CN101018773A

CN101018773A - Hetroaryl benzamide derivatives for use as glk activators in the treatment of diabetes.

Info

Publication number: CN101018773A
Application number: CNA2005800254863A
Authority: CN
Inventors: C·约翰斯顿; D·迈克克里彻; K·G·皮克; M·J·瓦宁
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-06-05
Filing date: 2005-06-01
Publication date: 2007-08-15
Also published as: ZA200610140B; UA87685C2; GB0412602D0

Abstract

Compounds of Formula (I) wherein: R<1> is hydroxymethyl; R<2> is selected from -C(O)NR<4>R<5>, -SO2NR<4>R<5>, -S(O)pR<4> and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R<3> is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R<4> is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R<5> is hydrogen or (1-4C)alkyl; or R<4> and R<5> together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.

Description

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

The present invention relates to the benzoyl-amido heterogeneous ring compound, its treatment or prevention by glucokinase (GLK or GK) mediation disease or medical conditions in effectively, can cause the threshold glucose value of insulin secretion is reduced.In addition, described compound is expected the lowering blood glucose by increasing the hepatic glucose picked-up.These compounds can help treating diabetes B and obesity.The invention still further relates to the medicinal compositions that comprises described compound and with the method for described compounds for treating by the disease of GLK mediation.

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 limiting speed of the total speed of glucose uptake in these cells.The speed that glucose uptake speed is subjected to be turned to G-6-P (G-6-P) by the catalytic glucose phosphate of glucokinase (GLK) [1] is limited.GLK has high (6-10mM) Km to glucose, and is not subjected to the G-6-P[1 of physiological concentration] suppress.GLK expresses and is limited to several tissues and cell type, and the most noticeable is pancreas beta cell and liver cell (hepatocytes) [1].The GLK activity is the limiting speed of glucose utilization in these cells, thereby regulates the insulin secretion and the liver glycogen synthetic degree of glucose induction.These processes are very crucial in the glucose homeostasis 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 cause [3,4] by the sudden change of GLK afunction.MODY-2 patient's hyperglycemia causes [5] by glucose utilization defective in pancreas and the liver.The glucose utilization defective causes the threshold value rising to the insulin secretion of glucose stimulation in MODY-2 patient's pancreas.On the contrary, rare GLK activated mutant reduces this threshold value, thereby causes familial Hyperinsulinism [6,6a, 7].Except that observing in the MODY-2 diabetes that GLK is active and reducing, the kinase whose activity of hepatic glucose also decrease [8] in diabetes B.Importantly, the overall or liver selectivity of GLK is crossed to express and is stoped or reversed the phenotypic generation of diabetes [9-12] in the diet model of this disease and the genetic model.In addition, with fructose the acute treatment of diabetes B has been improved glucose tolerance [13] by stimulating the hepatic glucose utilization.This result it is believed that it is mechanism by describing below, by active [13] that mediate that increase of kytoplasm GLK in the fructose inductive liver cell.

Liver GLK activity is suppressed by regulating the albumen association with GLK.The GLK/GLKRP mixture by fructose-6-phosphate (F6P) with combining of GLKRP stabilization, by replacing this sugar and stabilization removal with fructose-1-phosphate (F1P).F1P is produced by the phosphorylation of the meals fructose of fructokinase mediation.Subsequently, GLK/GLKRP mixture integrity and liver GLK activity are conditioned in nutrition dependent form mode, and 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 not expressed when having GLKRP.Therefore, beta cell GLK activity is regulated by the utilizability of its substrate glucose widely.Small molecules can be directly or by making GLK/GLKRP mixture stabilization removal activate GLK.The compound of former type estimates to stimulate the glucose utilization in liver and the pancreas, and the latter estimates that the energy selectively acting is in liver.But the compound with two specific characters is estimated effectively to treat diabetes B because this disease be characterized as glucose utilization defective in two kinds of tissues.

GLK, GLKRP and K _ATPPassage is expressed in hypothalamus neurons, and hypothalamus is an important area [14-18] of regulating energy balance and control ingestion of food in the brain.These neurones have shown to express and have improved a poor appetite and apocleisis neuropeptide [15,19,20], and are assumed that 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 many kind heredity of diabetes with testing in the inductive model.The ingestion of food [29,30] that can stimulate thin rat as Intraventricular (icv) perfusion of the glucalogue of the competitive inhibitor of glucokinase.On the contrary, the icv perfusion of glucose can suppress 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 can help treating eating disorder, comprises obesity.In the treatment of diabetes B, the hypothalamus effect can make the effect of glucose homeostasis normalizing rise the same compound that acts on liver and/or pancreas and add up or act synergistically.Therefore, the GLK/GLKRP system can be described to potent " diabetes and obesity (Diabesity) " target (being of value to diabetes and obesity).

GLK also expresses in the specificity enteroendocrine cell, wherein it is considered to control respectively 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, 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 with these compounds in the active mensuration of getting up with the NADH generic connection of GLK (generation of NADH detects with optical means again, sees the external test of hereinafter describing for details) direct effect and assess 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 (carboxamide) and sulfone amide derivative; Novo-Nordisk), WO2004/002481 (aryl carbonyl derivatives; Novo Nordisk) and WO03/080585 (the benzoyl-amido heterocycle of amino-replacement 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 as glucokinase (GLK) activator.

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

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

The compound of the subgroup that is generally the compound of describing among 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, usually be selected from the subgroup of the compound of WO03/015774 description, it has potent usually to the GLK enzyme, and has how useful physical properties, comprise, as higher water-soluble, higher perviousness and/or lower plasma protein binding ratio.Therefore, expectation can demonstrate higher plasma free levels of drugs in oral back to have these compounds of perfect combination of these characteristics, and have in vivo potent, such as in oral glucose tolerance test (OGTTs) mensuration.Therefore this group compound is estimated good oral endurance (oral exposure) can be provided at lower dosage, thereby is particularly suitable for treating or prevents disease by the GLK mediation.

Therefore, a first aspect of the present invention provides compound or its salt, prodrug or the solvate of formula (I):

Wherein:

R ¹Be methylol;

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

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

To be 4-, 5-or 6-unit comprise 1,2,3 or 4 heteroatomic heterocycle that independently is selected from O, N and S by what C-or N-connected to HET-2, 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace;

R ³Be selected from halogen, methyl fluoride, difluoromethyl, trifluoromethyl, methyl, methoxyl group and cyano group;

R ⁴Be selected from hydrogen, (1-4C) alkyl [optional 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 ⁵1 or 2 substituting 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 the heterocycle ring system that defines by HET-3 with the nitrogen-atoms that connects them;

R ⁶Independently be selected from (1-4C) alkyl, halogen, 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 HET-4;

R ⁷Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _PR ⁵

HET-3 is the saturated or part unsaturated heterocycle of 4-6 unit that connects by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) 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 and effectively independently is being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is 7 yuan of saturated or part unsaturated heterocycles that connect by N-, chooses wantonly to comprise 1 other heteroatoms (except that being connected the N atom) 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 and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is the saturated or part unsaturated heterocycle of 6-10 unit's dicyclo, optional 1 nitrogen-atoms (except that connecting the N atom) that also comprises, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement; Described ring is chosen wantonly and effectively independently is being selected from hydroxyl and R by 1 on carbon or the nitrogen-atoms ³Substituting group replace;

R ⁸Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, HET-3 (wherein said ring is undersaturated), (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _PR ⁵

HET-4 comprises 1,2 or 3 5-or first unsubstituted hetero-aromatic ring that is connected by C-or N-of 6-that independently is selected from the ring hetero atom of O, N and S;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2.

Its salt, prodrug or the solvate of the compound of formula (I) or definition as mentioned are provided in another aspect of this invention, and condition is to get rid of fall within the scope of the invention compound of example among the WO2004/076420.

Its salt, prodrug or the solvate of the compound of formula (I) or definition as mentioned are provided in another aspect of this invention, wherein:

R ¹Be methylol;

HET-2 comprises 1,2,3 or 4 independently to be selected from heteroatomic 4-, the 5-of O, N and S or the heterocycle that 6-unit is connected by C-or N-, 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace;

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] and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

HET-3 is the saturated or part unsaturated heterocycle of 4-6 unit that connects by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) that independently is selected from O, N and S, wherein-CH ₂-group can choose wantonly by-C (O)-displacement and wherein the sulphur atom on the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

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

HET-3 is the saturated or part unsaturated heterocycle of 6-10 unit's dicyclo, optional 1 nitrogen-atoms (except that connecting the N atom) that also comprises, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement; Described ring is chosen wantonly and effectively independently is being selected from R by 1 on carbon or the nitrogen-atoms ³Substituting group replace;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2.

Compound or its salt, prodrug or the solvate of the formula (I) of definition are as mentioned provided in another aspect of this invention, wherein

R ¹Be methylol;

R ²Be selected from-C (O)-HET-3 and-SO ₂-HET-3;

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;

HET-3 is 4,5 or 6 yuan of saturated or part unsaturated heterocycles that connect by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) that independently is selected from O, N and S, wherein-CH ₂-group can choose wantonly by-C (O)-displacement and wherein the sulphur atom on the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace;

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

Or HET-3 is the saturated or part unsaturated heterocycle of 6-10 unit dicyclo, optional also comprise 1 nitrogen-atoms (removing the connection N atom) wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement; Described ring is chosen wantonly and effectively independently is being selected from hydroxyl and R by 1 on carbon or the nitrogen-atoms ³Substituting group replace;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1; N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2.

Compound or its salt, prodrug or the solvate of the formula (I) of definition as mentioned are provided in another aspect of this invention, wherein:

HET-3 is the saturated or part unsaturated heterocycle of 4-6 unit that connects by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) that independently is selected from O, N and S, wherein-CH ₂-group can choose wantonly by-C (O)-displacement and wherein the sulphur atom on the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace.

R ¹Be methylol;

R ²Be selected from-C (O) NR ⁴¹R ⁵¹,-SO ₂NR ⁴¹R ⁵¹With-S (O) _PR ⁴¹

R ⁴¹Be selected from (1-4C) alkyl [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 ⁵¹Be hydrogen or (1-4C) alkyl;

R ⁴Be selected from (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;

HET-3 is 4,5 or 6 yuan of saturated or part unsaturated heterocycles that connect by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) that independently is selected from O, N and S, wherein-CH ₂-group can choose wantonly by-C (O)-displacement and wherein the sulphur atom on the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is the saturated or part unsaturated heterocycle of 6-10 unit dicyclo, optional also comprise 1 nitrogen-atoms (removing the connection N atom) wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement; Described ring is chosen wantonly and effectively independently is being selected from hydroxyl and R by 1 on carbon or the nitrogen-atoms ³Substituting group replace;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2;

HET-3 is the saturated or part unsaturated heterocycle of 6-10 unit dicyclo, optional also comprise 1 nitrogen-atoms (removing the connection N atom) wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, chooses wantonly effectively be selected from R by 1 on carbon atom or the nitrogen-atoms ³Substituting group replace.

R ¹Be methylol;

R ²Be HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2;

Should be appreciated that and work as R ⁴For-C (O) NR ⁵R ⁵, each R ⁵Independently be selected from hydrogen and (1-4C) during alkyl, R ⁴Definition include, but is not limited to-CONH ₂,-CONHMe ,-CONMe ₂With-CONMeEt.

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

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.

All other groups on formula (I) compound that similar convention is applied to define as mentioned.

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

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

On the other hand, the present invention relates to formula (I) compound or its prodrug that define as mentioned.The suitable example of the prodrug of formula (I) compound 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, general term " alkyl " comprises straight chain and branched-chain alkyl.But only refer to linear form when mentioning indivedual alkyl, only refer to the side chain form when mentioning the indivedual branched-chain alkyls such as the tertiary butyl as " propyl group ".For example " (1-4C) alkyl " comprises methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.Similarly convention is applied to other general term.

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

HET-1 is the 5-of definition as mentioned or the hetero-aromatic ring that 6-unit connects by C-, and 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 unsaturated 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-triazolidinge), 2- oxazolidone base, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo thiomorpholine generation, 1,3-dioxolane base, 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 effective C or N atom, therefore, for example, for the HET-2 of " imidazolyl " comprises 1-, 2-, 4-and 5-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.

Be the saturated or part unsaturated heterocycle of the dicyclo of the structure institute example that shows below (wherein dotted line is represented the point that is connected with the molecule other parts) as the suitable example of the HET-3 of 6-10 unit bicyclic heterocycle:

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).

The suitable example of HET-4 is furyl, pyrryl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl,  azoles base, different  azoles base and triazolyl.

Should be appreciated that, when the definition of HET-1-HET-4 heterocyclic group comprises on the nitrogen-atoms can substituted heteroaryl or during heterocycle, this replacement can not cause charged quaternary nitrogen atom or unstable structure (as the N-halogen compounds).The definition that should be appreciated that HET-1-HET-4 does not comprise any O-O, O-S or S-S key.The definition that should be appreciated that HET-1-HET-4 does not comprise unstable structure.

(1-4C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl; (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) alkyl S (O) _P(1-4C) example of 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 because the existence of one or more unsymmetrical carbons, the formula of some above-mentioned definition (I) compound can be optical activity or racemization form, and the present invention comprises that in its definition any of these has the optical activity or the raceme form of direct stimulation GLK or inhibition GLL/GLKRP interaction property.Can adopt organic chemistry standard technique well known in the art to carry out the synthetic of optical activity form, for example synthesize or split the racemization form and synthesize from optically active starting raw material.Should also be clear that some compound can be tautomeric form, the present invention also relates to any and all can activate the tautomeric form of the The compounds of this invention of 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 another embodiment, hydrolyzable ester in the body of formula (I) compound is provided in another embodiment again, the pharmaceutically acceptable salt of hydrolyzable ester in the body of formula (I) compound is provided in another embodiment again.

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

(1) R ¹For methylol and configuration are preferably (S), promptly

(2) R ²For-C (O) NR ⁴R ⁵

(3) R ²For-SO ₂NR ⁴R ⁵

(4) R ²For-S (O) _PR ⁴

(5) R ²Be HET-2

(6) m is 1 and preferred R ²Contraposition at ehter bond

(7) m be 1 and n be 0 or 1

(8) m be 1 and n be 0

(9) m is 1, and n is 0 and R ²Contraposition at ehter bond

(10) m is 1, and n is 1, R ²At the contraposition of ehter bond, R ³Ortho position at ehter bond

(11) m is 1, and n is 1, R ²At the contraposition of ehter bond, R ³Position between ehter bond

(12) n is 0

(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 halogen or methoxyl group

(17) m is 1, and n is 2 and R ²Contraposition at ehter bond

(18) m is 1, and n is 2, R ²Contraposition and each R at ehter bond ³Ortho position at ehter bond

(19) m is 1, and n is 2, two R ³All be halogen, R ²Contraposition and each R at ehter bond ³Ortho position at ehter bond

(20) m is 1, and n is 2, two R ³All be halogen, R ²Contraposition and a R at ehter bond ³At the ortho position of ehter bond, another R ³Position between ehter bond

(21) R ³Be methyl fluoride or difluoromethyl

(22) R ³Be halogen or trifluoromethyl

(23) R ³Be halogen

(24) R ³Be chlorine or fluorine

(25) R ³Be fluorine

(26) R ³Be methoxyl group

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

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

(29) n is 2, two R ³It all is fluorine and in relative 3-and 5-position (position) of ehter bond

(30) m is 1, and n is 2, R ²In the contraposition of ehter bond, two R ³It all is fluorine and in the relative 3-and the 5-position of ehter bond

(31) p is 0

(32) p is 1

(33) p is 2

(34) HET-1 is a 5-unit hetero-aromatic ring

(35) HET-1 is a 6-unit hetero-aromatic ring

(36) HET-1 independently is selected from R by 1 or 2 ⁶Substituting group replace

(37) HET-1 is selected from R by 1 ⁶Substituting group replace

(38) HET-1 is unsubstituted

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

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

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

(42) HET-1 is selected from thiazolyl, pyrazolyl and  azoles base

(43) HET-1 is selected from thiadiazolyl group and  di azoly

(44) HET-1 is selected from 1,3,4-thiadiazolyl group and 1,3,4- di azoly

(45) HET-1 is selected from 1,2,4- di azoly and 1,2,4- di azoly

(46) HET-1 is a pyrazolyl

(47) HET-1 is pyridyl or pyrazinyl

(48) HET-1 is a pyrazinyl

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

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

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

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

(53) R ⁶Be selected from methyl, ethyl, bromine, chlorine, fluorine, amino methyl, N-methylamino methyl and dimethylaminomethyl

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

(55) R ⁶Be selected from methyl, ethyl, bromine, chlorine and fluorine

(56) R ⁶Be methyl

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

(58) R ⁶Be selected from methyl, ethyl, amino methyl, N-methylamino methyl, dimethylaminomethyl, methylol and methoxymethyl

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

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

(61) as two R ⁶When substituting group existed simultaneously, the both was selected from methyl, ethyl, bromine, chlorine and fluorine; It preferably all is methyl

(62) R ⁶Be selected from (1-4C) alkyl S (O) _P(1-4C) alkyl, (1-4C) alkylamino (1-4C) alkyl, two (1-4C) alkylamino (1-4C) alkyl and HET-4

(63) R ⁶Be HET-4

(64) HET-4 is selected from furyl, pyrryl and thienyl

(65) HET-4 is a furyl

(66) R ⁴Be hydrogen

(67) R ⁴For (1-4C) alkyl [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]

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

(69) R ⁴Be (1-4C) alkyl

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

(7I) R ⁴Be (1-4C) alkyl that is replaced by HET-2

(72) R ⁴Be (3-6C) cycloalkyl, particularly cyclopropyl or cyclobutyl

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

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

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

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

(77) R ⁴Be HET-2

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

(79) HET-2 is unsubstituted

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

(81) HET-2 is complete saturated ring system

(82) HET-2 is complete undersaturated ring system

(83) 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-dioxolane base, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, pyranyl and 4-pyriconyl

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

(85) 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

(86) 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 base, tetrahydrofuran base, THP trtrahydropyranyl, 1,1-dioxo tetrahydro-thienyl and 2-oxo-imidazole alkyl

(87) HET-2 is selected from morpholino, furyl, imidazolyl,  azoles base, different  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

(88) HET-2 is selected from morpholino, furyl, imidazolyl, different  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

(89) HET-3 is  di azoly or pyrazolyl

(90) R ⁵Be hydrogen

(91) R ⁵For (1-4) alkyl, be preferably methyl

(92) R ⁵Be hydrogen or methyl

(93) R ⁷Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl and hydroxyl (1-4C) alkyl

(94) R ⁷Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵And hydroxyl (1-4C) alkyl

(95) R ⁷Be selected from hydroxyl, methoxyl group ,-COMe ,-CONH ₂,-CONHMe ,-CONMe ₂And methylol

(96) R ⁷Be selected from (1-4C) alkyl, hydroxyl and (1-4C) alkoxyl group

(97) R ⁷Be selected from methyl, ethyl, methoxyl group and hydroxyl

(98) R ⁷Be methyl

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

(100) R ⁸Be selected from morpholino, piperidyl, piperazinyl, pyrrolidyl and azetidinyl

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

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

(103) R is selected from methyl, methoxyl group and isopropoxy

(104) R ⁸Be methyl

(105) HET-3 is complete saturated ring

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

(107) R ⁴And R ⁵Form the ring that defines by HET-3 with the nitrogen that connects them

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

(109) HET-3 is an azetidinyl

(110) HET-3 is the saturated or part unsaturated heterocycle of 4-6-unit defined above

(111) HET-3 is the saturated or part unsaturated heterocycle of 7-unit defined above

(112) HET-3 is the saturated or part unsaturated heterocycle of 6-10-unit's dicyclo defined above

(113) HET-3 is 7-azabicyclo [2.2.1] heptan-7-base

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

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

(116) HET-3 is unsubstituted

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

According to additional features of the present invention, provide the preferred group of following The compounds of this invention:

Provide formula defined above (I) compound in another aspect of this invention, wherein 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] and HET-2.

Formula (I) compound or its salt, prodrug or solvate are provided in another aspect of this invention, wherein:

R ¹Be methylol;

HET-1 comprises 2-position nitrogen-atoms and the 5-of optional 1,2 or 3 other ring hetero atom that independently is selected from O, N and S or the hetero-aromatic ring that 6-unit is connected by C-; Described ring is chosen wantonly at effective carbon atom or independently be selected from R by 1 or 2 on theheterocyclic nitrogen atom ⁶Substituting group replace, condition is that nitrogen-atoms is not therefore and by quaternized;

HET-2 comprises 1,2,3 or 4 independently to be selected from the heteroatomic 5-of O, N and S or the heterocycle that 6-unit is connected by C-or N-, 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 optional on effective carbon or nitrogen-atoms independently to be selected from R by 1 or 2 ⁷Substituting group replace;

R ⁴Be selected from hydrogen, (1-4C) alkyl, [optional quilt-OR ⁵Replace] and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

Or R ⁴And R ⁵Form first heterocycle with the nitrogen-atoms that connects them by the 4-6 of HET-3 definition;

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

HET-3 is the saturated or part unsaturated heterocycle of 4-6 unit that connects by N-, chooses wantonly to comprise 1 or 2 other heteroatoms (except that being connected the N atom) that independently is selected from O, N and S, wherein-CH ₂-group can choose wantonly by-C (O)-displacement and wherein the sulphur atom on the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace;

R ⁸Be selected from-OR ⁵(1-4C) alkyl;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2;

Compound or its salt, prodrug or the solvate of formula (I) are provided in another aspect of this invention, wherein:

R ¹Be methylol;

HET-1 comprises 2-position nitrogen-atoms and the 5-of optional 1,2 or 3 other ring hetero atom that independently is selected from O, N and S or the hetero-aromatic ring that 6-unit is connected by C-; Described ring is chosen wantonly on effective carbon atom or independently be selected from R by 1 or 2 on theheterocyclic nitrogen atom ⁶Substituting group replace, condition is that nitrogen-atoms is not therefore and by quaternized;

HET-2 comprises 1,2,3 or 4 independently to be selected from the heteroatomic 5-of O, N and S or the heterocycle that 6-unit is connected by C-or N-, 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace;

R ⁴Be selected from hydrogen, (1-4C) alkyl [optional quilt-OR ⁵Replace] and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ⁸Be selected from-OR ⁵(1-4C) alkyl;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2.

Formula defined above (I) compound or its salt, prodrug or solvate are provided in another aspect of this invention, wherein:

R ¹Be methylol;

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

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁷Be selected from-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _PR ⁵

R ⁸Be selected from-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, HET-3 (wherein said ring is undersaturated), (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _PR ⁵

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2;

R ¹Be methylol;

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

R ⁵Be hydrogen or (1-4C) alkyl;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is a 5-or 6-unit hetero-aromatic ring, and optionally is selected from R by 1 or 2 ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

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];

R ⁵Be hydrogen or methyl;

R ⁶Be selected from (1-4C) alkyl, halogen, 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;

HET-2 is a 5-defined above or 6-unit heterocycle, comprise 1 or 2 heteroatoms 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 heterocycle can be chosen wantonly and is oxidized to S (O) or S (O) ₂Group, described ring are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be selected from methyl, ethyl, bromine, chlorine, fluorine, methylol, methoxymethyl, amino methyl, N-methylamino methyl and dimethylaminomethyl;

HET-2 is 5-defined above or 6-unit heterocycle, comprises 1 or 2 heteroatoms that independently is selected from O, N and S, 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl,  azoles base, different  azoles base and  di azoly, and optional is selected from R by 1 or 2 ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

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

R ⁵Be hydrogen or methyl;

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-dioxolane base, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, pyranyl and 4-pyriconyl, the wherein optional R that is selected from of HET-2 ⁷Substituting group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidyl, and optional is selected from R by 1 or 2 ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl,  azoles base, different  azoles base and  di azoly, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

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-triazolyl, the wherein optional R that is selected from of HET-2 ⁷Substituting group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidyl, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

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-triazolyl, and the optional R that is selected from ⁷Group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl,  azoles base, different  azoles base and  di azoly, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴Be selected from hydrogen, (1-4C) alkyl [optional quilt-OR ⁵Replace], (3-6C) cycloalkyl (optionally is selected from R by 1 ⁷Group replace) and HET-2;

R ⁵Be hydrogen or methyl;

HET-2 is selected from morpholino, furyl, imidazolyl, different  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, and the optional R that is selected from ⁷Group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from pyridyl and pyridazinyl, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-5O ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴Be selected from (1-4C) alkyl [optional quilt-OR ⁵Replace], (3-6C) cycloalkyl (optionally is selected from R by 1 ⁷Group replace) and HET-2;

R ⁵Be hydrogen or methyl;

HET-2 is selected from piperidyl, piperazinyl, 3-oxo piperazinyl, 2-Pyrrolidone base, 2,5-dioxo pyrrolidyl, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, THP trtrahydropyranyl, 2-oxo-imidazole alkyl and 2, and 4-dioxo alkyl imidazole base, optional by R ⁷Replace; And

R ⁷Be (1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl,  azoles base, different  azoles base and  di azoly, and the optional R that is selected from ⁶Group replace; R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

HET-2 is piperidyl or piperazinyl, and optional by R ⁷Replace; And

R ⁷Be (1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0;

HET-1 is selected from thiazolyl, thiadiazolyl group and pyrazolyl, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵

R ⁴Be piperidyl, optional by methyl substituted;

R ⁵Be hydrogen or methyl;

R ⁶Be methyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴Be selected from (1-4C) alkyl [optional quilt-OR ⁵Replace] and HET-2;

R ⁵Be hydrogen or methyl;

HET-2 is selected from piperidyl, piperazinyl, 3-oxo piperazinyl, 2-Pyrrolidone base, 2,5-dioxo pyrrolidyl, 2- oxazolidone base, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, THP trtrahydropyranyl, 2-oxo-imidazole alkyl and 2,4-dioxo alkyl imidazole base, and optional by R ⁷Replace; And

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴Be selected from (1-4C) alkyl [optional quilt-OR ⁵Replace] and HET-2;

R ⁵Be hydrogen or methyl;

HET-2 is piperidyl or piperazinyl, optional by R ⁷Replace; And

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴And R ⁵Form morpholino, piperidyl, piperazinyl, pyrrolidyl or azetidine basic ring with the nitrogen that connects them, described ring is chosen wantonly on carbon or nitrogen-atoms by R ⁸Replace;

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

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁸Be tetramethyleneimine or piperidines.

Formula defined above (1) compound or its salt, prodrug or solvate are provided in another aspect of this invention, wherein:

R ⁴Be methylol;

M be 1 and n be 0 or 1;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ⁴And R ⁵Form morpholino, piperidyl, piperazinyl, pyrrolidyl or azetidine basic ring with the nitrogen that connects them, described ring is chosen wantonly on carbon or nitrogen-atoms and is replaced by (1-4C) alkyl;

R ⁶Be selected from methyl, ethyl, bromine, chlorine, fluorine, methylol, methoxymethyl, amino methyl, N-methylamino methyl and dimethylaminomethyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from pyridyl and pyridazinyl, and optional quilt is selected from R ⁶Group replace;

R ²For-CONR ⁴R ⁵Or-SO ₂NR ⁴R ⁵

R ³Be halogen or trifluoromethyl;

R ¹Be methylol;

M be 1 and n be 0;

R ²For-CONR ⁴R ⁵

R ⁴And R ⁵Form piperidyl or piperazinyl ring with the nitrogen that connects them, described ring is chosen wantonly on carbon or nitrogen-atoms and is replaced by (1-4C) alkyl or by the tetramethyleneimine basic ring;

R ¹Be methylol;

M be 1 and n be 0;

R ²For-CONR ⁴R ⁵

R ⁴And R ⁵Form the azetidine basic ring with the nitrogen that connects them, described ring is chosen wantonly on carbon atom and is replaced by hydroxyl;

R ¹Be methylol;

M be 1 and n be 0;

HET-1 is selected from thiazolyl, thiadiazolyl group, pyrazolyl and pyrazinyl, and the optional R that is selected from ⁶Group replace;

R ²For-CONR ⁴R ⁵

R ⁴And R ⁵Form the azetidine basic ring with the nitrogen that connects them, described ring is chosen wantonly on carbon atom and is replaced by methyl, methoxyl group or isopropoxy;

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

R ¹Be methylol;

M be 1 and n be 1;

R ²For-CONR ⁴R ⁵

R ³Be chlorine or fluorine;

R ¹Be methylol;

M be 1 and n be 0;

R ²For-CONR ⁴R ⁵

R ⁴And R ⁵Form the ring HET-3 of 7-unit with the nitrogen that connects them, described ring is chosen wantonly on carbon or nitrogen-atoms by methyl substituted;

R ¹Be methylol;

M be 1 and n be 0;

R ²For-CONR ⁴R ⁵

R ⁴And R ⁵Form the bicyclic heterocycle HET-3 of 6-10 unit that defines as mentioned with the nitrogen that connects them, described ring is optional by hydroxyl or methyl substituted;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is 5-or 6-unit hetero-aromatic ring, chooses wantonly and independently is selected from R by 1 or 2 ⁶Group replace;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

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

HET-2 comprises 1 or 2 heteroatomic 5-or 6-unit heterocycle that independently is selected from O, N and S, 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon atom or the nitrogen-atoms ⁷Substituting group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

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

R ⁵Be hydrogen or methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

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-dioxolane base, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, pyranyl and 4-pyriconyl, and the optional R that is selected from ⁷Group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl; R ⁶Be selected from methyl, ethyl, bromine, chlorine, fluorine, methylol, methoxymethyl, amino methyl, N-methylamino methyl and dimethylaminomethyl; 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-triazolyl, and the optional R that is selected from ⁷Group replace; And

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be selected from methyl, ethyl, bromine, chlorine, fluorine, amino methyl, N-methylamino methyl and dimethylaminomethyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁴Be (1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0;

HET-1 is selected from thiazolyl, thiadiazolyl group and pyrazolyl, and optional by R ⁶Replace;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ⁴Be (1-4C) alkyl;

R ⁶Be methyl.

R ¹Be methylol;

M be 1 and n be 0;

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ⁴Be (3-6C) cycloalkyl;

R ⁶Be methyl.

R ¹Be methylol;

M be 1 and n be 0 or 1.

R ²For-S (O) _PR ⁴

P is 1 or 2;

R ³Be halogen or trifluoromethyl;

R ⁴Be (1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is 5-or 6-unit hetero-aromatic ring, and the optional R that is selected from ⁶Group replace;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or (1-4C) alkyl;

R ⁶Be methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl, imidazolyl,  azoles base, different  azoles base and  di azoly, and optional by R ⁶Group replaces;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl;

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidyl, and optional by R ⁶Group replaces;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁵Be hydrogen or methyl;

R ⁶Be methyl;

R ⁷Be selected from-OR ⁵(1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

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-dioxolane base, 2-oxo-imidazole alkyl, 2,4-dioxo alkyl imidazole base, pyranyl and 4-pyriconyl, and optional by R ⁷Group replaces; And

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

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, the 3-triazolyl, and optional by R ⁷Group replaces; And

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

R ²Be HET-2;

R ³Be halogen or trifluoromethyl;

R ⁷Be (1-4C) alkyl.

R ¹Be methylol;

M be 1 and n be 0 or 1;

HET-1 is selected from thienyl, pyrazolyl, thiadiazolyl group and pyrazinyl, and the optional R that is selected from ⁶Group replace;

R ⁶Be selected from methyl, ethyl, sec.-propyl and methoxymethyl;

R ²Be selected from methyl sulphonyl, azetidinyl carbonyl, dimethylamino carbonyl, ethylsulfonyl, dimethylamino alkylsulfonyl and pyrrolidyl carbonyl;

R ³Be selected from fluorine, chlorine and methoxyl group.

R ¹Be methylol;

M be 1 and n be 0,1 or 2;

R ⁶Be selected from methyl, ethyl, sec.-propyl and methoxymethyl;

R ²Be selected from methyl sulphonyl, azetidinyl carbonyl, dimethylamino carbonyl, ethylsulfonyl, dimethylamino alkylsulfonyl, methyl azetidine base carbonyl, methoxyl group azetidinyl carbonyl, isopropoxy azetidinyl carbonyl, azetidinyl alkylsulfonyl, cyclobutyl alkylsulfonyl, cyclopropyl alkylsulfonyl, 7-azabicyclo [2.2.1] heptan-7-base carbonyl, 2-azabicyclo [2.1.1] oneself-2-base carbonyl and pyrrolidyl carbonyl;

R ³Be selected from fluorine, chlorine and methoxyl group.

R ¹Be methylol;

M be 1 and n be 0,1 or 2;

R ⁶Be selected from methyl, ethyl, sec.-propyl and methoxymethyl;

R ²Be selected from methyl sulphonyl, azetidinyl carbonyl, dimethylamino carbonyl, ethylsulfonyl, dimethylamino alkylsulfonyl, methyl azetidine base carbonyl, methoxyl group azetidinyl carbonyl, isopropoxy azetidinyl carbonyl, azetidinyl alkylsulfonyl, cyclobutyl alkylsulfonyl, cyclopropyl alkylsulfonyl and pyrrolidyl carbonyl;

R ³Be selected from fluorine, chlorine and methoxyl group.

R ¹Be methylol;

M be 0 and n be 1 or 2;

R ⁶Be selected from methyl, ethyl, sec.-propyl and methoxymethyl;

R ³Be selected from fluorine, chlorine and methoxyl group;

The other preferred compound of the present invention is each compound of embodiment and/or reference example value, and they provide the present invention other independent aspects separately.Aspect other, the present invention also comprises two or more compounds of any embodiment and/or reference example.

In one aspect, specific compound of the present invention comprises following any one or a plurality of or its salt, prodrug or solvate:

1) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-1,3-thiazol-2-yl benzamide;

2) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-[4-(methoxymethyl)-1,3-thiazoles-2-yl]-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

3) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(4-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

4) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

5) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

6) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

7) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

8) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-1H-pyrazole-3-yl benzamide;

9) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

10) 3-[(3, the 5-difluorophenyl) the oxygen base]-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

11) 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

12) 3-chloro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino J carbonyl] phenoxy group }-N, the N-dimethyl benzamide;

13) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide; With

14) 3-({ 4-[(dimethylamino) carbonyl] phenyl } the oxygen base)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

12) 3-chloro-4-[(3-{[(IS)-and 2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide;

13) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

14) 3-({ 4-[(dimethylamino) carbonyl] phenyl } the oxygen base)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

15) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(IS)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

16) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

17) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

18) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

19) N-(1-ethyl-1H-pyrazole-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

20) amino 3-chloro-4-{3-{[(1-ethyl-1H-pyrazole-3-yl)] carbonyl }-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] phenoxy group }-N, the N-dimethyl benzamide;

21) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

22) carbonyl 3-{4-[(dimethylamino)] phenoxy group }-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

23) 3-(3-fluoro-4-methoxyl group phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

24) 3-(3,4-dimethoxy phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

25) 3-fluoro-4-[(3-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide;

26) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

27) 3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

28) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

29) 3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-sec.-propyl-1H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

30) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

31) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

32) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

33) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

34) 3-[4-(ethylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide; With

35) alkylsulfonyl 3-{4-[(dimethylamino)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide; And/or

36) N-(1-ethyl-1H-pyrazole-3-yl)-3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

37) 3-[2-chloro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

38) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

39) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

40) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide;

41) 3-[5-chloro-2-fluoro-4-(methyl sulphonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

42) 3-[2,5-two fluoro-4-(methyl sulphonyl) phenoxy groups]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

43) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1,2,4- diazole-3-yl) phenoxy group] benzamide; With

44) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide; And/or

45) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

46) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(4-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

47) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-[4-(methoxymethyl)-1,3-thiazoles-2-yl] benzamide;

48) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(piperidines-1-base carbonyl) phenoxy group] benzamide;

49) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(morpholine-4-base carbonyl) phenoxy group] benzamide;

50) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(4-methylpiperazine-1-yl) carbonyl] phenoxy group }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

51) carbonyl 3-{4-[(cyclopropyl amino)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

52) 3-[4-(7-azabicyclo [2.2.1] heptan-7-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

53) 3-[2-fluoro-4-(piperidines-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

54) 3-[2-fluoro-4-(morpholine-4-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

55) carbonyl 3-{2-fluoro-4-[(4-methylpiperazine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

56) N-cyclopropyl-3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) benzamide;

57) 3-[4-(7-azabicyclo [2.2.1] heptan-7-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

58) carbonyl 3-{2-fluoro-4-[(2-methyl azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

59) carbonyl 3-{2-fluoro-4-[(3-methoxyl group azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

60) carbonyl 3-{2-fluoro-4-[(3-isopropoxy azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

61) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

62) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(S-methylpyrazine-2-yl) benzamide;

63) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

64) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

65) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

66) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

67) 3-[4-(azetidine-1-base alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

68) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide;

69) 3-[4-(cyclobutyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

70) 3-[4-(cyclopropyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

71) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1H-pyrazole-3-yl) phenoxy group] benzamide;

72) 2-chloro-5-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

73) 2,5-two fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

74) 3-[4-(azetidine-1-base carbonyl)-2,5-two fluorophenoxies]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

75) 3-[4-(azetidine-1-base carbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

76) 3-[4-(azetidine-1-base carbonyl)-5-chloro-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

77) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

78) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

79) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

80) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

81) 3-[4-(azetidine-1-base carbonyl)-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

82) 3-[4-(2-azabicyclo [2.1.1] oneself-2-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

83) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide; With

84) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

On the other hand, the specific compound of the present invention comprises following any one or a plurality of or its salt, prodrug or solvate:

1) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(4-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

2) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

3) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

4) 3-[(3, the 5-difluorophenyl) the oxygen base]-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

5) 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

6) 3-chloro-4-[(3-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide;

7) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

8) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

9) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

10) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

11) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

12) N-(1-ethyl-1H-pyrazole-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

13) amino 3-chloro-4-{3-{[(1-ethyl-1H-pyrazole-3-yl)] carbonyl }-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] phenoxy group }-N, the N-dimethyl benzamide;

14) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

15) carbonyl 3-{4-[(dimethylamino)] phenoxy group }-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

16) 3-(3-fluoro-4-methoxyl group phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

17) 3-(3,4-dimethoxy phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

18) 3-fluoro-4-[(3-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide;

19) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

20) 3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

21) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

22) 3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-sec.-propyl-1H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

23) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

24) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

25) 3-[2-chloro-4-(ethylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

26) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

27) 3-[4-(ethylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide; With

28) alkylsulfonyl 3-{4-[(dimethylamino)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide; And/or

29) N-(1-ethyl-1H-pyrazole-3-yl)-3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

30) 3-[2-chloro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

31) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

32) 3-[2-chloro-4-(ethyl sulfinyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

33) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide;

34) 3-[5-chloro-2-fluoro-4-(methyl sulphonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

35) 3-[2,5-two fluoro-4-(methyl sulphonyl) phenoxy groups]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

36) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1,2,4- diazole-3-yl) phenoxy group] benzamide; With

37) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide; And/or

38) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

39) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(4-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

40) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-[4-(methoxymethyl)-1,3-thiazoles-2-yl] benzamide;

41) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(piperidines-1-base carbonyl) phenoxy group] benzamide;

42) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(morpholine-4-base carbonyl) phenoxy group] benzamide;

43) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(4-methylpiperazine-1-yl) carbonyl] phenoxy group }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

44) carbonyl 3-{4-[(cyclopropyl amino)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

45) 3-[4-(7-azabicyclo [2.2.1] heptan-7-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

46) 3-[2-fluoro-4-(piperidines-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

47) 3-[2-fluoro-4-(morpholine-4-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

48) carbonyl 3-{2-fluoro-4-[(4-methylpiperazine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

49) N-cyclopropyl-3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) benzamide;

50) 3-[4-(7-azabicyclo [2.2.1] heptan-7-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

51) carbonyl 3-{2-fluoro-4-[(2-methyl azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

52) carbonyl 3-{2-fluoro-4-[(3-methoxyl group azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

53) carbonyl 3-{2-fluoro-4-[(3-isopropoxy azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

54) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

55) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

56) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

57) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

58) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

59) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

60) 3-[4-(azetidine-1-base alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

61)-OS  S ' [4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide;

62) 3-[4-(cyclobutyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

63) 3-[4-(cyclopropyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

64) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1H-pyrazole-3-yl) phenoxy group] benzamide;

65) 2-chloro-5-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

66) 2,5-two fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide;

67) 3-[4-(azetidine-1-base carbonyl)-2,5-two fluorophenoxies]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

68) 3-[4-(azetidine-1-base carbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

69) 3-[4-(azetidine-1-base carbonyl)-5-chloro-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

70) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

71) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

72) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

73) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

74) 3-[4-(azetidine-1-base carbonyl)-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

75) 3-[4-(2-azabicyclo [2.1.1] oneself-2-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

76) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide; With

77) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide.

1) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

2) 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

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

4) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

5) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

6) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

7) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

8) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(IS)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

9) 3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

10) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

11) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

12) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

13) 3-[2-chloro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

14) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide; With

15) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide; And/or

16) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

17) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(4-methyl isophthalic acid, 3-thiazol-2-yl) benzamide;

18) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-[4-(methoxymethyl)-1,3-thiazoles-2-yl] benzamide;

19) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(piperidines-1-base carbonyl) phenoxy group] benzamide;

20) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(morpholine-4-base carbonyl) phenoxy group] benzamide;

21) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(4-methylpiperazine-1-yl) carbonyl] phenoxy group }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

22) 3-[4-(7-azabicyclo [2.2.1] heptan-7-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

23) 3-[2-fluoro-4-(piperidines-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

24) 3-[2-fluoro-4-(morpholine-4-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

25) carbonyl 3-{2-fluoro-4-[(4-methylpiperazine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

26) 3-[4-(7-azabicyclo [2-2-1] heptan-7-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

27) carbonyl 3-{2-fluoro-4-[(2-methyl azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

28) carbonyl 3-{2-fluoro-4-[(3-methoxyl group azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

29) carbonyl 3-{2-fluoro-4-[(3-isopropoxy azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

30) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

31) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(S-methylpyrazine-2-yl) benzamide;

32) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

33) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

34) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

35) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

36) 3-[4-(azetidine-1-base alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

37) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide;

38) 3-[4-(azetidine-1-base carbonyl)-2,5-two fluorophenoxies]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

39) 3-[4-(azetidine-1-base carbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

40) 3-[4-(azetidine-1-base carbonyl)-5-chloro-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

41) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

42) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide;

43) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

44) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide;

45) 3-[4-(azetidine-1-base carbonyl)-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

46) 3-[4-(2-azabicyclo [2.1.1] oneself-2-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

47) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide; With

48) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide.

1) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] benzamide;

2) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

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

5) 3-({ 4-[(dimethylamino) carbonyl] phenyl } the oxygen base)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

6) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

7) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

8) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1 S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

9) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

10) N-(1-ethyl-1H-pyrazole-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

11) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

12) 3-(3,4-dimethoxy phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

13) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

14) carbonyl 3-{2-fluoro-4-[(2-methyl azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

15) carbonyl 3-{2-fluoro-4-[(3-methoxyl group azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

16) carbonyl 3-{2-fluoro-4-[(3-isopropoxy azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

17) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

18) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

19) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

20) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-the N-3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

21) 3-[4-(cyclobutyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

22) 3-[4-(cyclopropyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

23) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide; With

24) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide.

1) carbonyl 3-{2-fluoro-4-[(2-methyl azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

2) carbonyl 3-{2-fluoro-4-[(3-methoxyl group azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

3) carbonyl 3-{2-fluoro-4-[(3-isopropoxy azetidine-1-yl)] phenoxy group }-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

4) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

5) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide.

2) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

7) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(IS)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

8) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

9) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1.S)-2-hydroxyl-1-methyl ethoxy] benzamide; With

10) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide.

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

3) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

4) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

5) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

6) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

7) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide.

1) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

2) 3-({ 4-[(dimethylamino) carbonyl] phenyl } the oxygen base)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

3) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

4) N-(1-ethyl-1H-pyrazole-3-yl)-3-[4-(ethylsulfonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide;

5) 3-(3,4-dimethoxy phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

6) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

7) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide;

8) 3-[4-(cyclobutyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

9) 3-[4-(cyclopropyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

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

1) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

2) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide;

3) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

4) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

5) 3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide;

6) 3-[2-fluoro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

7) 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

8) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

9) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide;

10) 3-[2-chloro-4-(tetramethyleneimine-1-base carbonyl) phenoxy group]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide;

11) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide; With

12) 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide.

Aspect other, the invention provides following formula: compound or its salt, prodrug or solvate:

3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1,2,4- diazole-3-yl) phenoxy group] benzamide.

Compound of the present invention can the prodrug forms administration.Prodrug can be accepted compound (as the ester and the acid amides of The compounds of this invention, particularly hydrolyzable ester in the body) for degradable in vivo produces the bioprecursor of The compounds of this invention or pharmacy.Known various forms of prodrugs in this area.These prodrug derivants for example, referring to:

A) Design of Prodrugs (medicinal design), edited by H.Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al. (Academic Press, 1985);

B) A Textbook of Drug Design and Development (medicinal design and exploitation study course), edited by Krogsgaard-Larsen;

c)H.Bundgaard，Chapter?5″Design?and?Application?of?Prodrugs″，by?H.Bundgaard?p.113-191(1991)；

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

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

f)N.Kakeya，et?al.，Chem?Pharm?Bull，32，692(1984).

The content of above-mentioned citing document is attached to herein by reference at this.

The example of prodrug is as follows.For example, comprise in the body of The compounds of this invention of carboxyl and oh group hydrolyzable ester in human body or animal body, producing the pharmacy acceptable ester of parent acid or alcohol.The pharmacy acceptable ester of suitable carboxyl 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 _1-6The alkoxy-carbonyl oxy ethyl ester.

The interior hydrolyzable ester of body that comprises the The compounds of this invention of hydroxyl comprises the related compound of hydrolysis in inorganic ester such as phosphoric acid ester (comprising ring phosphoramidate (phosphoramidic cyclic esters)) and alpha-acyloxy alkyl oxide and the ester body, and its degradable 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 formation hydroxyl comprises alkyloyl, benzoyl, phenylacetyl and substituted 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 carboxyl ethanoyl in the body.

The suitable pharmaceutically acceptable salt of The compounds of this invention is for example, to have the acid salt of the The compounds of this invention of enough alkalescence, for example inorganic or organic acid acid salt, for example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid citric acid or toxilic acid.The group that should be appreciated that available any enough alkalescence forms acid salt, and for example it can be HET-1 or is substituent R ²In addition, suitable pharmaceutically acceptable salt with enough tart benzoxazine ketone of the present invention (benzoxazinone) derivative is an alkali metal salt such as sodium or sylvite, alkaline earth salt such as calcium or magnesium salts, aluminium salt maybe can provide physiology can accept cationic and salt organic bases, for example with the salt of methylamine, dimethyl amine, Trimethylamine, piperidines, morpholine or three-(2-hydroxyethyl) amine.

Another feature of the present invention can be accepted the medicinal compositions of diluent or carrier for comprising formula defined above (I) compound or its salt, solvate or prodrug and pharmacy.

Another aspect of the present invention provides the compound of formula defined above (I) as medicine.

Again according to the present invention, provide formula (I) compound to be used to prepare the particularly medicine of diabetes B of the disease of treatment by the GLK mediation.

Compound suitably is formulated as medicinal compositions by this way and uses.

Another aspect of the present invention provides by formula (I) compound of significant quantity or its prodrug being needed the particularly method of diabetes of disease that the Mammals of this treatment treats the GLK mediation.

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

As mentioned above, the GLK/GLKRP system can be considered to potent " diabetes and obesity (diabesity) " target (can be of value to diabetes and obesity simultaneously).Therefore, another aspect of the present invention provides formula (I) compound or its salt, solvate or prodrug to be used for the purposes of the medicine of combination therapy or prevent diabetes and obesity in preparation.

Another aspect of the present invention provide formula (I) compound or its salt, solvate or prodrug preparation be used for the treatment of or the medicine of obesity prevention in purposes.

Another aspect of the present invention provides the method for combination therapy obesity and diabetes by formula (I) compound or its salt, solvate or the prodrug of the Mammals significant quantity that needs this treatment.

Another aspect of the present invention provides the method for treatment of obesity by formula (I) compound or its salt, solvate or the prodrug of the Mammals significant quantity that needs this treatment.

The compounds of this invention can be particularly suitable for as medicine, for example because its good physics and/or pharmacokinetic properties 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 fine powder (finelydivided powder) or liquid suspension particle (liquid aerosol)) by inhalation, (as be used for intravenous injection by the form (as fine powder) 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 adopt conventional pharmaceutical excipient to prepare the present composition by ordinary method well known in the art.Therefore, being used for oral composition can comprise, for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

The suitable pharmaceutical acceptable excipient that is used for tablet comprises, as inert diluent such as lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulation and disintegrating agent such as W-Gum or Lalgine (algenic acid); Tackiness agent such as starch; Lubricant such as Magnesium Stearate, stearic acid or talcum powder; Sanitas such as ethyl or propyl group be right-hydroxybenzoate, and antioxidant such as xitix.That tablet can be dressing not or dressing, with modify its disintegration and subsequently activeconstituents or improve its stability and close/or outward appearance in gastrointestinal absorption, all can adopt conventional Drug coating well known in the art and method in both cases.

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

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, tragakanta and gum arabic; The condenses (as polyoxyethylene stearic acid ester (polyoxethylene stearate)) of dispersion or wetting agent such as Yelkin TTS or alkene oxide and lipid acid, or the condenses of oxyethane and long chain aliphatic alcohol 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 alcohol 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 oxyethane and derive from lipid acid and the condenses of the partial ester of hexitol dehydrate such as the polyethylene sorbitol monooleate that anhydrates.Aqueous suspension also can comprise one or more sanitass (as ethyl or propyl group right-hydroxybenzoate), antioxidant (as xitix), tinting material, seasonings and/or sweeting agent (as sucrose, asccharin or aspartame (aspartame)).

The oiliness suspensoid can be by being suspended in activeconstituents preparation in vegetables oil (as peanut oil, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (as whiteruss).The oiliness suspensoid also can comprise thickening material such as beeswax, paraffinum durum or hexadecanol.Can add aforesaid sweeting agent, seasonings so that good to eat oral preparations to be provided.Can preserve these compositions by adding antioxidant such as xitix.

Be suitable for preparing by adding entry that the powder of aqueous suspension and granule comprise activeconstituents and dispersion or wetting agent usually, suspension agent closes one or more sanitass.Above example suitable dispersion or wetting agent and suspension agent.Also can exist other vehicle such as sweeting agent, seasonings to close tinting material.

Medicinal compositions of the present invention also can be the oil-in-water emulsion form.Oil phase can be vegetables oil such as sweet oil or peanut oil, or the mixture of mineral oil such as whiteruss or any of these.Suitable emulsifying agent can be as natural gum such as gum arabic or tragakanta, natural phospholipid such as soybean lecithin, derive from the ester of lipid acid and hexitol dehydrate 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 prepare with sweeting agent such as glycerine, propylene glycol, sorbyl alcohol, aspartame or sucrose, also can comprise negative catalyst, sanitas seasonings and/or tinting material.

Medicinal compositions also can be sterile injectable water-based or oil-based suspension, and one or more suitable dispersions that it has been described above can adopting or wetting agent and suspension agent prepare according to currently known methods.Aseptic injection preparation also can be aseptic parenteral solution or the suspension that can accept thinner or solvent such as 1,3 butylene glycol ester at nontoxic parenteral.

Composition by inhalation can be conventional pressurised aerosol, and activeconstituents is for comprising fine powder or small droplets.Available conventional aerosol propellant such as volatility hydrofluoric ether or hydrocarbon compound can discharge quantitative activeconstituents easily with the aerosol device.

In order further to obtain the information of preparation aspect, recommend the reader with reference to ComprehensiveMedicinal Chemistry (pharmaceutical chemistry complete works) (Corwin Hansch; Chairman ofEditorial Board), the 25.2nd chapter in the 5th of Pergamon Press 1990 the volume.

According to the host and the specific administration approach of required treatment, activeconstituents and one or more vehicle are mixed can do necessary adjustment with the amount that produces single formulation.For example, the human oral drug-delivery preparation comprises usually, for example the activeconstituents of 0.5mg-2g with suitably and the vehicle of appropriate amount, it can change the amount of vehicle between about 98% total composition weight of about 5-.Unit dosage form comprises the activeconstituents of the about 500mg of about 1mg-usually.In order further to obtain the information of route of administration and dosage regimen, recommend the reader with reference to ComprehensiveMedicinal Chemistry (Corwin Hansch; Chairman of Editorial 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 of formula (I) compound of purpose to understand different naturally according to well-known medicine principle.As treatment or prevention during purpose, its common administration per daily dose exists, in the 0.5mg-75mg/kg weight range, if the words gradation that needs gives at use formula (I) compound.When adopting the parenteral admin approach, give low dosage usually.Therefore, for example,, adopt the dosage range of 0.5mg-30mg/kg body weight usually for intravenous injection.Equally, for inhalation, adopt the dosage range of 0.5mg-5mg/kg body weight usually.But preferred oral administration.

GLK active height described herein can be used as independent treatment or unite use with the therapeutics of the indication of one or more other materials and/or needs treatment.This combination therapy can be by simultaneously, in succession or the mode of separate administration carry out.The tablet that treatment simultaneously can give single tablet or separate.For example, when the treatment diabetes, chemotherapy can comprise following main methods of treatment:

1) Regular Insulin and insulin analog;

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

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

4) euglycemic agent comprises 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 inhibitors (glycogen phopsphorylase inhibitor), glycogen synthase kinase inhibitor);

6) reduce the medicine (as acarbose) of glucose from intestinal absorption;

7) stop glucose by the re-absorbed medicine of kidney (SGLT inhibitor);

8) medicine (as aldose reductase inhibitor) of the long-term hyperglycemia complication of treatment;

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

10) anti--hyperlipemia 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 stanols), synthetic inhibitor); Bile acide absorption inhibitor (IBATi) and nicotinic acid and analogue (nicotinic acid 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 antiplatelet drug; The zymoplasm antagonist; The Xa factor inhibitor; The VIIa factor inhibitors); Antiplatelet drug (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).

Another aspect of the present invention provides as the individuation compound of end product in the following examples and salt thereof, solvate and has closed prodrug

Any currently known methods that can be used for preparing such compound or structurally associated compound all can be used to prepare compound or its salt of the present invention and can protect and deprotection functional group with ordinary method.For example blocking group is as amino and carboxylic acid protective group's (formation method and final deprotection method), referring to T.W.Greene and P.G.M.Wuts, and " Protective Groups inOrganic Synthesis ", second edition, John Wiley﹠amp; Sons, New York, 1991.

Additional features of the present invention has provided the synthetic method of formula (I) compound.Therefore, another aspect of the present invention provides the preparation method of formula (I) compound, comprising process a)-d) (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 ¹Be methylol or its protected form;

Or

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

X wherein ¹Be leavings group, and X ²Be hydroxyl, or X ¹Be hydroxyl and X ²Be leavings group, wherein R ¹Be methylol or its protected form;

The also available wherein P of process (b) ¹Be the intermediate ester of the formula (VII) of blocking group as described below, be used in other local finishing by ester hydrolysis and amidation of describing then with this area well-known method of ester those of skill in the art;

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 hydroxyl, or X ³Be hydroxyl and X ⁴Be leavings group or organometallic reagent, wherein R ¹Be methylol or its protected form;

The intermediate ester of the also available formula of process (c) (X) is used in other local finishing by ester hydrolysis and amidation with this area well-known method of ester those of skill 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; R wherein ¹Be methylol or its protected form;

Then, if desired:

I) formula (I) compound is converted into another formula (I) compound

Ii) remove any blocking group; And/or

Iii) form its salt, prodrug or solvate.

Process b)-d) suitable leavings group X ¹-X ⁵Any leavings group that is fit to these type reaction for this area ester is known is as halogen, alkoxyl group, trifluoromethane sulfonyl group oxygen base, methane sulfonyl oxygen base or p-toluenesulfonyl oxygen base; Or can be converted into the group (as hydroxyl) of leavings group (as oxygen base triphenyl phosphorus  group (oxytriphenylphosphonium group)) in position

R ¹Suitable value as hydroxy-protective group is the known any suitable hydroxy-protective group of ability thresholding, for example simple ether such as methyl ether, or silyl ether is as-OSi[(1-4C) alkyl] ₃(wherein each (1-4C) alkyl independently is selected from methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl).The example of these trialkylsilkls is trimethyl silyl, triethylsilyl, triisopropyl silyl and t-butyldimethylsilyl.Suitable silyl ether in addition comprises the phenyl conjunction for phenyl, as-Si (PhMe ₂) and-Si (ToIMe ₂) (wherein Tol=toluene).Hereinafter provided the other suitable value of hydroxy-protective group.

The compound of formula (III)-(XII) can be bought and obtain, or is as known in the art, or can be made as the method as shown in the following examples by as known in the art.The information of the method for this compounds of preparation in addition, the PCT that please refer to us discloses WO03/000267, WO03/015774 and WO03/000262 and reference wherein.Usually should be appreciated that affine replacement or metal catalytic process by choosing wantonly in the presence of suitable alkali can form any aryl-O or alkyl-O key.

The well-known formula of those of skill in the art (I) compound is converted into other formula (I) examples for compounds and comprises functional group's change such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction in this area, 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 is as by reacting in suitable solvent such as THF/ methyl alcohol or ethanol under barometric point or the elevated pressure with hydrogen.

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

Process a)-coupled reaction of amino well known in the art and carboxylic acid generates acid amides.

As

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

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

Process b)-can with formula V and (VI) compound together in suitable solvent such as DMF or tetrahydrofuran (THF) (THF) with alkali such as sodium hydride or potassium tert.-butoxide 0 ℃-200 ℃ reactions down, optional microwave heating or metal catalytic such as acid chloride (II), palladium carbon, venus crystals (II) or the cupric iodide (I) of adopting; Perhaps can be together in suitable solvent such as THF or DCM, with suitable phosphine such as triphenylphosphine and azodicarboxylate such as diethyl azodiformate with formula V and (VI) compound; Process b) also can adopt the precursor of ester of formula (VII) such as aryl nitrile or trifluoromethyl derivative to react, be translated into carboxylic acid then and form acid amides as previously mentioned;

Process c)-can be together in suitable solvent such as DMF or THF with the compounds (DC) of formula (VIII), with suitable alkali such as sodium hydride or potassium tert.-butoxide reaction under 0 ℃-200 ℃, optional microwave heating or metal catalytic such as acid chloride (II), palladium carbon, venus crystals (II) or the cupric iodide (1) of adopting; Process c) also can adopt the precursor of ester of formula (X) compound such as aryl nitrile or trifluoromethyl derivative to react, be translated into carboxylic acid then and form acid amides as previously mentioned;

Process 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 (1) of adopting with highly basic such as sodium hydride or potassium tert.-butoxide under 0 ℃-200 ℃.

Specific intermediate formula (III), (VI), (VII), (IX) and/or (XI) be considered to novel, and comprise independent aspects of the present invention.

R wherein ¹For the specific intermediate (III) of methylol, methoxymethyl or trialkylsilyl ethers, (IX) and/or (XI) be considered to novel and comprise independent aspects of the present invention.

In preparation process, be useful in that intramolecular functional group is protected.Can remove blocking group by the known method easily that is fit to remove mentioned blocking group of that describe in any document or skilled chemical personnel, in described method, select molecule in the minimum blocking group of other group influence remove method.

For convenience, provided the particular instance 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 particular instance of same method of removing blocking group given below neither exhaustive.The use of the blocking group of clearly not mentioning and deprotection method are certainly also within the scope of the invention.

Carboxy protective group can be the residue of the Fatty Alcohol(C12-C14 and C12-C18) that forms ester or aryl alcohols (araliphaticalcohol) 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 (as sec.-propyl, the tertiary butyl); The lower alkoxy low alkyl group is (as methoxymethyl, ethoxyl methyl, isobutoxy methyl; Lower aliphatic acyloxy low alkyl group (as acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl, valeryl oxygen ylmethyl); Elementary alkoxy carbonyl oxygen base low alkyl group (as 1-methoxycarbonyl oxygen base ethyl, 1-ethoxy carbonyl oxygen base ethyl); Aromatic yl elementary alkyl (as to methoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl (as trimethyl silyl and t-butyldimethylsilyl); Three (low alkyl group) silyl low alkyl group (as the trimethyl silyl ethyl); (2-6C) thiazolinyl (as allyl group and vinyl ethyl).

The method that is particularly suitable for removing carboxy protective group comprise as acid-, metal-or enzymatic hydrolytic action.

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

The example of amido protecting group comprises formyl radical, aralkyl (as benzyl and substituted benzyl, as to methoxy-benzyl, nitrobenzyl and 2,4-dimethoxy-benzyl and trityl group); The two pairs of anisyl methyl and furyl methyl; Elementary alkoxy carbonyl (as tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); The aryl-lower alkoxy carbonyl is (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.

Remove the suitable method that hydroxyl closes the amido protecting group and comprise as affine displacement, acid-, alkali, metal or enzymatic hydrolysis reaction, to as the catalytic hydrogenolysis/hydrogenation or the photodissociation of the group of adjacent nitro benzyloxycarbonyl, to the silyl fluoride ion.For example, available trimethyl silyl iodine is removed the methyl ether blocking group of hydroxyl.Can remove the tertbutyl ether blocking group of hydroxyl by hydrolysis, in methyl alcohol, be hydrolyzed as adopting hydrochloric acid.

The example of amide group blocking group comprises aralkoxy methyl (as benzyl oxygen ylmethyl and substituted benzyl oxygen ylmethyl); 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-two (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 alkane-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 is incorporated into amide group, available catalytic hydrogenation is removed described blocking group.Can introduce alkoxy methyl, trialkyl/aryl silyl and trialkyl/silyl oxygen ylmethyl by acid amides is reacted with suitable muriate, can remove described blocking group by acid.Or, use fluoride ion comprising under the situation of silyl.Can be by introducing alkoxyl phenyl and alkoxybenzyl easily with suitable halid arylation reaction or alkylated reaction, can be by removing described blocking group with the oxygenizement of ceric ammonium nitrate.At last, can be by acid amides and suitable aldehyde reaction to be introduced alkane-1-thiazolinyl, usable acid is removed described blocking group.

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

(i) evaporation is undertaken by rotation vacuum-evaporation, and finishing sequence is being undertaken by after removing by filter residual solids such as siccative;

(ii) operation at room temperature promptly 18-25 ℃, is carried out under rare gas element such as argon gas or nitrogen;

(iii) to provide throughput/yield only be for example but not maximum can obtain throughput/yield;

(iv) unless otherwise stated, the structure of formula (I) compound final product is by nuclear (be generally proton) mr and the mass-spectrometric technique conclusive evidence of intensity of field (to proton) for 300MHz (using Varian Gemini 2000 usually) or 400MHz (using BrukerAvance DPX400 usually); The proton resonance chemical displacement value represents that with δ the peak multiplicity is as follows: s, singlet; D, doublet; T, triplet; M, multiplet; Br, broad peak; Q, quartet, quin, quintet;

(v) intermediate is not all proved conclusively usually, and its purity is measured by tlc (TLC), high performance liquid chromatography (HPLC), infrared spectra (IR) or NMR;

(vi) unless otherwise stated, typically refer to the hurried column chromatography of the hurried post of silica gel with chromatography purification.Column chromatography adopts the silica gel tube (from 4g-400g) of pre-packing as Redisep usually ^TM(can buy and obtain, as from Presearch Ltd, Hitchin, Herts, UK) or Biotage (Biotage UK Ltd, Hertford, Herts, UK), wash-out uses the pump interflow to divide a 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 Phemonenex Gemini C 185 μ m, 50 * 2mm post (or similarly) is gone up operation, available acid elutriant (as, adopting gradient is water/acetonitrile of 0-95% and 50: 50 water of 5% 1% formic acid: the mixture of acetonitrile (v/v) solution; Or adopt the methyl alcohol be equal to replace the acetonitrile solvent system), or alkaline eluant (as, adopt that gradient is arranged is the mixture of acetonitrile solution of 0.1%880 ammonia of 0-95% water/acetonitrile and 5%) wash-out; The MS assembly comprises Waters ZQ spectrograph usually.Produce the color atlas of electrospray (ESI) positive and negative base peak intensity and the UV of 220-300nm and always absorb color atlas, provide the m/z value; Usually unless otherwise stated, only the ion of parent quality represented in record, and 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 diethyl azodiformate;

DIAD azoformic acid diisopropyl ester;

DIPEA N, the N-diisopropyl ethyl amine;

The DMSO methyl-sulphoxide;

The DMF dimethyl formamide;

EDAC 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide salt

Hydrochlorate;

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

Urea  hexafluorophosphate

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-;

NMR nucleus magnetic resonance chromatography;

The RT room temperature;

The THF tetrahydrofuran (THF);

The TFA trifluoroacetic acid;

CDCl ₃Deuterochloroform;

The Mpt/mpt fusing point;

MgSO ₄Sal epsom

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

Reference example 1:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[4-(methyl sulphonyl) Phenoxy group]-N-1,3-thiazol-2-yl benzamide

With tetra-n-butyl Neutral ammonium fluoride (the THF solution of 1.0M; 0.832mL; 0.832mmol) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4-(methyl sulphonyl) phenoxy group]-N-1; 3-thiazol-2-yl benzamide (425mg; 0.756mmol) THF (5mL) solution in, this reactant is stirred 1.5h.The THF solution that adds a tetra-n-butyl Neutral ammonium fluoride (0.83mL) again is with reactant restir 1.5h.Use ether (40mL) and 1M aqueous hydrochloric acid (20mL) dilution gained reactant then, water layer extracts with ether (20mL) again.Dry (MgSO ₄) organic layer that merges, filter also evaporation.Use the column chromatography purifying, use the hexane solution wash-out of the ethyl acetate of 50%-100%, obtain spumescence title compound (200mg, 60%).

¹H?NMRδ(CDCl ₃)：1.30(d，3H)，3.08(s，3H)，3.77(m，2H)，4.47(m，1H)，6.85(s，1H)，7.00(d，1H)，7.13(d，2H)，7.20(s，1H)，7.32(d，1H)，7.37(s，1H)，7.92(d，2H).m/z467(M-H) ^-

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) 5-[4- (methyl sulphonyl) phenoxy group]-N-1,3-thiazol-2-yl benzamide

With HATU (513mg; 1.35mmol) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4-(methyl sulphonyl) phenoxy group] phenylformic acid (520mg; 1.08mmol) in; add DMF (5mL), diisopropyl ethyl amine (0.48mL) and thiazolamine (135mg then; 1.35mmol), reactant is stirred 4h under argon gas.Steaming desolventizes, and residue is dissolved in saturated sodium bicarbonate aqueous solution (30mL) and ethyl acetate (50mL).Separate organic layer, with saturated aqueous ammonium chloride (30mL) washing, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, with 1: 2-2: 1 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (425mg, 70%).

¹H?NMRδ(CDCl ₃)：0.02(s，3H)，0.04(s，3H)，0.84(s，9H)，1.30(d，3H)，3.08(s，3H)，3.76(m，2H)，4.50(m，1H)，6.89(s，1H)，7.00(d，1H)，7.18(m，3H)，7.37(m，2H)，7.94(d，2H).m/z561(M-H) ^-

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4- (methyl sulphonyl) phenoxy group] phenylformic acid

With lithium hydroxide monohydrate (346mg; 8.24mmol) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4-(methyl sulphonyl) phenoxy group] methyl benzoate (3.70g; 7.49mmol) THF (50mL) and water (10mL) solution in, reactant is stirred 2h.And then (346mg 8.24mmol), heats 1.5h with reactant down at 450 ℃ to add a lithium hydroxide monohydrate.Steam then and remove THF, with ether (10mL) aqueous layer extracted.Remaining water layer usefulness 5%w/v aqueous citric acid solution acidifying, and the usefulness ethyl acetate extraction (2 * 50mL), dry (MgSO ₄) organic layer that merges, filter also evaporation, obtain title compound, be jelly (2.54g, 71%).

¹H?NMRδ(d ₆-DMSO)：0.00(s，3H)，0.02(s，3H)，0.80(s，9H)，1.22(d，3H)，3.20(s，3H)，3.71(m，2H)，4.60(m，1H)，7.00(s，1H)，7.12(s，1H)，7.22(d，2H)，7.36(s，1H)，7.94(d，2H).m/z479(M-H) ^-

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4- (methyl sulphonyl) phenoxy group] methyl benzoate

With (2R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } propan-2-ol (2.18g; 11.47mmol) join 3-hydroxyl-5-[4-(methyl sulphonyl) phenoxy group] methyl benzoate (2.76g; 8.57mmol) anhydrous DCM (100mL) solution in; at room temperature add (polymer-supported) triphenylphosphine (3.0mmol/g (Fluka) that is loaded on the polymkeric substance then; 8.57g; 25.71mmol) and DIAD (3.37mL, 17.1mmol).Reactant is stirred 3h, then by diatomite filtration, and evaporation.Use the column chromatography purifying, with 1: 4-1: 2 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (3.70g, 87%).

¹H?NMRδ(CDCl ₃)：0.03(m，6H)，0.84(s，9H)，1.33(d，3H)，3.07(s，3H)，3.48(dd，1H)，3.79(dd，1H)，3.92(s，1H)，4.50(m，1H)，6.92(s，1H)，7.11(d，2H)，7.29(s，1H)，7.47(s，1H)，7.92(d，2H).m/z493(M-H) ^-

3-hydroxyl-5-[4-(methyl sulphonyl) phenoxy group] methyl benzoate

With 3-(phenyl methyl) oxygen base-5-[4-(methyl sulphonyl) phenoxy group] (3.50g 8.50mmol) is dissolved in THF (60mL) to methyl benzoate, adds 10% palladium carbon (500mg) then.By vacuum backfill technology (evacuation-backfill technique) reactant is placed under the hydrogen then.With reactant vigorous stirring 4h, then filter then, evaporation obtains title compound, is colorless oil (2.75g, 100%).

¹H?NMRδ(CDCl ₃)：3.07(s，3H)，3.93(s，3H)，6.90(s，1H)，7.13(d，2H)，7.31(s，1H)，7.40(s，1H)，7.96(d，2H).m/z321(M-H) ^-

3-(phenyl methyl) oxygen base-5-[4-(methyl sulphonyl) phenoxy group] methyl benzoate

With salt of wormwood (3.21g; 23.2mmol) join 3-hydroxyl-5-{[phenyl methyl] the oxygen base (3.00g in DMF 11.6mmol) (30mL) solution, adds 1-fluoro-4-(methyl sulphonyl) benzene (2.02g to methyl benzoate then; 11.6mmol), reactant is heated 3h down at 120 ℃.Solvent removed in vacuo places saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (150mL) with residue then, separates organic layer, with 1M aqueous hydrochloric acid (50mL) washing, and dry then (MgS0 ₄), filter and evaporation.Use the column chromatography purifying, with 1: 4-1: 1 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (3.50g, 73%).

¹H?NMRδ(CDCl ₃)：3.07(s，3H)，3.92(s，3H)，5.13(s，2H)，6.87(m，1H)，7.10(d，2H)，7.38(m，6H)，7.56(s，1H)，7.90(d，2H).m/z411(M-H) ^-

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

To 3 of stirring, add salt of wormwood (9mol) in DMF (6L) solution of 5-methyl dihydroxy benzoate (5.95mol), suspension is at room temperature stirred under argon gas.In this suspension, slowly add bromotoluene (8.42mol),, reaction mixture at room temperature stirred spend the night with slight exotherm through 1h.With ammonium chloride solution (5L), the careful quencher reaction of water (35L) then.(1 * 3L and 2 * 5L) extracts the gained aqueous suspension with DCM.Extraction liquid water (10L) washing that merges, dried overnight (MgSO ₄).With solution for vacuum evaporation, with crude product divide 3 batches with chromatography purification (hurried post, 3 * 2kg silica gel is with the hexane → pure DCM that comprises 10%DCM → the comprise DCM gradient elution of 50% ethyl acetate) to remove starting raw material.Thick elutriant is used chromatography purification (Amicon HPLC, the 5kg purification on normal-phase silica gel is with the isohexane wash-out that comprises the 20%v/v ethyl acetate) in batches once more with 175g, obtains required compound (21% productive rate);

¹H?NMR?δ(CDCl ₃)：3.07(s，3H)，3.92(s，3H)，5.13(s，2H)，6.87(m，1H)，7.10(d，2H)，7.38(m，6H)，7.56(s，1H)，7.90(d，2H).m/z411(M-H) ^-

(2R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } propan-2-ol

(5.90g 39.5mmol) joins (2R)-the third-1,2-glycol (3.00g with the tertiary butyl (dimethyl) silyl chloride, 39.5mmol) DCM (100mL) solution in, (7.10g 55.3mmol), stirs 72h with reactant under argon gas to add diisopropyl ethyl amine then.With ether (500mL) and water (140mL) diluting reaction thing, separate organic layer, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, with 1: 15-1: 10 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (6.00g, 80%).

¹H?NMRδ(CDCl ₃)：0.10(m，6H)，0.92(s，9H)，1.14(d，3H)，2.42(d，1H)，3.38(dd，1H)，3.60(dd，1H)，3.82(m，1H)。

These data consistent with bibliographical information (J.Org.Chem., 1998,53,2300).

Reference example 2:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-[4-(methoxy methyl Base)-1,3-thiazoles-2-yl]-5-[4-(methyl sulphonyl) phenoxy group] benzamide

With TFA (2mL) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-[4-(methoxymethyl)-1; the 3-thiazol-2-yl]-5-[4-(methyl sulphonyl) phenoxy group] benzamide (325mg; 0.536mmol) DCM (4mL) and water (1mL) solution in, reactant is stirred 1h.Reactant is alkalized to pH7-8 with saturated sodium bicarbonate aqueous solution, use DCM (2 * 20mL) extractions then.Dry (MgSO ₄) organic layer that merges, filter also evaporation, use the column chromatography purifying, the hexane solution wash-out of usefulness 50%-100% ethyl acetate obtains title compound, is white foam (147mg, 56%).

¹H?NMR?δ(CDCl ₃)：1.15(d，3H)，2.12(br?s，1H)，2.95(s，3H)，3.28(s，3H)，3.63(m，2H)，4.28(s，2H)，4.44(m，1H)，6.70(s，1H)，6.75(s，1H)，6.97(d，2H)，7.17(s，1H)，7.80(d，2H)，9.63(br?s，1H)。m/z491(M-H) ^-

Following compounds is synthetic with similar mode from suitable shielded ether:

Adopt ^$TFA:DCM: water (2: 2: 1, the 5mL cumulative volume), products therefrom column chromatography purifying is with 1: 20-1: 10 methyl alcohol: the DCM wash-out

The precursor of reference example 2 is prepared as follows:

3-(the 1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-[4- (methoxymethyl)-1,3-thiazoles-2-yl]-5-[4-(methyl sulphonyl) phenoxy group] benzamide

With HATU (446mg; 1.17mmol) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4-(methyl sulphonyl) phenoxy group] phenylformic acid (450mg; 0.94mmol) in; add DMF (4.5mL), DIPEA (0.42mL) and 4-(methoxymethyl)-1 then; 3-thiazole-2-amine (160mg; 1.11mmol), reactant is stirred 4h under argon gas.Steaming desolventizes, and residue is dissolved in saturated sodium bicarbonate aqueous solution (30mL) and the ethyl acetate (50mL).Separate organic layer, with the dry then (MgSO of saturated aqueous ammonium chloride washing (30mL) ₄), filter and evaporation.Use the column chromatography purifying, with 1: 2-2: 1 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (325mg, 56%).

m/z?607(M+H) ⁺，605(M-H) ^-

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-[4-(methyl sulphonyl) phenoxy group] describe among the benzoic synthetic superincumbent embodiment 1.

In the same way, the precursor for preparing embodiment 2a-2c with suitable amine:

Reference example 2 required amine are prepared as follows:

4-(methoxymethyl)-1,3-thiazoles-2-amine

(the THF solution of 1.0M, 0.67mL 0.67mmol) join 4-(chloromethyl)-1,3-thiazoles-2-amine (JIndian Chem.Soc.1960,57,241 with hexamethyl dimethyl silanyl sodium amide (Sodium hexamethyldisilazide); 100mg in methyl alcohol 0.67mmol) (5mL) solution, at room temperature stirs 72h then under argon gas.Removal of solvent under reduced pressure, residue place saturated sodium bicarbonate aqueous solution (20mL) and ethyl acetate (50mL).Separate organic layer, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, the hexane solution wash-out with the 80%-100% ethyl acetate obtains title compound, is colorless oil (20mg, 21%).

¹H?NMR?δ(CDCl ₃)：3.42(s，3H)，4.31(s，2H)，5.05(br?s，2H)，6.42(s，1H)。

The required amine of embodiment 2c is prepared as follows:

3-amino-5-methyl isophthalic acid H-pyrazoles-1-formic acid tertiary butyl ester

(800mg 8.25mmol) is dissolved in DMF (10mL), and (336mg 8.25mmol) handles, and then stirs 30min with sodium hydride with 5-methyl isophthalic acid H-pyrazoles-3-amine under 0 ℃.(1.80g 8.25mmol), rises to room temperature restir 1h with reactant slowly to add the tert-Butyl dicarbonate (di-tert-butyl dicarbonate) of heating with syringe through 5min then.The gained reactant is inserted in saturated sodium bicarbonate aqueous solution (50mL) and the ethyl acetate (100mL).Separate organic layer, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, the hexane solution wash-out with the 50%-100% ethyl acetate obtains title compound, is colorless oil (380mg, 23%).

¹H?NMR?δ(CDCl ₃)：1.62(s，9H)，2.43(s，3H)，3.87(br?s，2H)，5.60(s，1H)。

Reference example 3:

3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(first The base alkylsulfonyl) phenoxy group] benzamide

Under argon gas with trimethyl silyl iodine (11.1mL; 76.3mmol) join 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methyl sulphonyl) phenoxy group] (7.00g reacts 21h in anhydrous acetonitrile 15.3mmol) (100mL) solution to benzamide.Add entry (40mL) quencher reaction, vacuum is removed acetonitrile.Residue dilutes with ethyl acetate (200mL) and 1M aqueous hydrochloric acid.Separate organic layer, again with 10%w/v Sulfothiorine pentahydrate solution washing to remove residual iodine.Separate organic layer, dry (MgSO ₄), filtering and evaporation column chromatography purifying, the DCM eluant solution with 3%-5% methyl alcohol obtains title compound, is white foam (5.70g, 84%).Recrystallization from hot ethanol ethanol (125mg/mL) obtains title compound, is colourless spicule (87% rate of recovery).Mpt?126-132℃。

¹H?NMR?δ(CDCl ₃)：1.33(d，3H)，2.10(t，1H)，3.08(s，3H)，3.78(m，2H)，3.82(s，3H)，4.57(m，1H)，6.80(m，2H)，7.15(m，3H)，7.25(m，2H)，7.93(d，2H)，8.43(s，1H)。m/z444(M-H) ^-

Following compounds prepares in the same way:

^$Use the column chromatography purifying, with 7: 3 ethyl acetate: hexane-pure ethyl acetate wash-out

^$$Use the column chromatography purifying, with the ethyl acetate solution wash-out of 0-15% methyl alcohol

Preparation reference example 3 and the required starting raw material of 3a are prepared as follows:

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4- (methyl sulphonyl) phenoxy group] benzamide and 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen Base]-5-[4-(methyl sulphonyl) phenoxy group]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide

DIPEA (2.5 equivalent) is joined 3-{ (1S)-2-methoxyl group-(1-methylethyl) oxygen base }-5-{[4-(methyl sulphonyl) phenyl] the oxygen base } in the suspension of DMF (20mL) of phenylformic acid (1 equivalent), HATU (1.25 equivalent) and suitable amine (1.25 equivalent).The suspension of beginning is dissolved as dark tangerine look solution.The gained mixture at room temperature stirs 2h.Vacuum is removed DMF, residue and methylbenzene azeotropic.Add entry, with gained mixture ethyl acetate extraction.Combining extraction liquid is used 1M hydrochloric acid, saturated sodium bicarbonate solution and salt water washing successively.Dry (MgSO ₄) gained solution, filter, and vacuum-evaporation, obtain crude product, it with chromatography purification (the isohexane solution of 50% ethyl acetate), is obtained required compound (40-70% productive rate).

3-{ (1S)-2-methoxyl group-(1-methylethyl) oxygen base }-5-{[4-(methyl sulphonyl) phenyl] oxygen Base } phenylformic acid

With 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-5-{[4-(methyl sulphonyl) phenyl] the oxygen base } THF (400mL) solution of methyl benzoate (60.9mmol) is with 1M sodium hydroxide (125mmol) solution-treated, and reaction mixture at room temperature stirs 13h.Vacuum is removed most of organic solvents, remaining solution with water (150mL) dilution.Obtained aqueous solution is acidified to pH4 with the 1M citric acid solution, with ethyl acetate (2 * 100mL) extractions.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), evaporation obtains required compound (83% productive rate).

¹H?NMR?δ(d ₆-DMSO)：1.2(d，3H)，3.2(s，3H)，3.26(s，3H)，3.44(m，2H)，4.63(m，1H)，7.05(s，1H)，7.11(s，1H)，7.2(d，2H)，7.3(s，1H)，7.9(d，2H).m/z?479(M-H) ^-

3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-5-{[4-(methyl sulphonyl) phenyl] oxygen Base } methyl benzoate

With 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base] DCM (500mL) suspension of methyl benzoate (154mmol), boric acid (boric acid) (1.1 equivalent), venus crystals (II) (1.1 equivalent), triethylamine (5 equivalent) and fresh activatory 4  molecular sieves (200g) depresses at room temperature with at ambient atmosphere and stirred 2 days.Filter reaction mixture, vacuum is removed DCM, and residual oily matter is distributed between ethyl acetate and 1-2M hydrochloric acid.The separating ethyl acetate layer, with sodium bicarbonate aqueous solution and salt water washing, dry (MgSO ₄), evaporation obtains residue, and it with silica gel chromatography purifying (the isohexane solution of using the 20-60% ethyl acetate is as eluent), is obtained required ester (58% productive rate).

¹H?NMR?δ(d ₆-DMSO)：1.2(d，3H)，3.2(s，3H)，3.26(s，3H)，3.44(m，2H)，3.8(s，3H)，4.65(m，1H)，7.05(s，1H)，7.11(s，1H)，7.2(d，2H)，7.3(s，1H)，7.9(d，2H)

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 } (50.0g 0.152mmol) is dissolved in THF to methyl benzoate: in the mixture of ethanol (600mL), flask vacuumized and with nitrogen purge (3 times).Add 10% palladium carbon (5.0g), once more flask is vacuumized, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 20h until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer, the filtrate vacuum concentration obtains required compound (36.7g).

¹H?NMR?δ(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 } phenylformic acid Methyl esters

To 3-hydroxyl-5-{[phenyl methyl] the oxygen base add in the THF solution of methyl benzoate (77.4mmol) triphenylphosphine that is loaded on the polymkeric substance (the 3mmol/g loading amount of 51.7g, 155mmol) and (R)-(-)-1-methoxyl group-2-propyl alcohol (102mmol).The solution that cover to stir with argon gas also cools off in ice bath.Dripped DIAD (116mmol) solution through 10 minutes with syringe.With gained solution stirring 20min, filter, with THF (500mL) wash residual thing.Merging filtrate and washing lotion, evaporation obtains required compound, and it need not to be further purified and uses.

¹H?NMR?δ(d ₆-DMSO)：3.26(s，3H)，3.44(m，2H)，3.82(s，3H)，4.63(m，1H)，5.14(s，2H)，6.85(s，1H)，7.05(s，1H)，7.11(s，1H)，7.30-7.47(m，5H).

¹H NMR spectrum also comprises and a small amount of two (1-methylethyl) hydrazines-1,2-two carbonic ethers (bis (1-methylethyl) hydrazine-1,2-dicarboxylate) Yi Zhi signal.

In the top reference example 1 3-hydroxyl-5-{[phenyl methyl has been described] the oxygen base } methyl benzoate.

The required starting raw material of embodiment 3b is prepared as follows:

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group]-N- 1H-pyrazole-3-yl benzamide

TFA (0.5mL) is joined 3-({ 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group] benzoyl } amino)-(180mg is in anhydrous DCM (3mL) solution 0.330mmol) for 1H-pyrazoles-1-t-butyl formate.Reactant is stirred 3h under argon gas.And then add a TFA (0.2mL), and reactant is stirred 30min, vacuum is removed all solvents then.Residue is placed ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (15mL), and evaporation gained residue with DCM/ hexane revaporization, obtains title compound then, is colourless foam (145mg, 100%).

¹H?NMR?δ(d ₆-DMSO)：1.27(d，3H)，3.22(s，3H)，3.31(s，3H)，3.60(m，2H，partially?obscured?by?HOD)，4.78(m，1H)，6.62(s，1H)，6.93(s，1H)，7.27(d，2H)，7.32(s，1H)，7.53(s，1H)，7.65(s，1H)，7.96(d，2H)，10.86(s，1H)。m/z?444(M-H) ^-

3-(3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(methyl sulphonyl) phenoxy group] benzene Formyl radical } amino)-1H-pyrazoles-1-t-butyl formate

With HATU (375mg; 1.17mmol) join 3-{ (1S)-2-methoxyl group-(1-methylethyl) oxygen base-5-{[4-(methyl sulphonyl) phenyl] the oxygen base } phenylformic acid (300mg; 0.79mmol); add DMF (5mL), DIPEA (0.35mL) and 3-amino-1H-pyrazoles-1-t-butyl formate (155mg then; 0.85mmol), reactant is stirred 4h under argon gas.Steaming desolventizes, and residue is dissolved in saturated sodium bicarbonate aqueous solution (30mL) and the ethyl acetate (50mL).Separate organic layer, with saturated aqueous ammonium chloride washing (30mL), dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, the hexane solution wash-out with 50% ethyl acetate obtains title compound, is colorless oil (185mg, 43%).

¹H?NMR?δ(CDCl ₃)：1.37(d，3H)，1.63(s，9H)，3.09(s，3H)，3.40(s，3H)，3.58(m，2H)，4.61(m，1H)，6.85(s，1H)，7.08(m，2H)，7.15(d，2H)，7.30(s，1H)，7.92(d，2H)，8.01(d，1H)，8.58(br?s，1H)。m/z?544(M-H) ^-

3-amino-1H-pyrazoles-1-t-butyl formate

(428mg 5.15mmol) is dissolved in DMF (5mL), and (206mg 5.15mmol) handles, and then stirs 30min with sodium hydride with 1H-pyrazoles-3-amine under 0 ℃.(1.12g 5.15mmol), rises to room temperature with reactant, restir 2h slowly to add tert-Butyl dicarbonate with syringe through 5min then.Reactant is placed saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (100mL).Separate organic layer, dry then (MgSO ₄), filter and evaporation.With the column chromatography purifying (with 1: 1 ethyl acetate: hexane-pure ethyl acetate wash-out) obtain title compound, be white solid (117mg, 18%).

¹H?NMR?δ(CDCl ₃)：1.62(s，9H)，4.00(br?s，2H)，5.81(d，1H)，7.82(d，1H)。

Embodiment 4:3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-the 2-hydroxyl Base-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With DIPEA (93mg, 0.72mmol; 4.0 equivalent) join 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] phenylformic acid (70mg), HATU (144mmol; 2.1 equivalent) and in DMF (2mL) suspension of 1-methyl isophthalic acid-H-pyrazoles-3-amine (26mg, 0.27mmol, 1.5 equivalents).The gained mixture at room temperature stirs 16h.Vacuum is removed DMF, adds entry, gained mixture ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtain crude product, it is used chromatography purification, the isohexane eluant solution with the 0-100% ethyl acetate obtains required compound (45mg).

¹H?NMR?δ(d ₆-DMSO)：1.22(d，3H)，2.24(m，2H)，3.51(m，2H)，3.76(s，3H)，4.03(m，2H)，4.34(m，2H)，4.56(m，1H)，4.83(t，1H)，6.54(s，1H)，6.78(m，1H)，7.14(s，1H)，7.21(t，1H)，7.41(s，1H)，7.48(d，1H)，7.56(s，1H)，7.62(d，1H)，10.83(br?s，1H)。m/z?469(M+H) ⁺

Through chromatography purification (on silica gel, then/or on the neutral alumina) after, the gained material can crystallization from ethyl acetate, toluene and isohexane mixture, if desired, available activated carbon treatment.mpt?142℃.

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl Oxyethyl group] phenylformic acid

With 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] methyl benzoate (100mg, 0.25mmol) be dissolved in THF (2.0Ml) solution, add then entry (0.2mL) and solid hydrogen Lithium Oxide 98min (21mg, 0.5mmol).The gained mixture at room temperature stirs 16h.Add entry (10mL),, use ethyl acetate extraction then partial concentration in the mixture vacuum (themixture partially reduced in vacuo).Water layer 1M hcl acidifying is with ethyl acetate (2 * 10mL) extractions again.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtaining crude product (70mg), it need not to be further purified and uses.

¹H NMR δ (d ₆-DMSO): 1.16 (d, 3H), 2.24 (m, 2H), 3.46 (m, 2H), 4.02 (m, 2H), 4.33 (m, 2H), 4.45 (m, 1H), 4.82 (t, 1H), 6.89 (s, 1H), 7.00 (m, 1H), 7.23 (m, 2H), 7.48 (d, 1H), 7.61 (d, 1H), COOH does not see.m/z?390(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl Oxyethyl group] methyl benzoate

To a 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-methyl hydroxybenzoate (102mg; 0.3mmol) and 1-(3; the 4-difluoro benzoyl) azetidine (71mg; 0.36mmol) DMF (2.0mL) solution in add salt of wormwood (207mg; 1.5mmol), and with stirred mixture in ' Smith Creator Microwave ' at 160 ℃ of heating 120min down.Make the gained mixture reach envrionment temperature and pressure, then with its ethyl acetate (2 * 25mL) and water (25mL) between distribute.Separate organic layer, use the salt water washing, dry (MgSO ₄), vacuum-evaporation obtains crude product, and it need not to be further purified and uses (100mg).

m/z?404(M+H) ⁺

3-((1S)-2-{[tertiary butyl (methyl) silyl] the oxygen base }-the 1-methyl ethoxy)-the 5-hydroxyl Methyl benzoate

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-the 5-[(phenyl methyl) the oxygen base] (1000mg 2.33mmol) is dissolved in methyl alcohol (30mL) to methyl benzoate, adds 10% palladium carbon (100mg).Mixture is at room temperature stirred 36h, filter, chromatography purification is used in vacuum-evaporation, with the isohexane wash-out of 0-100% ethyl acetate, obtain 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-methyl hydroxybenzoate (750mg).This material need not to be further purified and uses.

m/z?341(M+H) ⁺

3-((1S)-2-{[tertiary butyl (dimethyl) silicomethane] the oxygen base }-the 1-methyl ethoxy)-the 5-[(phenyl Methyl) oxygen base] methyl benzoate

Following at 0 ℃ with (2R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } propan-2-ol (3.31g 17.4mmol) joins 3-hydroxyl-5-{[phenyl methyl] the oxygen base } (3.00g is in THF 11.6mmol) (50mL) solution for methyl benzoate.(4.57g, 17.4mmol), (3.43mL 17.4mmol), rises to reactant room temperature and stirs 16h to add DIAD then to add triphenylphosphine then.Water (100mL) and ether (400mL) quencher reaction separate organic layer, dry then (MgSO ₄), evaporation.Use the column chromatography purifying, with 1: 15-1: 5 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (4.00g, 80%).

¹H?NMR?δ(CDCl ₃)：0.03(s，3H)，0.05(s，3H)，0.89(s，9H)，1.29(d，3H)，3.63(dd，1H)，3.78(dd，1H)，3.92(s，3H)，4.44(m，1H)，5.08(s，2H)，6.77(m，1H)，7.40(m，7H)

Embodiment 5:3-[(3, the 5-difluorophenyl) the oxygen base]-5-{[(1S)-2-hydroxyl-1-methylethyl] The oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (202mg, 0.5mmol), 3,5-difluorophenyl boric acid (156mg, 1.0mmol), venus crystals (II) (182mg, 1.0mmol), triethylamine (252mg, 2.5mmol) and DCM (10mL) solution of fresh activatory 4  molecular sieves (1.5g) depress at room temperature and ambient atmosphere and stir 64h.Filter reaction mixture, (2 * 10mL) washings, vacuum-evaporation distributes residual oily matter between ethyl acetate (25mL) and 1M hydrochloric acid (10mL) with DCM.The separating ethyl acetate layer is used sodium bicarbonate aqueous solution and salt water washing successively, dry (MgSO ₄), evaporation obtains residue, with it with preparation HPLC chromatography purification, on the C18 reversed-phase column with the 5-95% acetonitrile (+0.2%TFA) water (+0.2%TFA) solution obtains title compound (45mg) as elutriant.

¹H?NMR?δ(d ₆-DMSO)：1.27(d，3H)，3.56(m，2H)，3.82(s，3H)，4.61(m，1H)，5.06(br?s，1H)，6.58(m，1H)，6.85(dd，2H)，6.89，(m，1H)，7.07(m，1H)，7.28(m，1H)，7.51(m，1H)，7.63(m，1H)，10.89，(br?s，1H)。m/z?404(M+H) ⁺，402(M-H) ^-

The starting raw material of embodiment 5 is prepared as follows:

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5- Hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-(phenyl methyl) oxygen base-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (1.8g, 3.64mmol) be dissolved in methyl alcohol (50mL), flask is vacuumized, and with nitrogen purge (3 times), add 10% palladium carbon (0.2g), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 16h up to reacting completely.Reaction mixture is vacuumized, and with nitrogen purge (3 times).Leach catalyzer, the filtrate vacuum concentration obtains required compound (1.45g).

¹H?NMR?δ(d ₆-DMSO)：0.02(d，6H)，0.83(s，9H)，1.18(d，3H)，3.66(m，2H)，3.72(s，3H)，4.51(m，1H)，6.42(m，1H)，6.52(m，1H)，6.90(s，1H)，7.02(s，1H)，7.55(m，1H)，9.58(br?s，1H)，10.59(br?s，1H)。m/z?406(M+H) ⁺

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5- (phenyl methyl) oxygen base-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With DIPEA (4.06g, 23.4mmol) join 3-{ (phenyl methyl) oxygen base-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (2.43g, 5.84mmol), 1-methyl isophthalic acid H-pyrazoles-3-amine (0.85g, 8.76mmol) and HATU (4.66g, 12.3mmol) DMF (50mL) suspension in, at room temperature stir 16h.The gained mixture is partial concentration (The resultant mixture was partially reduced invacuo) in a vacuum, is poured on the water (100mL), with ether (2 * 50mL) extractions.Extraction liquid water and salt water washing, dry then (MgSO ₄), filter, be decompressed to the opaque jelly of generating portion crystalline.Crude product column chromatography purifying, the isohexane eluant solution with the 0-100% ethyl acetate obtains title compound, is colorless oil (1.87g).

¹H?NMR?δ(d ₆-DMSO)：0.02(d，6H)，0.84(s，9H)，1.21(d，3H)，3.68(d，2H)，3.76(s，3H)，4.58(m，1H)，5.13(s，2H)，6.56(m，1H)，6.70(m，1H)，7.1?8(s，1H)，7.24(s，1H)，7.29-7.46(m，5H)，7.57(m，1H)，10.74(br?s，1H)。m/z?496(M+H) ⁺

3-{ (phenyl methyl) oxygen base }-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }- The 1-methyl ethoxy) phenylformic acid

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-the 5-[(phenyl methyl) the oxygen base] methyl benzoate (3.0g, 6.98mmol) be dissolved in THF (50mL) and the water (10mL), the adding lithium hydroxide monohydrate (586mg, 13.95mmol).The gained mixture under agitation heats 2h down at 45 ℃, at room temperature stirs 16h then, stirs 4h down at 45 ℃ again.Add entry (40mL), solvent removed in vacuo.1M citric acid (2 equivalent) acidifying of gained solution, water and salt water washing, dry then (MgSO ₄), filter and vacuum-evaporation, obtain title compound, be colourless jelly (2.58g).

¹H?NMR?δ(d ₆-DMSO)：0.02(d，6H)，0.84(s，9H)，1.17(d，3H)，3.66(m，2H)，4.43(m，1H)，5.05(s，2H)，6.56(br?s，1H)，7.10(br?s，1H)，7.17(br?s，1H)，7.25-7.44(m，5H)，7.60(br?s，1H)。

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-the 5-[(phenyl methyl) the oxygen base] describe among the synthetic superincumbent embodiment 4 of methyl benzoate.

Embodiment 6:3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-} the oxygen base }-5- [(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

To 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (215mg; 0.53mmol) and 1-(3-chloro-4-fluoro benzoyl) azetidine (135mg; 0.63mmol) DMF (2.0mL) mixture in add salt of wormwood (146mg; 1.06mmol), in ' Smith Creator Microwave ' with stirred mixture at 160 ℃ of heating 120min down.Reaction mixture is risen to envrionment temperature and pressure, reduced volume then.Use the column chromatography purifying, the DCM solution washing with 0-20% methyl alcohol obtains title compound (130mg).

¹H?NMR?δ(CDCl ₃)：1.22(d，3H)，2.14(m，2H)，3.50(m，2H)，3.76(s，3H)，4.05(m，2H)，4.33(m，2H)，4.56(m，1H)，4.84(t，1H)，6.53(d，1H)，6.78(m，1H)，7.12(m，2H)，7.42(s，1H)，7.59(m，2H)，7.80(m，1H)，10.84(br?s，1H)。m/z?485/487(M+H) ⁺

In the same way, with 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(.1-methyl isophthalic acid H-pyrazole-3-yl) benzamide and suitable acid amides prepare embodiment 6a:

Synthetic embodiment 6 and the required acid amides of 6a are prepared as follows by 3-chloro-4-fluorobenzoic acid:

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).Mixture is at room temperature stirred 16h, and vacuum is steamed and is removed DCM and excessive oxalyl chloride.(1.12g 12mmol) places DCM (25mL), and (4.18mL 30mmol), at room temperature stirs 2h with it to add triethylamine in mixture with residual acyl chlorides and azetidine hydrochloride.Vacuum is steamed and is removed DCM, and the gained residue is distributed between ethyl acetate (100mL) and 1N hydrochloric acid (50mL).Use saturated sodium bicarbonate aqueous solution and salt water washing ethyl acetate layer successively, dry (MgSO ₄), evaporation.With the crystallization from ethyl acetate/isohexane of gained residue, obtain title compound (1.64g).

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

In the same way, also prepared the required acid amides of embodiment 6a:

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-describe among the synthetic superincumbent embodiment 5 of 5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

Embodiment 7:3-{[4 (azetidine-1-base carbonyl) phenyl] the oxygen base }-5-{[(1S)-the 2-hydroxyl Base-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 2-hydroxyl-1-methylethyl] the oxygen base }-(104mg 0.215mmol) is dissolved in methyl alcohol (3mL) and THF (3mL) to N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.(65mg 0.644mmol), vacuumizes flask and with nitrogen purge (3 times) to add triethylamine.Add 10% palladium carbon (25mg), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 16h until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer, the filtrate vacuum concentration is dissolved in ethyl acetate (10mL) then, water (2 * 10mL, saturated sodium-chloride water solution (10mL) washing, dry (MgSO ₄), obtain title compound (95mg).

¹H?NMR?δ(d ₆-DMSO)：1.22(d，3H)，2.24(m，2H)，3.51(m，2H)，3.76(s，3H)，4.02(m，2H)，4.30(br?s，2H)，4.56(m，1H)，4.84(t，1H)，6.53(d，1H)，6.80(m，1H)，7.06(d，2H)，7.21(m，1H)，7.43(m，1H)，7.57(m，1H)，7.66(d，2H)，10.83(br?s，1H)。m/z?451(M+H) ⁺

Through chromatography purification (on silica gel, then/or on the neutral alumina) after, the gained material can crystallization from ethyl acetate and toluene mixture, if desired, available activated carbon treatment; 131 ℃ of mpt.

In the same way, with 3-chloro-4-[(3-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide prepares reference example 7a:

Describe among the synthetic superincumbent embodiment 6 of chloro precursor and the 6a.

Embodiment 8:3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5- [(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide

With salt of wormwood (182mg; 1.32mol) join 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base-N-(5-methylpyrazine-2-yl) benzamide (200mg; 0.66mmol) and 1-(3; the 4-difluoro benzoyl) azetidine (137mg; 0.69mmol) the mixture of acetonitrile (5.0mL) solution in, in ' Smith Creator Microwave ' with stirred mixture at 160 ℃ of heating 4h down.Reaction mixture is risen to envrionment temperature and pressure, vacuum concentration.Residual oily matter distributes between ethyl acetate (50mL) and water (50mL).The separating ethyl acetate layer is used the salt water washing, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (34mg).

¹H?NMR?δ(CDCl ₃)：1.31(d，3H)，2.36(quin，2H)，2.57(s，3H)，3.76(m，2H)，3.20-4.40(brm，4H)，4.56(m，1H)，6.75(m，1H)，7.07(m，2H)，7.27(m，2H)，7.41(d，1H)，7.51(d，1H)，8.11(s，1H)，8.43(s，1H)，9.50(s，1H)。m/z?481(M+H) ⁺

Following compound prepares with similar mode.

The 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) Benzamide

With trimethyl silyl iodine (6.06mL, 42.75mmol) join 3-hydroxyl-5-{[(1S)-1-methyl-2-(methyl oxygen base) ethyl] the oxygen base-(2.71g is in anhydrous acetonitrile 8.55mmol) (150mL) solution and stir 24h for N-(5-methylpyrazine-2-yl) benzamide.Add methyl alcohol (30mL) quencher reaction and stir 10min.Add the 10%w/v Sulfothiorine pentahydrate aqueous solution (20mL) in reaction mixture, vacuum is removed organic solvent.With 1M hydrochloric acid residue is transferred to pH5, add ethyl acetate (80mL).By filtering separation yellow solid (1.4g).(2 * 80mL) extract aqueous filtrate again, dry (MgSO with ethyl acetate ₄) organic layer that merges, filter solvent removed in vacuo.This residue merges with the yellow solid that obtains above, uses the column chromatography purifying, and the DCM eluant solution with 5%-10% methyl alcohol obtains title compound (1.70g).

¹H?NMR?δ(d ₆-DMSO)：1.21(d，3H)，2.50(s，3H)，3.40-3.60(m，2H)，4.45(sex，1H)，4.80(t，1H)，6.50(s，1H)，6.97(s，1H)，7.08(s，1H)，8.32(s，1H)，9.21(s，2H)，9.63(s，1H)，10.80(brs，1H)。m/z?304(M+H) ⁺

The 3-hydroxyl-5-{[(1S)-1-methyl-2-(methyl oxygen base) ethyl] the oxygen base }-N-(the 5-methylpyrazine- The 2-yl) benzamide

With 3-{[(1S)-1-methyl-2-(methyl oxygen base) ethyl] the oxygen base }-N-(5-methylpyrazine-2-yl)-5-[(phenyl methyl) the oxygen base] benzamide (4.5g, 11mmol) be dissolved among ethanol (35mL) and the THF (35mL), flask vacuumized and with purification for argon (3 times).Add 10% palladium carbon (0.45g), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 20 hours until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer by diatomite, the filtrate vacuum concentration obtains required compound (3.21g).

¹H?NMR?δ(d ₆-DMSO)：1.23(d，3H)，2.45(s，3H)，3.28(s，3H)，3.48(m，2H)，4.65(m，1H)，6.51(s，1H)，6.97(s，1H)，7.10(s，1H)，8.34(s，1H)，9.22(s，1H)，9.70(s，1H)，10.89(br?s，1H)。m/z?318(M+H) ⁺

3-{[(1S)-and 1-methyl-2-(methyl oxygen base) ethyl] the oxygen base }-N-(5-methylpyrazine-2-yl)-5- [(phenyl methyl) oxygen base] benzamide

DMF (2) is joined 3-{[(1S)-1-methyl-2-(methyl oxygen base) ethyl] the oxygen base-the 5-[(phenyl methyl) the oxygen base] phenylformic acid (6.0g, 19.0mmol) and oxalyl chloride (1.99mL is in DCM 22.8mmol) (40mL) solution.Mixture was at room temperature stirred 2 hours, and vacuum is steamed and is removed DCM and excessive oxalyl chloride.Residual acyl chlorides is dissolved in DCM, under 0 ℃, it is added dropwise to 2-amino-5 methylpyrazine [Tett lett.2002,9287-90] (2.28g, 19.8mmol) and pyridine (2.56mL is in DCM 38mmol) (40mL) solution.At room temperature stirred 24 hours.Vacuum is steamed and is removed DCM, and the gained residue is distributed between ethyl acetate (100mL) and 1N hydrochloric acid (50mL).Use saturated sodium bicarbonate aqueous solution (50mL) and salt solution (50mL) washing ethyl acetate layer successively, dry (MgSO ₄), vacuum-evaporation.Residue silica gel chromatography purifying, the isohexane eluant solution with the 30-100% ethyl acetate obtains required compound (7.6g).

¹H?NMR?δ(CDCl ₃)：1.32(d，3H)，2.55(s，3H)，3.40(s，3H)，3.50-3.62(m，2H)，4.60(m，1H)，5.10(s，2H)，6.75(s，1H)，7.09(m，1H)，7.13(m，1H)，7.32-7.46(m，5H)，8.13(s，1H)，8.38(s，1H)，9.55(s，1H)。m/z408(M+H) ⁺

The aryl fluorochemical of preparation embodiment 8 is prepared as follows:

1-(3, the 4-difluoro benzoyl) azetidine

(1.05mL 12.0mmol) joins 3, and (1.58g is in DCM (50mL) solution that comprises DMF (1) 10mmol) for the 4-difluoro-benzoic acid with oxalyl chloride.Reactant was at room temperature stirred 16 hours, be evaporated to dried then.Residue is dissolved among the DCM (25mL) again, add the azetidine hydrochloride (1.12g, 12.0mmol), then add triethylamine (4.18mL, 30.0mmol).Mixture was at room temperature stirred 2 hours, then vacuum concentration.Residue is distributed between ethyl acetate and 1N hydrochloric acid, then use salt water washing organic phase, dry (MgSO with saturated sodium bicarbonate aqueous solution ₄), vacuum concentration.Crystallization goes out title compound from the ethyl acetate/hexane mixture, obtains white crystalline solid (1.0g).

¹H?NMR?δ(CDCl ₃)：2.4(m，2H)，4.3(m，4H)，7.2(m，1H)，7.4(m，1H)，7.5(t，1H)。

The aryl fluorochemical of preparation embodiment 8a is described in embodiment 6a

Perhaps embodiment 8 can prepare in the following manner:

Embodiment 8:3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl]-5-{[(1S)-the 2-hydroxyl Base-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide

With 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-(3.6g, the mixture of methyl alcohol 5.96mmol) (60mL) and 1M hydrochloric acid (60mL) at room temperature stirred 30 minutes N-(5-methylpyrazine-2-yl) benzamide.Vacuum is removed volatile matter, and residue transfers to pH6 with saturated sodium bicarbonate aqueous solution, uses ethyl acetate (3 * 100mL) extractions then.The organic layer that water (100mL), salt solution (100mL) washing merge, dry (MgSO ₄), filter solvent removed in vacuo.Add the ethyl acetate solution of 10% methyl alcohol, leach white solid.Crystallization from ethyl acetate/methanol obtains required compound (1.24g), 172 ℃ of mpt.The data consistent of gained data and the sample for preparing by other approach.

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-(the 1S)-2{[tertiary butyl (diformazan Base) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(5-methylpyrazine-2-yl) benzamide

With 1-chloro-N, N, 2-trimethylammonium-1-propenyl amine (0.86g, 6.56mmol) join 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (3g, 5.96mmol) DCM (100mL) solution in, and at room temperature stirred 1 hour.Add 2-amino-5-methylpyrazine (1.3g, 11.9mmol) and pyridine (0.94mL 11.9mmol), will react restir 30 minutes.Solvent removed in vacuo.Add entry (100mL), (3 * 50mL) extract with ethyl acetate with the gained mixture.Combining extraction liquid, water (100mL), salt solution (100mL) washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (3.6g).

¹H?NMR?δ(CDCl ₃)：0.00(s，3H)，0.03(s，3H)，0.81(s，9H)，1.30(d，3H)，2.32(quin，2H)，2.51(s，3H)，3.60-3.80(m，2H)，4.20-4.39(brm，4H)，4.45(m，1H)，6.75(m，1H)，7.03(d，2H)，7.21(s，1H)，7.40(d，1H)，7.50(d，1H)，8.10(s，1H)，8.27(s，1H)，9.48(s，1H)。m/z?595(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (two Methyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid

With 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] phenylformic acid (9.8g, 0.025mol), tert-butyldimethylsilyl chloride (11.3g, 0.075mol) and imidazoles (17.08g, DMF 0.25mol) (100mL) mixture at room temperature stirred 24 hours.Add entry (100mL), (3 * 100mL) extract with ether with the gained mixture.Combining extraction liquid, water (3 * 100mL), salt solution (100mL) washing, dry (MgSO ₄), filter, and vacuum-evaporation, golden yellow oily matter obtained.Add saturated sodium bicarbonate aqueous solution (100mL) and ether (100mL), stirred 30 minutes.With 1M citric acid acidifying water layer, use ether (3 * 100mL) extractions, combining extraction liquid, dry (MgSO then ₄), filter, and vacuum-evaporation, crude product silica gel chromatography purifying is used eluent ethyl acetate, obtains required compound (6.32g).

¹H?NMR?δ(CDCl ₃)：0.00(s，3H)，0.03(s，3H)，0.84(s，9H)，1.27(d，3H)，2.35(quin，2H)，3.60-3.80(m，2H)，4.20-4.38(brm，4H)，4.46(m，1H)，6.78(s，1H)，7.03(t，1H)，7.25(m，1H)，7.38(m，2H)，7.47(d，1H)。m/z?504(M+H) ⁺

With 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy] methyl benzoate (10.65g; 0.047mmol), cesium carbonate (30.71g; 0.094mol) and 1-(3; the 4-difluoro benzoyl) (9.28g, N,N-DIMETHYLACETAMIDE 0.047mol) (80mL) suspension heated 22 hours down at 120 ℃ azetidine.Reaction mixture adds entry (60mL), then adds lithium hydroxide monohydrate (1.97g, water 0.047mol) (45mL) solution.With reactant restir 24 hours.Add entry (100mL), (3 * 50mL) extractions are to remove any ester with ethyl acetate with the gained mixture.With the water layer acidifying, with ethyl acetate (5 * 50mL) extractions.Combining extraction liquid, water (100mL), salt solution (100mL) washing, dry (MgSO ₄), filter, and vacuum-evaporation, yellow liquid obtained.Add ether/ethyl acetate mixture (3: 1) with solution with water (100mL), salt solution (100mL) washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain required compound (9.8g).

¹H?NMR?6(CDCl ₃)：1.28(d，3H)，2.35(quin，2H)，3.71(m，2H)，4.30(brm，4H)，4.54(m，1H)，6.80(m，1H)，7.05(t，1H)，7.25(m，1H)，7.40(m，2H)，7.48(dd，1H)。

m/z?390(M+H) ⁺

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

With trimethyl silyl iodine (115mL 0.79mol) joins 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base] (38.01g in acetonitrile 0.158mol) (500mL) solution, and stirred 24 hours methyl benzoate.Add methyl alcohol (300mL), will react and stir 10 minutes.The 10%w/v Sulfothiorine pentahydrate aqueous solution (100mL) is joined in this mixture, stirred 20 minutes.With saturated sodium bicarbonate aqueous solution neutralization reaction mixture, vacuum is removed organic solvent, and (4 * 100mL) extract products therefrom with ethyl acetate.Dry (MgSO ₄) organic layer that merges, filter solvent removed in vacuo.The crystallization from ethyl acetate of the thick material of gained obtains title compound (16.80g).

¹H?NMR?δ(d ₆-DMSO)：1.18(d，3H)，3.40-3.55(m，2H)，3.80(s，3H)，4.35(sex，1H)，4.80(t，1H)，6.57(m，1H)，6.90(m，2H)，9.75(s，1H)；m/z?304(M+H) ⁺

3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base] preparation of methyl benzoate describes in embodiment 3.

Available similar program is from 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(5-methylpyrazine-2-yl) benzamide prepares embodiment 8a.Required then product can be on silica gel purifying and separated, with the ethyl acetate solution wash-out of 5% methyl alcohol, crystallization from ethyl acetate/isohexane, 133 ℃ of mpt.

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl group (dimethyl) silicyl] the oxygen base }-the 1-methyl ethoxy)-N-(5-methylpyrazine-2-yl) benzamide is from 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy] methyl benzoate is with being similar to preparation 3-[4-(the basic carbonyl of azetidine-1-)-2-fluorophenoxy]-5-((1S)-2-{[/er/-butyl (dimethyl) silicyl] the oxygen base }-the 1-methyl ethoxy)-mode of N-(5-methylpyrazine-2-yl) benzamide prepares; But replace 1-(3,4-difluoro benzoyl) azetidine with 1-(3-chloro-4-fluoro benzoyl) azetidine.

Embodiment 9:3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-N-(1-second Base-1H-pyrazole-3-yl)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base } benzamide

With 3-[((1S)-2-{[(1; the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base }-the 1-methylethyl) the oxygen base]-N-(1-ethyl-1H-pyrazole-3-yl)-5-hydroxybenzamide (200mg; 0.477mmol), salt of wormwood (132mg; 2.0 equivalent) and 1-(3; the 4-difluoro benzoyl) acetonitrile (2mL) suspension of azetidine (113mg, 1.2 equivalents) heated in microwave reactor 15 hours.With ethyl acetate/aqueous ammonium chloride solution quencher reaction mixture, water ethyl acetate extraction (X2).Dry (MgSO ₄) organic layer, filter vacuum concentration.Use the chromatography purification residue then, use eluent ethyl acetate, obtain product, be white foam (135mg, 59%).

Available following method crystallization title compound:

Sample is dissolved in ethyl acetate, and the phial that will contain this solution is statically placed in another sealing phial that contains toluene the inside up to forming crystallization.Filter this crystallization, wash with isohexane then with toluene.Mpt?124℃.

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，1.45(t，3H)，1.95(t，1H)，2.4(m，2H)，3.7(m，2H)，4.1(m，2H)，4.25(s，br，2H)，4.35(s，br，2H)，4.55(m，1H)，6.75(d，2H)，7.1(s，1H)，7.15(t，1H)，7.25(s，1H)，7.35(s，1H)，7.4(d，1H)，7.55(d，1H)，8.3(s，1H)。m/z?481(M-H) ^-80％

Below compound with similar mode from 3-[((1S)-2-{[(1, the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base-the 1-methylethyl) the oxygen base]-N-(1-ethyl-1H-pyrazole-3-yl)-5-hydroxybenzamide and suitable aryl fluorochemical prepare.

3-[((1S)-and 2-{[(1, the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base }-1-methyl second Base) oxygen base]-N-(1-ethyl-1H-pyrazole-3-yl)-5-hydroxybenzamide

With 3-[((1S)-2-{[(1, the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base }-the 1-methylethyl) the oxygen base]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(phenyl methyl) the oxygen base] benzamide (2.40g, 4.71mmol) and THF (80mL) vacuumizes and with purification for argon (X3).Adding palladium carbon (10%, 422mg), reaction mixture is vacuumized, use hydrogen cleaning at last.Reaction mixture placed at room temperature stirred under the hydrogen 16 hours.Leach Pd/C, vacuum concentration obtains product, is colorless oil (1.87g, 95%).

¹H?NMR?δ(CDCl ₃)：0.01(s，3H)，0.03(s，3H)，0.88(s，9H)，1.27(d，3H)，1.49(t，3H)，3.64(dd，1H)，3.78(dd，1H)，4.10(q，2H)，4.43(m，1H)，6.60(s，1H)，6.81(s，1H)，6.98(s，1H)，7.00(s，1H)，7.37(s，1H)，8.61(br.s，1H)。m/z?420(M+H) ⁺，418(M-H) ^-。

3-[((1S)-and 2-{[(1, the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base }-1-methyl second Base) oxygen base]-N-(1-ethyl-1H-pyrazole-3-yl)-5-[(phenyl methyl) the oxygen base] benzamide

With DIPEA (3.11mL, 18.03mmol) join 3-{ (phenyl methyl) oxygen base-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (3.00g, 7.21mmol), HATU (3.41g, 9.01mmol) and 1-ethyl-1H-pyrazoles-3-amine [Chem.Heterocycl.Compd. (Engl.Transl), 11,1975,212] (1.20g is in DMF 10.8mmol) (10mL) solution.The gained mixture at room temperature stirred 3 hours.Vacuum is removed DMF.Steaming desolventizes, and residue is dissolved in 5%w/v citric acid (50mL), ethyl acetate (30mL) and ether (30mL), and organic layer is used saturated NaHCO again ₃The aqueous solution (30mL) washing and salt solution (30mL).Separate organic layer, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, with 1: 5-1: 2 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (2.40g, 65%).

¹H?NMR?δ(CDCl ₃)∶0.01(s，3H)，0.03(s，3H)，0.83(s，9H)，1.24(d，3H)，1.42(t，3H)，3.62(dd，1H)，3.75(dd，1H)，4.01(q，2H)，4.40(m，1H)，5.03(s，2H)，6.67(s，1H)，6.78(s，1H)，6.97(s，1H)，7.04(s，1H)，7.33(m，6H)，8.38(b?r.s，1H)。m/z?510(M+H) ⁺，508(M-H) ^-。

Describe among the aryl fluorochemical embodiment in front that uses among preparation embodiment 9,9a and the 9c.Used aryl fluorochemical is prepared as follows in the embodiment 9b preparation:

3,4-difluorophenyl ethyl sulfone

To 4-ethyl sulfenyl-1, add 75%-chlorine peroxybenzoic acid (2.97g) in DCM (50mL) solution of 2-two fluorobenzene (1.50g), mixture was at room temperature stirred 16 hours.Use unsaturated carbonate potassium solution (20mL) and salt solution (30mL) purging compound successively, use dried over mgso then, filter vacuum concentration.The transparent oily matter of gained silica gel chromatography purifying, with the isohexane eluant solution of 0-50% ethyl acetate, separate the product (0.90g) that comparatively fast flows down required 3,4-difluorophenyl ethyl sulfone need not to be further purified and uses.

Adopt suitable amine, prepare aryl fluorochemical used among the embodiment 9d-e with the mode that is similar to preparation 1-(3, the 4-difluoro benzoyl) azetidine of describing among the embodiment 8.

1-(3, the 4-difluoro benzoyl) tetramethyleneimine

¹H?NMR?δ(CDCl ₃)：1.8-2.1(m，4H)，3.4(t，2H)，3.7(t，2H)，7.2(m，1H)，7.3(m，1H)，7.4(t，1H)。

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

¹H?NMR?δ(d ₆-DMSO)：1.8(m，4H)，3.4(t，2H)，3.5(t，2H)，7.4(t，1H)，7.5(m，1H)，7.7(d，1H)。m/z?228，230(M+H) ⁺。

Embodiment 10:3-{[4-(azetidine-1-base carbonyl) phenyl] the oxygen base }-N-(1-ethyl -1H-pyrazole-3-yl)-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base } benzamide

With 3-{[4-(azetidine-1-base carbonyl)-2-chloro-phenyl-] the oxygen base }-N-(1-ethyl-1H-pyrazole-3-yl)-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base } benzamide (246mg, 0.504mmol) and triethylamine (0.42mL, THF 3.02mmol) (6mL) and methyl alcohol (6mL) solution vacuumize and with purification for argon (X3).(10%w/w 52mg), vacuumizes reaction mixture, charges into hydrogen at last to add palladium carbon.Place hydrogen at room temperature to stir 2 hours reaction mixture.Leach Pd/C, mixture is distributed between ethyl acetate and 1M hydrochloric acid.Dry (MgSO ₄) organic phase, the filtrate vacuum concentration obtains product (170mg, 73%).

¹H?NMR?δ(CDCl ₃)：1.25(d，3H)，1.45(t，3H)，2.35(m，2H)，3.75(m，2H)，4.1(q，2H)，4.3(m，4H)，4.6(m，1H)，6.8(m，2H)，7.0(d，2H)，7.1(s，1H)，7.3(s，1H)，7.35(s，1H)，7.65(d，2H)，8.6(s，1H)。m/z?464(M+H) ⁺

Following compound is synthetic from corresponding aryl fluorochemical with similar mode.

Embodiment 11:3-(3-fluoro-4-methoxyl group phenoxy group)-5-[(1S)-2-hydroxyl-1-methyl ethoxy Base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (0.30g, 0.74mmol), 3-fluoro-4-anisole ylboronic acid (255mg, 1.5mmol), venus crystals (II) (0.202g, 1.11mmol), triethylamine (0.517mL, 3.71mmol) and DCM (40mL) solution of fresh activatory 4  molecular sieves (1g) depress at room temperature and ambient atmosphere and stirred 2 days.By the diatomite filtration reaction mixture, (2 * 10mL) washings, vacuum is removed DCM with DCM.Residue is distributed between ethyl acetate and saturated sodium bicarbonate solution, with salt water washing organic layer, dry (MgSO ₄), vacuum concentration.Be dissolved in to residual oily matter and add 3.5M hydrochloric acid (0.5mL) in the solution of methyl alcohol (5mL), at room temperature stirred 20 minutes, use in the saturated sodium bicarbonate solution then and gained solution.With gained reaction mixture water (10mL) dilution, with ethyl acetate (20mL) extraction.With salt water washing organic layer, dry (MgSO ₄), vacuum concentration.Residue silica gel chromatography purifying is used eluent ethyl acetate, obtains required compound (95mg).

¹H?NMR?δ(CDCl ₃)：1.24(d，3H)，2.2(brs，1H)，3.6-3.8(m，5H)，3.9(s，3H)，4.4-4.6(m，1H)，6.7(s，1H)，6.8(m，3H)，6.95(m，2H)，7.15(s，1H)，7.2(s，1H)，8.6(brs，1H)；m/z?416(M+H) ⁺

Use above-mentioned the same manner, from 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-compound below 5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide and the preparation of suitable boric acid.

Embodiment 12:3-fluoro-4-[(3-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-the 5-{[(1-first Base-1H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide

Salt of wormwood (276mg) is joined 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (291mg) and 3,4-two fluoro-N, in acetonitrile (3.5mL) solution of N-dimethyl benzamide (204mg), with stirred mixture in ' SmithCreator Microwave ' 160 ℃ of heating 15 hours down.Mixture is returned to envrionment temperature and pressure, steam and remove acetonitrile, gained residue silica gel chromatography purifying, the ethyl acetate solution wash-out with 0-5% methyl alcohol obtains required compound (63mg).

¹H?NMR?δ(d ₆-DMSO)：1.22(d，3H)，2.94(s，6H)，3.49(m，2H)，3.76(s，3H)，4.54(m，1H)，4.83(t，1H)，6.53(m，1H)，6.76(m，1H)，7.14(s，1H)，7.24(m，2H)，7.40(s，1H)，7.47(d，1H)，7.57(m，1H)，10.83(br?s，1H)。m/z?457(M+H) ⁺

With universal mode from 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base-compound below N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide and the suitable aryl fluorochemical preparation.

^*Embodiment 12c and 12d are obtained from the chiral separation of non-enantiomer mixture among the embodiment 12a.Described fractionation is finished on Gilson semi prep system (200mL heads), adopts Merck 50mm 16um Chirose Bond C2 NCB post, with the flow velocity wash-out of t-butyl methyl ether/ethanol (85/15) with 80mL/min.Embodiment 12c is the isomer under first wash-out (retention time 16.08 minutes), and embodiment 12d is second isomer (retention time 20.88 minutes) under the wash-out.

The 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazoles-3- Base) benzamide

Under argon gas to 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-add trimethyl silyl iodine (23.8mL) in acetonitrile (200mL) solution of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (10.0g), the gained mixture stirred 16 hours.Add methyl alcohol (30mL) then, mixture was stirred 15 minutes, add saturated potassium carbonate (30mL) and Sulfothiorine (0.5g) then, the gained mixture was stirred 2 hours.Vacuum is removed acetonitrile, and residue water-soluble (150mL) was used ethyl acetate extraction 16 hours continuously.Vacuum is removed ethyl acetate, and residue with silica gel chromatography purifying (with the ethyl acetate solution wash-out of 0-5% methyl alcohol), is obtained required compound (7.1g).

¹H?NMR?δ(d ₆-DMSO)：1.20(d，3H)，3.44(m，1H)，3.53(m，1H)，3.75(s，3H)，4.45(m，1H)，4.79(t，1H)，6.44(m，1H)，6.52(m，1H)，6.92(m，1H)，7.02(m，1H)，7.56(m，1H)，9.58(s，1H)，10.60(br?s，1H)。m/z292(M+H) ⁺

The 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazoles- The 3-yl) benzamide

To 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[(phenyl methyl) the oxygen base] add the slurries of 10% palladium carbon (727mg) in THF (1mL) and methyl alcohol (1mL) in the THF (50mL) of benzamide (7.07g) and methyl alcohol (50mL) solution.The gained mixture is placed under the vacuum, and under hydrogen, stirred 70 hours.By the diatomite filtration mixture, with methyl alcohol (2 * 100mL) washings, then vacuum-evaporation.Residue is dissolved in ethyl acetate (10mL), handles with isohexane (40mL), leach solid, with isohexane (50mL) washing, obtain required compound (5.17g), it need not to be further purified and uses.

¹H NMR δ (d ₆-DMSO): 1.22 (d, 3H), 3.28 (s, 3H are sheltered by hydrogen), 3.38-3.53 (m, 2H), 3.76 (s, 3H), 4.65 (m, 1H), 6.44 (m, 1H), 6.54 (m, 1H), 6.93 (s, 1H), 7.04 (s, 1H), 7.57 (m, 1H), 9.63 (br s, 1H), 10.60 (s, 1H).m/z?306(M+H) ⁺，304(M-H) ^-

3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5- [(phenyl methyl) oxygen base] benzamide

With 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } DCM (150mL) solution of phenylformic acid (8.73g) is chilled to 0 ℃.Under agitation slowly add oxalyl chloride (4.81mL) and DMF (0.15mL).Mixture is risen to room temperature and stirred 16 hours, vacuum is removed organism then, residue and toluene (75mL) azeotropic.Crude product is dissolved in DCM (75mL), slowly joins in DCM (75mL) solution of the 1-methyl isophthalic acid H-pyrazoles-3-amine (3.35g) of stirring and DIPEA (14.4mL).Mixture was at room temperature stirred 18 hours, and the vacuum-evaporation organism is dissolved in ethyl acetate (150mL) with residue then.With 1M aqueous hydrochloric acid (100mL) and salt solution (50mL) washing organism, dry (MgSO ₄), vacuum-evaporation then obtains crude product.Use chromatography at 200g Biotage Flash 75 SiO it ₂Purifying on the post (with the isohexane eluant solution of 30-90% ethyl acetate), vacuum-evaporation obtains required compound (7.07g).

¹H NMR δ (d ₆-DMSO): 1.23 (d, 3H), 3.28 (s, 3H are sheltered by water), 3.40-3.52 (m, 2H), 3.77 (s, 3H), 4.70 (m, 1H), 5.03 (s, 2H), 6.56 (m, 1H), 6.71 (m, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.32-7.47 (br m, 5H), 7.58 (m, 1H), 10.73 (s, 1H).m/z?396(M+H) ⁺。

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

With 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } 2M sodium hydroxide (232mmol) processing of the solution of methyl benzoate (77.4mmol) in THF (232mL) and methyl alcohol (232mL) mixture, reaction mixture was at room temperature stirred 4 hours.Gained solution with water (250mL) dilution, vacuum is removed most organic solvent.(3 * 200mL) washings discard organic washing lotion with ether with the gained suspension.Obtained aqueous solution is acidified to pH4 with the 2M hydrochloric acid soln, with ethyl acetate (2 * 200mL) extractions.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), evaporation obtains required compound (99% productive rate).

¹H?NMR?δ(d ₆-DMSO)：1.20(d，3H)，3.46(m，2H)，4.64(m，1H)，5.15(s，2H)，6.83(app?t，1H)，7.06(s，1H)，7.13(s，1H)，7.30-7.49(m，5H)，12.67(br?s，1H)

To 3-hydroxyl-5-{[phenyl methyl] the oxygen base add in the THF solution of methyl benzoate (77.4mmol) triphenylphosphine that is loaded on the polymkeric substance (the 3mmol/g carrying capacity of 51.7g, 155mmol) and (R)-(-)-1-methoxyl group-2-propyl alcohol (102mmol).The solution that stirs is covered with argon gas and in ice bath, cool off.Dripped DIAD (116mmol) with syringe through 10 minutes, gained solution stirring 20 minutes is filtered, with THF (500mL) wash residual thing.Merging filtrate and washing lotion, evaporation obtains required compound, and it need not to be further purified and uses.

¹H?NMR?δ(d ₆-DMSO)：3.26(s，3H)，3.44(m，2H)，3.82(s，3H)，4.63(m，1H)，5.14(s，2H)，6.85(s，1H)，7.05(s，1H)，7.11(s，1H)，7.30-7.47(m，5H)..11

¹H NMR spectrum also comprises and a small amount of two (1-methylethyl) hydrazines-1, the signal of 2-two carbonic ether unanimities.

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

To stir 3, add salt of wormwood (9mol) in DMF (6L) solution of 5-methyl dihydroxy benzoate (5.95mol), the gained suspension under argon gas in stirring at room.,, reaction mixture at room temperature stirred spend the night slowly to wherein adding bromotoluene (8.42mol) through 1 hour with slight exotherm.Careful with then water (35L) quencher reaction of ammonium chloride solution (5L).(1 * 3L and 2 * 5L) extracts the gained aqueous suspension with DCM.The extraction liquid that water (10L) washing merges, dry (MgSO ₄) spend the night.With solution for vacuum evaporation, crude product divide 3 batches with chromatography purification (hurried post, 3 * 2kg silica gel is with the hexane → pure DCM that comprises 10%DCM → the comprise DCM gradient elution of 50% ethyl acetate) to remove starting raw material.Thick eluate further obtains required compound (21% productive rate) with the batch of 175g with chromatography purification (Amicon HPLC, the 5kg purification on normal-phase silica gel is with the isohexane wash-out that comprises the 20%v/v ethyl acetate).

¹H?NMR?δ(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)。

Being similar to the mode of preparation 1-(3, the 4-difluoro benzoyl) azetidine of describing among the preparation embodiment 8,, suitable phenylformic acid and suitable amine prepares aryl fluorochemical used in the preparation of embodiment 12,12b by being reacted.

3,4-two fluoro-N, N-dimethyl benzamide

¹H?NMR?δ(CDCl ₃)：2.9-3.2(m，6H)，7.2(m，2H)，7.3(m，1H)。m/z186(M+H) ⁺。

1-(3, the 4-difluoro benzoyl) tetramethyleneimine

Aryl fluorochemical used in the preparation of embodiment 12a is prepared as follows.

2-chloro-4-(ethyl sulfinyl)-1-fluorobenzene

In the DCM (100mL) of 2-chloro-4-ethylmercapto group (ethanesulphanyl)-1-fluorobenzene (2.40g) solution, add 75% metachloroperbenzoic acid (4.35g), mixture is carried under the room temperature stirred 16 hours.Use salt of wormwood (30mL) and salt solution (30mL) purging compound successively, dry then (MgSO ₄), filter vacuum concentration.The gained residue separates the product (1.26g) under the slow wash-out with silica gel chromatography purifying (with the isohexane eluant solution of 0-50% ethyl acetate).

¹H?NMR?δ(d ₆-DMSO)：1.01(t，3H)，2.80(m，1H)，3.06(m，1H)，7.64(m，2H)，7.84(dd，1H)

Embodiment 13:3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide

With salt of wormwood (182mg; 1.32mmol) join 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-hydroxy-n-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide (350mg; 0.81mmol) and 1-(3-chloro-4-fluoro benzoyl) azetidine (181mg; 0.85mmol) in the mixture in acetonitrile (5mL), in ' Smith CreatorMicrowave ' with stirred mixture 160 ℃ of heating 15 hours down.Make the gained mixture reach envrionment temperature and pressure, vacuum concentration.Residual oily matter is distributed between ethyl acetate (50mL) and water (50mL).The separating ethyl acetate layer is used the salt water washing, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (331mg).

¹H?NMR?δ(CDCl ₃)：1.28(d，3H)，1.46(d，6H)，2.05(brs，1H)，2.38(quin，2H)，3.75(m，2H)，4.20-4.40(brm，5H)，4.55(m，1H)，6.71(m，1H)，7.01(m，2H)，7.25(m，2H)，7.31(m，1H)，7.51(d，1H)，7.79(d，1H)，8.39(brs，1H)。m/z?513，515(M+H) ⁺

Also prepared following compound with above-mentioned same mode;

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-the 5-hydroxyl Base-N-(1-sec.-propyl-1 H-pyrazole-3-yl) benzamide

With 3-(benzyloxy)-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide (1.97g, 3.77mmol) and the solution of THF (70mL) vacuumizes and with purification for argon (X3).(10%w/w 400mg), vacuumizes reaction mixture, uses hydrogen cleaning at last to add palladium carbon.With reaction mixture under hydrogen stirring at room 16 hours.Leach Pd/C, vacuum concentration obtains product, is colorless oil (1.58g, 97%).

¹H?NMR?δ(CDCl ₃)：0.02(s，3H)，0.04(s，3H)，0.85(s，9H)，1.27(d，3H)，1.53(s，3H)，1.55(s，3H)，3.63(dd，1H)，3.77(dd，1H)，4.41(m，1H)，6.60(s，1H)，6.81(s，1H)，7.00(s，1H)，7.07(s，1H)，7.38(s，1H)，8.78(br.s，1H)。m/z?434(M+H) ⁺，432(M-H) ^-。

3-(benzyloxy)-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl second The oxygen base)-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide

With DIPEA (3.11mL, 18.03mmol) join 3-{ (phenyl methyl) oxygen base-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (3.00g, 7.21mmol), HATU (3.12g, 8.21mmol) and 1-sec.-propyl-1H-pyrazoles-3-amine (1.13g is in DMF 9.01mmol) (10mL) solution.The gained mixture at room temperature stirred 16 hours.Vacuum is removed DMF.Steaming desolventizes, and residue is dissolved in 5%w/v citric acid (50mL) and ethyl acetate (30mL) and the ether (30mL), uses saturated sodium bicarbonate aqueous solution (30mL) and salt solution (30mL) washing organic layer again.Separate organic layer, dry then (MgSO ₄), filter and evaporation.Use the column chromatography purifying, with 1: 4-1: 3 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (2.40g, 65%).

¹H?NMR?δ(CDCl ₃)：0.01(s，3H)，0.03(s，3H)，0.86(s，9H)，1.24(d，3H)，1.49(s，3H)，1.51(s，3H)，3.64(dd，1H)，3.78(dd，1H)，4.39(m，1H)，4.46(m，1H)，5.09(s，2H)，6.70(s，1H)，6.78(s，1H)，7.02(s，1H)，7.08(s，1H)，7.35(m，6H)，8.32(br.s，1H)。m/z?524(M+H) ⁺，522(M-H) ^-。

1-sec.-propyl-1H-pyrazoles-3-amine

With the 2-chloroacrylonitrile (3.41mL, 42.59mmol) at room temperature join stirring N-sec.-propyl hydrazonium salt hydrochlorate (4.71g, 42.6mmol), (11.8g is in water 85.2mmol) (50mL) solution for salt of wormwood.Reaction is risen to 45 ℃ of reactions 4 hours, be chilled to room temperature then.With ethyl acetate (5 * 30mL) aqueous layer extracted, dry (MgSO ₄) organic layer that merges, use activated carbon treatment, filter also and evaporate.The residue chromatography purification, the hexane solution wash-out with the 67%-100% ethyl acetate obtains title compound (3.08g, 58%), and 6: 1 mixtures for real product and regional isometry (regioisomeric) product are oily matter.This product need not to be further purified and uses.

¹H?NMR?δ(CDCl ₃)：1.42(m，6H)，3.58(br.s，2H)，4.25(sept，1H)，5.58(d，1H)，7.15(d，1H)。

The aryl fluorochemical embodiment in front that is used for preparing embodiment 13,13a, 13b describes.Used 4-fluorophenyl methyl sulfone can be bought and obtain in the preparation of embodiment 13c.The used aryl fluorochemical of preparation embodiment 13d is prepared as follows.

2-chloro-4-(ethylsulfonyl)-1-fluorobenzene

In the DCM (100mL) of 2-chloro-4-ethylmercapto group (ethanesulphanyl)-1-fluorobenzene (2.40g) solution, add 75% metachloroperbenzoic acid (4.35g), mixture was at room temperature stirred 16 hours.Use saturated potassium carbonate (30mL) and salt solution (30mL) washing gained mixture successively, dry then (MgSO ₄), filter vacuum concentration.The gained residue separates the product (0.99g) under the very fast wash-out with silica gel chromatography purifying (with the isohexane eluant solution of 0-50% ethyl acetate).

¹H NMR δ (d ₆-DMSO): 1.08 (t, 3H), 3.36 (q, 2H), 7.69 (t, 1H), 7.90 (m, 1H), 8.10 (dd, 1H) Embodiment 14:3-[4-(azetidine-1-base carbonyl) benzene oxygen Base]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzoyl Amine

With 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-sec.-propyl-1H-pyrazole-3-yl) benzamide (0.33g, 0.644mmol) be dissolved among methyl alcohol (4mL) and the THF (4mL), flask is vacuumized and with purification for argon (3 times).Add 10% palladium carbon (0.033g), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture was at room temperature stirred 20 hours.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer by diatomite, the filtrate vacuum concentration.Residue silica gel chromatography purifying, the isohexane eluant solution with the 0-100% ethyl acetate obtains required compound (0.15g);

¹H?NMR?δ(CDCl ₃)：1.30(d，3H)，1.45(d，6H)，2.20(brs，1H)，2.35(quin，2H)，3.71(m，2H)，4.20-4.40(brm，5H)，4.54(m，1H)，6.77(m，2H)，7.00(d，2H)，7.08(m，1H)，7.23(m，1H)，7.34(m，1H)，7.63(d，2H)，8.49(brs，1H)；m/z?479(M+H) ⁺

Also prepared following compound with above-mentioned same mode;

Embodiment 15:3-{4-[(dimethylamino) alkylsulfonyl] phenoxy group }-5-[(1S) 2-hydroxyl-1- Methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

To the 3-{4-[(dimethylamino) alkylsulfonyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (500mg; 1.0mmol) acetonitrile (30mL) solution in drip trimethyl silyl iodine (0.73mL; 1.0g, 5.1mmol).The gained mixture at room temperature stirred 20 hours.Slow adding sodium bicarbonate aqueous solution (saturated, 5mL), gained mixture concentrating under reduced pressure.Add entry (50mL), the gained mixture extracts with ethyl acetate (50mL).With salt solution (50mL) washing organic layer, dry (MgSO ₄), evaporation obtains crude product.It with hurried chromatography purification (using the isohexane solution gradient wash-out of the 60-100% ethyl acetate of progressive concentration), is obtained pure title compound (216mg, 45%).

¹H?NMR?δ(d ₆-DMSO)：1.23(s，3H)，2.61(s，6H)，3.53(m，2H)，3.76(s，3H)，4.57(m，1H)，4.84(t，1H)，6.55(s，1H)，6.90(s，1H)，7.21(d，2H)，7.30(t，1H)，7.48(t，1H)，7.58(d，1H)，7.75(d，2H)，10.85(br?s，1H)；m/z?475(M+H) ⁺。

The 3-{4-[(dimethylamino) alkylsulfonyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl ethoxy Base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

To 3-{2-chloro-4-[(dimethylamino) alkylsulfonyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-(1.0g adds triethylamine (1.5mL) and 10% palladium carbon (100mg) to N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide in methyl alcohol 1.9mmol) (20mL) and THF (20mL) solution.The gained mixture stirred 10 hours under hydrogen.Pass through celite ^Filtering mixt, reduction vaporization.Residue is dissolved among the DCM (100mL), and washs with 2M hydrochloric acid (100mL).Separate organic phase, water is used DCM (100mL) extraction again.Dry (MgSO ₄) organic extract liquid that merges, evaporation obtains title compound (300mg, 32%).

¹H NMR δ (d ₆-DMSO): 1.23 (d, 3H), 2.60 (s, 6H), 3.27 (s, 3H is sheltered by hydrogen), and 3.43-3.54 (m, 2H), 3.75 (s, 3H), 4.75 (m, 1H), 6.54 (m, 1H), 6.91 (m, 1H), 7.21 (d, 2H), 7.29 (s, 1H), 7.48 (s, 1H), 7.58 (m, 1H), 7.75 (d, 2H), 10.84 (s, 1H); M/z 489 (M+H) ⁺

3-{2-chloro-4-[(dimethylamino) alkylsulfonyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl Oxyethyl group]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

To 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (152mg, 0.50mmol) acetonitrile (3.5mL) solution in add salt of wormwood (345mg, 2.5mmol) and 3-chloro-4-fluoro-N, N-dimethyl benzene sulfonamide (237mg, 1.0mmol), mixture was heated 2 hours down at 160 ℃ under microwave condition.Filter the gained mixture, evaporation.Residue obtains title compound (1.8g, 98%) with hurried chromatography purification (with the isohexane solution gradient wash-out of the 60-100% ethyl acetate of progressive concentration).

¹H NMR δ (d ₆-DMSO): 1.24 (d, 3H), 2.65 (s, 6H), 3.27 (s, 3H, sheltered by hydrogen), 3.42-3.54 (m, 2H), 3.76 (s, 3H), 4.72-4.81 (m, 1H), 6.55 (m, 1H), 6.93 (m, 1H), 7.20 (d, 1H), 7.26 (s, 1H), 7.48 (s, 1H), 7.58 (m, 1H), 7.70 (dd, 1H), 7.91 (m, 1H), 10.84 (s, 1H); M/z 523,525 (M+H) ⁺

3-chloro-4-fluoro-N, the N-dimethyl benzene sulfonamide

(5.9mL, 12mmol) solution dilutes with DCM (25mL) and is chilled to 0 ℃ with the THF of 2M dimethyl amine.Add DIPEA (2.8mL), then add 3-chloro-4-fluorobenzene SULPHURYL CHLORIDE (2.5g, DCM 11mmol) (25mL) solution.The gained mixture is risen to room temperature and stirred 3 hours.Add entry (5mL) and 1M hydrochloric acid (16mL).Separate organic layer, reduction vaporization obtains title compound (2.4g, 94%).

¹H?NMR?δ(d ₆-DMSO)：2.64(s，6H)，7.68(t，1H)，7.78(m，1H)，7.94(m，1H)。

Embodiment 16:3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-1H-pyrazole-3-yl benzamide

With 4-{3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[(1H-pyrazole-3-yl amino) carbonyl] phenoxy group } phenylformic acid (130mg, 0.327mmol), HATU (156mg, 0.41mmol), the azetidine hydrochloride (38mg, 0.41mmol) and DIPEA (0.143mL; 0.82mmol) DMF (2mL) suspension at room temperature stirred 16 hours.Water is joined in the reaction mixture, with ethyl acetate (3 * 30mL) extractions.Merge organic phase, with the salt brine solution washing, dry (MgSO ₄).The filtrate vacuum concentration, the residue chromatography purification, the DCM eluant solution with 0-50% methyl alcohol obtains clarifying oily matter, and it is foam (65mg, 46%) under high vacuum.

¹H?NMR?δ(d ₆-DMSO)：1.2(d，3H)，2.2(s，2H)，2.95(s，6H)，3.2(s，3H)，3.5(m，2H)，4.0(m，2H)，4.3(m，2H)，4.6(m，1H)，4.80(t，1H)，6.6(s，1H)，6.8(s，1H)，7.05(d，2H)，7.2(s，1H)，7.4(s，1H)，7.6(s，1H)，7.65(d，2H)，10.8(s，1H)。m/z?437(M+H) ⁺，435(M-H) ⁺.

4-{3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[(1H-pyrazole-3-yl amino) carbonyl] phenoxy group } phenylformic acid is prepared as follows:

4-{3-[(1S)-and 2-hydroxyl-1-methyl ethoxy 1-5-[(1H-pyrazole-3-yl amino) carbonyl] benzene The oxygen base] phenylformic acid

With 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[(1H-pyrazole-3-yl amino) carbonyl] phenoxy group } ethyl benzoate (175mg, 0.4mmol) THF (5mL) and water (1mL) solution handle with 1N sodium hydroxide solution (3mL), will react and at room temperature stir 16 hours.After reaction is finished, solvent removed in vacuo, adding the 1N citric acid is 3-4 until pH.Filter and collect white depositions, vacuum-drying obtains required product, is white solid (138mg, 85%).

¹H NMR δ (d ₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H is sheltered peak by hydrogen), 3.5 (m, 2H), 4.55 (m, 1H), 4.80 (t, 1H), 6.6 (d, 1H), 6.8 (app s, 1H), 7.1 (d, 2H), 7.2 (s, 1H), 7.4 (s, 1H), 7.6 (d, 1H), 8.0 (d, 2H), 10.8 (s, 1H).m/z?398(M+H) ⁺，396(M-H) ⁺95％

4-{3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-[(1H-pyrazole-3-yl amino) carbonyl] benzene The oxygen base } ethyl benzoate

With trimethyl silyl iodine (0-27mL) under argon gas, be added drop-wise to 3-(3-[4-(ethoxy carbonyl) phenoxy group]-5-[(1S)-2-methoxyl group-1-methyl ethoxy] benzoyl amino)-1H-pyrazoles-1-t-butyl formate (167mg; 0.38mmol) acetonitrile (5mL) solution in, and at room temperature stirred 16 hours.Add hypo solution quencher reaction, (3 * 25mL) extract with ethyl acetate with reaction mixture.Merge organic phase, dry (MgSO ₄), the filtrate vacuum concentration obtains clarifying oily matter (180mg), and it need not to be further purified.

m/z?426(M+H) ⁺，424(M-H) ⁺88％

3-(3-[4-(ethoxy carbonyl) phenoxy group]-5-[(1S)-and 2-methoxyl group-1-methyl ethoxy] benzene Formyl radical } amino)-1H-pyrazoles-1-t-butyl formate

Depress 3-({ 3-hydroxyl-5-[(1S)-2-methoxyl group-1-methyl ethoxy] benzoyl } amino)-1H-pyrazoles-1-t-butyl formate (391mg at ambient atmosphere, 1mmol), 4-boric acid-ethyl benzoate (388mg, 2.0 equivalent), venus crystals (II) (363mg, 2.0 equivalents) and triethylamine (0.7mL; 5.0 equivalent) be suspended among the anhydrous DCM and cross the Powdered 4  molecular sieves (ca.1g) of fresh activatory 7 hours.By the diatomite filtration reaction mixture, with DCM (X3) washing.The filtrate vacuum concentration places ethyl acetate, with 1M hydrochloric acid, saturated sodium bicarbonate, saturated brine washing, dry (MgSO ₄).Filter, the filtrate vacuum concentration, chromatography purification (0-50% ethyl acetate/isohexane) obtains brown oil (210mg, 39%).

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，1.4(t，3H)，1.6(s，9H)，3.4(s，3H)，3.5(m，2H)，4.35(q，2H)，4.5(m，1H)，6.8(s，1H)，7.0(d，2H)，7.05(s，2H)，7.2(s，1H)，8.0(s，1H)，8.05(d，2H)，9.2(s，br，1H)；m/z?440(M+H) ⁺。

3-(3-hydroxyl-5-[(1 S)-2-methoxyl group-1-methyl ethoxy] benzoyl } amino)-1H- Pyrazoles-1-t-butyl formate

(23g, THF 47.8mmol) (140mL) and ethanol (140mL) solution vacuumize, and with nitrogen purge (X3) with 3-({ 3-(benzyloxy)-5-[(1S)-2-methoxyl group-1-methyl ethoxy] benzoyl } amino)-1H-pyrazoles-1-t-butyl formate.(2.3g 10%w/w), vacuumizes reaction mixture, uses hydrogen cleaning at last to add 10% palladium carbon.Reaction mixture was at room temperature stirred in hydrogen chamber 16 hours.Leach Pd/C by diatomite, the filtrate vacuum concentration obtains white foam (18g, 97%).

¹H NMR δ (d ₆-DMSO): 1.2 (d, 3H), 1.55 (s, 9H), 3.25 (s, 3H is sheltered peak by hydrogen), 3.4-3.5 (m, 2H), 4.7 (m, 1H), 6.5 (s, 1H), 6.95 (d, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 8.2 (d, 1H), 9.65 (s, 1H), 11.2 (s, br, 1H); M/z 392 (M+H) ⁺

3-(3-(benzyloxy)-5-[(1S)-2-methoxyl group-1-methyl ethoxy] and benzoyl } amino)- 1H-pyrazoles-1-t-butyl formate

To 3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } phenylformic acid (20.7g, 65.6mmol), HATU (31.2g, 82.0mmol) and 3-amino-1H-pyrazoles-1-t-butyl formate (15.0g, 82.0mmol) DMF (30mL) suspension in, add DIPEA (28.5mL, 164mmol), reaction mixture at room temperature stirred 16 hours.In reaction mixture, add entry (250mL) then, with ether (3 * 150mL) extractions.Wash organic layer with saturated brine solution, dry (MgSO ₄).Vacuum concentrated filtrate, residue leaves standstill crystallization and washs with isohexane, obtains yellow crystals (23.4g, 73%).

m/z?482(M+H) ⁺。

The preparation of 3-amino-1H-pyrazoles-1-t-butyl formate is described in embodiment 3.

3-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-the 5-{[phenyl methyl] the oxygen base } benzoic preparation describes in embodiment 12.

Embodiment 17:3-[5-chloro-2-fluoro-4-(methyl sulphonyl) phenoxy group]-5-[(1S)-the 2-hydroxyl- The 1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

Salt of wormwood (1.00g) is joined 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (1.41g) and 1-chloro-4, in NMP (20mL) solution of 5-two fluoro-2-(methyl sulphonyl) benzene (0.79g).With this mixture heating up to 115 ℃ reaction 3.5 hours, cooling was poured in the water (300mL) then, with ethyl acetate (2 * 150mL) extractions.The organism water, the salt water washing that merge, dry (MgSO ₄), vacuum-evaporation then.The silica gel chromatography purifying, the ethyl acetate solution wash-out of 0-10% methyl alcohol obtains required compound (0.86g).

¹H?NMR?δ(d ₆-DMSO)：1.23(d，3H)，3.27(s，3H)，3.45-3.60(brm，2H)，?3.76(s，?3H)，4.58(m，?1H)，?4.85(t，1H)，6.55(m，1?H)，6.95(m，?1H)，7.27(s，1H)，7.47(m，2H)，7.58(d，1H)，7.97(d，1H)，10.84(brs，1H)；m/z?498，500(M+H) ⁺，496，498(M-H) ^-。

3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-preparation of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide describes in embodiment 12.

1-chloro-4, being prepared as follows of 5-two fluoro-2-(methyl sulphonyl) benzene:

1-chloro-4,5-two fluoro-2-(methylsulfonyl) benzene

With 2-chloro-4,5-difluoro chloride (300mg) joins in water (4mL) solution of S-WAT (306mg) and sodium bicarbonate (153mg).In airtight microwave phial with this mixture heating up to 150 ℃ 400 seconds, cooling.With water (1mL) solution-treated of gained mixture with bromoacetic acid (253mg), and be heated to 150 ℃ 300 seconds, cooling is filtered then and is shifted out throw out, vacuum-drying obtains required compound (132mg).This material need not to be further purified and uses.

¹H?NMR?δ(d ₆-DMSO)：3.38(s，3H)，7.99-8.12(m，2H).

Embodiment 18:3-[2,5-two fluoro-4-(methyl sulphonyl) phenoxy groups]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

Cesium carbonate (523mg) is joined 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (234mg) and 1; 2, in acetonitrile (5mL) solution of 4-three fluoro-5-(methyl sulphonyl) benzene (169mg).With this mixture heating up to 160 ℃ 7000 seconds, cooling was filtered then, with acetonitrile (10mL) washing in airtight microwave phial.The silica gel chromatography purifying is used in filtrate vacuum-evaporation, with the ethyl acetate solution wash-out of 0-10% methyl alcohol.This obtains incomplete isolating product, therefore this mixture is used preparation HPLC purifying, and the aqueous solution gradient elution with the 5-95% acetonitrile obtains required compound (5.1mg).

¹H?NMR?δ(d ₆-DMSO)：1.24(d，3H)，3.33(s，3H)，3.45-3.59(brm，2H)，3.77(s，3H)，4.58(m，1H)，4.85(m，1H)，6.55(m，1H)，6.95(m，1H)，7.28(m，1H)，7.36(m，1H)，7.48(m，1H)，7.58(m，1H)，7.83(m，1H)，10.84(brs，1H)；m/z?482(M+H) ⁺，480(M-H) ^-

1,2, being prepared as follows of 4-three fluoro-5-(methyl sulphonyl) benzene:

1,2,4-three fluoro-5-(methyl sulphonyl) benzene

With 2,4,5-trifluorophenyl SULPHURYL CHLORIDE (279mg) joins in water (4mL) solution of S-WAT (306mg) and sodium bicarbonate (153mg).In airtight microwave phial with this mixture heating up to 150 ℃ 400 seconds, cooling.With this mixture water (1mL) solution-treated with bromoacetic acid (253mg), be heated to 150 ℃ 300 seconds, cooling is then then filtered and is shifted out throw out, vacuum-drying obtains required compound (169mg).This material need not to be further purified and uses.

¹H?NMR?δ(d ₆-DMSO)：3.35(s，3H)，7.87-8.01(m，2H).

Embodiment 19:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazoles-3- Base)-and 5-[4-(1,2,4- diazole-3-yl) phenoxy group] benzamide

With trimethyl silyl iodine (0.062mL, 0.434mmol) join 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1,2,4- diazole-3-yl) phenoxy group] benzamide (78mg, 0.174mmol) acetonitrile (2mL) solution in, reaction mixture was at room temperature stirred 18 hours.With ethyl acetate (15mL) diluting reaction thing, add saturated sodium bicarbonate aqueous solution (20mL) quencher reaction.With saturated aqueous sodium thiosulfate (20mL) washing organic phase, dry (MgSO ₄).Volatile matter is removed in decompression, gained oil silica gel chromatography purifying, and the isohexane eluant solution with the 0-100% ethyl acetate obtains title compound, is colorless solid (64mg).

¹H?NMR?δ(d ₆-DMSO)：1.22(d，3H)，3.52(m，2H)，3.75(s，3H)，4.56(q，1H)，4.83(t，1H)，6.54(d，1H)，6.85(d，1H)，7.23(m，3H)，7.44(s，1H)，7.57(d，1H)，8.06(d，2H)，9.65(s，1H)，10.82(s，1H)；m/z?436(M+H) ⁺。

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4- (1,2,4- diazole-3-yl) phenoxy group] benzamide

With the 3-{4-[(hydroxyl amino) (imino-) methyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide places trimethyl orthoformate (3mL), adds 2 boron trifluoro compounds (borontrifluoroetherate).With gained solution in CEM explorer microwave, be heated to 55 ℃ 80 minutes.Volatile matter is removed in decompression, gained oil silica gel chromatography purifying, and the isohexane eluant solution with the 0-100% ethyl acetate obtains required compound, is white foam (295mg).

¹H?NMR?δ(d ₆-DMSO)δ1.23(d，3H)，3.40-3.58(m，2H)，3.75(s，3H)，4.71?m，1H)，6.54(s，1H)，6.86(s，1H)，7.18-7.28(m，3H)，7.44(s，1H)，7.57(s，1H)，8.06(d，2H)，9.65(s，1H)，10.82(s，1H)；m/z?450(M+H) ⁺。

The 3-{4-[(hydroxyl amino) (imino-) methyl] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl Oxyethyl group]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With the azanol (solution of 50%w/w, 1mL) join 3-(4-cyano-benzene oxygen)-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (300mg, 0.74mmol) ethanol (3mL) solution in, reaction mixture was at room temperature stirred 18 hours.Vacuum is removed volatile matter, obtains required compound, is colourless foam (325mg).

m/z?440(M+H) ⁺

3-(4-cyano-benzene oxygen)-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl -1H-pyrazole-3-yl) benzamide

To 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-add THF (0.164mmol) solution of 1M hexamethyl dimethyl silanyl sodium amide in DMF (1mL) solution of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (0.164mmol).Reactant was at room temperature stirred 10 minutes, add 4-fluorobenzonitrile (0.164mmol) then.Reactant at room temperature stirred spend the night, be heated to 60 ℃ of restir then 4 hours.Reactant is chilled to room temperature, handles with 0.2 normal 4-fluorobenzonitrile and hexamethyl dimethyl silanyl sodium amide again, be heated to 70 ℃ and under this temperature, stirred 3 hours.Reaction is chilled to room temperature, handles with 0.2 normal hexamethyl dimethyl silanyl sodium amide again, be warming up to 70 ℃, under this temperature, stir and spend the night.Solvent removed in vacuo, residual oily matter distributes between ethyl acetate and water.Separate water layer, use ethyl acetate extraction again.With the organic layer that the salt water washing merges, dry (MgSO ₄), filter and evaporation, obtain residue, it is used the silica gel chromatography purifying, the DCM that uses 0-1% methyl alcohol obtains required product (60% productive rate) as elutriant.

¹H?NMR?δ(CDCl ₃)：1.35(d，3H)，3.40(s，3H)，3.55(m，2H)，3.78(s，3H)，4.60(m，1H)，6.80(m，2H)，7.10(m，3H)，7.30(m，2H)，7.62(d，2H)，8.55(br?s，1H)；m/z?407(M+H) ⁺，405(M-H) ^-

The 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-describe synthesizing in embodiment 12 of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

Embodiment 20:3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-(5-methylpyrazine-2-yl) benzamide

With DIPEA (0.4mL, 2.08mmol) join 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl } phenoxy group) phenylformic acid (110mg, 0.26mmol), HATU (210mg, 0.55mmol) and azetidine hydrochloride (49mg, 0.52mmol) DMF (3mL) suspension in, the gained mixture was at room temperature stirred 24 hours.Add entry (30mL), with ethyl acetate (3 * 15mL) extraction mixtures.With the organic extract liquid that the salt water washing merges, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the ethyl acetate solution wash-out with 5% methyl alcohol obtains required compound (55mg.

¹H?NMR?δ(CDCl ₃)：1.30(d，3H)，2.35(m，2H)，2.57(s，2H)，3.77(m，2H)，4.20-4.40(brm，4H)，4.57(m，1H)，6.80(m，1H)，7.03(d，2H)，7.12(m，1H)，7.30(m，1H)，7.64(d，2H)，8.11(s，1H)，8.42(brs，1H)，9.51(s，1H)；m/z?463(M+H) ⁺

4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl Base } phenoxy group) phenylformic acid

With 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl } phenoxy group) ethyl benzoate (0.4g, 0.88mmol) THF (16mL) solution join lithium hydroxide monohydrate (0.19g be in water 4.43mmol) (8mL) solution.This mixture was at room temperature stirred 72 hours, and vacuum is removed THF.With 1M hydrochloric acid (10mL) acidifying water layer, leach solid sediment, wash with water, vacuum-drying obtains required compound (0.22g).This material need not to be further purified and uses.

m/z?424(M+H) ⁺

4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl Base } phenoxy group) ethyl benzoate

With cesium carbonate (8.45g, 26mmol) join 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide (4g, 13mmol) with 4-ethyl fluoro benzoate (ethyl-4-fluorobenzoate) (2.33g, in N,N-DIMETHYLACETAMIDE 13mmol) (70mL) mixture, stirred mixture was heated 72 hours down at 130 ℃.Make mixture reach room temperature, add ethyl acetate (100mL).Water (5 * 4OmL), salt solution (40mL) purging compound, dry (MgSO ₄), filter vacuum concentration.Residue silica gel chromatography purifying, the isohexane solution gradient wash-out of the ethyl acetate with 50% obtains required compound (0.18g).

¹H?NMR?δ(CDCl ₃)：1.33(d，3H)，1.40(t，3H)，2.62(s，3H)，3.75(m，2H)，4.39(q，2H)，4.60(m，1H)，6.83(m，1H)，7.05(d，2H)，7.19(m，1H)，7.27(m，1H)，7.39(m，1H)，8.05(d，2H)，8.18(m，1H)，8.98(brs，1H)，9.65(m，1?H)。m/z?452(M+H) ⁺

3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-preparation of N-(5-methylpyrazine-2-yl) benzamide describes in embodiment 8.

Embodiment 20 also can be from 3-[4-, (azetidine-1-base carbonyl) phenoxy group]-5-, (, (1S)-the 2-{[tertiary butyl, (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-, (5-methylpyrazine-2-yl) benzamide with previously described from 3-[4-, (azetidine-1-base carbonyl)-2-fluorophenoxy]-5-, (, (1S)-the 2-{[tertiary butyl, (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-, the similar mode that (5-methylpyrazine-2-yl) benzamide prepares embodiment 8 prepares.Separate desired substance (169 ℃ of mpt) with crystallization the isohexane from ethyl acetate subsequently, the gained spectroscopic data with report previously consistent.

3-[4- ( -1- ) ]-5- ( ( 1S )-2-{[ ( ) ]}-1- )-N- ( 5--2- ) 3-[4- ( -1- ) ]-5- ( ( 1S )-2-{[ ( ) ]}-1- ) 83-[4- ( -1- )-2-]-5- ( ( 1S )-2-{[ ( ) ]}-1- ) 3-[4- ( -1- )-2-]-5- ( ( 1S )-2-{[ ( ) ]}-1- )-N- ( 5--2- ) 。

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) Silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid

With 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) (3.08g 5.93mmol) is dissolved among methyl alcohol (30mL) and the THF (30mL) phenylformic acid.Add triethylamine (2mL), flask is vacuumized and with nitrogen purge (3 times).Add 10% palladium carbon (200mg), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture was at room temperature stirred 16 hours, and LC-MS shows only 26% required product.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer, the flask that will comprise filtrate vacuumizes and with nitrogen purge (3 times).Add fresh 10% palladium carbon (200mg), flask is vacuumized once more, use hydrogen cleaning at last.With reaction mixture restir 16 hours at room temperature.The LC-MS demonstration reacts completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer, the filtrate vacuum concentration is dissolved in the ether (50mL), water (20mL), 1N citric acid (20mL), saturated sodium-chloride water solution (20mL) washing, dry (MgSO ₄) obtain title compound (2.16g).

¹H?NMR?δ(CDCl ₃)：0.0(d，6H)，0.85(s，9H)，1.25(d，3H)，2.35(m，2H)，3.6-3.8(m，2H)，4.15-4.4(d，4H)，4.45(m，1H)，6.8(s，1H)，7.0(d，2H)，7.25(s，1H)，7.4(s，1H)，7.65(d，2H)；m/z?486(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) benzoic preparation describes in embodiment 8a.

Embodiment 21:344-(azetidine-1-base carbonyl)-2-fluorophenoxy 1-5-| (1S)-2- Hydroxyl-1-methyl ethoxy 1-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide

With salt of wormwood (143mg; 1.04mmol) join 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid; the 3-thiazol-2-yl) benzamide (160mg; 0.52mmol) and 1-(3; the 4-difluoro benzoyl) azetidine (102mg; 0.52mmol) acetonitrile (5.0mL) mixture in, with stirred mixture in ' Smith Creator Microwave ' 160 ℃ of heating 15 hours down.Make mixture reach room temperature, vacuum concentration.Residual oil distributes between ethyl acetate (50mL) and water (50mL).The separating ethyl acetate layer is used the salt water washing, dry (MgSO ₄), evaporation obtains residue, and it with the ethyl acetate solution gradient elution of silica gel chromatography purifying with 0-10% methyl alcohol, is obtained required compound (30mg).

¹HNMR?δ(CDCl ₃)：1.25(d，3H)，2.35(s&m，5H)，3.75(m，2H)，4.20-4.40(brm，4H)，4.56(m，1H)，6.72(s，1H)，6.91(s，1H)，7.08(t，1H)，7.15(s，1H)，7.30(m，1H)，7.40(d，1H)，7.50(d，1H)；m/z?486(M+H) ⁺

Following compound is synthetic from suitable phenol with similar mode:

The precursor of embodiment 21 is prepared as follows:

The 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) Benzamide

Under argon gas with triethylamine (0.11mL, 0.79mmol) and triethyl-silicane (4.88mL, (56mg is in DCM 9mol%) (14mL) solution 27.3mmol) to join acid chloride (II).Reactant was stirred 15 minutes, drip then 3-(benzyloxy)-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(5-methyl isophthalic acid, the 3-thiazol-2-yl) benzamide (1.4g, DCM 2.73mmol) (14mL) solution, restir 48 hours.By the diatomite filtration reactant, the filtrate vacuum concentration obtains residue, and it is used the silica gel chromatography purifying, and the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (0.18g).

¹H?NMR?δ(d ₆-DMSO)：1.21(d，3H)，2.38(s，3H)，3.50(m，2H)，4.46(sex，1H)，4.81(t，1H)，6.51(m，1H)，7.01(s，1H)，7.15(s，1H)，7.21(s，1H)，7.92(s，2H)，9.72(s，1H)。m/z?309(M+H) ⁺

3-(benzyloxy)-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl second The oxygen base)-N-(5-methyl isophthalic acid, 3-thiazol-2-yl) benzamide

DIPEA (7.5mL) is joined 3-{ (phenyl methyl) oxygen base }-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (4.5g, 0.01 1mol), HATU (8.6g, 0.023mol) and 2-amino-5-methylthiazol (2.46g is in DMF 0.022mol) (70mL) suspension.The gained mixture at room temperature stirred 72 hours.Vacuum is removed DMF.Add entry (100mL), (3 * 50mL) extract the gained mixture with ethyl acetate.Combining extraction liquid is with salt solution (100mL) washing.Dry (MgSO ₄) gained solution, filter, and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (1.7g).

¹H?NMR?δ(CDCl ₃)：0.03(s，3H)，0.07(s，3H)，0.85(s，9H)，1.30(d，3H)，2.33(s，3H)，3.65(m，1H)，3.75(m，1H)，4.46(m，1H)，5.04(s，2H)，6.78(m，1H)，6.88(m，1H)，7.12(d，2H)，7.38(m，5H)，11.30(brs，1H)；m/z?513(M+H) ⁺

3-{ (phenyl methyl) oxygen base }-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) benzoic preparation describes in embodiment 5.

In the same way, prepare embodiment 21a and 21b from suitable benzylic ether deprotection:

Adopt suitable amine from 3-{ (phenyl methyl) oxygen base }-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid prepares benzylic ether used the preparation of embodiment 21a and 21b:

Embodiment 22:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazoles-3- Base)-and 5-[4-(piperidines-1-base carbonyl) phenoxy group] benzamide

With DIPEA (0.36mL, 1.95mmol) join 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid (200mg, 0.49mmol), HATU (390mg, 1.02mmol) and piperidines (0.19mL, 1.95mmol) DMF (3mL) suspension in, the gained mixture was at room temperature stirred 24 hours.Evaporating solvent.Add entry (30mL), (3 * 15mL) extract the gained mixture with ethyl acetate.With the organic extract liquid that salt solution (30mL) washing merges, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the ethyl acetate solution gradient elution with 0-20% methyl alcohol obtains required compound (167mg).

¹H?NMR?δ(CDCl ₃)：1.28(d，3H)，1.58-1.78(brm，6H)，2.15(brt，1H)，3.25-3.75(brm，4H)，3.76(m，2H)，3.78(s，3H)，4.51(m，1H)，6.75(m，2H)，7.03(d，2H)，7.08(m，1H)，7.21(m，1H)，7.30(m，1H)，7.41(d，2H)，8.51(brs，1H)；m/z?479(M+H) ⁺

Below compound in the same way from 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl phenoxy group) phenylformic acid and suitable amine is synthetic:

4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid is prepared as follows:

4-(3-(1S)-2-hydroxyl-1-methyl ethoxy)-5-{[1-methyl isophthalic acid H-pyrazole-3-yl) amino] Carbonyl } phenoxy group) phenylformic acid

With 4-(3-(and (1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base-the 1-methyl ethoxy)-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl phenoxy group) ethyl benzoate (3.78g, 6.84mmol) THF (100mL) solution join lithium hydroxide monohydrate (1.44g be in water 33mmol) (50mL) solution.Mixture was at room temperature stirred 72 hours.Add 1M hydrochloric acid to pH=2, gained mixture restir 1 hour.Vacuum is removed THF, leaches solid sediment, washes with water, and vacuum-drying obtains required compound (3.06g).

¹H?NMR?δ(d ₆-DMSO)：1.28(d，3H)，3.58(m，2H)，3.81(s，3H)，4.61(sex，1H)，6.60(m，1H)，6.88(m，1H)，7.12(d，2H)，7.25(m，1H)，7.51(m，1H)，7.63(d，1H)，8.02(d，2H)，10.87(brs，1H)；

4-(3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5- { [(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) ethyl benzoate

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (4.5g, 0.011mol), 4-ethoxy carbonyl phenyl-boron dihydroxide (3.24g, 0.016mol), venus crystals (II) (3.06g, 0.016mol), triethylamine (7.74mL, 0.055mol) and DCM (180mL) suspension of fresh activatory 4  molecular sieves (13g) at room temperature depress and stirred 3 days at ambient atmosphere.By the diatomite filtration reaction mixture, with DCM (2 * 50mL) washings.Vacuum is removed DCM, and residual oil distributes between ethyl acetate (100mL) and water (100mL), filters, with salt solution (50mL) washing ethyl acetate layer, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (3.78g).

¹H?NMR?δ(CDCl ₃)：0.04(s，3H)，0.06(s，3H)，0.88(s，9H)，1.30(d，3H)，1.41(t，3H)，3.67(m，1H)，3.78(m，1H)，3.79(s，3H)，4.38(q，2H)，4.46(m，1H)，6.78(m，2H)，7.01(m，1H)，7.03(m，2H)，7.23(m，1H)，7.29(m，1H)，8.03(d，2H)，8.39(brs，1H)。

m/z?554(M+H) ⁺

3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-preparation of 5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide describes in embodiment 5.

Embodiment 23:3-[2-fluoro-4-(piperidines-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

With DIPEA (0.36mL, 1.95mmol) join 3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid (209mg, 0.49mmol), HATU (390mg, 1.02mmol) and piperidines (0.19mL, 1.95mmol) DMF (3mL) suspension in, mixture was at room temperature stirred 24 hours.Add entry (30mL), with 4: 1 (3 * 20mL) extraction gained mixtures of ether/ethyl acetate.With the organic extract liquid that salt solution (30mL) washing merges, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the ethyl acetate solution gradient elution with 0-20% methyl alcohol obtains required compound (116mg).

¹H?NMR?δ(CDCl ₃)：1.31(d，3H)，1.55-1.78(brm，6H)，2.40(brt，1H)，3.40-3.90(brm，4H)，3.75(m，2H)，3.81(s，3H)，4.58(m，1H)，6.74(m，1H)，6.81(m，1H)，7.07(m，2H)，7.18(m，1H)，7.23(m，1H)，7.28(m，1H)，7.3?1(m，1H)，8.85?(brs，1H)；m/z?497(M+H) ⁺

Following compound is in a similar fashion from 3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid and suitable amine preparation:

3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid is prepared as follows:

3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) Amino] carbonyl } phenoxy group) phenylformic acid

With 3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) ethyl benzoate (1.8g, 3.94mmol) THF (60mL) solution join lithium hydroxide monohydrate (0.83g be in water 19.7mmol) (30mL) solution.The gained mixture was at room temperature stirred 72 hours, and vacuum is removed THF.Water layer extracts to remove any impurity with ethyl acetate (100mL).Use the 1M hcl acidifying then, with ethyl acetate (2 * 100mL) extractions.Dry (MgSO ₄) extraction liquid that merges, solvent removed in vacuo obtains required compound (1.62g).

¹H?NMR?δ(d ₆-DMSO)：1.23(d，3H)，3.50(m，2H)，3.76(s，3H)，4.58(sex，1H)，4.82(brs，1H)，6.54(d，1H)，6.84(m，1H)，7.21(m，2H)，7.42(m，1H)，7.58(d，1H)，7.81(m，2H)，10.82(brs，1H)；m/z430(M+H) ⁺

3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) Amino] carbonyl } phenoxy group) ethyl benzoate

With cesium carbonate (8.3g, 25.4mmol) join 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (3.7g, 12.7mmol) and 3,4-difluoro-benzoic acid ethyl ester (ethyl-3,4-difluorobenzoate) (2.36g, 12.7mmol) N,N-DIMETHYLACETAMIDE (60mL) mixture in, with stirred mixture 115 ℃ the heating 3 hours.The gained mixture is chilled to room temperature, adds ethyl acetate (100mL).Water (5 * 40mL), salt solution (40mL) purging compound, dry (MgSO ₄), filtering, vacuum concentration, residue silica gel chromatography purifying with the isohexane eluant solution of 50% ethyl acetate, obtains required compound (1.8g).

¹H?NMR?δ(CDCl ₃)：1.31(d，3H)，1.41(t，3H)，3.72(d，2H)，3.83(s，3H)，4.39(q，2H)，4.57(sex，1H)，6.75(m，1H)，6.83(m，1H)，7.09(m，2H)，7.30(d，2H)，7.83(m，2H)，8.91(brs，1H)。m/z?458(M+H) ⁺

Be used in JOC, the method for describing in 26,1,961 138 prepares 2-methyl azetidine required in the preparation of embodiment 23e.

Be prepared as follows 3-methoxyl group azetidine hydrochloride required in the preparation of embodiment 23f:

3-methoxyl group azetidine hydrochloride.

(0.32g, 1.71mmol) solution in ethyl acetate (10mL) solution of 3M hydrogenchloride at room temperature stirred 3 hours with 3-methoxyl group azetidine-1-t-butyl formate.Vacuum is removed volatile matter, and ethyl acetate is joined in the residue, slowly pours out then, and vacuum-drying gained residue obtains required compound (0.16g).

¹H?NMR?δ(d ₆-DMSO)：3.21(s，3H)，3.75(m，2H)，4.07(m，2H)，4.23(m，1H)，9.08(brs.1H)。

3-methoxyl group azetidine-1-t-butyl formate

In that (83mg, (0.3g is in THF 1.73mmol) (10mL) solution 3.46mmol) to join 3-hydroxy azetidine-1-t-butyl formate (JMedchem., 44 (1), 2001,94) with sodium hydride (60% oily dispersion liquid) under argon gas under 0 ℃.Reactant was stirred 30 minutes, add then methyl iodide (0.13mL, 4.15mmol).Stirred 30 minutes down at 0 ℃, at room temperature stir 3 hours then after, vacuum is removed volatile matter.Add ethyl acetate (40mL), with salt solution (40mL) washing gained mixture, dry (MgSO ₄), filtering, vacuum concentration obtains required compound (0.32g).

¹H?NMR?δ(CDCl ₃)：1.42(s，9H)，3.27(s，3H)，3.81(m，2H)，4.06(m，2H)，4.11(m，1H)。

Prepare 3-isopropoxy azetidine hydrochloride used the embodiment 23g with the mode that is similar to preparation 3-methoxyl group azetidine hydrochloride from 3-hydroxy azetidine-1-t-butyl formate:

Embodiment 24:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(2-methyl nitrogen heterocyclic Butane-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide

With DIPEA (0.20mL, 1.04mmol) join 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl } phenoxy group) phenylformic acid (0.11g, 0.26mmol), HATU (210mg, 0.55mmol) and 2-methyl azetidine (37mg, 0.52mmol) DMF (3mL) suspension in, the gained mixture at room temperature stirred 24 hours.Add ethyl acetate (30mL), water (3 * 20mL), salt solution (20mL) washing, dry (MgSO ₄), filter and evaporation, obtain residue, it is used the silica gel chromatography purifying, the ethyl acetate solution gradient elution with 0-20% methyl alcohol obtains required compound (54mg).

¹H?NMR?δ(CDCl ₃)：1.23(d，3H)，1.40(brs，3H)，1.81(brm，1H)，2.42(m，1H)，2.45(s，3H)，2.70(m，1H)，3.65(d，2H)，4.01(m，1H)，4.46(sex，1H)，4.61(m，1H)，6.68(m，1H)，6.91(d，2H)，7.05(m，1H)，7.11(m，1H)，7.56(d，2H)，8.05(s，1H)，8.60(s，1H)，9.41(s，1H)；m/z?477(M+H) ⁺

Below compound with similar mode from 4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl phenoxy group) phenylformic acid and suitable amine synthesizes:

4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(5-methylpyrazine-2-yl) amino] carbonyl } phenoxy group) benzoic preparation describes in embodiment 20.

Embodiment 25:3-f4-(azetidine-1-base carbonyl)-2-fluorophenoxy 1-5-[(17? )-2- Hydroxyl-1-methyl ethoxy 1-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide.

With cesium carbonate (780mg; 2.40mmol) join 3-hydroxyl-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (350mg; 1.2mmol) and 1-(3; the 4-difluoro benzoyl) azetidine (235mg; 1.2mmol) N,N-DIMETHYLACETAMIDE (5.0mL) mixture in, with stirred mixture in ' Smith Creator Microwave ' 160 ℃ of heating 2 hours down.Mixture is returned to envrionment temperature and pressure, between ethyl acetate (50mL) and water (50mL), distribute.The separating ethyl acetate layer, water (5 * 50mL), salt solution (50mL) washing, dry (MgSO ₄), evaporation obtains residue, and it use the silica gel chromatography purifying, and the DCM solution gradient wash-out with 0-10% methyl alcohol prepares the HPLC chromatography purification with anti-phase C18 then, usefulness 5-95% acetonitrile (+0.2%TFA) water (+0.2%TFA) solution is as eluent.Also has 10% impurity.With this mixture (0.12g 0.26mmol) is dissolved among the DMF (3mL), add imidazoles (0.123g, 1.79mmol) and tert-butyldimethylsilyl chloride (77mg, 0.51mmol).After 24 hours, add entry (30mL) in stirring at room, (2 * 50mL) extract the gained material with ether.With the extraction liquid that salt solution (50mL) washing merges, dry (MgSO ₄), evaporation obtains residue, and it use the silica gel chromatography purifying, and the chloroformic solution gradient elution with 0-10% methyl alcohol prepares the HPLC chromatography purification with anti-phase C18 then, usefulness 5-95% acetonitrile (+0.2%TFA) water (+0.2%TFA) solution is as eluent.With the flow point standing over night, vacuum is removed acetonitrile.With saturated sodium bicarbonate aqueous solution alkalization gained water-based residue, (2 * 50mL) extractions, the extraction liquid that vacuum concentration merges obtains required compound with ethyl acetate.

¹H?NMR?δ(CDCl ₃)：1.23(d，3H)，2.28(quin，2H)，2.80(brs，1H)，3.63(d，2H)，3.70(s，3H)，4.22(brm，4H)，4.46(sex，1H)，6.63(m，1H)，6.73(m，1H)，6.98(m，2H)，7.15(m，1H)，7.21(m，1H)，7.32(d，1H)，7.44(dd，1H)，8.99(brs，1H)。m/z?469(M+H) ⁺

3-hydroxyl-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-being prepared as follows of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide:

The 3-hydroxyl-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) Benzamide

With trimethyl silyl iodine (6.64mL, 47mmol) join 3-hydroxyl-5-[(1R)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (2.86g, 9.38mmol) acetonitrile (120mL) solution in, the gained mixture stirred 24 hours.Add methyl alcohol (30mL), mixture was stirred 30 minutes, add saturated potassium carbonate (30mL) and saturated sodium thiosulfate (30mL) then, the gained mixture was stirred 20 minutes.Vacuum is removed acetonitrile, adds entry (50mL).With 1M hydrochloric acid mixture is transferred to pH4, (3 * 100mL), extraction is washed the extraction liquid that merges with salt solution (50mL), dry (MgSO with ethyl acetate ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the ethyl acetate solution gradient elution with 0-50% methyl alcohol obtains required compound (1.75g).

¹H?NMR?δ(d ₆-DMSO)：1.21(d，3H)，3.41-3.58(m，2H)，3.77(s，3H)，4.45(sex，1H)，4.79(t，1H)，6.44(m，1H)，6.51(m，1H)，6.91(s，1H)，7.04(s，1H)，7.58(m，1H)，9.58(s，1H)，10.58(brs，1H)。m/z?292(M+H) ⁺

The 3-hydroxyl-5-[(1R)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) Benzamide

With 3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy]-(4.23g 0.011mol) is dissolved in ethanol (35mL) and THF (35mL) to N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide, flask is vacuumized and with purification for argon (3 times).Add 10% palladium carbon (0.42g), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 20 hours until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer by diatomite, the filtrate vacuum concentration obtains required compound (2.86g).

¹H?NMR?δ(CDCl ₃)：1.25(d，3H)，3.38(s，3H)，3.43-3.60(m，2H)，3.77(s，3H)，4.54(m，1H)，6.61(m，1H)，6.80(m，1H)，6.98(m，2H)，7.30(m，1H)，9.11(brs，1H)。m/z?306(M+H) ⁺。

3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazoles- The 3-yl) benzamide

DMF (2) is joined 3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy] phenylformic acid (3.79g, 0.012mol) and oxalyl chloride (1.25mL, 0.015mol) DCM (60mL) solution in, stirred 3 hours, vacuum is removed organism then.Crude product is dissolved in DCM (30mL), under 0 ℃, slowly join 1-methyl isophthalic acid H-pyrazoles-3-amine (1.22g, 0.013mol) and triethylamine (3.5mL is in DCM 0.025mol) (30mL) suspension.Mixture was at room temperature stirred 24 hours, and vacuum is steamed organic matter removal.The gained residue is dissolved in ethyl acetate (100mL) and washs with 1M aqueous hydrochloric acid (50mL) and salt solution (50mL), dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the isohexane eluant solution of 50% ethyl acetate, obtain required compound (4.23g).

¹H?NMR?δ(CDCl ₃)：1.31(d，3H)，3.39(s，3H)，3.45-3.61(m，2H)，3.81(s，3H)，4.55(m，1H)，5.08(s，2H)，6.73(m，1H)，6.86(m，1H)，7.08(s，1H)，7.11(s，1H)，7.30-7.50(m，6H)，8.88(brs，1H)。m/z?396(M+H) ⁺。

3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy] phenylformic acid

With lithium hydroxide monohydrate (1.30g, 0.03mol) water (40mL) solution join 3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy] methyl benzoate (4.11g, 0.012mol) THF (80mL) solution in, the gained reaction mixture at room temperature stirred 20 minutes.Vacuum is removed THF.With 1M hydrochloric acid the water-based residue is transferred to pH3, with ethyl acetate (2 * 100mL) extractions.With the extraction liquid that salt solution (50mL) washing merges, dry (MgSO ₄), to filter, evaporation obtains required compound (3.79g).

¹H NMR δ (d ₆-DMSO): 1.21 (d, 3H), 3.25 (s, 3H are sheltered by hydrogen), 3.45 (m, 2H), 4.61 (m, 1H), 5.12 (s, 2H), 6.81 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7.50 (m, 5H) .m/z 315 (M-H) ^-

3-(benzyloxy)-5-[(1R)-2-methoxyl group-1-methyl ethoxy] methyl benzoate

Under argon gas at 0 ℃ with DIAD (4.6g, 0.029mol) be added drop-wise to 3-hydroxyl-5-{[phenyl methyl] the oxygen base methyl benzoate (6g, 0.023mol), (S)-(+)-1-methoxyl group-2-propyl alcohol (2.59g, 0.029mol) and triphenylphosphine (7.53g is in THF 0.029mol) (100mL) solution.Reactant was stirred 1 hour down at 0 ℃, at room temperature stirred then 20 hours.Vacuum is removed volatile matter, adds isohexane/ethyl acetate 2: 1, stirs then 1 hour.Filtration leaches white solid, and the filtrate evaporation obtains residue, and it is used the silica gel chromatography purifying, and the isohexane solution gradient wash-out with the 0-20% ethyl acetate obtains required compound (5.11g).

¹H?NMRδ(CDCl ₃)：1.31(d，3H)，3.40(s，3H)，3.45-3.60(m，2H)，3.88(s，3H)，4.57(sex，1H)，5.07(s，2H)，6.76(m，1H)，7.25(m，2H)，7.40(m，5H).m/z?331(M+H) ⁺。

3-hydroxyl-5-{[phenyl methyl] the oxygen base } preparation of methyl benzoate describes in embodiment 1.

Embodiment 26:3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1R)-the 2-hydroxyl- The 1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (0.23g, (0.48mmol 60% is pure)) and triethylamine (0.2mL, 1.44mmol) be dissolved in the ethanol (8mL), flask is vacuumized and with purification for argon (3 times).Add 10% palladium carbon (23mg), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture was at room temperature stirred 6 days, until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer by diatomite, the filtrate vacuum concentration obtains residue, and it is used the silica gel chromatography purifying, with the ethyl acetate solution gradient elution of 0-10% methyl alcohol.Impurity also remains on 40% level.With this mixture (0.27g 0.6mmol) is dissolved in DMF (5mL), add imidazoles (0.29g, 4.2mmol) and tert-butyldimethylsilyl chloride (180mg, 1.2mmol).After at room temperature stirring 20 hours, add entry (30mL), with ether (2 * 50mL) extraction gained mixtures.The extraction liquid that merges washs with salt solution (50mL), dry (MgSO ₄) evaporation obtains residue, it is used the ethyl acetate solution gradient elution of 0-10% methyl alcohol with the silica gel chromatography purifying, prepare the HPLC chromatography purification with anti-phase C18 then, adopt the 5-95% acetonitrile (+0.2%TFA) water (+0.2%TFA) solution is as eluent.With the flow point standing over night, vacuum is removed acetonitrile.With saturated sodium bicarbonate aqueous solution alkalization gained water-based residue, (2 * 50mL) extractions, the extraction liquid that vacuum concentration merges obtains required compound (28mg) with ethyl acetate.

¹H?NMR?δ(CDCl ₃)：1.32(d，3H)，2.38(quin，2H)，3.75(m，2H)，3.90(s，3H)，4.30(t，4H)，4.60(m，1H)，6.79(m，1H)，6.90(m，1H)，7.03(d，2H)，7.17(m，1H)，7.38(m，2H)，7.68(d，2H)，9.28(brs，1H)。m/z451(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-being prepared as follows of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide:

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxyl-1-methyl Oxyethyl group]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With cesium carbonate (1.12g; 3.44mmol) join 3-hydroxyl-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (500mg; 1.72mmol) and 1-(3-chloro-4-fluoro benzoyl) azetidine (367mg; 1.72mmol) the mixture of N,N-DIMETHYLACETAMIDE (5.0mL) in, with stirred mixture in ' Smith Creator Microwave ' 160 ℃ of heating 2 hours down.The gained mixture is returned to envrionment temperature and pressure, between ethyl acetate (50mL) and water (50mL), distribute.The separating ethyl acetate layer, water (5 * 50mL), salt solution (50mL) washing, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, ethyl acetate solution gradient elution with 0-10% methyl alcohol, then, prepare the HPLC chromatography purification with anti-phase C18, adopt the 5-95% acetonitrile (+0.2%TFA) water (+0.2%TFA) solution is as eluent.Impurity still remains on 40% level.This material is used for next step (0.21g) as crude product.

m/z?485，487(M+H) ⁺

3-hydroxyl-5-[(1R)-2-hydroxyl-1-methyl ethoxy]-preparation of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide describes in embodiment 25.

Embodiment 27:3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide

10% hydrochloric acid (2mL) is joined 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) (950mg is in methyl alcohol 1.58mmol) (20mL) solution for benzamide.The gained reactant at room temperature stirred 1 hour, added saturated sodium bicarbonate solution, steamed and removed methyl alcohol.The water-based residue is transferred to pH2, use ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, use eluent ethyl acetate, obtain required compound (400mg), with its recrystallization (173 ℃-175 ℃ of mpt) from ethyl acetate.

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，2.4(m，2H)，2.5(s，3H)，3.75(d，2H)，4.2-4.4(m，4H)，4.6(m，1H)，6.85(s，1H)，7.1(d，1H)，7.15(s，1H)，7.20(s，1H)，7.4(d，1H)，7.5(s，1H)。m/z?487(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-being prepared as follows of N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide:

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (two Methyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzene Methane amide

With DIPEA (0.8mL, 4.77mmol) join 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (800mg, 1.59mmol), HATU (787mg, 2.07mmol) and 5-amino-3-methyl isophthalic acid, 2, (549mg is in DMF 4.77mmol) (10mL) suspension for 4 thiadiazoles.The gained mixture at room temperature stirred 16 hours, added entry (150mL), gained mixture ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the isohexane eluant solution of 75% ethyl acetate, obtain required compound (950mg).

m/z?601(M+H) ⁺。

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) benzoic preparation describes in embodiment 8.

Embodiment 28:3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide

Base 10% hydrochloric acid (2mL) joins 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) (580mg is in methyl alcohol 1.0mmol) (20mL) solution for benzamide.Reactant at room temperature stirred 1 hour, added saturated sodium bicarbonate solution, steamed and removed methyl alcohol.The water-based residue is transferred to pH2, use ethyl acetate extraction, combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtain crude product (275mg), with it from re-crystallizing in ethyl acetate

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，2.4(m，2H)，2.5(s，3H)，3.75(d，2H)，4.2-4.4(m，4H)，4.6(m，1H)，6.8(s，1H)，7.0(d，1H)，7.2(s，1H)，7.25(s，1H)，7.3(s，1H)，7.65(d，2H).m/z?468(M+H) ⁺。

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-being prepared as follows of N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzamide:

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) Silyl] the oxygen base }-the 1-methyl ethoxy)-N-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-yl) benzoyl Amine

With DIPEA (0.5mL, 3.0mmol) join 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (485mg, 1.0mmol), HATU (495mg, 1.3mmol) and 5-amino-3-methyl isophthalic acid, 2, (345mg is in DMF 3.0mmol) (6mL) suspension for 4 thiadiazoles.The gained mixture at room temperature stirred 16 hours, added entry (90mL), with ethyl acetate extraction gained mixture.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the isohexane eluant solution of 75% ethyl acetate, obtain required compound (580mg).

m/z?583(M+H) ⁺。

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) benzoic preparation describes in embodiment 20.

Embodiment 29:3-[4-(azetidine-1-base alkylsulfonyl) phenoxy group]-5-[(1S)-the 2-hydroxyl Base-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With the 1-[(4-fluorophenyl) alkylsulfonyl] azetidine (108mg; 0.5mmol), 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (202mg; 0.5mmol) and cesium carbonate (325mg, N,N-DIMETHYLACETAMIDE 1.0mmol) (10mL) suspension be heated to 115 ℃ 4-5 hour.In reaction mixture, add entry, with ethyl acetate (3 * 30mL) extractions.With the organic extract liquid that the salt brine solution washing merges, dry (MgSO ₄).Filter, vacuum concentration, residue silica gel chromatography purifying, the isohexane eluant solution with the 20-80% ethyl acetate obtains faint yellow oily thing, its spume (122mg) under high vacuum.

¹H?NMR?δ(d ₆-DMSO)：1.20(d，3H)，2.0(m，2H)，3.5(m，2H)，3.65(m，4H)，3.75(s，3H)，4.6(m，1H)，4.8(m，1H)，6.55(d，1H)，6.9(app?s，1H)，7.25(d，2H)，7.3(app?s?1H)，7.5(app?s?1H)，7.6(d，1H)，7.8(d，2H)；m/z?487(M+H) ⁺，485(M-H) ^-

The 1-[(4-fluorophenyl) alkylsulfonyl] being prepared as follows of azetidine:

The 1-[(4-fluorophenyl) alkylsulfonyl] azetidine

Under 0 ℃, (0.25g, (0.85g, in THF 4.6mmol) (10mL) solution, reaction mixture stirred 10 minutes 4.35mmol) to join hexamethyl dimethyl silanyl sodium amide (sodium hexamethyldisilylazide) with azetidine.(0.85g 4.35mmol), rises to ambient temperature overnight with reaction mixture and spends the night then to add 4-fluorobenzene SULPHURYL CHLORIDE.Vacuum concentration reaction mixture, residue place ethyl acetate and water.Separate organic layer, dry then (MgSO ₄), filter and evaporation, obtain wax shape yellow solid (75mg).

¹H?NMR?δ(CDCl ₃)：2.1(m，2H)，3.8(t，4H)，7.25(app?t，2H)，7.85(dd，2H).m/z?216(M+H) ⁺

Embodiment 30:3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy 1-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-1H-pyrazole-3-yl benzamide

With 3-[(3-hydroxyl-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group } benzoyl) amino]-1H-pyrazoles-1-t-butyl formate (66mg; 0.12mmol), 1-(3; the 4-difluoro benzoyl) azetidine (24mg; 0.12mmol) and cesium carbonate (59mg, DMF 0.18mmol) (2mL) suspension in microwave 150 ℃ of down heating 2 hours.Water is joined in the reaction mixture, with ethyl acetate (3 * 30mL) extractions.Water (3 * 25mL) organic layers that washing merges with saturated brine solution, dry then (MgSO ₄), filter and evaporation, obtain yellow/tangerine look oily matter.It with preparation HPLC purifying, with water (0.2%TFA modifier) eluant solution of 5-95% acetonitrile, is adopted Phenomenex column Luna 10u C18 (2) 100A (150 * 21.2mm) posts; Obtain white foam (20mg).

¹H?NMR?δ(CDCl ₃)：1.05(2H，m)，1.3(d，3H)，1.35(m，2H)，2.45(m，1H)，3.75(m，2H)，3.8(s，3H)，4.6(m，1H)，6.8()，7.1()，7.3(d，2H)，7.9(d，2H)，8.5(s?br，1H)；m/z?455(M+H) ⁺，453(M-H) ^-

1-(3; the 4-difluoro benzoyl) azetidine synthesize in embodiment 8 3-[(3-hydroxyl-5-{ (1S)-1-methyl-2-[(triisopropyl silyl is described) the oxygen base] oxyethyl group benzoyl) amino]-1H-pyrazoles-1-t-butyl formate synthetic as described below:

3-[(3-hydroxyl-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } benzoyl) amino]-1H-pyrazoles-1-t-butyl formate

With 3-[(3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group } benzoyl) amino]-(90mg, the solution of 1: 1 mixture of THF/ ethanol 0.144mmol) vacuumize and with nitrogen purge (x3) 1H-pyrazoles-1-t-butyl formate.Add 10% palladium carbon, reaction mixture is vacuumized and uses nitrogen purge, vacuumize then, use hydrogen cleaning at last.Reaction mixture was at room temperature stirred 6 hours under hydrogen.Leach palladium catalyst by diatomite.Evaporated filtrate obtains solid crude product (70mg).

m/z?534(M+H) ⁺，532(M-H) ^-

3-[(3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } benzoyl) amino]-1H-pyrazoles-1-t-butyl formate

With DIPEA (0.21mL, 1.2mmol) join 3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group phenylformic acid (220mg, 0.48mmol), HATU (228mg, 0.6mmol) and 3-amino-1H-pyrazoles-1-t-butyl formate (110mg, 0.6mmol) DMF (2mL) solution in, reaction mixture is in stirred overnight at room temperature.In the gained reaction mixture, add entry, with ethyl acetate (3 * 25mL) extractions.Separate the organic extract liquid that merges, with 1M hydrochloric acid, saturated sodium bicarbonate solution, saturated brine solution washing, dry (MgSO4) filters and evaporation.With residue silica gel chromatography purifying, the hexane solution wash-out with the 0%-50% ethyl acetate obtains clarifying oily matter (90mg).

m/z?624(M+H) ⁺，622(M-H) ^-

3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } phenylformic acid

With lithium hydroxide monohydrate (12.14g, 0.289mol) water (100mL) solution join 3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group methyl benzoate (62g, 0.131mol) THF (300mL) solution in, be warming up to 43 ℃.Reactant was stirred 16 hours.Vacuum is removed THF.To pH5, (2 * 300mL) extractions, the organic layer that dry (MgSO4) merges filter and evaporation the gained mixture, obtain title compound (60.2g) with ethyl acetate with the acidifying of 10%w/v citric acid.

¹H?NMR?δ(CDCl ₃)： ¹H?NMR?δ(CDCl ₃)：1.05(s，18H)，1.05-1.1(m，3H)，1.35(d，3H)，3.7(m，1H)，3.9(m，1H)，4.5(m，1H)，5.1(s，2H)，6.8(s，1H)，7.3-7.5(m，7H).m/z?457(M-H) ^-

3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } methyl benzoate

Following at 0 ℃ with (2R)-1-[(triisopropyl silyl) the oxygen base] propan-2-ol (56.1g, 242mmol) join 3-hydroxyl-5-{[phenyl methyl] the oxygen base } methyl benzoate (50g, 194mmol) and triphenylphosphine (63.5g, in anhydrous THF (500mL) solution 242mmol), under argon gas, added then through 45 minutes DIAD (47.6mL, 242mmol).Reactant stirred 1 hour down at 0 ℃, rose to room temperature through 1 hour, at room temperature stirred then 1 hour.Steam and remove THF, add the mixture of ethyl acetate (80mL) and hexane (120mL).This mixture was stirred 2 hours, filter.With the mixture washing precipitate of ethyl acetate (20mL) and hexane (180mL), the filtrate evaporation.With residue column chromatography purifying, with 1: 20-1: 10 ethyl acetate: the hexane wash-out obtains title compound (65.5g).

¹H?NMR?δ(CDCl ₃)：1.05(s，18H)，1.05-1.1(m，3H)，1.35(d，3H)，3.7(m，1H)，3.9(m，1H)，3.9(s，3H)，4.5(m，1H)，5.05(s，2H)，6.75(s，1H)，7.2(s，1H)。7.3-7.5(m，6H).m/z?471(M-H) ^-

(2R)-and 1-[(triisopropyl silyl) the oxygen base] propan-2-ol

(83.8mL 390mmol) slowly joined (2R)-the third-1 through 15 minutes, (29.7g in DMF 390mmol) (100mL) solution, keeps internal reaction temperature to be lower than 15 ℃ to the 2-glycol with the triisopropyl silyl chloride under 0 ℃.(66.4g 975mmol), rises to room temperature with reaction mixture, stirs 20 hours under argon gas to add imidazoles then therein.React with 1M hydrochloric acid/ether (300mL/800mL) quencher.Separate organic layer, then wash with saturated brine solution with 1M hydrochloric acid.Dry (MgSO4) organic layer filters and evaporation.By at 10mmHg, 90-104 ℃ of distillation and purifying obtains title compound down is colorless oil (69.5g).

¹H?NMR?δ(CDCl ₃)：1.05(s，18H)，1.05-1.1(m，3H)，1.05(d，3H)，2.55(s，1H)，3.45(dd，1H)，3.7(dd，1H)，3.85(m，1H)。

Embodiment 31:3-[4-(cyclobutyl alkylsulfonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 1-(cyclobutyl alkylsulfonyl)-4-fluorobenzene (100mg; 0.47mmol), cesium carbonate (162mg; 0.5mmol) and 3-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group (210mg, N,N-DIMETHYLACETAMIDE 0.47mmol) (10mL) suspension heated about 6 hours down at 115 ℃ benzamide.In reaction mixture, add entry, with ethyl acetate (3 * 40mL) extractions.Water (3 * 30mL), saturated brine solution washing organic phase, dry (MgSO4), evaporation, gained residue silica gel chromatography purifying, hexane solution wash-out with the 50-100% ethyl acetate obtains clarifying oily matter, its spume under high vacuum (65mg).

¹H?NMR?δ(d ₆-DMSO)：1.20(d，3H)，1.9(m，2H)，2.1(m，2H)，2.3(m，2H)，3.5(m，2H)，3.75(s，3H)，4.05(m，1H)，4.6(m，1H)，4.85(m，1H)，6.55(d，1H)，6.9(app?s，1H)，7.2(d，2H)，7.3(app?s?1H)，7.5(app?s1H)，7.6(d，1H)，7.8(d，2H)，10.83(br?s，1H)；m/z?486(M+H) ⁺，484(M-H) ^-

Being prepared as follows of 1-(cyclobutyl alkylsulfonyl)-4-fluorobenzene is described:

1-(cyclobutyl alkylsulfonyl)-4-fluorobenzene

(558mg 3.05mmol) is dissolved among the DCM (10mL) and is chilled to-15 ℃ with 1-(cyclobutyl sulfo-)-4-fluorobenzene.Gradation adds metachloroperbenzoic acid, and (1.11g 6.44mmol), keeps reaction ℃ between-15 ℃ and-10 ℃.Remove cooling bath, mixture was at room temperature stirred 3-4 hour.The gained reaction mixture is distributed between DCM (40mL) and water (40mL).With sodium hydrogen carbonate solution, saturated brine solution washing organic phase, dry (MgSO4), evaporation gained solution obtains white solid (578mg).

¹H?NMR?δ(CDCl ₃)：2.0(m，2H)，2.2(m，2H)，2.6(m，2H)，3.8(m，1H)，7.2(t，2H)，7.9(m，2H)

1-(cyclobutyl sulfo-) 4-fluorobenzene

With 4-fluorine thiophenol (0.5g, 3.9mmol), (1.39g, 4.3mmol) (0.58g, DMSO 4.3mmol) (10mL) solution is heated to 70 ℃ and spends the night cesium carbonate with the cyclobutyl bromine.Leach inorganic salt, filtrate is distributed between ether and water.Use ether (3 * 35mL) aqueous layer extracted then.Water (2 * 30mL), the extraction liquid that merges of saturated brine solution washing, dry (MgSO4) filters also evaporation, obtains weak yellow liquid (0.65g).

¹H?NMR?δ(CDCl ₃)：2.0(m，4H)，2.4(m，2H)，3.8(m，1H)，7.0(t，2H)，7.25(m，2H).

3-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } benzamide synthetic as described below:

3-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } benzamide

Under argon gas, 10% palladium carbon joined 3-(benzyloxy)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group } (21.7g is in anhydrous THF (480mL) solution 40.4mmol) for benzamide.Reaction mixture is carried out degasification, place then under the hydrogen balloon and stirred 16 hours.Gas is replaced with argon gas, and by the diatomite filtration mixture, then with the filtrate evaporation, drying is 1 hour under high vacuum, obtains title compound (18.2g).

¹H?NMR?δ(CDCl ₃)：1.05(s，18H)，1.05-1.1(m，3H)，1.3(d，3H)，3.7(m，1H)，3.8(s，3H)，3.9(m，1H)，4.5(m，1H)，6.6(s，1H)，6.8(s，1H)，7.0(m，2H)，7.20(s，1H)，7.3(s，1H)，8.7(s，1H)。m/z?448(M+H) ⁺，446(M-H) ^-

3-(benzyloxy)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(three different third The base silyl) oxygen base] oxyethyl group } benzamide

With HATU (23.5g 61.8mmol) joins 3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group phenylformic acid (23.6g, 51.5mmol) in, add DMF (140mL) then and be chilled to 0 ℃.Add 1-methyl isophthalic acid H-pyrazoles-3-amine (6.00g.61.8mmol), then add DIPEA (21.3mL), reactant was stirred 3 hours at 0 ℃ under argon gas.Steaming desolventizes, and residue is dissolved in the ethyl acetate (500mL), with (2 * 150mL) washings of citric acid solution (200mL), sodium hydrogen carbonate solution (150mL) and saturated brine solution.Separate organic layer, dry (MgSO ₄), filter and evaporation.Use the column chromatography purifying, with 1: 4-1: 1 ethyl acetate: the hexane wash-out, obtain title compound, be colorless oil (21.7g).

¹H?NMR?δ(CDCl ₃)： ¹H?NMR?δ(CDCl ₃)：1.05(s，18H)，1.05-1.1(m，3H)，1.3(d，3H)，3.7(m，1H)，3.8(s，3H)，3.9(m，1H)，4.5(m，1H)，5.1(s，2H)，6.7(s，1H)，6.8(s，1H)，7.0(m，2H)，7.1(s，1H)，7.3(s，1H)，7.35-7.5(m，5H)，8.5(s，1H)。m/z?538(M+H) ⁺

3-(benzyloxy)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) oxygen base] oxyethyl group } benzoic preparation describes in embodiment 30.

Following compound is with being similar to the mode of embodiment 31 from 3-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-{ (1S)-1-methyl-2-[(triisopropyl silyl) the oxygen base] oxyethyl group } benzamide and 1-(cyclopropyl alkylsulfonyl)-4-fluorobenzene preparation.

Prepare 1-(cyclopropyl alkylsulfonyl)-4-fluorobenzene with the similar mode of describing preparation 1-(cyclobutyl alkylsulfonyl)-4-fluorobenzene among the embodiment 31.

Embodiment 32:3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazoles-3- Base)-and 5-[4-(1H-pyrazole-3-yl) phenoxy group] benzamide

With trimethyl silyl iodine (0.080mL, 0.559mmol) join 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1H-pyrazole-3-yl) phenoxy group] benzamide (50mg, 0.112mmol) acetonitrile (2mL) solution in, reaction mixture was at room temperature stirred 18 hours.With ethyl acetate (15mL) diluting reaction thing, add saturated aqueous solution of sodium bicarbonate (20mL) quencher reaction.With saturated thiosulfuric acid salt brine solution (20mL) washing organic phase, dry (MgSO ₄).Volatile matter is removed in decompression, gained oil silica gel chromatography purifying, and the isohexane eluant solution with the 0-100% ethyl acetate obtains title compound, is colorless solid (40mg).

¹H?NMRδ(CDCl ₃)：1.21(d，3H)，3.59-3.72(m，2H)，3.77(s，3H)，4.35-4.47(m，1H)，6.56(d，1H)，6.64(t，1H)，6.85(d，1H)，6.94(d，2H)，7.06-7.13(m，2H)，7.28(d，2H)，7.58-7.65(m，3H)，9.64(s，1H)；m/z?434(M+H) ⁺。

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(1H-pyrazole-3-yl) phenoxy group] benzamide be prepared as follows described:

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4- (1H-pyrazole-3-yl) phenoxy group] benzamide

With 3-{4-[(2E)-3-(dimethylamino) third-2-enoyl-] phenoxy group }-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (100mg; 0.209mmol) and hydrazine hydrate (0.204mL, ethanol 4.18mmol) (3mL) solution in ' SmithCreator ' microwave, be heated to 100 ℃ 5 minutes.Vacuum is removed volatile matter, obtains product, is colourless foam (92mg).

¹H?NMR?δ(CDCl ₃)：1.26(d，3H)，3.38(s，3H)，3.41-3.49(m，1H)，3.54(dd，1H)，3.74(s，3H)，4.48-4.60(m，1H)，6.55(s，1H)，6.74(s，1H)，6.83(s，1H)，6.99(d，2H)，7.09(s，1H)，7.21(s，1H)，7.57-7.72(m，3H)，9.42(s，1H)；m/z?448(M+H) ⁺。

3-{4-[(2E)-and 3-(dimethylamino) third-2-enoyl-] phenoxy group }-5-[(1S)-the 2-methoxyl group -1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-(4-ethanoyl phenoxy group)-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (812mg; 1.92mmol) and N; the dinethylformamide dimethyl-acetal (10.2mL, 77mmol) in ' Smith Creator ' microwave, be heated to 100 ℃ 140 minutes.Volatile matter is removed in decompression, gained oil silica gel chromatography purifying, and the DCM eluant solution with 0-20% methyl alcohol obtains required product (765mg).

m/z＝479(M+H) ⁺

3-(4-ethanoyl phenoxy group)-5-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(the 1-methyl- The 1H-pyrazole-3-yl) benzamide

With 3-hydroxyl-5-[(1S)-2-methoxyl group-(1-methylethyl) oxygen base]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (400mg, 1.31mmol), PS-BEMP (2-tertbutylimido-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorus heterocycle hexatriene (phosphorine), be incorporated into polymkeric substance, loading amount 2.2mmol/g) (894mg, 1.97mmol), potassium benzoate (210mg, 1.31mmol) and the 4-fluoro acetophenone (0.160mL, NMP 1.31mmol) (10mL) mixture in ' Smith Creator ' microwave, be heated to 200 ℃ 1 hour.Leach the alkali that is loaded on the polymkeric substance, with ethyl acetate (100mL) washing resin, water (100mL) distributes organic phase, and must add salt solution to dissolve each layer this moment.Water discards then with ethyl acetate (50mL) washed twice.The organic extract liquid that merges with the saturated lithium chloride aqueous solution (2 * 100mL), the 2M sodium hydroxide solution (2 * 100mL), water (2 * 100mL), salt solution (100mL) washing, drying (MgSO ₄).Remove volatile matter, gained oil silica gel chromatography purifying, the isohexane eluant solution with the 0-100% ethyl acetate obtains required product, is colourless foam (276mg).

¹H?NMR?δ(CDCl ₃)：1.28(d，3H)，2.58(s，3H)，3.40(s，3H)，3.52(dd，1H)，3.58(dd，1H)，3.78(s，3H)，4.56(m，1H)，6.80(m，2H)，6.98-7.08(m，3H)，7.24(m，2H)，7.96(d，2H)，8.58(s，1H)；m/z?424(M+H) ⁺

Embodiment 33:2-chloro-5-fluoro-4-(3-(1S)-2-hydroxyl-1-methyl ethoxy)-5-{[(1-first Base-1H-pyrazole-3-yl) amino] carbonyl } phenoxy group)-N, the N-dimethyl benzamide

With 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (200mg, 0.477mmol), salt of wormwood (136mg, 0.95mmol) and 2-chloro-4,5-two fluoro-N, (106mg, acetonitrile 0.45mmol) (3.5mL) suspension heated 2 hours down at 160 ℃ in microwave reactor the N-dimethyl benzamide.Water quencher reaction mixture is with DCM (2 * 6mL) extractions.Dry (MgSO ₄) organic layer, filter and wipe, vacuum concentration.Then with residue with anti-phase preparation HPLC chromatography purification, (wash-out on 150 * 21.2mm) posts obtains title compound (37mg) at Phenomenex Luna1Ou C 18 (2) 100A with the aqueous solution (containing 0.2%TFA) of 5-95% acetonitrile.

¹H?NMR?δ(d ₆-DMSO)：1.22(d，3H)，2.76(s，3H)，2.83(s，3H)，3.44-3.58(brm，2H)，3.77(s，3H)，4.56(m，1H)，4.83(t，1H)，6.53(m，1H)，6.82(m，1H)，7.36-7.45(m，2H)，7.52-7.62(m，2H)，7.80(m，1H)，10.84(brs，1H)。m/z?491，493(M+H) ⁺489，49(M-H) ^-

2-chloro-4,5-two fluoro-N, being prepared as follows of N-dimethyl benzamide is described:

2-chloro-4,5-two fluoro-N, N-dimethyl benzamide

With 2-chloro-4, (385mg, (293mg 2.2mmol) handles DCM 2.0mmol) (5mL) solution the 5-difluoro-benzoic acid, stirs 1 hour under argon gas with (1-chloro-2-methyl-prop-1-alkene-1-yl) dimethyl amine.Then with this mixture with triethylamine (0.56mL, 4.0mmol) and the THF of 2M dimethyl amine (1.2mL, 2.4mmol) solution-treated stirred 18 hours, the gained mixture with DCM (5mL) with 2M hydrochloric acid (4mL) dilution and separate.Dry (MgSO ₄) organic layer, filtering, vacuum concentration obtains title compound (425mg).This residue need not to be further purified and uses.

¹H?NMR?δ(d ₆-DMSO)：2.77(s，3H)，3.00(s，3H)，7.58(m，1H)，7.80(m，1H)。

Below compound from 3-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methylethyl oxygen base)-5-hydroxy-n-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide and 2,4,5-three fluoro-N, the N-dimethyl benzamide prepares in the mode that is similar to embodiment 33.

2,4,5-three fluoro-N, the N-dimethyl benzamide prepares 2-chloro-4 with being similar to, 5-two fluoro-N, the mode of N--dimethyl benzamide prepares.

Embodiment 34:3-[4-(azetidine-1-base carbonyl)-2,5-two fluorophenoxies]-5- [(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 2,4,5-trifluoro-benzoic acid (123mg, 0.7mmol) DCM (1.7mL) solution (103mg 0.77mmol) handles, and stirs 1 hour under argon gas in (1-chloro-2-methyl-prop-1-alkene-1-yl) dimethyl amine, then with gained mixture triethylamine (0.29mL, 2.1mmol) and the azetidine hydrochloride (78mg 0.84mmol) handles, and stirs then 18 hours.The gained mixture is diluted with DCM (5mL) and 2M hydrochloric acid (4mL) and separate.Dry (MgSO ₄) organic layer, filter vacuum concentration.Gained residue 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (200mg, 0.477mmol) and salt of wormwood (284mg, 2.05mmol) acetonitrile (3.5mL) suspension handle, in microwave reactor 160 ℃ of heating 1.5 hours down.Filter reaction mixture, vacuum concentration.With silica gel chromatography purifying residue, the ethyl acetate solution wash-out with 0-15% methyl alcohol obtains title compound (74mg).

¹H?NMRδ(d ₆-DMSO)：1.23(d，3H)，2.18-2.30(m，2H)，3.44-3.58(m，2H)，3.77(s，3H)，3.98-4.11(m，4H)，4.57(m，1H)，4.83(m，1H)，6.54(m，1H)，6.84(m，1H)，7.19(m，2H)，7.43(m，1H)，7.53-7.58(m，2H)，10.83(brs，1H；m/z?487(M+H) ⁺

Below compound with similar mode from 3-hydroxyl-5-{[(1S)-2-hydroxyl-1-methylethyl] the oxygen base-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide and suitable phenylformic acid prepare.

Embodiment 35:3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-1,3-thiazol-2-yl benzamide

10% hydrochloric acid (2mL) is joined 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-1, (585mg is in methyl alcohol 1.0mmol) (20mL) solution for 3-thiazol-2-yl benzamide.Reactant was at room temperature stirred 1 hour, add saturated sodium bicarbonate solution, evaporation methyl alcohol.The water-based residue is transferred to pH2, use ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the ethyl acetate solution wash-out of 1% methyl alcohol, obtain required compound (283mg).

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，2.4(m，2H)，3.75(d，2H)，4.2-4.4(m，4H)，4.6(m，1H)，6.75(s，1H)，7.0(d，1H)，7.1(t，1H)，7.2(s，1H)，7.3(t，1H)，7.35(s，1H)，7.4(d，1H)，7.5(d，1H)。m/z?472(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-1, being prepared as follows of 3-thiazol-2-yl benzamide is described:

3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (two Methyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-1,3-thiazol-2-yl benzamide

With DIPEA (0.5mL, 3.0mmol) join 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (503mg, 1.0mmol), HATU (495mg, 1.3mmol) and 2-amino-1, (300mg is in DMF 3.0mmol) (6mL) suspension for 3 thiazoles.The gained mixture at room temperature stirred 16 hours.Add entry (90mL), gained mixture ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the isohexane eluant solution of 75% ethyl acetate, obtain required compound (585mg).

m/z?586(M+H) ⁺。

Embodiment 36:3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-[(1S)-2-hydroxyl-1- Methyl ethoxy]-N-1,3-thiazol-2-yl benzamide

10% hydrochloric acid (1mL) is joined 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-1, (284mg is in methyl alcohol 0.5mmol) (10mL) solution for 3-thiazol-2-yl benzamide.The gained mixture at room temperature stirred 1 hour, added saturated sodium bicarbonate solution, evaporation methyl alcohol.Gained water-based residue is transferred to pH2, use ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the ethyl acetate solution wash-out of 1% methyl alcohol, obtain required compound (113mg).

¹H?NMRδ(CDCl ₃)：1.3(d，3H)，2.4(m，2H)，3.75(d，2H)，4.2-4.4(m，4H)，4.6(m，1H)，6.8(s，1H)，7.0(m，3H)，7.2(s，1H)，7.3(d，1H)，7.4(s，1H)，7.65(d，2H).m/z?454(M+H) ⁺。

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-1, being prepared as follows of 3-thiazol-2-yl benzamide is described:

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) Silyl] the oxygen base }-the 1-methyl ethoxy)-N-1,3-thiazol-2-yl benzamide

With DIPEA (0.25mL, 1.5mmol) join 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (243mg, 0.5mmol), HATU (248mg, 0.65mmol) and 2-amino-1, (150mg is in DMF 1.5mmol) (3mL) suspension for 3 thiazoles.The gained mixture was at room temperature stirred 16 hours, add entry (45mL), gained mixture ethyl acetate extraction.Combining extraction liquid is used the salt water washing, dry (MgSO ₄), filter and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, with the isohexane solution of 75% ethyl acetate, obtain required compound (284mg).

m/z?568(M+H) ⁺

Embodiment 37:3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-pyrazine-2-yl-benzamide

With 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-(37mg, the mixture of methyl alcohol 0.062mmol) (0.5mL) and 3.5M hydrochloric acid (0.018mL) at room temperature stirred 30 minutes N-pyrazine-2-yl-benzamide.With saturated sodium bicarbonate aqueous solution gained solution is transferred to pH6.Vacuum is removed volatile matter.Residue is placed ethyl acetate (10mL), water (2mL), salt solution (2mL) washing, dry (MgSO ₄), to filter, solvent removed in vacuo obtains crude product, and it is used the silica gel chromatography purifying, and the ethyl acetate solution wash-out with 0-10% methyl alcohol obtains required compound, is white foam (21mg).

¹H?NMR?δ(CDCl ₃)：1.3(d，3H)，2.05(b，1H)，2.4(m，2H)，3.75(s，2H)，4.2-4.5(bd，4H)，4.55(m，1H)，6.8(s，1H)，7.0(d，1H)，7.1(s，1H)，7.25(m，1H)，7.55(d，1H)，7.8(s，1H)，8.3(s，1H)，8.4(s，1H)，8.5(b，1H)，9.60(s，1H)。m/z?483(M+H) ⁺

Below compound with similar mode from 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-pyrazine-2-yl-benzamide synthesizes:

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-pyrazine-2-yl-benzamide be prepared as follows described:

3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (two Methyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-pyrazine-2-yl-benzamide

With 1-chloro-N, N, 2-trimethylammonium-1-propenyl amine (0.073mL, 0.55mmol) join 3-[4-(azetidine-1-base carbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (260mg, 0.5mmol) DCM (10mL) solution in, at room temperature stirred 1 hour.Add 2-amino-5-methylpyrazine (95mg, 1mmol) and pyridine (0.081mL 1.0mmol), will react restir 30 minutes.Solvent removed in vacuo.Add entry (10mL), with ethyl acetate (2 * 10mL) extraction gained mixtures.Combining extraction liquid is with 1N citric acid, water (10mL) and salt solution (10mL) washing, dry (MgSO ₄), filter, and vacuum-evaporation, obtain crude product, it is used the silica gel chromatography purifying, the isohexane solution gradient wash-out with the 50-100% ethyl acetate obtains required compound (37mg).

m/z?597(M+H) ⁺

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-pyrazine-2-yl-benzamide with similar mode from 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid prepares:

Embodiment 38:3-[4-(azetidine-1-base carbonyl)-3-fluorophenoxy]-5-[(1S)-2- Hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With 3-[4-(azetidine-1-base carbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide (162mg; 0.322mmol) be dissolved in the methyl alcohol (10mL).(97mg 0.967mmol), vacuumizes flask and with nitrogen purge (3 times) to add triethylamine.Add 10% palladium carbon (25mg), flask is vacuumized once more, use hydrogen cleaning at last.Reaction mixture is at room temperature stirred 7 days until reacting completely.Reaction mixture vacuumized and with nitrogen purge (3 times).Leach catalyzer, the filtrate vacuum concentration with anti-phase preparation HPLC purifying, adopts water (containing 0.2%TFA) solution gradient elution on Phenomenex Luna 10u C 18 (2) 100A posts of 5-95% acetonitrile, obtains title compound (60mg).

¹H?NMR?δ(CDCl ₃)：1.31(d，3H)，2.32(m，2H)，3.78(m，3H)，3.96(s，3H)，4.16(t，2H)，4.72(t，2H)，4.69(m，1H)，6.22(d，1H)，6.30(s，1H)，6.35(d，1H)，6.46(s，1H)，7.28(s，1H)，7.36(s，1H)，7.41(s，1H)，7.53(t，1H)，10.16(br?s，1H)。m/z?469(M+H) ⁺

3-[4-(azetidine-1-base carbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-preparation of N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide describes in embodiment 34a.

Embodiment 39:3-[4-(2-azabicyclo [2.1.1] oneself-2-base carbonyl)-2-fluorophenoxy]-5- (1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide

With DIPEA (0.80mL, 4.32mmol) join 3-fluoro-4-(3-[(1 S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) phenylformic acid (230mg, 0-54mmol)/HATU (430mg, 1.29mmol) and 2-azabicyclo [2.1.1] hexane hydrochloride salt (96mg, 0.81mmol) DMF (4mL) suspension in, the gained mixture at room temperature stirred 24 hours.Add ethyl acetate, water (3 * 30mL), salt solution (30mL) washing, dry (MgSO ₄), evaporation obtains residue, and it is used the silica gel chromatography purifying, and the DCM solution gradient wash-out with 0-10% methyl alcohol obtains required compound (51mg).

¹H?NMR?δ(CDCl ₃)：1.21(d，3H)，1.40(m，1H)，1.51(brm，1H)，1.92(m，2H)，2.15(t，1H)，2.90(m，1H)，3.42(m，1H)，3.55(m，1H)，3.69(m，2H)，3.71(s，3H)，4.37(m，1H)，4.45(m，1H)，6.70(m，1H)，6.73(s，1H)，6.98(m，1H)，7.05(t，1H)，7.12(s，1H)，7.27(m，2H)，7.30-7.50(brm，1H)，8.61(brs，1H)；m/z?495(M+H) ⁺

3-fluoro-4-(3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenoxy group) benzoic preparation describes in embodiment 23.

Being prepared as follows of 2-azabicyclo [2.1.1] hexane hydrochloride salt is described:

2-azabicyclo [2.1.1] hexane hydrochloride salt

With 2-azabicyclo [2.1.1] hexane-2-ethyl formate (0.35g, 2.25mmol) and concentrated hydrochloric acid (10mL) refluxed 4 hours, cooling, vacuum is removed volatile matter.Add toluene, vacuum is removed then, and the products therefrom drying under reduced pressure obtains required compound, and it need not to be further purified and uses (0.24g).

2-azabicyclo [2.1.1] hexane-2-ethyl formate is according to there being the preparation of (J.Org.chem.1998,63,8558) document earlier, and its spectroscopic data is consistent with literature value.

Embodiment 40:3-[4-(azetidine-1-base carbonyl) phenoxy group]-N-(1, the 5-dimethyl- The 1H-pyrazole-3-yl)-5-[(1S)-and 2-hydroxyl-1-methyl ethoxy] benzamide

3.5M hydrochloric acid (1.0mL) is joined 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(1,5-dimethyl-1H-pyrazole-3-yl) (232mg is in methyl alcohol 0.4mmol) (10mL) solution for benzamide.Reaction mixture was stirred 45 minutes, add saturated sodium bicarbonate solution then and transferred to 7 until pH.This mixture of vacuum concentration.The gained residue is dissolved in ethyl acetate (50mL), water (25mL) and salt solution (25mL) washing.Dry (MgSO ₄), the simmer down to white foam.With this crude product silica gel chromatography purifying, the ethyl acetate solution wash-out with 0-10% methyl alcohol obtains required product, is white foam (123mg).

¹H?NMR?δ(CDCl ₃)：1.39(d，3H)，2.21(br?s，1H)，2.27(s，3H)，2.34(m，2H)，3.64(s，3H)，3.73(br?s，2H)，4.24(br?s，2H)，4.34(br?s，2H)，4.52(m，1H)，6.56(s，1H)，6.75(s，1H)，7.01(d，2H)，7.08(d，1H)，7.21(s，1H)，7.65(d，2H)，8.49(s，1H)。m/z?465(M+H) ⁺

The following examples with similar mode from 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-preparation of N-(1,5-dimethyl-1H-pyrazole-3-yl) benzamide

3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) Silyl] the oxygen base }-the 1-methyl ethoxy)-N-(1,5-dimethyl-1H-pyrazole-3-yl) benzoyl Amine

With DIPEA (517mg, 3.00mmol) join 3-[4-(azetidine-1-base carbonyl) phenoxy group]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) phenylformic acid (364mg, 0.75mmol), 3-amino-1,5-dimethyl pyrazole (100mg, 0.90mmol) and HATU (599mg, 1.58mmol) DMF (3.0mL) solution in, the gained mixture stirred 24 hours.Add entry (25mL), (2 * 25mL) extract the gained mixture, dry (MgSO with ethyl acetate ₄), the simmer down to brown oil.This crude product silica gel chromatography purifying is used eluent ethyl acetate, obtains required product, is clarification oily matter (232mg).

m/z?480(M+H) ⁺

Used 3-[4-in the preparation of embodiment 40a (azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy)-N-(1,5-dimethyl-1H-pyrazole-3-yl) benzamide is in a similar fashion from 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-methyl ethoxy) the phenylformic acid preparation.

3-amino-1, the preparation of 5-dimethyl pyrazole is described in document (J.Het.Chem.1982,19 (6) .1267).

Biology

Test:

Mode below available is tested the biological effect of formula (I) compound:

(1) enzymic activity

The enzymic activity of recombinant human pancreas GLK can be measured by hatching GLK, ATP and glucose.Product forms speed can be by measuring and G-6-P desaturase, the coupling of NADP/NADPH system, and detecting then in 340nm absorbancy linearity in time increases to determine (Matschinsky et al 1993).Available this measuring method is in the presence of the GLKRP or do not have in the presence of the GLKRP assessing compound to the GLK activation, as Brocklehurst etal (Diabetes 2004,53,535-541) described in.

The generation of reorganization GLK and GLKRP:

Adopt Sambrook J, Fritsch EF﹠amp; Maniatis T, the technology of describing in 1989 of determining obtains people GLK and GLKRPcDNA from people's pancreas and liver mRNA respectively by PCR.According to Tanizawa et al 1991 and Bonthron, GLK and GLKRP cDNA sequence that D.T.et al 1994 (afterwards at Warner, proofreading and correct among the J.P.1995) shows design the PCR primer.

In Bluescript II carrier, clone

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

Transform

Intestinal bacteria transform and are undertaken by electroporation usually.With the culture of 400mL bacterial strain DH5a or BL21 (DE3) in L-broth culture (broth), cultivate to OD 600 be 0.5,2, the centrifugal results of 000g.The gained cell is preserved at-70 ℃ of following equal portions in lmL 10% glycerine with ice-cold deionized water wash twice, resuspending.Carry out desalination with Millipore V seriesTM film ((0.0025mm) aperture) to connecting mixture (Ligation mixes).The 40ml cell is connected mixture or plasmid DNA in 0.2cm electroporation cuvette, hatched 10 minutes with 1mL, use Gene Pulser then on ice ^TMInstrument (BioRad) is at 0.5kVcm ^-1, the 250mF pulse.Transformant is selected on the L-agar that is supplemented with 10mg/mL tsiklomitsin or 100mg/mL Ampicillin Trihydrate.

Express

The pTB375NBSE vector expression of GLK from E.coli BL21 cell produces the recombinant protein that comprises the 6-His mark that is close to N-end methionine(Met).Perhaps, another suitable carriers is pET21 (+) DNA, Novagen, product batch number 697703.The 6-His mark is used for purification of recombinant proteins on being equipped with available from the pillar of Qiagen (cat no 30250) nickel-complexon I agarose.

PFLAG CTC (IBI Kodak) vector expression of GLKRP from E.coli BL21 cell produces the recombinant protein that comprises C-end FLAG mark.This albumen is used the DEAESepharose ion-exchange purification at first, then utilize FLAG be marked at available from the M2 of Sigma-Aldrich (cat no.A1 205) anti--carry out last purifying on the FLAG immunoaffinity post.

(2) oral glucose tolerance test (OGTT)

Oral glucose tolerance test carries out with the fat fa/fa rat of clear-headed Zucker (age 12-13 week or more than), feeds at least before the experiment and raises high fat diet (45%kcal fat) two weeks.The animal fasting is two hours before the test.At preceding 120 minutes orally give test-compounds of the glucose solution of oral 2g/kg body weight dosage or vehicle.Before taking glucose and different time points afterwards (time-histories 60 minutes) gather the afterbody blood sample, detect glucose level with Accucheck blood sugar detection instrument.Draw the glucose level time curve, calculate 120 minutes area under curve (AUC) (time of taking glucose is the zero-time).The AUC that adopts the vehicle control group (promptly 0 percent) in contrast determines the percentage of glucose clearance reduction.

Embodiment 3a example II 107

Compound of the present invention activates glucokinase usually, its EC ₅₀Be no more than about 500nM.For example, the EC of embodiment 3a ₅₀Be 50nM.

Embodiment 3a among the WO03/015774 and example II 107 have general similarly EC ₅₀Value.But embodiment 3a has good oral endurance (oral exposure), shows the 17%OGTT activity at 3mg/kg, and the example II 107 among the WO03/015774 does not have activity at 10mg/kg.

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Claims

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

Wherein:

R ¹Be methylol;

HET-1 comprises 2 nitrogen-atoms and optional 5-or 6 yuan of hetero-aromatic rings that C-is connected that pass through that also comprise 1 or 2 ring hetero atom that independently is selected from O, N and S; Described ring is chosen wantonly on effective carbon atom or independently be selected from R by 1 or 2 on theheterocyclic nitrogen atom ⁶Substituting group replace, condition is that described nitrogen-atoms is not therefore and by quaternized;

HET-2 comprises 1,2,3 or 4 heteroatomic 4-, 5-or 6-unit heterocycle that is connected by C-or N-that independently is selected from O, N and S, wherein-and CH ₂-can choose 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 are chosen wantonly and effectively independently are being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁷Substituting group replace;

R ⁵Be hydrogen or (1-4C) alkyl;

HET-3 is the saturated or part unsaturated heterocycle of 4-6 unit that connects by N-, chooses wantonly also to comprise 1 or 2 heteroatoms (except that being connected the N atom) 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 and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is 7 yuan of saturated or part unsaturated heterocycles that connect by N-, chooses wantonly also to comprise 1 heteroatoms (except that being connected the N atom) that independently is selected from O, S and N, wherein-CH ₂-group can be chosen wantonly by-C (O)-group 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 and effectively independently is being selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is the saturated or unsaturated bicyclic heterocycle of part of 6-10 unit, optional 1 nitrogen-atoms (except that connecting the N atom) that also comprises, wherein-CH ₂-group can be chosen wantonly by-C (O)-group displacement; Described ring is chosen wantonly and effectively is being selected from hydroxyl and R by 1 on carbon or the nitrogen-atoms ³Substituting group replace;

R ⁸Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, HET-3 (wherein said ring is unsubstituted), (14C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _PR ⁵

HET-4 is the unsubstituted hetero-aromatic ring of 5-or 6-unit that C-or N-are connected that passes through that comprises 1,2 or 3 ring hetero atom that independently is selected from O, N and S;

Independently be 0,1 or 2 when P occurs at every turn;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2.

2. the formula of claim 1 (I) compound or its salt, prodrug or solvate, condition are the compounds in the scope of the invention of dropping on of getting rid of example among the WO2004/076420.

3. claim 1 or 2 formula (I) compound or its salt, prodrug or solvate, wherein R ¹Has (S) configuration.

4. claim 1,2 or 3 formula (I) compound or its salt, prodrug or solvate, wherein HET-1 is a 5-unit ring.

5. each formula (I) compound or its salt, prodrug or solvate, wherein R among the claim 1-4 ²Be selected from-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵, R ⁴And R ⁵Can form the heterocycle ring system that defines by HET-3 with the nitrogen-atoms that connects them.

6. each formula (I) compound or its salt, prodrug or solvate among the claim 1-5, wherein HET-3 is 4 to 6-unit's rings.

7. claim 1,2 or 3 formula (I) compound or its salt, prodrug or solvate, wherein R ²Be selected from-C (O) NR ⁴R ⁵With-SO ₂NR ⁴R ⁵, and R ⁴Be selected from (1-4C) alkyl [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.

8. claim 1,2 or 3 formula (I) compound or its salt, prodrug or solvate, wherein R ²For-SO ₂R ⁴, and R ⁴Be selected from (1-4C) alkyl [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.

9. claim 1,2 or 3 formula (I) compound or its salt, prodrug or solvate, wherein R ²Be HET-2.

10. the formula of claim 1 (I) compound is one or more following compounds or its salt, prodrug or solvate:

12) 3-chloro-4-[(3-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-5-{[(1-methyl isophthalic acid H-pyrazole-3-yl) amino] carbonyl } phenyl) the oxygen base]-N, the N-dimethyl benzamide;

15) 3-{[4-(azetidine-1-base carbonyl)-2-fluorophenyl] the oxygen base }-5-{[(1S)-and 2-hydroxyl-1-methylethyl] the oxygen base }-N-(5-methylpyrazine-2-yl) benzamide;

62) 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-5-{4-[(3-methoxyl group azetidine-1-yl) carbonyl] phenoxy group }-N-(5-methylpyrazine-2-yl) benzamide;

82) 3-[4-(2-azabicyclo [2-1-1] oneself-2-base carbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl) benzamide;

84) 3-[4-(azetidine-1-base carbonyl)-2-fluorophenoxy]-N-(1,5-dimethyl-1H-pyrazole-3-yl)-5-[(1S)-2-hydroxyl-1-methyl ethoxy] benzamide.

11. comprising among the claim 1-10 each compound or its salt, prodrug or solvate and pharmacy, a medicinal compositions, described composition can accept diluent or carrier.

12. each compound or its pharmaceutically acceptable salt, solvate or prodrug among the claim 1-10 are as medicine.

13. the purposes of each compound in the medicine of the disease that the preparation treatment mediates by GLK among the claim 1-10.

14. the purposes of each compound in the medicine of preparation treatment diabetes B among the claim 1-10.

15. a method for the treatment of the disease of GLK mediation, described method are formula (I) compound or its salt, solvate or the prodrug that needs among the claim 1-10 of Mammals significant quantity of this treatment each.

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

17. a method for preparing each formula (I) compound among the claim 1-10, it comprises that process a)-d) (defines in the formula as claimed in claim 1 of variable wherein (I) compound) except as otherwise noted:

Or

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

X wherein ¹Be leavings group, X ²Be hydroxyl, or X ¹Be hydroxyl, X ²Be leavings group, wherein R ¹Be methylol or its protected form;

[or with the compound of formula V and the intermediate ester reaction of formula (VII), wherein P ¹Be blocking group, then carry out ester hydrolysis and amidation];

Or

X wherein ³Be leavings group or organometallic reagent, X ⁴Be hydroxyl, or X ³Be hydroxyl, X ⁴Be leavings group or organometallic reagent, wherein R ¹Be methylol or its protected form;

[or, then carrying out ester hydrolysis and amidation] with the compound of (VIII) and the intermediate ester reaction of formula (X);

Or

X wherein ⁵Be leavings group, wherein R ¹Be methylol or its protected form;

Then, if desired:

I) formula (I) compound is converted into another formula (I) compound;

Ii) remove any blocking group; And/or

Iii) form salt, prodrug or solvate.