxy, adjacent chlorine benzyloxy, o-chlorine benzylamine base, m-chloro benzyloxy, 2-fluorine benzyloxy, 2-(thiophene-2) oxyethyl group, phenoxy, 3,5-two fluorophenoxies, to chlorophenoxy, to n n dimetylaniline formyl phenoxy, methylamino, dimethylin, ethylamino-, isopropylamine base, benzamido group, adjacent flunamine base, chloroanilino, methylthio group, to toluene sulfenyl, hydroxyethyl sulfenyl, o-methyl-benzene formamido-, 2-(4-methylthiazol) oxyethyl group, to the methylsulfonyl phenoxy, to the fluorobenzene sulfenyl;
The A ring can be selected from thiazol-2-yl, 4-methylthiazol-2-base; 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl; Pyrazine-2-base, 5-methylpyrazine-2-base, 5-carboxyl pyridine-2-base, 5-fluorine pyridine-2-base, 5-carbalkoxyl yl pyridines-2-base, 5-amido formyl radical pyridine-2-base; Pyrazole-3-yl, N-methylpyrazole-3-base, 5-methyl-isoxazole-3-base;
6. according to the compound of claim 1-, described compound is selected from:
6-(2,6-diisopropoxy pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
6-(2-chloro-6-isopropoxy pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid
6-(2-chloro-6-is to chlorophenoxy pyrimidine-4-carboxamide groups) pyridine-3-carboxylic acid isopropyl ester
2,6-two chloro-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
2,6-dimethoxy-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
2,6-benzyloxy-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2-chloro-6-benzene oxyethyl group-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-(3-chlorine benzyloxy)-2-chloro-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2,6-two (2-chlorine benzyloxy)-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2,6-two (4-chlorophenoxy)-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-(4-chlorophenoxy)-2-chloro--N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2,6-two ((furans-2) methoxyl group)-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-benzyloxy-2-chloro--N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-(4-chlorophenoxy)-2-chloro-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-(1-methoxy-propyl-2-oxygen base)-2-chloro-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2,6-diethoxy-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
6-(4-chlorophenoxy)-2-chloro-N-(thiazole-2) pyrimidine-4-carboxylic acid amide
6-(3-chloroanilino)-2-chloro-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
2-chloro-6-isopropylamine base-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-benzyloxy amido-2-chloro-N-(4-methylthiazol-2) pyrimidine-4-carboxylic acid amide
6-(2,6-diisopropoxy pyrimidine-4-carboxylic acid amides) pyridine-3-carboxylic acid
6-(6-(3-chloroanilino)-2-chloropyrimide-4-carboxamide groups) pyridine-3-carboxylic acid isopropyl ester
2, two couples of toluene sulfenyl-N-of 6-(pyridine-2) pyrimidine-4-carboxylic acid amide
2, two couples of toluene sulfenyl-N-of 6-(thiazole-2) pyrimidine-4-carboxylic acid amide
6-(2-(2-hydroxyethyl sulfenyl)-6-is to toluene sulfenyl pyrimidine-4-carboxylic acyloxy amido) pyridine-3-carboxylic acid ethyl ester
2-(2-hydroxyethyl sulfenyl)-6-is to toluene sulfenyl-N-(pyridine-2) pyrimidine-4-carboxylic acid amide
6-(2-hydroxyethyl sulfenyl)-2-is to toluene sulfenyl-N-(pyridine-2) pyrimidine-4-carboxylic acid amide
2-(2,6-dichloro pyrimidine-4-carboxylic acid amides) thiazole-5-carboxylic acid ethyl ester
6-(2,6-benzyloxy pyrimidine-4-formamido group) isopropyl nicotinate
6-(2,6-two (2-chlorine benzyloxy) pyrimidine-4-formamido group) isopropyl nicotinate
6-(6-chloro-2-(2-fluorine benzyloxy) pyrimidine-4-formamido group) isopropyl nicotinate
6-(2,6-diisobutyl oxygen yl pyrimidines-4-carboxylic acid amides) pyridine-3-carboxylic acid isopropyl ester
7. according to the compound of claim 1-6, it is characterized in that described medicinal salt comprises with mineral acid, organic acid, alkalimetal ion, alkaline earth metal ion maybe can provide physiologically acceptable cationic organic bases to combine salt and the ammonium salt that forms.
8. according to the compound of claim 1-6, it is characterized in that described mineral acid is selected from hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid; Described organic acid is selected from methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid tartrate, fumaric acid, Hydrocerol A or lactic acid; Described alkalimetal ion is selected from lithium ion, sodium ion, potassium ion; Described alkaline earth metal ion comprises calcium ion, mg ion; Describedly can provide physiologically acceptable cationic organic bases to be selected from methylamine, n n dimetylaniline, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine.
9. the method for preparing the said compound of claim 1-7 comprises following method:
(i) with the vitamin B13 be raw material, through with PCl
3Or PCl
5Or POCl
3Or SOCl
2Deng chlorination reaction, obtain 2,6 dichloro pyrimidines-4-formyl chloride.Then with assorted arylamine (R
3NH
2) reaction, obtain 2,6 dichloro pyrimidines-4-methane amide.Again with nucleophilic substitution reagent HR
1Or HR
2Reaction obtains 2-R
1-6-chloropyrimide-4-methane amide or 2-chloro-6-R
2Pyrimidine-4-methane amide, then further with nucleophilic substitution reagent HR
1Or HR
2Reaction obtains 2-R
1-6-R
2Pyrimidine-4-methane amide.
(ii) be raw material, can be converted into 2,6 dihydroxy-pyrimidines-4-formyl chloride earlier, again with assorted arylamine (R with the vitamin B13
3NH
2) reaction, or direct and assorted arylamine (R
3NH
2) reaction, obtain 2,6 dihydroxy-pyrimidines-4-methane amide.But and then with the instead reagent XR that has leavings group
3Or XR
5(but X is a leavings group, like the halogen ion, sulphonyl oxonium ion etc.) reaction obtains 2-R
4O-6-hydroxy pyrimidine-4-methane amide or 2-hydroxyl-6-R
5O pyrimidine-4-methane amide.Then further with reagent XR
5Or XR
3Reaction obtains 2-R
4O-6-R
5O pyrimidine-4-methane amide, wherein R
4O is at R
1Within the scope, R
5O is at R
2Within the scope.
10. according to the preparation method of claim 9, it is characterized in that, described with carboxyl and R
3NH
2The prepared in reaction acid amides comprise earlier with carboxyl become acyl chlorides again with R
3NH
2Reaction, or with carboxyl directly and R
3NH
2Reaction obtains acid amides.
11. a pharmaceutical composition comprises as carrier commonly used on the described compound of the claim 1-8 of effective constituent or its pharmaceutically useful salt and the pharmacopedics.
12. the salt of the described compound of claim 1-8 or its pharmaceutically acceptable acid or alkali the preparation prevention with or the medicine of treatment and gk diseases associated in application.
13. the application according to claim 12 is characterized in that, described and gk diseases related is selected from the chronic complicating diseases and the obesity of mellitus, mellitus.
14. the application according to claim 13 is characterized in that, described mellitus are selected from type 1 diabetes or diabetes B; The chronic complicating diseases of described mellitus is selected from retinopathy, ephrosis, neurosis, ischemic heart disease or arteriosclerosis.
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