CN107108656B - N- substitution -3,5- disubstituted benzenes Carbox amide and its preparation method and application - Google Patents

N- substitution -3,5- disubstituted benzenes Carbox amide and its preparation method and application Download PDF

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CN107108656B
CN107108656B CN201680004411.5A CN201680004411A CN107108656B CN 107108656 B CN107108656 B CN 107108656B CN 201680004411 A CN201680004411 A CN 201680004411A CN 107108656 B CN107108656 B CN 107108656B
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oxygroup
base
preparation
pyridine
alkyl
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CN107108656A (en
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段文虎
沈旭
陈静
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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Abstract

The present invention discloses a kind of N- and replaces -3,5- disubstituted benzenes Carbox amide and its preparation method and application, and the compound structure is as shown in general formula I, in formula, m, X, Y, R1、R2And R3As shown in claims and specification.The invention also discloses the pharmaceutical compositions comprising chemical combination shown in general formula I.The compound of the present invention can be used as glucokinase agonist, for preventing and/or treating disease relevant to abnormal glucose metabolism.

Description

N- substitution -3,5- disubstituted benzenes Carbox amide and its preparation method and application
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to N- replaces -3,5- disubstituted benzenes formamide Class compound, its pharmaceutical salts, its prodrug and its hydrate or solvate, are also related to the preparation method of the compound, include The pharmaceutical composition as well as glucokinase agonist of the compound are prevented and/or are treated and 2 type glycosurias in preparation Purposes in the relevant drug of disease.
Background technique
Glucokinase (GK) is distributed mainly on hepatic parenchymal cells and beta Cell of islet.Glucokinase can be catalyzed liver reality The glucose of cell plastid is converted into G-6-P, this is the first step of glucose metabolism in liver cell.Glucokinase Glucorceptor of the energy as beta Cell of islet controls reaction of the insulin for a certain specific glucose load.
Studies have shown that closely related (the Nissim of morbidity of glucokinase gene and diabetes positioned at chromosome 7p I.et al,The Biochemical journal 2012,444(3):537-51).The homozygote GK of high activity can cause to surpass Hyperinsulinemia and hypoglycemia；And the heterozygote GK for losing function will lead to teenager's maturity-onset diabetes (MODY-2) (Shammas C.et al,Metabolism 2013,62(11):1535-42).In addition, the reduction of liver GK activity may participate in Insulin resistance is induced, leads to blood glucose rise, islet function is impaired and insulin resistance aggravates.This prompt activation activation glucose Thus kinases causes liver cell that will be used for the phosphorylation of glucose and/or reduction beta Cell of islet for the set point of glucose load Treat hyperglycemia and diabetes B.
GK is in terms of adjusting blood glucose balance mainly by 6-phosphofructo-2-kinase/fructose -2,6- dual phosphorylation enzyme (6- Phosphofructo-2-kinase/fructose-2,6-bisphosphatase, PFK-2/FBPase-2), pro apoptotic protein The adjusting of BAD and Glucokinase regulatory protein (GKRP) etc..In liver and islet cells, PFK-2/FBPase-2 is as GK The binding partners of activation, this bifunctional enzyme are combined by a diphosphatase site with GK.Under high sugared state, pancreas islet β PFK-2/FBPase-2 is activated in cell to activate the insulin secretion that glucose can be caused to stimulate after GK.Pro apoptotic protein BAD is primarily present in the mitochondria of liver and islet cells as GK binding protein, by the line grain for adjusting glucose stimulation Body breathing promotes hepatic glycogen synthesis, enhances insulin secretion, and protect β cell survival.GKRP is that specificity is present in liver Molecular weight is the protein of 68KDa, is the endogenous inhibitor of GK, is formed in conjunction with GK under low glucose concentrations state compound Object and stop GK to nucleus.GKRP determine the subcellular location of GK and under fast state enzyme in nucleus It is free.Bourbonais F J etc. reports that some glucokinase agonists can directly act on GK or make GK-GKRP Unstability shifts to outside core out of core come the GK that dissociates and plays activation (Bourbonais F J.et al, the The to GK Biochemical journal 2012,441(3):881-7)。
As previously mentioned, being the Critical policies for treating diabetes B by the activity for directly and/or indirectly adjusting GK.At present Many compounds that can effectively activate GK and there is adjusting blood glucose balance are had discovered that, to activate or enhancing glucokinase Activity, need to carry out more researchs.
Summary of the invention
The purpose of the present invention is to provide a kind of N- substitution -3,5- disubstituted benzenes Carbox amide, its pharmaceutical salts, its Prodrug and its hydrate or solvate and preparation method and application.
The first aspect of the present invention, provide compound shown in a kind of general formula I, its pharmaceutically acceptable salt, its prodrug, its Hydrate or solvate:
In formula, m 0,1,2 or 3；
X is-O- ,-S- ,-(CH2)nOr-C (O)-, wherein n is 1,2 or 3；
Y is-O- ,-S- ,-N- or-CH-；
R1For substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C6- C10Aryl or substituted or unsubstituted 3-8 unit's heteroaryl, wherein the substitution refers to substituent group selected from the group below: C3- C8Naphthenic base, C6-C10Aryl, C1-C6Alkoxy, 3-8 unit's heteroaryl；
R2For substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 3-8 Unit's heteroaryl, wherein the substitution refers to substituent group selected from the group below: halogen, cyano, halogenated C1-C6Alkyl ,-SO2(C1- C6Alkyl) ,-SO2(C3-C8Naphthenic base) ,-SO2(3-8 membered heterocycloalkyl) ,-CO (3-8 membered heterocycloalkyl)-,-CO (C1-C6Alkane Base)-,-CO (C3-C8Naphthenic base)-,-CO2(3-8 membered heterocycloalkyl)-,-CO2(C1-C6Alkyl)-,-CO2(C3-C8Cycloalkanes Base)-,-CONR4R5-、C6-C10Aryl；
R3For nothing, hydrogen, C1-C6Alkyl, C6-C10Aryl, C1-C3Carboxyl ,-COO (C1-C6Alkyl), 3-8 unit's heteroaryl ,- NR4R5-、-CO(C1-C6Alkyl) ,-COO (C6-C10Aryl) ,-COO (3-8 unit's heteroaryl) ,-CO (C6-C10Aryl) ,-CO (3-8 Unit's heteroaryl)；
Each R4、R5Independently selected from: C1-C6Alkyl, hydrogen ,-COC1-C6Alkyl；
Condition is R1、R2It is not simultaneously unsubstituted C1-C6Alkyl；And work as R2For substituted or unsubstituted 3-8 unit's heteroaryl When, Y is-O- ,-S- ,-N- or R3It is not hydrogen.
In another preferred example, R1For substituted or unsubstituted C1-C6Alkyl or substituted or unsubstituted C3-C8Naphthenic base, Wherein, the substitution refers to substituent group selected from the group below: C3-C8Naphthenic base, C6-C10Aryl, C1-C6Alkoxy.
In another preferred example, R1For C1-C6Alkyl, C3-C8Naphthenic base, C3-C8The C that naphthenic base replaces1-C6Alkyl, C1-C4 The C that alkoxy replaces1-C6The C that alkyl, phenyl replace1-C4Alkyl.
In another preferred example, R1For C1-C4Alkyl, C3-C6Naphthenic base, C3-C6The C that naphthenic base replaces1-C4Alkyl, C1-C4 The C that alkoxy replaces1-C4The C that alkyl, phenyl replace1-C3Alkyl.
In another preferred example, R1For isopropyl ,-CH (CH3)CH2OCH3, cyclopenta ,-CH2C5H9, cyclohexyl or benzene first Base.
In another preferred example, R2For substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C6-C10Aryl takes Generation or unsubstituted 5-7 unit's heteroaryl, wherein the substitution refers to substituent group selected from the group below: halogen ,-SO2(C1-C4Alkane Base) ,-SO2(C3-C6Naphthenic base) ,-SO2(3-6 membered heterocycloalkyl) ,-CO (3-6 membered heterocycloalkyl)-,-CON (C1-C6Alkyl) (C1-C6Alkyl)-, C6-C10Aryl.
In another preferred example, R2The C replaced for phenyl1-C4The C that alkyl or group selected from the group below replace6-C10Aryl Or 5-7 unit's heteroaryl: halogen ,-SO2(C1-C4Alkyl) ,-SO2(C3-C6Naphthenic base) ,-SO2(3-6 membered heterocycloalkyl) ,-CO (3- 6 membered heterocycloalkyls)-,-CON (C1-C4Alkyl) (C1-C4Alkyl)-.
In another preferred example, R2Are as follows:
Benzyl or C6H5(CH2)2-。
In another preferred example, m is 0 or 1.
In another preferred example, X is-CH2Or-C (O)-.
In another preferred example, Y is-N- ,-CH- or-O-.
In another preferred example, R3For nothing, hydrogen, C1-C4Alkyl, C1-C2Carboxyl ,-COO (C1-C6Alkyl), C6-C10Aryl, 3-8 unit's heteroaryl ,-NH (COC1-C6Alkyl)-,-N (C1-C6Alkyl) (COC1-C4Alkyl)-,-CO (C1-C6Alkyl).
In another preferred example, R3For nothing, hydrogen, C1-C4Alkyl ,-COOH ,-COO (C1-C6Alkyl), phenyl, 5-7 member heteroaryl Base ,-NH (COC1-C4Alkyl)-,-CO (C1-C4Alkyl).
In another preferred example, R3For nothing, hydrogen ,-COOH ,-COOC (CH3)3, phenyl, pyridyl group ,-NHCOCH3、- COCH3、-CH(CH3)2、-CH2CH3、-CH3。
In another preferred example, compound shown in the general formula I is any of the I-1~I-44 prepared in embodiment.
The second aspect of the present invention provides the preparation method of compound shown in general formula I described in first aspect, including Formula II Compound reacts the step of obtaining compound shown in general formula I with formula III compound,
Wherein, m, X, Y, R1、R2And R3Definition as described in relation to the first aspect.
The third aspect of the present invention provides a kind of pharmaceutical composition, comprising:
(1) compound shown in general formula I described in first aspect, its pharmaceutically acceptable salt, its prodrug, its hydrate or Solvate；With
(2) pharmaceutically acceptable carrier.
The fourth aspect of the present invention provides medicine described in compound shown in general formula I described in first aspect or the third aspect The purposes of compositions, which is characterized in that be used for:
(1) glucokinase agonist；
(2) drug of glucokinase agonist is prepared；And/or
(3) drug of preparation prevention and/or treatment disease relevant to abnormal glucose metabolism.
In another preferred example, the relevant disease of the abnormal glucose metabolism is related to glucokinase shortage Disease or disorder.
In another preferred example, disease relevant to glucokinase shortage or disorder are diabetes and diabetes phase The microvascular complication of pass, macrovascular complications relevant to diabetes, cardiovascular disease, metabolic syndrome and its each component disease Disease (componentconditions), hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, Retinopathy, neuropathy, nephrosis, the wound healing of delay, the positive sequelae of atherosclerosis, abnormal cardiac function, the heart Blood in short supply, apoplexy, metabolic syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, increased TG, high gallbladder are solid Alcoholemia, low HDL, high LDL, non-cardiac ischemic, infection, cancer, reangiostenosis, pancreatitis, neurodegenerative disease, lipid Disorder, cognition dysfunction and dementia, osteopathy, glaucoma and hiv protease related lipid dysbolism.
In another preferred example, disease relevant to glucokinase shortage or disorder are diabetes B.
In addition, according to the present invention, provide prevention, inhibition or treatment it is relevant to glucokinase shortages such as above and The progress or morbidity of disease or disorder defined below, wherein compound shown in the logical formula (I) of therapeutically effective amount is given lactation Animal, i.e., people in need, patient.
In addition, the method that the present invention provides prevention, inhibits or treat the disease defined above and below, formula of (I) combination of compound and/or at least one other kinds of therapeutically effective amount shown in compound shown in and another logical formula (I) It is given mammal, i.e., people in need, patient.
In another embodiment, the present invention relates to prevention, inhibition or treatment diabetes, hyperglycemia, obesity, exception The method of blood lipid disease, the progress of hypertension and cognition dysfunction or morbidity needs prevention, inhibition or treatment including giving Mammalian subject, for example, human patients therapeutically effective amount the compound of the present invention (individually or optionally with this another hair Bright compound and/or at least one other kinds of therapeutic agent combination) the step of.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows influence of the I-13 to ob/ob mouse fasting blood-glucose.*, P < 0.05；*, P < 0.01；* *, P < 0.001。
Influence Fig. 2 shows I-20 to ob/ob mouse fasting blood-glucose.*, P < 0.05.
Fig. 3 shows influence of the I-13 to ob/ob mouse glycosylated hemoglobin.* *, P < 0.001.
Fig. 4 shows influence of the I-20 to ob/ob mouse glycosylated hemoglobin.*, P < 0.05；*, P < 0.01.
Specific embodiment
Present inventor develops a kind of N- substitution -3,5- disubstituted benzenes by depth studying extensively for the first time Carbox amide can be used as glucokinase agonist, prevention and/or treatment and abnormal glucose metabolism related disease. On this basis, the present invention is completed.
Term
The term " substitution " that the present invention is said, it is intended that one or more hydrogen on any specified atom or ring are substituted, preceding The normal chemical valence for being no more than specified atom is mentioned, and replaces and generates stable compound.In another preferred example, the substitution Be it is monosubstituted, two replace, three replace or four replace.When with more than two substituent groups, each substituent group can be identical or different.
Term " alkyl " or " alkane " are herein individually or as a part of another group in use, be included in normal chain On the straight chain containing 1~6 carbon and branch " alkyl " or " alkane ", such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, different Butyl, amyl, hexyl, isohesyl, its various branched isomer etc.；Such group can optionally include 1~4 substituent group, Such as F, Cl, Br, I, halogenated C1-C6Alkyl such as CF3、C1-C6Alkoxy, C3-C8Naphthenic base, C6-C10Aryl, 3-8 unit's heteroaryl, ammonia Base, hydroxyl, acyl group, alkylthio group, nitro, cyano, thiol base ,-SO2(C1-C6Alkyl) ,-SO2(C3-C8Naphthenic base) ,-SO2(3-8 Membered heterocycloalkyl) ,-CO (3-8 membered heterocycloalkyl)-,-CO (C1-C6Alkyl)-,-CO (C3-C8Naphthenic base)-,-CO2(3-8 member is miscellaneous Naphthenic base)-,-CO2(C1-C6Alkyl)-,-CO2(C3-C8Naphthenic base)-,-CONR4R5-(R4R5It is as defined above) replace.Unless another Indicate outside, term " naphthenic base " used herein individually or as another group a part when, including saturation or portion Divide the cyclic hydrocarbon group of unsaturated (containing 1 or 2 double bond).The naphthenic base include cyclopropane, cyclobutane, pentamethylene, hexamethylene, Cycloheptane, cyclooctane, cyclodecane and cyclo-dodecyl, any one of these groups can optionally be taken by 1~4 substituent group Generation, the substituent group are halogen, C1-C6Alkyl, C1-C6Alkoxy, hydroxyl, C6-C10Aryl, C6-C10Aryloxy, C6-C10Virtue Base C1-C6Alkyl, C3-C8Naphthenic base, 3-8 unit's heteroaryl, C1-C6Alkylamidoalkyl, C1-C6Alkanoylamino, oxo, acyl group, virtue Base carbonylamino, amino, nitro, cyano, thiol base and/or alkylthio group.
The term as used herein " halogen " or " halo " individually or as another group a part when, refer to fluorine, chlorine, bromine With iodine and CF3, preferably fluorine and chlorine.
Term " aryl " individually or as another group a part when, refer to and contain the list of 6~10 carbon in loop section Ring and bicyclic aromatic group, aryl group can optionally be replaced by 1,2 or 3 substituent group by available carbon atom, described to take Dai Ji has for example, C3-C8Naphthenic base, C6-C10Aryl, C1-C6Alkoxy, 3-8 unit's heteroaryl, halogenated, halogenated alkyl, alkyl halide Oxygroup, CF3、OCF3, cycloheteroalkyl, cycloheteroalkyl alkyl, aryl, heteroaryl, aryl alkyl, aryloxy, cycloalkyl-alkyl oxygen Base, amino, hydroxyl, hydroxy alkyl, acyl group, heteroaryl, heteroaryl oxygroup, heteroaryl alkyl, heteroarylalkoxy, aryloxy Alkyl, alkylthio group, alkylthio-aryl, Aryloxyaryl, alkylamidoalkyl, alkanoylamino, aryl-amino-carbonyl, nitro, Cyano, thiol base, halogenated alkyl, tri haloalkyl and/or alkylthio group.
Term " heterocycle " or " heterocycle " or " Heterocyclylalkyl " refer to substituted and unsubstituted non-aromatic 3~8 unit monocycle base Group, 7~11 membered bicyclic groups and 10~15 membered tricyclic groups, wherein at least one ring has at least one hetero atom, described miscellaneous Atom is O, S or N.Each ring containing heteroatomic " heterocycle " or " heterocycle " or " Heterocyclylalkyl " can contain one or two Oxygen or sulphur atom and/or 1~4 nitrogen-atoms, on condition that the hetero atom sum of each ring be 4 or less, and further before Mention is that the ring contains at least one carbon atom.The bicyclic and tricyclic group for forming fused rings can contain only carbon atom and can be It is saturation, fractional saturation or unsaturated.Nitrogen and sulphur atom can optionally be oxidized and can optionally be quaternized with nitrogen-atoms.It is " miscellaneous Ring " or " heterocycle " or " Heterocyclylalkyl " may connect on any available nitrogen or carbon atom." heterocycle " or " heterocycle " or " Heterocyclylalkyl " can contain 0,1,2 or 3 substituent group, and the substituent group is halogen, C1-C6Alkyl, C1-C6Alkoxy, hydroxyl, C6-C10Aryl, C6-C10Aryloxy, C6-C10Aryl C1-C6Alkyl, C3-C8Naphthenic base, 3-8 unit's heteroaryl, C1-C6Alkyl acyl Amido, C1-C6Alkanoylamino, oxo, acyl group, aryl-amino-carbonyl, amino, nitro, cyano, thiol base and/or alkylthio group.
Term " hetero atom " should include O, S, N.
Term " heteroaryl " indicates the heteroatomic aromatic ring group that N, O, S are selected from comprising 1-4, without limitation includes pyrrole Oxazolyl, thienyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, furyl, pyrrole radicals, oxazolyl, isoxazolyl, imidazole radicals, Thiazolyl, isothiazolyl, quinazolyl, quinolyl, isoquinolyl and indyl.
Phrase is " pharmaceutically acceptable " for herein referring to such compound, substance, composition and/or dosage form, they It is contacted within a reasonable range of medical judgment suitable for fish humans and animals body tissue, and without excessive toxicity, irritation, allergy Property reaction or other problems or complication, and match in reasonable interests/Hazard ratio.
Term " pharmaceutically acceptable salt " is preferably hydrochloride, hydrobromate, sulfate, nitrate, phosphate, lemon Lemon hydrochlorate, mesylate, trifluoroacetate, acetate, oxalates, succinate, malate, toluene fulfonate, tartaric acid Salt, fumarate, glutamate, glucuronate, lactate, glutarate, arginine salt or maleate.
Term " prodrug " is showed give patient after, by metabolism or chemical process undergo chemical conversion, obtain the structural formula Compound and/or its salt and/or solvate compound.For example, the compound containing carboxyl can in physiology The ester of hydrolysis works and is hydrolyzed in vivo, obtains the prodrug of formula compound itself.Such prodrug is preferably oral to be given, because For in many cases, hydrolysis occurs mainly under the influence of digestive ferment.Occur when ester itself is active, or in hydrolysis in blood In the case where in liquid, parenteral can be used.
One or more can be contained in compound shown in general formula I, its pharmaceutical salts, its prodrug and its hydrate and solvate A asymmetric center.Asymmetric carbon atom can exist with (R) or (S) conformation or (R, S) conformation.Substituent group on ring can also be with Exist in the form of cis- (cis) or trans- (trans).All such conformations (including enantiomer and diastereoisomer) include Within the scope of the invention.Preferred isomers be those have generate with greater need for biological activity conformation isomers. The racemic mixture of separate, pure or partially purified isomers or compound of the present invention is also contained in the scope of the invention Within.The isomers may be implemented using routine techniques known in the art or from the synthesis of optically active starting material The separation of purifying and the heterogeneous mixture.In include all chiralitys, diastereomer, racemic form and be known as several The structure of what isomeric form, the spatial chemistry or isomeric form having unless specifically stated otherwise.
Preparation method
Compound shown in logical formula (I) can be prepared as shown in following reaction process and its description, and according to this field The adoptable pertinent literature method preparation of technical staff.Exemplary agents and program for these reactions are real with work below It applies in example and shows.
Compound I is reacted and is obtained by compound 3 and compound 7, such as by according in WO2008/154563 The program of description uses suitable amide condensed reagent selected from the group below: I-hydroxybenzotriazole, N- hydroxyl -7- azo benzo Triazole, N, N'- dicyclohexylcarbodiimide (DCC), N- (3- dimethylamino-propyl)-N'- ethyl carbodiimide or its hydrochloric acid Salt (EDC or EDC.HCl), phosphinylidyne diimidazole (CDI), N, N'- diisopropylcarbodiimide (DIC), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU), O- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluoro phosphorus Acid esters (HATU), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), benzotriazole -1- base oxygroup Three (dimethylamino) phosphorus hexafluorophosphates (BOP) and hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl One or more of (PyBOP), preferred condensing agent is 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid Salt/I-hydroxybenzotriazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate/N- hydroxyl -7- azo benzo Triazole etc..
Compound 4 and R1OH can be prolonged reaction by light and obtain compound 5, and catalytic reagent used is azoformic acid in reaction Other condensation examinations that diisopropyl ester/triphenylphosphine or diethyl azodiformate/triphenylphosphine or those skilled in the art use Agent.Then compound 5 and R are used2Br by cesium carbonate/cuprous iodide/DPM dpm,dipivalomethane or potassium carbonate/ Other coupling catalysed reagents that n,N-Dimethylformamide or those skilled in the art use, obtain compound 6 under heating.Change Conjunction object 6 is the hydrolysis of alkali completion benzoic ether with 2 moles every liter of sodium hydrate aqueous solution again, obtains benzoic acid compounds 7。
Be starting material with compound 1, by with amino nitrile and sulphur powder in pyridine or ethylenediamine or those skilled in the art Reflux can obtain corresponding thiazole and cycle compound 3 under the conditions of the alkaline reagent used.
In addition, being starting material with compound 1, by obtaining the compound 2 of bromine substitution with bromo-reaction.Compound 2 is again Corresponding thiazole and cycle compound 3 can also be obtained with thiocarbamide heat together.
Unless otherwise indicated, m, X, Y, R1、R2And R3It is defined as described above.
Pharmaceutical composition
The compound of the present invention can activate or enhance the activity of glucokinase, can be used as glucokinase agonist use In prevention and/or treatment and abnormal glucose metabolism related disease such as diabetes B.
The present invention also provides a kind of pharmaceutical composition, N- shown in the general formula I comprising therapeutically effective amount or safe and effective amount is taken Generation -3,5- disubstituted benzenes Carbox amide, its pharmaceutical salts, its prodrug and its one of hydrate and solvate or more It plants and optionally, pharmaceutically acceptable carrier can be used for preventing and/or treating and abnormal glucose metabolism related disease Such as diabetes B.
" active constituent " of the present invention refers to compound shown in general formula I of the present invention.
Inventive compound can individually, with other the compound of the present invention combine, or with one or more other treatments Agent is applied in combination.
" therapeutically effective amount " be intended to include effectively treat or prevent with abnormal glucose metabolism related disease such as diabetes and/ Fat individual the compounds of this invention amount or claimed compound combined amount or the compound of the present invention with The amount of other activating agents combination.
" safe and effective amount " refers to that the amount of active constituent is enough to be obviously improved the state of an illness, and is unlikely to generate serious secondary work With.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition Middle each component energy and active constituent of the invention and they between mutually admix, and significantly reduce the drug effect of active constituent. Pharmaceutically acceptable carrier part example have cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, Cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as)、 Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
Described pharmaceutical composition can be prepared into various forms according to different way of administration.Administration route does not limit especially System, representative administration route include (but being not limited to): oral, rectum, parenteral (intravenous, intramuscular or subcutaneous) etc..
In another preferred example, compound shown in general formula I of the present invention can pass through nonbonding with macromolecular compound or macromolecule Cooperation is with forming compound.In another preferred example, compound shown in general formula I of the present invention can also pass through chemical bond as small molecule It is connected with macromolecular compound or macromolecule.The macromolecular compound can be large biological molecule such as high glycan, albumen, core Acid, polypeptide etc..
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.
In these solid dosage forms, active constituent is mixed at least one conventional inert excipients (or carrier), such as lemon Sour sodium or Dicalcium Phosphate, or mixed with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, sweet Reveal pure and mild silicic acid；(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Ah Draw primary glue；(c) moisturizer, for example, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, algae Sour, certain composition silicates and sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound； (g) wetting agent, such as cetanol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, Or mixtures thereof talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate,.Capsule, tablet and ball In agent, dosage form also may include buffer.
Coating and shell material preparation also can be used in the solid dosage forms, such as casing and other materials well known in the art.It May include opacifying agent, also, in this composition active constituent release can in a delayed fashion it is in the digestive tract certain It is discharged in a part.The example of adoptable embedding component is polymeric material and wax material.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. Other than active constituent, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, solubilising Agent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide And oil, the especially mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweetener, rectify Taste agent and fragrance.
Other than active constituent, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene mountain The pure and mild Isosorbide Dinitrate of pears, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000 milligram, preferably 20~500 milligrams.Certainly, specific dosage is also contemplated that administration route, patient health shape The factors such as condition, within the scope of these are all skilled practitioners technical ability.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification All features can be used in combination with any composition form, each feature disclosed in specification, can by it is any provide it is identical, The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy The general example of sign.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and Number is calculated by weight.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong The preferred implement methods and materials are for illustrative purposes only.
Embodiment 1
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- isopropyl oxybenzamide (I-1)
Step 1: preparing 2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester
19.9 grams of (0.1 mole) N- tertbutyloxycarbonyl -4- piperidones and 0.2 are put into the there-necked flask dry to 500 milliliters Chloroform is risen, stirs to obtain light yellow clarifying liquid in 0 DEG C of condition under argon gas protection.It is slowly added dropwise 5.1 milliliters of bromine (0.1 mole), it is molten Liquid becomes brown liquid, continues stirring 2 hours, obtains light yellow clarifying liquid body.After fully reacting, vacuum concentration reaction solution obtains light Yellow powder.After 0.1 liter of above-mentioned pale yellow powder of acetone solution, 7.6 grams of thiocarbamides are added and continue stirring 12 hours in room temperature. Reaction solution is concentrated in vacuo to obtain faint yellow solid；With 50.0 milliliters of acetone washing solids, yellow is then obtained with 0.1 liter of water Clear solution, slowly adjusting pH value with 2N sodium hydroxide solution is 9.0~9.5, and a large amount of light yellow solids are precipitated, and vacuum filtration is received Collect filter cake, then wash filter cake with 30.0 ml methanols, obtains 21.8 grams of white solid as compound 2- amino -6,7- thiazoline And [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester, yield 85.4%.
1H NMR(300MHz,CDCl3, δ ppm): 4.80 (d, J=0.5Hz, 2H), 4.42 (s, 2H), 3.69 (t, J= 5.6Hz, 2H), 2.64 (t, J=5.8Hz, 2H), 1.48 (s, 9H).
Step 2: the preparation bromo- 4- methylsulfonyl benzene of 1-
20.3 grams of (0.1 mole) 4- bromine thioanisoles, 0.1 liter of steaming are successively put into the there-necked flask dry to 500 milliliters Distilled water and 0.1 liter of ethyl alcohol stir under ice bath.Then 92.1 grams of (0.3 mM mM) potassium peroxymonosulfates are added After being slowly added to there-necked flask, after being to slowly warm up to room temperature, stir 12 hours.TLC detection display fully reacting, with 0.3 liter of acetic acid Ethyl ester washs one time, point takes organic phase, and organic phase is with 0.5 liter after saturated common salt water washing one time, then is dried over anhydrous sodium sulfate, Filtering obtains 21.6 grams of white powders after being concentrated in vacuo solvent as the bromo- 4- methylsulfonyl benzene of compound 1-,Yield 92.1%.
1H NMR(300MHz,d6-DMSO,δppm):7.92-7.84(m,4H),3.25(s,3H)。
Step 3: preparation 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters
1.9 grams of (10.0 mMs) 3,5- methyl dihydroxy benzoates, isopropanol are put into 500 milliliters of dry there-necked flasks The THF of 1.0 milliliters of (10.0 mMs) and 0.2L is stirred under ice bath.Then it is 5.2 grams of (20.0 mmoles that triphenylphosphine, which is added, You), it is sufficiently displaced from reaction unit after gas with argon gas, it is different to be slowly added to 3.9 milliliters of (20.0 mMs) azoformic acids two Propyl ester.So that reaction mixture is warming up to room temperature and stirs 48 hours.Reaction mixture distilled water dilutes and is extracted with ethyl acetate It takes.Organic phase is dried, filtered with anhydrous sodium sulfate, vacuum concentration, and obtaining crude product is viscous deep yellow grease.Crude product is through column layer (petroleum ether: ethyl acetate=2:1) separation is analysed, obtains 1.2 grams of colorless oil as compound 3- hydroxyl -5- isopropyl oxygroup benzene Formic acid acid methyl esters, yield 57.5%.
1H NMR(300MHz,CDCl3, δ ppm): 7.16 (s, 1H), 7.13 (s, 1H), 6.61 (dd, J=4.1,2.1Hz, 1H), 6.13 (s, 1H), 4.55 (dt, J=12.0,6.1Hz, 1H), 3.90 (s, 3H), 1.32 (d, J=6.0Hz, 6H).
Step 4: preparation 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate
420.4 milligrams of (2.0 mMs) 3- hydroxyl -5- isopropyl oxygroup benzene first are put into 100 milliliters of dry there-necked flasks Sour methyl esters, the bromo- 4- methylsulfonyl benzene of 467.9 milligrams of (2.0 mMs) 1-, 1.3 grams of (4.0 mMs) cesium carbonates, 76.2 milligrams (0.4 mM) cuprous iodide and 10.0 milliliters of DMAC N,N' dimethyl acetamide.It stirs under ice bath, and is sufficiently displaced from instead with argon gas Answer gas in device.Then the DPM dpm,dipivalomethane of 0.2 milliliter (0.8 mM) is slowly added dropwise.Make to react Mixture is warming up to 85 DEG C and stirs 24 hours, and reaction solution becomes brown solution from yellow, and generates a small amount of blue precipitate.Reaction After completely, reaction solution is cooled to room temperature, is diluted and is extracted with ethyl acetate with 50.0 milliliters of saturated aqueous ammonium chlorides.Organic phase It is dried, filtered, is concentrated in vacuo with anhydrous sodium sulfate, obtaining crude product is yellow color grease.Crude product chromatographs (petroleum ether: second through column Acetoacetic ester=1:1) separation, 395.1 milligrams of yellow oil are obtained as compound 3- isopropyl oxygroup -5- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) methyl benzoate, yield 49.3%.
1H NMR(300MHz,CDCl3,δppm):7.95-7.88(m,2H),7.42(s,1H),7.28(s,1H),7.15- 7.09 (m, 2H), 6.80 (d, J=2.0Hz, 1H), 4.62 (dq, J=12.0,6.1Hz, 1H), 3.90 (s, 3H), 3.07 (s, 3H), 1.36 (d, J=6.0Hz, 6H).
Step 5: preparation 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid
The 3- isopropyl oxygroup -5- ((4- (first of 365.0 milligrams (1.0 mMs) is put into 100 milliliters of dry there-necked flasks Base sulfonyl) phenyl) oxygroup) methyl benzoate, 2.0 ml methanols and 6.0 milliliters of tetrahydrofurans, are stirred under ice bath.Slowly add 2.3 milliliters of the sodium hydrate aqueous solution (3.0 mMs) for entering 1 mole every liter, is stirred at room temperature 4 hours.After fully reacting, vacuum is dense Contract crude product be light yellow oil.After crude product is with 2.0 milli liter of water, slowly adjusting pH value with 1N hydrochloric acid solution is 4, analysis White precipitate out.It is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, and vacuum concentration obtains white powder 332.1 milligrams are compound 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, and yield is 94.9%.
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.7Hz, 2H), 7.46 (d, J=0.9Hz, 1H), 7.33 (d, J=1.1Hz, 1H), 7.12 (d, J=8.7Hz, 2H), 6.83 (d, J=1.9Hz, 1H), 4.60 (dt, J=12.0, 6.1Hz, 1H), 3.07 (s, 3H), 1.36 (d, J=6.0Hz, 6H).
Step 6: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- isopropyl oxybenzamide (I-1)
3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzene is put into 100 milliliters of dry there-necked flasks 52.6 milligrams of formic acid (0.2 mM), 2- amino -6,7- thiazoline simultaneously [5,4-c] pyrimidine -5 (4H) carboxylic acid tert-butyl ester 114.9 Milligram (0.5 mM), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate are 57.5 milligrams of (0.3 mmoles You), I-hydroxybenzotriazole be 60.9 milligrams (0.5 mMs) and 5.0 milliliters of N,N-dimethylformamide.It is stirred under ice bath It mixes, and gas in reaction unit is sufficiently displaced from argon gas.Reaction solution is stirred at room temperature 6 hours.After fully reacting, with 10.0 milliliters Saturated aqueous ammonium chloride is diluted and is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, and vacuum concentration obtains Crude product is pale yellow powder.Crude product obtains 66.0 milligrams of white powder through column chromatography (methylene chloride: methanol=20:1) separation For compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- isopropyl oxybenzamide (I-1), yield 74.9%.
1H NMR(300MHz,CDCl3, δ ppm): 7.92 (d, J=8.7Hz, 2H), 7.27 (d, J=2.1Hz, 1H), 7.18-7.07(m,3H),6.79(s,1H),4.59(s,2H),4.55-4.46(m,1H),3.65(s,2H),3.08(s,3H), 2.47 (s, 2H), 1.49 (s, 9H), 1.33 (d, J=6.0Hz, 6H).
Embodiment 2
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- cyclopentyloxy benzamide (I-2)
Step 1: preparation 3- cyclopentyloxy -5- hydroxybenzoic acid acid methyl esters
1.7 grams of (10.0 mMs) 3,5- methyl dihydroxy benzoates, 2.6 grams are put into 100 milliliters of dry there-necked flasks Iodo pentamethylene (13.0 mMs), 1.8 grams of potassium carbonate (13.0 mMs) and 30.0 milliliters of N,N-dimethylformamide (DMF), it is stirred under ice bath.It is sufficiently displaced from reaction unit after gas with argon gas, 1.5 milliliters of (13.0 mMs) iodine is slowly added dropwise For pentamethylene.So that reaction mixture is warming up to 50 DEG C and stirs 8 hours.After fully reacting, reaction mixture is diluted with distilled water And it is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, vacuum concentration, and obtaining crude product is viscous deep yellow oily Object.Through column chromatography, (petroleum ether: ethyl acetate=10:1 to 3:1) is separated crude material, obtains 1.6 grams of brown oil as chemical combination Object 3- cyclopentyloxy -5- hydroxybenzoic acid acid methyl esters, yield 67.3%.
1H NMR(300MHz,CDCl3, δ ppm): 7.12 (dd, J=14.7,1.3Hz, 3H), 6.60 (t, J=2.0Hz, 1H), 4.72 (dd, J=6.9,4.0Hz, 1H), 3.88 (s, 3H), 1.91-1.73 (m, 6H), 1.60 (dt, J=9.8,6.9Hz, 2H)。
Step 2: preparation 3- cyclopentyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate
Change 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters into 3- cyclopentyloxy -5- hydroxybenzoic acid acid methyl esters, With the step 4 in embodiment I-1, obtaining yellow oil is compound 3- cyclopenta for remaining required raw material, reagent and preparation method Oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate.
1H NMR (300MHz, CDCl3, δ ppm): 7.92-7.87 (m, 2H), 7.40 (dd, J=2.3,1.3Hz, 1H), 7.27-7.25 (m, 1H), 7.12-7.07 (m, 2H), 6.78 (t, J=2.3Hz, 1H), 4.79 (td, J=5.7,2.8Hz, 1H), 3.89 (s, 3H), 3.06 (s, 3H), 1.91 (dd, J=8.5,4.4Hz, 2H), 1.86-1.81 (m, 2H), 1.79 (d, J= 1.6Hz,2H),1.65-1.60(m,2H)。
Step 3: preparation 3- cyclopentyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- cyclopenta oxygen Base -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and the same embodiment of preparation method Step 5 in I-1, obtaining colorless oil is compound 3- cyclopentyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzene Formic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.91-7.87 (m, 2H), 7.40 (dd, J=2.3,1.3Hz, 1H), 7.27-7.25 (m, 1H), 7.12-7.08 (m, 2H), 6.78 (t, J=2.3Hz, 1H), 4.78 (td, J=5.7,2.8Hz, 1H), 3.06 (s, 3H), 1.91 (dd, J=8.5,4.4Hz, 2H), 1.86-1.81 (m, 2H), 1.78 (d, J=1.6Hz, 2H), 1.65- 1.60(m,2H)。
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclopentyloxy benzamide (I-2)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- cyclopentyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-1 Rapid 6, obtaining pale powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) - 3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclopentyloxy benzamide (I-2).
1H NMR(300MHz,CDCl3, δ ppm): 7.96-7.88 (m, 2H), 7.23 (t, J=2.4Hz, 1H), 7.13 (t, J=5.3Hz, 2H), 7.10 (d, J=3.2Hz, 1H), 6.81-6.77 (m, 1H), 4.73 (td, J=4.6,2.3Hz, 1H), 4.58 (s, 2H), 3.68 (t, J=5.0Hz, 2H), 3.08 (s, 3H), 2.59-2.50 (m, 2H), 1.91 (dd, J=8.5, 4.4Hz, 2H), 1.86-1.81 (m, 2H), 1.79 (d, J=1.6Hz, 2H), 1.67-1.58 (m, 2H), 1.48 (s, 9H).
Embodiment 3
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- cyclopentylmethoxy benzamide (I-3)
Step 1: preparation 3- cyclopentylmethoxy -5- hydroxybenzoic acid acid methyl esters
Change iodo pentamethylene into iodomethyl pentamethylene, remaining required raw material, reagent and preparation method are the same as in embodiment I-2 Step 1, obtain yellow oil be compound 3- cyclopentylmethoxy -5- hydroxybenzoic acid acid methyl esters.
1H NMR(300MHz,CDCl3, δ ppm): 7.21-7.17 (m, 1H), 7.15-7.10 (m, 1H), 6.64 (dd, J= 4.1,2.1Hz, 1H), 3.90 (s, 3H), 3.80 (dd, J=6.9,2.3Hz, 2H), 2.33 (dt, J=14.8,7.4Hz, 1H), 1.87-1.75 (m, 2H), 1.67-1.52 (m, 4H), 1.32 (dd, J=11.2,6.8Hz, 2H).
Step 2: preparation 3- cyclopentylmethoxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate
Change 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters into 3- cyclopentylmethoxy -5- hydroxybenzoic acid acid first Ester, with the step 4 in embodiment I-1, obtaining yellow oil is compound 3- ring penta for remaining required raw material, reagent and preparation method Ylmethoxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.92 (d, J=8.9Hz, 2H), 7.47 (d, J=2.1Hz, 1H), 7.37-7.34 (m, 1H), 7.14 (d, J=8.9Hz, 2H), 6.86 (t, J=2.2Hz, 1H), 3.90 (s, 3H), 3.87 (d, J= 6.9Hz, 2H), 3.07 (s, 3H), 2.37 (dt, J=14.9,7.5Hz, 1H), 1.90-1.79 (m, 2H), 1.62 (dd, J= 11.8,5.9Hz,4H),1.41-1.31(m,2H)。
Step 3: preparation 3- cyclopentylmethoxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- cyclopenta methoxy Base -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and the same embodiment of preparation method Step 5 in I-1, obtaining white powder is compound 3- cyclopentylmethoxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzene Formic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.9Hz, 2H), 7.47 (d, J=2.1Hz, 1H), 7.37-7.34 (m, 1H), 7.12 (d, J=8.9Hz, 2H), 6.86 (t, J=2.2Hz, 1H), 3.87 (d, J=6.9Hz, 2H), 3.07 (s, 3H), 2.37 (dt, J=14.9,7.5Hz, 1H), 1.90-1.79 (m, 2H), 1.62 (dd, J=11.8,5.9Hz, 4H),1.41-1.32(m,2H)。
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclopentylmethoxy benzamide (I-3)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- cyclopentylmethoxy - 5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining white powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) - 3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclopentylmethoxy benzamide (I-3).
1H NMR(300MHz,CDCl3, δ ppm): 7.92 (d, J=7.8Hz, 2H), 7.42-7.38 (m, 1H), 7.31- 7.27 (m, 1H), 7.14 (d, J=8.9Hz, 2H), 6.85 (t, J=2.2Hz, 1H), 4.59 (t, J=4.0Hz, 2H), 3.90 (d, J=6.9Hz, 2H), 3.73 (t, J=4.8Hz, 2H), 3.07 (s, 3H), 2.76-2.66 (m, 2H), 2.40-2.32 (m, 1H), 1.84 (dd, J=13.5,7.3Hz, 4H), 1.49 (s, 9H), 1.41-1.30 (m, 4H).
Embodiment 4
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- cyclohexyloxy benzamide (I-4)
Step 1: preparation 3- cyclohexyl oxygroup -5- hydroxybenzoic acid acid methyl esters
Change isopropanol into cyclohexanol, remaining required raw material, reagent and preparation method are obtained with the step 3 in embodiment I-1 Pale powder is compound 3- cyclohexyl oxygroup -5- hydroxybenzoic acid acid methyl esters.
1H NMR(300MHz,CDCl3, δ ppm): 7.42 (d, J=1.3Hz, 1H), 6.81 (t, J=2.2Hz, 1H), 6.85 (d, J=2.1Hz, 1H), 6.13 (s, 1H), 4.36-4.27 (m, 1H), 3.90 (s, 3H), 1.98 (d, J=14.2Hz, 2H), 1.85-1.75 (m, 2H), 1.60-1.52 (m, 2H), 1.39 (dd, J=17.1,4.2Hz, 4H).
Step 2: preparation 3- cyclohexyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate
Change 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters into 3- cyclohexyl oxygroup -5- hydroxybenzoic acid acid methyl esters, With the step 4 in embodiment I-1, obtaining yellow oil is compound 3- cyclohexyl for remaining required raw material, reagent and preparation method Oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.96-7.85 (m, 2H), 7.42 (d, J=1.3Hz, 1H), 7.27 (d, J =2.1Hz, 1H), 7.16-7.06 (m, 2H), 6.81 (t, J=2.2Hz, 1H), 4.36-4.27 (m, 1H), 3.90 (s, 3H), 3.06 (s, 3H), 1.98 (d, J=14.2Hz, 2H), 1.85-1.75 (m, 2H), 1.60-1.52 (m, 2H), 1.39 (dd, J= 17.1,4.2Hz,4H)。
Step 3: preparation 3- cyclohexyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- cyclohexyl oxygen Base -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and the same embodiment of preparation method Step 5 in I-1, obtaining yellow oil is compound 3- cyclohexyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzene Formic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.8Hz, 2H), 7.47 (d, J=0.7Hz, 1H), 7.33 (d, J=1.9Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 6.85 (d, J=2.1Hz, 1H), 4.37-4.25 (m, 1H), 3.07 (s, 3H), 2.03-1.93 (m, 2H), 1.80 (d, J=5.3Hz, 2H), 1.59-1.52 (m, 2H), 1.37 (dd, J=14.3, 9.3Hz,4H)。
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclohexyloxy benzamide (I-4)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- cyclohexyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-1 Rapid 6, obtaining pale powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) - 3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- cyclohexyloxy benzamide (I-4).
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.8Hz, 2H), 7.29 (d, J=1.2Hz, 1H), 7.13 (dd, J=9.6,5.0Hz, 3H), 6.81 (t, J=2.0Hz, 1H), 4.58 (s, 2H), 4.29-4.22 (m, 1H), 3.66 (d, J =4.5Hz, 2H), 3.07 (s, 3H), 2.53 (s, 2H), 1.94 (d, J=13.5Hz, 2H), 1.77 (d, J=5.2Hz, 2H), 1.55 (d, J=12.9Hz, 2H), 1.48 (s, 9H), 1.32 (d, J=8.4Hz, 4H).
Embodiment 5
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- benzyloxy yl-benzamide (I-5)
Step 1: preparation 3- benzyloxy -5- hydroxybenzoic acid acid methyl esters
Change iodo pentamethylene into cylite, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-2 1, obtaining light yellow oil is compound 3- benzyloxy -5- hydroxybenzoic acid acid methyl esters.
1H NMR(300MHz,d6-DMSO,δppm):9.88(s,1H),7.43-7.38(m,2H),7.38-7.33(m, 2H), 7.30 (d, J=7.1Hz, 1H), 6.99-6.93 (m, 2H), 6.62 (t, J=2.3Hz, 1H), 5.07 (s, 2H), 3.77 (s,3H)。
Step 2: preparation 3- benzyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate
Change 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters into 3- benzyloxy -5- hydroxybenzoic acid acid methyl esters, remaining With the step 4 in embodiment I-1, obtaining yellow oil is compound 3- benzyloxy -5- for required raw material, reagent and preparation method ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.89 (dd, J=8.8,1.3Hz, 2H), 7.55-7.50 (m, 1H), 7.46-7.34 (m, 5H), 7.33-7.31 (m, 1H), 7.08 (dd, J=8.8,1.2Hz, 2H), 6.87 (t, J=2.2Hz, 1H), 5.09(s,2H),3.90(s,3H),3.06(s,3H)。
Step 3: preparation 3- benzyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- benzyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 5, obtain white powder be compound 3- benzyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.8Hz, 2H), 7.57 (d, J=1.2Hz, 1H), 7.46-7.37 (m, 5H), 7.36 (d, J=6.9Hz, 1H), 7.11 (d, J=8.7Hz, 2H), 6.93 (t, J=2.0Hz, 1H), 5.12(s,2H),3.07(s,3H)。
Step 4:N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) -5- benzyloxy yl-benzamide (I-5)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- benzyloxy -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method with the step 6 in embodiment I-1, White powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- benzyloxy yl-benzamide (I-5).
1H NMR(300MHz,CDCl3, δ ppm): 7.89 (dd, J=8.4,6.4Hz, 2H), 7.44-7.36 (m, 5H), 7.36-7.32(m,1H),7.22-7.16(m,1H),7.14-7.05(m,2H),6.92–6.86(m,1H),5.05(s,2H), 4.56 (s, 2H), 3.73-3.62 (m, 2H), 3.07 (s, 3H), 2.52 (t, J=7.7Hz, 2H), 1.48 (s, 9H).
Embodiment 6
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-6)
Step 1: preparation 3- hydroxyl -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzic acid methyl esters
Change isopropanol into propylene glycol monomethyl ether, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-1 3, obtaining light yellow oil is compound 3- hydroxyl -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzic acid methyl esters.
1H NMR(300MHz,d6- DMSO, δ ppm): 9.82 (s, 1H), 6.95 (dd, J=2.2,1.4Hz, 1H), 6.91 (dd, J=2.3,1.4Hz, 1H), 6.58 (t, J=2.3Hz, 1H), 4.61-4.51 (m, 1H), 3.81 (s, 3H), 3.44 (qd, J =10.5,5.0Hz, 2H), 3.28 (s, 3H), 1.20 (d, J=6.2Hz, 3H).
Step 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) Methyl benzoate
Change 3- hydroxyl -5- isopropyl p-methoxybenzoic acid acid methyl esters into 3- hydroxyl -5- (2- methoxyl group-(1- Methylethyl) Oxygroup) benzic acid methyl esters, remaining required raw material, reagent and preparation method obtain yellow oily with the step 4 in embodiment I-1 Object is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid first Ester.
1H NMR(300MHz,d6- DMSO, δ ppm): 7.94 (d, J=8.8Hz, 2H), 7.33 (s, 1H), 7.23 (d, J= 8.8Hz, 2H), 7.14 (s, 1H), 7.08 (t, J=2.2Hz, 1H), 4.72 (qd, J=10.5,5.7Hz, 1H), 3.83 (s, 3H), 3.47 (dd, J=4.8,2.3Hz, 2H), 3.27 (s, 3H), 3.21 (s, 3H), 1.22 (d, J=6.3Hz, 3H).
Step 3: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining yellow oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygen Base) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,d6- DMSO, δ ppm): 13.16 (s, 1H), 7.94 (d, J=8.7Hz, 2H), 7.32 (s, 1H), 7.24 (d, J=8.8Hz, 2H), 7.12 (s, 1H), 7.03 (s, 1H), 4.72 (qd, J=10.5,5.7Hz, 1H), 3.47 (dd, J=4.5,3.6Hz, 2H), 3.27 (s, 3H), 3.21 (s, 3H), 1.22 (d, J=6.2Hz, 3H).
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-6)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-6).
1H NMR(300MHz,d6-DMSO,δppm):12.61(s,1H),7.98–7.92(m,2H),7.58(s,1H), 7.38 (d, J=1.6Hz, 1H), 7.28-7.22 (m, 2H), 7.00 (t, J=2.2Hz, 1H), 4.84-4.74 (m, 1H), 4.52 (s, 2H), 3.66 (t, J=5.7Hz, 2H), 3.54-3.45 (m, 2H), 3.29 (s, 3H), 3.22 (s, 3H), 2.67 (t, J= 5.0Hz, 2H), 1.42 (s, 9H), 1.25 (d, J=6.2Hz, 3H) .MS (ESI): 617.3 [M-H]+。
Embodiment 7
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((6- (sulfonyloxy methyl Base) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-7)
Step 1: the preparation bromo- 2- methyl sulfone yl pyridines of 5-
137.2 milligrams of bromo- 2- of (0.7 mM) 5- (sulphomethyl) are successively put into the there-necked flask dry to 100 milliliters Pyridine and 8.0 milliliters of methylene chloride stir under ice bath.Then 0.3 gram of (1.7 mMs) metachloroperbenzoic acid is added, delays Slowly after being warming up to room temperature, 6h is stirred.TLC detection display fully reacting, reaction mixture distilled water dilute and use ethyl acetate Extraction.Organic phase is dried, filtered with anhydrous sodium sulfate, vacuum concentration, obtains 74.9 milligrams of pale yellow powder as the bromo- 2- of compound 5- Methyl sulfone yl pyridines, yield 47.4%.
1H NMR(300MHz,CDCl3, δ ppm): 8.78 (d, J=2.2Hz, 1H), 8.11 (dd, J=8.3,2.2Hz, 1H), 7.98 (dd, J=8.3,0.6Hz, 1H), 3.23 (s, 3H).
Step 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((6- (methyl sulphonyl) pyridine) oxygroup) Methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into 5- bromo- 2- methyl sulfone yl pyridines, remaining required raw material, reagent and preparation method are same Step 4 in embodiment I-1, obtaining light yellow oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((6- (methyl sulphonyl) pyridine) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 8.48-8.41 (m, 1H), 8.05 (d, J=8.6Hz, 1H), 7.49 (d, J =1.2Hz, 1H), 7.41 (dd, J=8.7,2.7Hz, 1H), 7.31-7.27 (m, 1H), 6.87 (t, J=2.3Hz, 1H), 4.64-4.57 (m, 1H), 3.90 (s, 3H), 3.61-3.48 (m, 2H), 3.39 (s, 3H), 3.22 (s, 3H), 1.32 (d, J= 6.3Hz,3H)。
Step 3: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((6- (methyl sulphonyl) pyridine) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((6- (methyl sulphonyl) pyridine) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining yellow powder is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup)- 5- ((6- (methyl sulphonyl) pyridine) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 8.47 (s, 1H), 8.06 (d, J=8.6Hz, 1H), 7.54 (s, 1H), 7.43 (dd, J=8.6,1.2Hz, 1H), 7.35 (s, 1H), 6.91 (s, 1H), 4.69-4.57 (m, 1H), 3.66-3.50 (m, 2H), 3.41 (s, 3H), 3.23 (s, 3H), 1.33 (d, J=6.1Hz, 3H).
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((6- (methyl sulphonyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-7)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((6- (methyl sulphonyl) pyridine) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- ((6- (methyl sulphonyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-7).
1H NMR(300MHz,CDCl3, δ ppm): 8.46 (d, J=2.2Hz, 1H), 8.10-8.03 (m, 1H), 7.48- 7.42 (m, 1H), 7.37-7.33 (m, 1H), 7.19 (d, J=1.4Hz, 1H), 6.87 (t, J=2.1Hz, 1H), 4.58 (s, 2H), 4.54 (dd, J=9.3,3.2Hz, 1H), 3.68 (t, J=5.2Hz, 2H), 3.57-3.48 (m, 2H), 3.38 (s, 3H), 3.24 (s, 3H), 2.55 (s, 2H), 1.48 (s, 9H), 1.30 (d, J=6.3Hz, 3H).
Embodiment 8
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((3- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-8)
Step 1:3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((3- (methyl sulphonyl) phenyl) oxygroup) benzene first Sour methyl esters
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- bromo- 3- methylsulfonyl benzene, remaining required raw material, reagent and preparation method are the same as real The step 4 in an I-1 is applied, obtaining colorless oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((3- (first Base sulfonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.71 (d, J=7.9Hz, 1H), 7.60-7.52 (m, 2H), 7.28 (dd, J=3.3,2.7Hz, 2H), 7.10 (d, J=0.4Hz, 1H), 6.82 (s, 1H), 4.56-4.48 (m, 1H), 3.90 (s, 3H), 3.52 (dd, J=12.7,3.9Hz, 2H), 3.38 (s, 3H), 3.07 (s, 3H), 1.30 (d, J=6.1Hz, 3H).
Step: 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((3- (methyl sulphonyl) phenyl) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((3- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining yellow powder is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup)- 5- ((3- (methyl sulphonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.70 (d, J=7.9Hz, 1H), 7.60-7.52 (m, 2H), 7.28 (dd, J=3.3,2.7Hz, 2H), 7.11 (d, J=0.4Hz, 1H), 6.82 (s, 1H), 4.56-4.48 (m, 1H), 3.52 (dd, J= 12.7,3.9Hz, 2H), 3.38 (s, 3H), 3.07 (s, 3H), 1.31 (d, J=6.1Hz, 3H).
Step 3: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((3- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-8)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((3- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- ((3- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-8).
1H NMR(300MHz,CDCl3, δ ppm): 7.71 (d, J=7.9Hz, 1H), 7.60-7.52 (m, 2H), 7.28 (dd, J=3.3,2.7Hz, 2H), 7.13 (d, J=0.4Hz, 1H), 6.83 (s, 1H), 4.59 (s, 2H), 4.56-4.49 (m, 1H), 3.68 (s, 2H), 3.52 (dd, J=12.8,3.9Hz, 2H), 3.38 (s, 3H), 3.07 (s, 3H), 2.53 (d, J=1.4Hz, 2H), 1.49 (s, 9H), 1.30 (d, J=6.2Hz, 3H).
Embodiment 9
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((2- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-9)
Step 1:3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) benzene first Sour methyl esters
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- bromo- 2- methylsulfonyl benzene, remaining required raw material, reagent and preparation method are the same as real The step 4 in an I-1 is applied, obtaining light yellow oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): δ 8.14-8.01 (m, 1H), 7.62-7.51 (m, 1H), 7.46 (d, J= 0.8Hz, 1H), 7.39-7.31 (m, 1H), 7.28 (t, J=7.7Hz, 1H), 6.97 (d, J=8.3Hz, 1H), 6.90 (s, 1H), 4.65-4.56 (m, 1H), 3.89 (s, 3H), 3.54 (ddd, J=14.2,10.4,5.1Hz, 2H), 3.40 (d, J=1.2Hz, 3H), 3.30 (s, 3H), 1.32 (d, J=6.3Hz, 3H).
Step 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining pale yellow powder is compound 3- (2- methoxyl group-(1- Methylethyl) oxygen Base) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 8.08 (dd, J=7.9,1.6Hz, 1H), 7.61-7.53 (m, 1H), 7.52-7.47 (m, 1H), 7.39 (dd, J=2.2,1.3Hz, 1H), 7.34-7.27 (m, 1H), 6.99 (dd, J=8.3, 0.8Hz, 1H), 6.93 (t, J=2.3Hz, 1H), 4.61 (td, J=6.2,4.1Hz, 1H), 3.62-3.49 (m, 2H), 3.41 (s, 3H), 3.31 (s, 3H), 1.32 (d, J=6.3Hz, 3H).
Step 3: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((2- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-9)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((2- (methyl sulphonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- ((2- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-9).
1H NMR(300MHz,CDCl3, δ ppm): 8.10-8.05 (m, 1H), 7.61-7.54 (m, 1H), 7.32 (d, J= 8.4Hz, 2H), 7.22-7.18 (m, 1H), 7.03-6.98 (m, 1H), 6.90 (d, J=1.0Hz, 1H), 4.65-4.58 (m, 2H),4.57-4.53(m,1H),3.75-3.67(m,2H),3.58-3.50(m,2H),3.39(s,3H),3.28(s,3H), 2.70-2.60 (m, 2H), 1.48 (s, 9H), 1.31 (d, J=6.3Hz, 3H).
Embodiment 10
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (ethyl sulphonyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-10)
Step 1: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (ethylsulfonyl) phenyl) oxygroup) Methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- bromo- 4- ethyl sulfone benzene, remaining required raw material, reagent and preparation method are the same as real The step 4 in an I-1 is applied, obtaining yellow oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (second Base sulfonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.88-7.82 (m, 2H), 7.46 (dd, J=2.2,1.3Hz, 1H), 7.30 (dd, J=2.1,1.3Hz, 1H), 7.13-7.07 (m, 2H), 6.86 (t, J=2.3Hz, 1H), 4.61 (td, J=6.2, 4.0Hz, 1H), 3.90 (s, 3H), 3.54 (dt, J=18.5,5.3Hz, 2H), 3.40 (s, 3H), 3.12 (q, J=7.4Hz, 2H), 1.33 (d, J=3.1Hz, 3H), 1.32-1.30 (t, J=7.3Hz, 3H).
Step: 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (ethylsulfonyl) phenyl) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((4- (ethylsulfonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining pale yellow powder is compound 3- (2- methoxyl group-(1- Methylethyl) oxygen Base) -5- ((4- (ethylsulfonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.87 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 7.35 (s, 1H), 7.11 (d, J=8.8Hz, 2H), 6.90 (t, J=2.1Hz, 1H), 4.68-4.56 (m, 1H), 3.56 (ddd, J=14.2, 10.4,5.0Hz, 2H), 3.41 (s, 3H), 3.13 (q, J=7.4Hz, 2H), 1.33 (d, J=6.2Hz, 3H), 1.32-1.27 (t, J=7.2Hz, 3H).
Step 3: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (ethylsulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-10)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (ethylsulfonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- ((4- (ethylsulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-10).
1H NMR(300MHz,CDCl3, δ ppm): 7.87-7.81 (m, 2H), 7.30 (d, J=1.5Hz, 1H), 7.17 (s, 1H), 7.11-7.05 (m, 2H), 6.83 (t, J=2.1Hz, 1H), 4.56 (s, 2H), 4.52-4.45 (m, 1H), 3.63 (s, 2H), 3.55-3.44 (m, 3H), 3.35 (s, 3H), 3.11 (q, J=7.4Hz, 2H), 2.43 (s, 2H), 1.46 (s, 9H), 1.29 (d, J=7.6Hz, 3H), 1.26 (t, J=7.1Hz, 3H).
Embodiment 11
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (cyclopropyl sulphur Acyl group) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-11)
Step 1: the preparation bromo- 4- cyclopropyl sulfuryl benzene of 1-
Change 4- bromine thioanisole into 1- bromo- 4- cyclopropyl sulfuryl benzene, remaining required raw material, reagent and preparation method are same Step 2 in embodiment I-1, obtaining light yellow oil is the bromo- 4- cyclopropyl sulfuryl benzene of compound 1-.
1H NMR(300MHz,CDCl3, δ ppm): 7.39 (d, J=8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 2.21-2.10(m,1H),1.12-1.03(m,2H),0.73-0.64(m,2H)。
Step 2: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygen Base) methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into the bromo- 4- cyclopropyl sulfuryl benzene of 1-, remaining required raw material, reagent and preparation method With the step 4 in embodiment I-1, obtaining yellow oil is compound 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.86 (t, J=5.8Hz, 2H), 7.48-7.43 (m, 1H), 7.32- 7.29 (m, 1H), 7.10 (t, J=5.8Hz, 2H), 6.86 (t, J=2.2Hz, 1H), 4.61 (td, J=6.1,4.2Hz, 1H), 3.90 (s, 3H), 3.61-3.50 (m, 2H), 3.41 (s, 3H), 2.47 (tt, J=8.0,4.8Hz, 1H), 1.39-1.29 (m, 6H)。
Step 3: preparation 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygen Base) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (2- methoxyl group - (1- Methylethyl) oxygroup) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) methyl benzoate, remaining required raw material, reagent And preparation method, with the step 5 in embodiment I-1, obtaining pale yellow powder is compound 3- (2- methoxyl group-(1- Methylethyl) oxygen Base) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.89-7.83 (m, 2H), 7.50 (d, J=1.4Hz, 1H), 7.37- 7.34 (m, 1H), 7.11 (d, J=8.8Hz, 2H), 6.90 (t, J=2.3Hz, 1H), 4.62 (td, J=6.2,4.0Hz, 1H), 3.62-3.49 (m, 2H), 3.42 (s, 3H), 2.47 (dq, J=7.9,4.8Hz, 1H), 1.38-1.34 (m, 2H), 1.33 (d, J =6.3Hz, 3H), 1.04 (dd, J=7.4,5.3Hz, 2H).
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-11)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation side For method with the step 6 in embodiment I-1, obtaining white powder is that (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole is simultaneously for compound N - [5,4-c] pyridine -2- base) -3- ((4- (Cyclopropylsulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygen Base) benzamide (I-11).
1H NMR(300MHz,CDCl3, δ ppm): δ 7.85-7.77 (m, 2H), 7.22 (d, J=1.1Hz, 1H), 7.04 (dd, J=10.4,1.8Hz, 3H), 6.79 (d, J=1.2Hz, 1H), 4.56-4.45 (m, 3H), 3.63 (t, J=5.8Hz, 2H), 3.53-3.41 (m, 2H), 3.32 (s, 3H), 2.57 (t, J=6.2Hz, 2H), 2.45-2.36 (m, 1H), 1.41 (s, 9H), 1.39-1.34 (m, 2H), 1.32 (d, J=6.2Hz, 2H).
Embodiment 12
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidin Alkane -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-12)
Step 1: preparation 1- (4- bromophenyl sulphonyl) azetidine
Azetidine hydrochloride 0.5g (5.0 mMs) and 1.0 milliliters of distillations are added into dry 100 milliliters of there-necked flasks Water stirs under ice bath, after replacing reaction system gas with argon gas, after being slowly added to 0.2 gram of sodium hydroxide (5.9 mMs), rises It warms to room temperature, stirring 2h solution colour clarification is concentrated in vacuo the faint yellow thick substances of reaction solution, is then added 14.0 milliliters DCM, 1.6 grams of (4.2 mMs) 4- bromobenzene sulfonyl chlorides and 4N K2CO310.0 milliliters of aqueous solution.8h is stirred at room temperature.TLC detection is aobvious After showing fully reacting, is diluted and be extracted with dichloromethane with distilled water.Organic phase is dried, filtered with anhydrous sodium sulfate, and vacuum is dense Contracting, obtaining 0.9 gram of white crystal is compound 1- (4- bromophenyl sulphonyl) azetidine, yield 71.9%.
1H NMR(300MHz,CDCl3,δppm):7.84-7.54(m,4H),3.81-3.74(m,4H),2.15-2.04(m, 2H)。
Step 2: preparation 3- (4- (azetidine -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) Oxygroup) methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- (4- bromophenyl sulphonyl) azetidine, remaining required raw material, reagent and preparation side For method with the step 4 in embodiment I-1, obtaining yellow oil is compound 3- (4- (azetidine -1- sulfonyl) phenoxy group) - 5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.80 (d, J=8.7Hz, 2H), 7.46 (d, J=0.5Hz, 1H), 7.32 (s, 1H), 7.11 (d, J=8.8Hz, 2H), 6.87 (t, J=2.0Hz, 1H), 4.67-4.55 (m, 1H), 3.89 (s, 3H), 3.79 (t, J=7.6Hz, 4H), 3.63-3.49 (m, 2H), 3.40 (s, 3H), 2.10 (dd, J=15.2,7.6Hz, 2H), 1.32 (d, J=6.3Hz, 3H).
Step 3: preparation 3- (4- (azetidine -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) Oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (4- (azacyclo- Butane -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, remaining required raw material, examination With the step 5 in embodiment I-1, obtaining yellow oil is compound 3- (4- (azetidine -1- sulphonyl for agent and preparation method Base) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.84-7.78 (m, 2H), 7.53-7.49 (m, 1H), 7.37 (d, J= 1.2Hz, 1H), 7.15-7.09 (m, 2H), 6.91 (t, J=2.2Hz, 1H), 4.69-4.56 (m, 1H), 3.79 (t, J= 7.6Hz, 4H), 3.63-3.49 (m, 2H), 3.42 (s, 3H), 2.17-2.06 (m, 2H), 1.33 (d, J=6.3Hz, 3H).
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-12)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (4- (azetidin Alkane -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, reagent and system For Preparation Method with the step 6 in embodiment I-1, obtaining white powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiophene Azoles simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- methyl second Base) oxygroup) benzamide (I-12).
1H NMR(300MHz,CDCl3,δppm):7.85-7.79(m,2H),7.35-7.32(m,1H),7.23-7.20(m, 1H), 7.16-7.10 (m, 2H), 6.88 (t, J=2.2Hz, 1H), 4.61 (dd, J=6.2,2.3Hz, 1H), 4.58 (t, J= 4.9Hz, 2H), 3.80 (t, J=7.6Hz, 4H), 3.71 (t, J=5.8Hz, 2H), 3.54 (dt, J=16.4,5.4Hz, 2H), 3.39 (s, 3H), 2.64 (t, J=6.2Hz, 2H), 2.17-2.08 (m, 2H), 1.48 (s, 9H), 1.32 (d, J=6.3Hz, 3H)。
Embodiment 13
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-13)
Step 1: preparation 1- (4- benzoyl bromide) azepine butane
4- bromobenzoic acid, the drop of 50.0 milliliters of DCM and 1 of 2.0 grams (10.0 mMs) are added into 100 milliliters of there-necked flasks DMF.Then 1.1 milliliters of oxalyl chloride (12.0 mMs) are slowly added dropwise in ice bath stirring.12h is stirred at room temperature in completion of dropwise addition.TLC inspection After surveying display fully reacting, vacuum concentration obtains clear yellow viscous object.The lower DCM for being added 25.0 milliliters, 1.1 grams are protected in argon gas The TEA of (12.0 mMs) azetidine hydrochloride and 4.2 milliliters (30.0 mMs).After being stirred at room temperature 2.5 hours, 1N is used It is 6 that HCl solution, which slowly adjusts pH value, is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, and vacuum concentration obtains Crude product is yellow oil.Crude product obtains White crystal powder 1.5 through column chromatography (methylene chloride: methanol=50:1) separation Gram be compound 1- (4- benzoyl bromide) azepine butane, yield 60.4%.
1H NMR(300MHz,CDCl3,δppm):7.73-7.32(m,4H),3.80-3.72(m,4H),2.16-2.01(m, 2H)。
Step 2: preparation 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) Oxygroup) methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- (4- benzoyl bromide) azepine butane, remaining required raw material, reagent and preparation For method with the step 4 in embodiment I-1, obtaining yellow oil is compound 3- (4- (azetidine -1- formoxyl) benzene oxygen Base) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 7.63 (d, J=8.7Hz, 2H), 7.41-7.37 (m, 1H), 7.26- 7.23 (m, 1H), 7.00 (t, J=5.7Hz, 2H), 6.81 (t, J=2.3Hz, 1H), 4.64-4.53 (m, 1H), 4.33 (t, J= 7.3Hz,2H),4.26-4.19(m,2H),3.87(s,3H),3.61-3.48(m,2H),3.39(s,3H),2.40-2.29(m, 2H), 1.30 (d, J=6.3Hz, 3H).
Step 3: preparation 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) Oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (4- (azacyclo- Butane -1- sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, remaining required raw material, examination With the step 5 in embodiment I-1, obtaining yellow oil is compound 3- (4- (azetidine -1- formyl for agent and preparation method Base) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.64 (d, J=8.5Hz, 2H), 7.44 (s, 1H), 7.31 (s, 1H), 7.00 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 4.58 (dt, J=11.9,5.9Hz, 1H), 4.43-4.30 (m, 2H), 4.30-4.20 (m, 2H), 3.63-3.50 (m, 2H), 3.40 (s, 3H), 2.42-2.28 (m, 2H), 1.31 (d, J=6.2Hz, 3H)。
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-13)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, reagent and system For Preparation Method with the step 6 in embodiment I-1, obtaining white powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiophene Azoles simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- methyl second Base) oxygroup) benzamide (I-13).
1H NMR(300MHz,CDCl3, δ ppm): 7.56 (d, J=8.3Hz, 2H), 7.20 (d, J=2.9Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=8.4Hz, 2H), 6.73 (s, 1H), 4.51 (s, 2H), 4.43 (dd, J=5.6,3.2Hz, 1H), 4.25 (d, J=6.2Hz, 2H), 4.15 (s, 2H), 3.57 (s, 2H), 3.45 (dd, J=16.7,10.7Hz, 2H), 3.30 (s, 3H), 2.37 (s, 2H), 2.32-2.23 (m, 2H), 1.41 (s, 9H), 1.20 (d, J=6.0Hz, 3H).
Embodiment 14
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (dimethylamino first Acyl group) phenoxy group)) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-14)
Step 1: preparation N, N- dimethyl -4- brombenzamide
Azetidine hydrochloride is changed into and methylamine hydrochloride, remaining required raw material, reagent and preparation method are the same as implementation Step 1 in example I-13, obtaining yellow powder is compound N, N- dimethyl -4- brombenzamide.
1H NMR(300MHz,CDCl3,δppm):7.57-7.50(m,2H),7.34-7.28(m,2H),3.10(s,3H), 2.97(s,3H)。
Step 2: preparation 3- (4- (dimethylamino formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) Methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into N, N- dimethyl -4- brombenzamide, remaining required raw material, reagent and preparation For method with the step 4 in embodiment I-1, obtaining light yellow oil is compound 3- (4- (dimethylamino formoxyl) phenoxy group)- 5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3,δppm):8.55(s,2H),7.50-7.47(m,1H),7.30-7.27(m,1H), 7.26 (s, 2H), 6.88 (t, J=2.3Hz, 1H), 4.63 (dd, J=9.3,2.2Hz, 3H), 4.60 (dd, J=5.0,2.8Hz, 1H), 4.35-4.24 (m, 3H), 3.91 (s, 3H), 3.62-3.52 (m, 2H), 3.41 (s, 3H), 1.33 (d, J=6.3Hz, 3H)。
Step 3: preparation 3- (4- (dimethylamino formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) Benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (4- (dimethylamine Base formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, remaining required raw material, reagent and For preparation method with the step 5 in embodiment I-1, obtaining white powder is compound 3- (4- (dimethylamino formoxyl) phenoxy group)- 5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3,δppm):8.54(s,2H),7.50-7.46(m,1H),7.30-7.27(m,1H), 7.26 (s, 2H), 6.89 (t, J=2.2Hz, 1H), 4.63 (dd, J=9.3,2.1Hz, 3H), 4.60 (dd, J=5.0,2.8Hz, 1H), 4.35-4.24 (m, 3H), 3.62-3.52 (m, 2H), 3.41 (s, 3H), 1.33 (d, J=6.1Hz, 3H).
Step 4:N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (diformazan Amido formacyl) phenoxy group)) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-14)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (4- (dimethylamino first Acyl group) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method With the step 6 in embodiment I-1, obtain white powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base) -3- (4- (dimethylamino formoxyl) phenoxy group)) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene Formamide (I-14).
1H NMR(300MHz,CDCl3, δ ppm): 7.45 (d, J=8.7Hz, 2H), 7.29 (s, 1H), 7.16 (s, 1H), 7.04 (d, J=8.7Hz, 2H), 6.83 (d, J=2.0Hz, 1H), 4.62 (dd, J=5.2,1.3Hz, 1H), 4.60-4.56 (m, 2H),3.76-3.69(m,2H),3.57-3.49(m,2H),3.40(s,3H),3.11(s,3H),3.05(s,3H),2.73- 2.65 (m, 2H), 1.49 (s, 9H), 1.31 (d, J=6.3Hz, 3H).
Embodiment 15
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (3,5- difluorophenyl Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-15)
Step 1: preparation 3- (3,5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid first Ester
0.2 gram of (1.0 mMs) 3- hydroxyl -5- (2- methoxyl group-(1- methyl second is separately added into 100 milliliters of there-necked flasks Base) oxygroup) benzic acid methyl esters, 0.2 gram of (1.4 mMs) 3,5- difluoro phenyl boric acid, 0.2 gram (1.2 mMs) of copper acetate, 1.0 gramsMolecular sieve, DCM and 0.7 of 30.0 milliliters milliliter (5.0 mMs) of TEA.It is stirred at room temperature 48 hours, has reacted Quan Hou filters reaction solution, and vacuum concentration filtrate obtains pale tan oil.Above-mentioned brown color is dissolved with 10.0 milliliters of ethyl acetate After grease, respectively with the NaHCO of 20.0% aqueous citric acid solution and 1N3Aqueous solution respectively washed once to obtain faint yellow organic phase. It is concentrated in vacuo organic phase, through column chromatography (petroleum ether: ethyl acetate=1:1) separation, obtains 74.8 milligrams of colorless oil to change Object 3- (3,5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate is closed, yield is 21.2%.
1H NMR(300MHz,CDCl3, δ ppm): 7.36 (dd, J=2.4,1.3Hz, 1H), 7.23-7.18 (m, 1H), 6.75 (t, J=2.3Hz, 1H), 6.54-6.35 (m, 3H), 4.56-4.49 (m, 1H), 3.82 (s, 3H), 3.54-3.40 (m, 2H), 3.33 (s, 3H), 1.25 (d, J=6.3Hz, 3H)
Step 2: preparation 3- (3,5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (3,5- difluoro Phenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, remaining required raw material, reagent and preparation method With the step 5 in embodiment I-1, obtaining grey powder is compound 3- (3,5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- first Base ethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.48 (dd, J=2.2,1.3Hz, 1H), 7.33 (dd, J=2.1, 1.4Hz, 1H), 6.87 (t, J=2.3Hz, 1H), 6.61-6.46 (m, 3H), 4.62 (td, J=6.2,4.1Hz, 1H), 3.56 (dt, J=18.0,5.3Hz, 2H), 3.42 (s, 3H), 1.33 (d, J=6.3Hz, 3H).
Step 3: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (3, 5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-15)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (3,5- difluorophenyl Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, reagent and the same embodiment of preparation method Step 6 in I-1, obtaining grey powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyrrole Pyridine -2- base) -3- (3,5- difluorophenyl oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-15).
1H NMR(300MHz,CDCl3, δ ppm): 7.33-7.29 (m, 1H), 7.16 (d, J=1.5Hz, 1H), 6.84 (t, J =2.1Hz, 1H), 6.62-6.50 (m, 3H), 4.58 (s, 2H), 4.56-4.51 (m, 1H), 3.73-3.65 (m, 2H), 3.53 (dd, J=11.7,5.0Hz, 2H), 3.39 (s, 3H), 2.59 (dd, J=8.2,3.0Hz, 2H), 1.48 (s, 9H), 1.31 (d, J =6.3Hz, 3H).
Embodiment 16
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- benzyloxy -5- (2- first Oxygroup-(1- Methylethyl) oxygroup) benzamide (I-16)
Step 1: preparation 3- benzyloxy -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate
0.6 milliliter of (5.3 mMs) cylite, 1.2 grams of (5.0 mMs) 3- are separately added into 100 milliliters of there-necked flasks Hydroxyl -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzic acid methyl esters, DMF and 1.4 of 10.0 milliliters gram of (10.0 mmoles You) potassium carbonate.Reaction solution is stirred at room temperature 8 hours.After fully reacting, with 50.0 milliliters of saturation NH4Cl aqueous solution dilutes and uses second Acetoacetic ester extraction.Organic phase is dried, filtered with anhydrous sodium sulfate, vacuum concentration, and obtaining crude product is yellow oil.Crude product is through column (petroleum ether: ethyl acetate=9:1) separation is chromatographed, obtains 1.4 grams of light yellow oil as compound 3- benzyloxy -5- (2- first Oxygroup-(1- Methylethyl) oxygroup) methyl benzoate, yield 83.2%.
1H NMR(300MHz,CDCl3, δ ppm): 7.37 (ddd, J=11.6,8.6,6.2Hz, 5H), 7.29-7.26 (m, 1H), 7.25 (dd, J=2.9,1.9Hz, 1H), 6.77 (t, J=2.2Hz, 1H), 5.07 (s, 2H), 4.58 (td, J=6.0, 4.5Hz, 1H), 3.89 (s, 3H), 3.52 (ddd, J=14.5,10.2,4.3Hz, 2H), 3.40 (s, 3H), 1.31 (d, J= 6.3Hz,3H)。
Step 2: preparation 3- benzyloxy -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- benzyloxy -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, remaining required raw material, reagent and preparation method are the same as embodiment I-1 In step 5, obtain grey powder be compound 3- benzyloxy -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.48-7.34 (m, 5H), 7.33 (dd, J=2.3,1.2Hz, 1H), 7.31 (dd, J=2.3,1.3Hz, 1H), 6.82 (t, J=2.3Hz, 1H), 5.08 (s, 2H), 4.65-4.54 (m, 1H), 3.55 (ddd, J=14.5,10.3,5.1Hz, 2H), 3.42 (s, 3H), 1.32 (d, J=6.3Hz, 3H).
Step 3: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- benzyloxy Base -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-16)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- benzyloxy -5- (2- first Oxygroup-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, reagent and preparation method with the step 6 in embodiment I-1, Grey powder is compound N-(6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- benzyloxy Base -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-16).
1H NMR(300MHz,CDCl3, δ ppm): 7.43-7.31 (m, 5H), 7.10 (d, J=2.0Hz, 1H), 7.08 (d, J =1.7Hz, 1H), 6.78 (t, J=2.0Hz, 1H), 5.03 (s, 2H), 4.56 (s, 2H), 4.55-4.48 (m, 1H), 3.76- 3.60 (m, 2H), 3.52 (ddd, J=14.4,10.3,5.0Hz, 2H), 3.39 (s, 3H), 2.59 (s, 2H), 1.48 (s, 9H), 1.29 (d, J=6.3Hz, 3H).
Embodiment 17
N- (6- phenyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-17)
Step 1: preparing 5- phenyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- phenyl -4- piperidones, remaining required raw material, reagent and preparation side For method with the step 1 in embodiment I-1, obtaining yellow powder is compound 5- phenyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyrrole Pyridine -2- amine.
1H NMR(300MHz,CDCl3, δ ppm): 8.29-7.88 (m, 5H), 4.80 (d, J=0.5Hz, 2H), 4.38 (s, 2H), 3.69 (t, J=5.5Hz, 2H), 2.64 (t, J=5.6Hz, 2H).
Step 2: preparation N- (6- phenyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl Sulfonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-17)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- phenyl -4,5,6,7- into Simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method obtain tetrahydro-thiazoles with the step 6 in embodiment I-1 Grey powder is compound N-(6- phenyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphur Acyl group) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-17).
1H NMR(300MHz,CDCl3, δ ppm): 7.79 (d, J=8.8Hz, 2H), 7.23-7.10 (m, 5H), 7.04- 6.96 (m, 3H), 6.87 (d, J=8.0Hz, 2H), 6.75 (dd, J=10.8,4.6Hz, 2H), 4.48-4.41 (m, 1H), 4.29 (s, 2H), 3.51 (t, J=5.6Hz, 2H), 3.46-3.36 (m, 2H), 3.27 (s, 3H), 2.96 (s, 3H), 2.57 (t, J= 5.2Hz, 2H), 1.19 (d, J=6.3Hz, 3H).
Embodiment 18
N- (6- (4- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-18)
Step 1: preparation 1- (4- pyridine) -4- piperidones
It is added into 25 milliliters of microwave reaction bottles to 6.2 grams of bromopyridine, 5.2 grams of 4- piperidones condensed ethandiol, catalytic amount vinegar Sour palladium, 2- dicyclohexyl phosphorus -2,4,0.9 gram of 6- tri isopropyl biphenyl, 3.0 grams of sodium tert-butoxide, 15.0 milliliters of toluene, the tert-butyl alcohol 3.0 milliliters, microwave heating is cooled to room temperature after reacting 15 minutes to 160 DEG C, filters to take filtrate, and filter vacuum concentration obtains Huang 1.5 grams of color powder.The yellow powder not after further treatment, is directly transferred in 100 milliliters dry of two-mouth bottle, then plus Enter 30.0 milliliters of tetrahydrofurans, is stirred at room temperature to dissolution.After being cooled to interior temperature lower than 10 DEG C with ice bath again, it is slowly added to dropwise 6 moles every liter of aqueous hydrochloric acid solution is stirred overnight at room temperature after being added dropwise to complete.After fully reacting, it is solid to obtain yellow for vacuum concentration Body.It is dissolved in 20 milliliters of water, 20%NaOH tune PH to 10, chloroform extraction, organic phase anhydrous sodium sulfate dry filter, vacuum is dense Contracting, obtains crude product.Through column chromatography (methylene chloride: methanol=20:1) separation, 345.5 milligrams of golden powder is obtained, is target product, Yield is 36.9%.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.27 (d, J=8.8Hz, 2H), 7.20 (d, J=8.8Hz, 2H), 3.74(m,4H),2.68(m,4H)。
Step 2: preparing 5-(pyridin-4-yl)-4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine-2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into 1- (4- pyridine) -4- piperidones, remaining required raw material, reagent and system Preparation Method is with the step 1 in embodiment I-1, and obtaining yellow powder is compound 5- (pyridin-4-yl) -4, and 5,6,7- tetrahydro-thiazoles are simultaneously [5,4-c] pyridine -2- amine.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.28 (d, J=8.8Hz, 2H), 7.14 (d, J=8.8Hz, 2H), 4.79 (d, J=0.5Hz, 2H), 4.42 (s, 2H), 3.69 (t, J=5.6Hz, 2H), 2.63 (t, J=5.7Hz, 2H).
Step 4: preparation N- (6- (4- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-18)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- (pyridin-4-yl)-into 4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining yellow powder is compound N-(6- (4- pyridyl group) -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) - 3- ((4- (methyl sulphonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-18)。
1H NMR (300MHz, d6-DMSO, δ ppm): 8.28 (d, J=5.8Hz, 2H), 7.91 (d, J=8.8Hz, 2H), 7.46 (s, 1H), 7.30 (s, 1H), 7.13 (d, J=8.8Hz, 2H), 6.87 (t, J=1.7Hz, 1H), 6.80 (d, J= 5.9Hz, 2H), 4.71-4.64 (m, 1H), 4.58 (s, 2H), 3.83 (t, J=5.3Hz, 2H), 3.55 (dt, J=17.6, 5.3Hz, 2H), 3.40 (s, 3H), 3.07 (s, 3H), 2.84 (s, 2H), 1.33 (d, J=6.2Hz, 3H).
Embodiment 19
N- (5- tertbutyloxycarbonyl -5,6- dihydro -4H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-19)
Step 1: preparation 2- amino -4H- pyrrolo- [3,4-d] thiazole -5 (6H)-carboxylic acid tert-butyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into 1- t-butoxycarbonyl -3- pyrrolidones, remaining required raw material, reagent And preparation method is with the step 1 in embodiment I-1, obtain yellow powder be compound 2- amino -4,6- dihydro -5H- pyrrolo- [3, 4-d] the thiazole-5-carboxylic acid tert-butyl ester.
1H NMR(300MHz,CDCl3, δ ppm): 5.44 (d, J=10.6Hz, 2H), 4.53-4.45 (m, 2H), 4.40- 4.30(m,2H),1.48(s,9H)。
Step 2: preparation N- (5- tertbutyloxycarbonyl -5,6- dihydro -4H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-19)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -4,6- two into Hydrogen -5H- pyrrolo- [3,4-d] thiazole-5-carboxylic acid tert-butyl ester, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtain yellow powder be compound N-(5- tertbutyloxycarbonyl -5,6- dihydro -4H- pyrrolo- [3,4-d] thiazole -2- Base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-19).
1H NMR(300MHz,CDCl3, δ ppm): 7.88 (d, J=8.9Hz, 2H), 7.42-7.38 (m, 1H), 7.25- 7.22 (m, 1H), 7.08 (d, J=8.8Hz, 2H), 6.86 (t, J=2.2Hz, 1H), 6.13 (d, J=3.4Hz, 1H), 4.58- 4.50(m,1H),3.55-3.46(m,2H),3.37(s,3H),3.07(s,3H),1.68(s,9H),1.55(s,2H),1.49 (s, 2H), 1.27 (d, J=6.3Hz, 3H).
Embodiment 20
N- (6- acetylaminohydroxyphenylarsonic acid 4,5,6,7- tetrahydro benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) - 5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-20)
Step 1: preparation N- (2- amino -4,5,6,7- tetrahydro -6- benzo (d) thiazolyl) acetamide
15.6 grams of (0.1 mole) 4- acetylamino cyclohexanone and 0.2L ice vinegar are put into the there-necked flask dry to 500 milliliters Acid obtains light yellow clarifying liquid in 60 DEG C of heating stirrings under argon gas protection；It is slowly added dropwise 5.1 milliliters of bromine (0.1 mole), solution becomes For brown liquid, continues to stir 2h, obtain light yellow clarifying liquid body.Stop heating, after reaction is cooled to room temperature, thiocarbamide is added 8.0 grams (0.1 mole), 120 DEG C, back flow reaction 1 hour are to slowly warm up under argon gas protection.After fully reacting, it is cooled to room temperature, Faint yellow solid is filtered by vacuum to obtain；50.0 milliliters of acetone washing filter cakes, it is molten that filter cake then obtains yellow transparent with 0.1 liter of water Liquid, slowly adjusting pH value with 2 moles every liter of sodium hydrate aqueous solution is 9~9.5, and a large amount of light yellow solids are precipitated, and vacuum is taken out Filter cake is filtered and collected, then washs filter cake with 30.0 ml methanols, obtains 17.7 grams of light grey solid as compound N-(2- amino- 4,5,6,7- tetrahydro -6- benzo (d) thiazolyls) acetamide, yield 84.0%.
1H NMR(300MHz,CDCl3, δ ppm): 7.92 (d, J=7.6Hz, 1H), 6.67 (s, 2H), 4.01-3.87 (m, 1H), 2.72 (dd, J=15.4,5.1Hz, 1H), 2.49-2.39 (m, 2H), 2.37-2.28 (m, 1H), 1.89-1.81 (m, 1H),1.80(s,3H),1.71-1.57(m,1H)。
Step 2: preparation N- (6- acetylaminohydroxyphenylarsonic acid 4,5,6,7- tetrahydro-tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (first Base sulfonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-20)
By 2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester change into N- (amino -4,5 2-, 6,7- tetrahydro -6- benzo (d) thiazolyls) acetamide, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-6 Rapid 4, obtaining white powder is compound N-(6- acetylaminohydroxyphenylarsonic acid 4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-20).
1H NMR(300MHz,CDCl3, δ ppm): 7.89 (d, J=8.6Hz, 2H), 7.23 (d, J=5.6Hz, 1H), 7.18 (s, 1H), 7.09 (d, J=8.6Hz, 2H), 6.80 (s, 1H), 6.06 (dd, J=35.4,7.4Hz, 1H), 4.32 (d, J= 3.9Hz, 2H), 3.53-3.42 (m, 2H), 3.36 (d, J=2.0Hz, 3H), 3.07 (s, 3H), 2.57 (d, J=15.2Hz, 1H), 2.37 (dd, J=18.0,11.0Hz, 2H), 2.16 (d, J=16.3Hz, 1H), 1.95 (s, 3H), 1.83 (d, J= 5.2Hz, 2H), 1.23 (dd, J=6.0,3.0Hz, 3H).
Embodiment 21
N- (6- acetyl-amino -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-21)
Step 1: preparing 5- acetyl group -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- acetyl group -4- piperidones, remaining required raw material, reagent and preparation For method with the step 1 in embodiment I-1, obtaining pale yellow powder is compound 5- acetyl group -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4- C] pyridine -2- amine.
1H NMR(300MHz,CDCl3, δ ppm): 4.79 (d, J=0.5Hz, 2H), 4.41 (s, 2H), 3.68 (t, J= 5.6Hz, 2H), 3.06 (s, 3H), 2.64 (t, J=5.6Hz, 2H).
Step 2: preparation N- (6- acetyl-amino -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-21)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes acetyl group -4,5,6 5- into, 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method with the step 4 in embodiment I-6, Yellow powder is compound N-(6- acetyl-amino -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-21).
1H NMR(300MHz,CDCl3, δ ppm): 7.92 (d, J=8.7Hz, 2H), 7.36 (s, 1H), 7.15 (dd, J= 15.4,7.2Hz, 3H), 6.87 (s, 1H), 4.76 (s, 1H), 4.60 (dd, J=10.2,6.1Hz, 2H), 3.88 (dd, J= 11.4,5.9Hz, 1H), 3.74 (t, J=5.6Hz, 1H), 3.54 (ddd, J=14.0,10.3,5.0Hz, 2H), 3.39 (s, 3H), 3.08 (s, 3H), 2.74-2.63 (m, 2H), 2.18 (dd, J=5.5,1.6Hz, 3H), 1.32 (d, J=6.3Hz, 3H).
Embodiment 22
N- (6- isopropyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-22)
Step 1: preparing 5- isopropyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- isopropyl -4- piperidones, remaining required raw material, reagent and preparation For method with the step 1 in embodiment I-1, obtaining brownish-yellow powder is compound 5- isopropyl -4,5,6,7- tetrahydros-thiazole simultaneously [5, 4-c] pyridine -2- base amine.
1H NMR(300MHz,CDCl3, δ ppm): 5.07 (d, J=35.4Hz, 2H), 3.55 (s, 2H), 2.94-2.87 (m, 1H), 2.83-2.75 (m, 2H), 2.63 (s, 2H), 1.09 (dd, J=6.4,3.4Hz, 6H).
Step 2: preparation N- (6- isopropyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-22)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes isopropyl -4,5,6 5- into, 7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base amine, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-6 Rapid 4, obtaining yellow powder is compound N-(6- isopropyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-22).
1H NMR(300MHz,CDCl3, δ ppm): 7.95-7.87 (m, 2H), 7.42 (d, J=1.4Hz, 1H), 7.27 (d, J =1.5Hz, 1H), 7.20-7.10 (m, 2H), 6.87 (t, J=2.1Hz, 1H), 4.69-4.62 (m, 1H), 3.93 (s, 2H), 3.55 (dt, J=16.7,5.3Hz, 2H), 3.39 (s, 3H), 3.24 (dd, J=9.1,6.6Hz, 1H), 3.07 (s, 5H), 2.93 (d, J=1.2Hz, 2H), 1.33 (d, J=6.3Hz, 3H), 1.31-1.25 (m, 6H).
Embodiment 23
N- (6- ethyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-23)
Step 1: preparing 5- ethyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- ethyl -4- piperidones, remaining required raw material, reagent and preparation side Method is with the step 1 in embodiment I-1, and obtaining brownish-yellow powder is compound 5- ethyl -4,5, and 6,7- tetrahydros-thiazole is simultaneously [5,4-c] Pyridine -2- base amine.
1H NMR(300MHz,CDCl3, δ ppm): 5.16 (d, J=0.7Hz, 2H), 3.39 (s, 2H), 2.77 (t, J= 5.7Hz, 2H), 2.65-2.61 (m, 2H), 2.60-2.54 (m, 2H), 1.13 (t, J=7.2Hz, 3H).
Step 2: preparation N- (6- ethyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl Sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-23)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- ethyl -4,5,6,7- into Tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base amine, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-6 4, obtaining yellow powder is compound N-(6- ethyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-23).
1H NMR(300MHz,CDCl3, δ ppm): 7.96-7.87 (m, 2H), 7.34 (s, 1H), 7.16 (d, J=1.2Hz, 1H), 7.13 (d, J=8.8Hz, 2H), 6.87 (t, J=2.0Hz, 1H), 4.64-4.57 (m, 1H), 3.70 (s, 2H), 3.54 (ddd, J=13.5,10.0,4.7Hz, 2H), 3.39 (s, 3H), 3.08 (s, 3H), 2.86 (t, J=5.4Hz, 2H), 2.73 (t, J=6.1Hz, 2H), 2.68 (dd, J=8.5,5.6Hz, 2H), 1.32 (d, J=6.3Hz, 3H), 1.21 (t, J=7.2Hz, 3H)。
Embodiment 24
N- (6- methyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-24)
Step 1: preparing 5- methyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- methyl -4- piperidones, remaining required raw material, reagent and preparation side Method is with the step 1 in embodiment I-1, and obtaining brownish-yellow powder is compound 5- methyl -4,5, and 6,7- tetrahydros-thiazole is simultaneously [5,4-c] Pyridine -2- base amine.
1H NMR(300MHz,CDCl3, δ ppm): 4.85 (s, 2H), 3.46-3.45 (m, 2H), 2.75 (t, J=5.3Hz, 2H), 2.68 (dd, J=4.8,2.5Hz, 2H), 2.46 (s, 3H).
Step 2: preparation N- (6- ethyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl Sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-24)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- methyl -4,5,6,7- into Tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base amine, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-6 4, obtaining yellow powder is compound N-(6- methyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-24).
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.8Hz, 2H), 7.38 (s, 1H), 7.22 (s, 1H), 7.17-7.09 (m, 2H), 6.87 (d, J=1.8Hz, 1H), 4.65-4.57 (m, 1H), 3.63 (s, 2H), 3.57-3.48 (m, 2H), 3.39 (s, 3H), 3.07 (s, 3H), 2.77 (dd, J=14.3,4.5Hz, 4H), 2.51 (s, 3H), 1.32 (d, J= 6.2Hz,3H)。
Embodiment 25
N- (4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-25)
Step 1: preparation N- (4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (methyl sulphonyl) benzene Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-25)
Into 25 milliliters of dry two-mouth bottles, N- is added, and (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole is simultaneously [5,4-c] Pyridine -2- base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-6) 0.3 gram, 5 milliliters of methylene chloride, after dissolution is stirred at room temperature, ice bath is cooled to 0 DEG C, and triethylamine is added dropwise, and is added dropwise to complete After be stirred overnight at room temperature.After fully reacting, reaction solution is poured into 10 milliliters of water, is filtered after excess 1N HCl is added.Filtrate is used Ethyl acetate extraction, water layer use 20% sodium hydrate aqueous solution tune PH to 9, methylene chloride extract, organic phase anhydrous slufuric acid Sodium dries, filters, and vacuum concentration obtains crude product.Through column chromatography (methylene chloride: methanol=20:1) separation, yellow powder 0.2 is obtained Gram, it is target product, yield 90.3%.
1H NMR(300MHz,CDCl3, δ ppm): 7.98-7.91 (m, 2H), 7.58 (d, J=1.3Hz, 1H), 7.37 (d, J =1.3Hz, 1H), 7.25 (d, J=8.8Hz, 2H), 6.99 (d, J=1.6Hz, 1H), 4.79 (dd, J=10.4,5.9Hz, 1H), 3.93 (s, 2H), 3.58-3.43 (m, 3H), 3.22 (s, 3H), 3.17 (s, 2H), 3.09 (t, J=5.4Hz, 2H), 2.64 (t, J=5.1Hz, 2H), 1.25 (d, J=6.2Hz, 3H).
Embodiment 26
N- (5H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- methoxy Base-(1- Methylethyl) oxygroup) benzamide (I-26)
Step 1: preparation N- (5,6- dihydro -4H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-26)
By N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphur Acyl group) phenyl) oxygroup) and -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-6) change into preparation N- (the tertiary fourth oxygen of 5- Carbonyl -5,6- dihydro -4H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) -5- (2- first Oxygroup-(1- Methylethyl) oxygroup) benzamide (I-19), remaining required raw material, reagent and preparation method are the same as embodiment I-25 In step 1, obtain brown ceramic powder be compound N-(5,6- dihydro -4H- pyrrolo- [3,4-d] thiazol-2-yl) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-26).
1H NMR(300MHz,CDCl3, δ ppm): 7.85 (d, J=8.3Hz, 2H), 7.39 (s, 1H), 7.34-7.27 (m, 1H), 7.07 (d, J=8.1Hz, 2H), 6.76 (s, 1H), 4.62 (d, J=4.4Hz, 1H), 4.54-4.36 (m, 2H), 4.26 (d, J=5.5Hz, 2H), 3.50 (dt, J=10.0,8.4Hz, 2H), 3.34 (s, 3H), 3.04 (s, 3H), 1.26 (d, J= 6.7Hz,3H)。
Embodiment 27
N- (4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxy Base-(1- Methylethyl) oxygroup) benzamide (I-27)
Step 1: preparation 4,5,6,7- tetrahydro benzo (d) thiazole -2- amine
Into 25 milliliters of dry sealing reaction flasks, add after being added 1.0 milliliters of cyclohexanone, 1.5 grams of thiocarbamide, 2.5 grams of iodine grain Hot 110 DEG C of about 12 hours.After being cooled to room temperature, simultaneously 10 milliliters of distilled water are added into reaction flask and stir 30 minutes to be quenched Reaction.After stirring, after being slowly added to solid sodium bicarbonate to no gas releasing.It is extracted with methylene chloride, organic phase nothing Aqueous sodium persulfate dries, filters, vacuum concentration, and obtaining crude product is yellow oil.(ethyl acetate: petroleum ether=1:2) is chromatographed through column Separation, obtains 0.9 gram of yellow oil, yield 56.3%.
1H NMR(300MHz,CDCl3,δppm):4.84-4.66(s,2H),2.73-2.65(m,2H),2.64-2.58(m, 2H),2.55-2.27(m,4H)。
Step 2: preparation N- (4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) - 5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-27)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 4,5,6,7- tetrahydro benzene into And thiazole -2- amine, with the step 4 in embodiment I-6, obtaining yellow powder is chemical combination for remaining required raw material, reagent and preparation method Object N- (4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-27).
1H NMR(300MHz,CDCl3, δ ppm): 7.89 (d, J=8.8Hz, 2H), 7.29 (s, 1H), 7.13 (d, J= 1.4Hz, 1H), 7.08 (d, J=8.8Hz, 2H), 6.83 (d, J=1.9Hz, 1H), 4.45 (dt, J=10.2,5.0Hz, 1H), 3.53-3.44(m,2H),3.35(s,3H),3.06(s,3H),2.88-2.61(m,2H),2.35-2.25(m,2H),1.84 (dd, J=22.8,9.5Hz, 2H), 1.51-1.30 (m, 2H), 1.26 (d, J=6.3Hz, 3H).
Embodiment 28
N- (5,6- dihydro -4H- cyclopentano (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxy Base-(1- Methylethyl) oxygroup) benzamide (I-28)
Step 1: preparation 5,6- dihydro -4H- cyclopentano thiazole -2- amine
Change cyclohexanone into cyclopentanone, remaining required raw material, reagent and preparation method with the step 1 in embodiment I-27, Obtaining yellow powder is compound 5,6- dihydro -4H- cyclopentano thiazole -2- amine.
1H NMR(300MHz,CDCl3,δppm):4.92-4.78(s,2H),2.78-2.70(m,2H),2.68-2.58(m, 2H),2.42-2.30(m,2H)。
Step 2: preparation N- (5,6- dihydro -4H- cyclopentano (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) benzene oxygen Base) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-28)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5,6- dihydro -4H- ring into Penta and thiazole -2- amine, remaining required raw material, reagent and preparation method obtain yellow powder with the step 6 in embodiment I-1 to change Close object N- (5,6- dihydro -4H- cyclopentano (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxyl group - (1- Methylethyl) oxygroup) benzamide (I-28).
1H NMR(300MHz,CDCl3, δ ppm): 7.92-7.86 (m, 2H), 7.32 (d, J=1.5Hz, 1H), 7.21- 7.15 (m, 1H), 7.12-7.06 (m, 2H), 6.83 (t, J=2.2Hz, 1H), 4.51 (td, J=6.2,4.1Hz, 1H), 3.50 (dt, J=16.9,5.3Hz, 2H), 3.37 (d, J=6.6Hz, 3H), 3.06 (d, J=2.8Hz, 3H), 2.87 (dd, J=7.6, 5.6Hz, 2H), 2.46-2.30 (m, 4H), 1.27 (d, J=6.3Hz, 3H).
Embodiment 29
N- (6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- Methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-29)
Step 1: preparing 2- amino -6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazole
Into 25 milliliters of dry two-mouth bottles, 1.0 grams of tetrahydro pyrone and 10mL methylene chloride is added, stirs at room temperature 5.0 milli of bromine is added dropwise after reacting liquid temperature is down to 10 DEG C or less in connecting stirring dropwise under the conditions of going to ice-water bath after dissolution It rises, is stirred at room temperature after being added dropwise to complete to solution and is clarified.After reaction solution clarification, the carbonic acid of 2.0g is continuously added under the conditions of ice-water bath Hydrogen sodium powder end, continues stirring 30 minutes, reaction solution becomes faint yellow, precipitation after filtering, obtains 1.2 grams of light yellow oil.It will be upper It states light yellow oil to be transferred in 50 milliliters of dry two-mouth bottles, 1.3 grams of 3- bromine tetrahydro -4H- pyrans -4- ketone, thiocarbamide is added After 0.5 gram and 20 milliliters of acetone, the lower reflux of argon gas protection, solution is turned yellow by light yellow, stops heating, room after a hour Temperature is stirred overnight.Precipitation, a small amount of methanol dissolution, generates pale solid after ethyl acetate is added, chromatographs (dichloro through column after filtering Methane: methanol=10:1), obtaining 0.4 gram of yellow powder is compound 2- amino -6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazole, Yield is 64.04%.
1H NMR(300MHz,d6- DMSO, δ ppm): 6.83 (d, J=19.9Hz, 2H), 4.47 (s, 2H), 3.81 (t, J= 5.0Hz, 2H), 2.44 (t, J=4.8,2H).
Step 2: preparation N- (6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl) -3- (4- (methyl sulphonyl) benzene Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-29)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -6,7- two into Simultaneously [4,3-d] thiazole, remaining required raw material, reagent and preparation method obtain light hydrogen -4H- pyrans with the step 6 in embodiment I-1 Yellow powder is compound N-(6,7- dihydro -4H- pyrans simultaneously [4,3-d] thiazol-2-yl) -3- (4- (methyl sulphonyl) benzene oxygen Base) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-29).
1H NMR(300MHz,CDCl3, δ ppm): 7.86 (d, J=8.8Hz, 2H), 7.60 (s, 1H), 7.44 (s, 1H), 7.10 (d, J=8.8Hz, 2H), 6.78 (t, J=2.2Hz, 1H), 5.26 (s, 2H), 4.82 (s, 1H), 4.74-4.55 (m, 3H), 4.15 (dd, J=35.6,11.0Hz, 2H), 3.61-3.49 (m, 2H), 3.38 (d, J=2.7Hz, 3H), 3.04 (s, 3H), 1.31 (d, J=6.2Hz, 3H).
Embodiment 30
N- (7- oxo -4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-30)
Step 1: preparation 2- amino -5,6- dihydro -1,3- benzothiazole -7- (4H) -one
Change tetrahydro pyrone into 2- bromo- 1, hydroresorcinol, remaining required raw material, reagent and the same embodiment of preparation method Step 1 in I-29, obtaining yellow powder is compound 2- amino -5,6- dihydro -1,3- benzothiazole -7- (4H) -one.
1H NMR(300MHz,CDCl3, δ ppm): 5.49 (s, 2H), 2.81 (t, J=6.2Hz, 2H), 2.56-2.50 (m, 2H), 2.16 (dd, J=12.6,6.4Hz, 2H).
Step 2: preparation N- (7- oxo -4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) Phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-30)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -5,6- two into Hydrogen -1,3- benzothiazole -7- (4H) -one, remaining required raw material, reagent and preparation method are obtained with the step 6 in embodiment I-1 Yellow powder is compound N-(7- oxo -4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl) -3- (4- (methyl sulphonyl) benzene Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-30).
1H NMR(300MHz,CDCl3, δ ppm): 7.89 (d, J=8.7Hz, 2H), 7.53 (s, 1H), 7.41 (s, 1H), 7.14 (d, J=8.7Hz, 2H), 6.91 (d, J=2.0Hz, 1H), 4.74-4.67 (m, 1H), 3.55 (dd, J=10.4, 5.0Hz, 2H), 3.39 (s, 3H), 3.05 (s, 3H), 2.92 (t, J=6.0Hz, 2H), 2.68-2.55 (m, 2H), 2.21 (dt, J =12.2,6.1Hz, 2H), 1.33 (d, J=6.3Hz, 3H).
Embodiment 31
N- (6- acetylaminohydroxyphenylarsonic acid 4,5,6,7- tetrahydro-benzo (d) thiazol-2-yl)-(3 (4- (azetidine -1- formyls Base) phenoxy group) -5- isopropoxy benzamide (I-31)
Step 1: preparation 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- isopropyl p-methoxybenzoic acid methyl esters
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- (4- benzoyl bromide) azepine butane, remaining required raw material, reagent and preparation For method with the step 4 in embodiment I-1, obtaining brown oil is compound 3- (4- (azetidine -1- formoxyl) benzene oxygen Base) -5- isopropyl p-methoxybenzoic acid methyl esters.
1H NMR(300MHz,CDCl3, δ ppm): 7.64 (d, J=8.6Hz, 2H), 7.40 (s, 1H), 7.30 (d, J= 0.6Hz, 1H), 7.00 (d, J=8.8Hz, 2H), 6.79 (t, J=2.4Hz, 1H), 4.58 (dt, J=12.1,6.0Hz, 1H), 4.34 (dd, J=9.8,5.0Hz, 2H), 4.29-4.20 (m, 2H), 3.90 (s, 3H), 2.41-2.30 (m, 2H), 1.33 (d, J =6.0Hz, 6H).
Step 2: preparation 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- isopropyl p-methoxybenzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (4- (azacyclo- Butane -1- formoxyl) phenoxy group) -5- isopropyl p-methoxybenzoic acid methyl esters, remaining required raw material, reagent and preparation method are the same as real The step 5 in an I-1 is applied, obtaining pale yellow powder is compound 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- isopropyl Base p-methoxybenzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 7.65 (d, J=8.7Hz, 2H), 7.40 (s, 1H), 7.30 (d, J= 0.6Hz, 1H), 7.01 (d, J=8.8Hz, 2H), 6.79 (t, J=2.3Hz, 1H), 4.58 (dt, J=12.1,6.0Hz, 1H), 4.34 (dd, J=9.8,5.0Hz, 2H), 4.29-4.20 (m, 2H), 2.41-2.30 (m, 2H), 1.34 (d, J=6.0Hz, 6H)
Step 3: preparation N- (6- acetylaminohydroxyphenylarsonic acid 4,5,6,7- tetrahydro benzo (d) thiazol-2-yl)-(3 (4- (azetidins Alkane -1- formoxyl) phenoxy group) -5- isopropoxy benzamide (I-31)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- isopropyl p-methoxybenzoic acid, remaining required raw material, reagent and preparation method are the same as embodiment I-1 In step 6, obtain grey powder be compound N-(4,5,6,7- tetrahydro benzo (d) thiazol-2-yl of 6- acetylaminohydroxyphenylarsonic acid)-(3 (4- (azetidine -1- formoxyl) phenoxy group) -5- isopropoxy benzamide (I-31).
1H NMR(400MHz,CDCl3, δ ppm): 7.62 (t, J=5.6Hz, 2H), 7.22 (s, 1H), 7.08 (s, 1H), 6.99-6.95 (m, 2H), 6.74 (t, J=2.1Hz, 1H), 5.84 (d, J=8.1Hz, 1H), 4.57-4.48 (m, 1H), 4.39- 4.34 (m, 1H), 4.34-4.29 (m, 2H), 4.20 (dd, J=8.0,7.2Hz, 2H), 3.08 (dd, J=16.1,5.0Hz, 1H), 2.61-2.50 (m, 2H), 2.46 (dd, J=15.0,8.4Hz, 1H), 2.38-2.29 (m, 2H), 1.97 (s, 3H), 1.95-1.89(m,1H),1.85-1.77(m,1H),1.32(s,3H),1.31(s,3H)。
Embodiment 32
N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (3- (6- (azacyclo- Butane -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-32)
Step 1: preparation 1- (5- bromo-2-pyridyl formoxyl) azepine butane
5- bromo-2-pyridyl carboxylic acid, 50.0 milliliters of the DCM of 1.0 grams (5.0 mMs) are added into 100 milliliters of there-necked flasks With 1 drop DMF.Then 0.50 milliliter of oxalyl chloride (6.0 mMs) are slowly added dropwise in ice bath stirring.It is stirred at room temperature after completion of dropwise addition 12h.After TLC detection display fully reacting, vacuum concentration obtains clear yellow viscous object.Lower 25.0 milliliters of addition is protected in argon gas The TEA of DCM, 0.6 gram of (6.0 mMs) azetidine hydrochloride and 2.2 milliliters (12.5 mMs).It is small to be stirred at room temperature 2.5 Shi Hou, slowly adjusting pH value with 1N HCl solution is 6, is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, Vacuum concentration, obtaining crude product is yellow oil.Crude product obtains brown through column chromatography (methylene chloride: methanol=20:1) separation 0.7 gram of powder is compound 1- (5- bromo-2-pyridyl formoxyl) azepine butane, yield 54.0%.
1H NMR(300MHz,CDCl3, δ ppm): 8.64-8.59 (m, 1H), 8.00 (dt, J=8.4,0.8Hz, 1H), 7.92 (ddd, J=3.6,2.3,0.9Hz, 1H), 4.72-4.64 (t, J=7.6Hz, 2H), 4.24 (t, J=7.7Hz, 2H), 2.41-2.29(m,2H)。
Step 2: preparation 3- (3- (6- (azetidine -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- methyl Ethyl) oxygroup) methyl benzoate
Change the bromo- 4- methylsulfonyl benzene of 1- into 1- (5- bromo-2-pyridyl formoxyl) azepine butane, remaining required raw material, reagent And preparation method, with the step 4 in embodiment I-1, obtaining colorless oil is compound 3- (3- (6- (azetidine -1- formyl Base) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate.
1H NMR(300MHz,CDCl3, δ ppm): 8.30 (d, J=2.8Hz, 1H), 8.09 (d, J=8.7Hz, 1H), 7.43 (d, J=1.1Hz, 1H), 7.34 (ddd, J=8.7,2.8,0.5Hz, 1H), 7.26 (s, 1H), 6.83 (t, J=2.0Hz, 1H), 4.69 (t, J=7.8Hz, 2H), 4.59 (td, J=6.1,4.2Hz, 1H), 4.24 (t, J=7.7Hz, 2H), 3.88 (s, 3H), 3.53 (ddd, J=14.3,10.3,5.1Hz, 2H), 3.39 (s, 3H), 2.40-2.28 (m, 2H), 1.31 (d, J=6.3Hz, 3H)。
Step 3: preparation 3- (3- (6- (azetidine -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- methyl Ethyl) oxygroup) benzoic acid
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) methyl benzoate into 3- (3- (6- (nitrogen Azetidine -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) methyl benzoate, needed for remaining With the step 5 in embodiment I-1, obtaining light yellow oil is compound 3- (3- (6- (azacyclo- for raw material, reagent and preparation method Butane -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid.
1H NMR(300MHz,CDCl3, δ ppm): 8.31 (d, J=5.3Hz, 1H), 8.12 (d, J=8.7Hz, 1H), 7.50-7.45 (m, 1H), 7.36-7.30 (m, 2H), 6.89-6.84 (m, 1H), 4.71 (t, J=7.7Hz, 2H), 4.65-4.58 (m, 1H), 4.27 (t, J=8.0Hz, 2H), 3.55 (qd, J=10.3,5.8Hz, 2H), 3.41 (s, 3H), 2.43-2.28 (m, 2H), 1.32 (d, J=6.2Hz, 3H).
Step 4: preparation N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (3- (6- (azetidine -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I- 32)
Change 3- isopropyl oxygroup -5- ((4- (methyl sulphonyl) phenyl) oxygroup) benzoic acid into 3- (3- (6- (azacyclo- Butane -1- formoxyl) pyridine) oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzoic acid, remaining required raw material, examination Agent and preparation method with the step 6 in embodiment I-1, obtain pale yellow powder be compound N-(6- tertbutyloxycarbonyl -4,5,6,7- Tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (3- (6- (azetidine -1- formoxyl) pyridine) oxygroup) -5- (2- first Oxygroup-(1- Methylethyl) oxygroup) benzamide (I-32).
1H NMR(300MHz,CDCl3, δ ppm): 8.31 (d, J=2.5Hz, 1H), 8.12 (d, J=8.6Hz, 1H), 7.37 (dd, J=8.6,2.6Hz, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 6.85 (t, J=2.0Hz, 1H), 4.71 (t, J= 7.4Hz,2H),4.63-4.52(m,3H),4.29-4.21(m,2H),3.77-3.68(m,2H),3.60-3.46(m,2H), 3.39 (s, 3H), 2.71-2.61 (m, 2H), 2.42-2.29 (m, 2H), 1.49 (s, 9H), 1.31 (d, J=6.3Hz, 3H).
Embodiment 33
N- (6- benzyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl sulphonyl) benzene Base) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide
Step 1: preparing 5- benzyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- phenyl -4- piperidones, remaining required raw material, reagent and preparation side For method with the step 1 in embodiment I-1, obtaining pale yellow powder is compound 5- benzyl -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyrrole Pyridine -2- amine.
1H NMR(300MHz,CDCl3,δppm):7.17-7.29(m,5H),3.70(s,2H),3.58(s,2H),2.80 (t, J=5.7Hz, 2H), 2.72-2.62 (m, 2H).
Step 2: preparation N- (6- benzyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (methyl Sulfonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-33)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- benzyl -4,5,6,7- into Simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method obtain tetrahydro-thiazoles with the step 6 in embodiment I-1 Faint yellow color powder is compound N-(6- benzyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-33).
1H NMR(300MHz,CDCl3, δ ppm): 7.95 (d, J=8.8Hz, 2H), 7.60-7.56 (m, 1H), 7.31 (dd, J=29.3,6.9Hz, 8H), 7.00 (s, 1H), 4.79 (td, J=11.0,6.2Hz, 1H), 3.70 (s, 2H), 3.58 (s, 2H), 3.52-3.45 (m, 2H), 3.29 (s, 3H), 3.22 (s, 3H), 2.80 (t, J=5.7Hz, 2H), 2.72-2.62 (m, 2H), 1.25 (d, J=6.1Hz, 3H).
Embodiment 34
N- (6- (2- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-34)
Step 1: preparation 1- (2- pyridine) -4- piperidones
0.2 gram of 2- bromopyridine of addition, 0.1 milliliter of 4- piperidones condensed ethandiol, catalytic amount into 25 milliliters of microwave reaction bottles Palladium acetate, 2- dicyclohexyl phosphorus -2,4,23.8 milligrams of 6- tri isopropyl biphenyl, 0.1 gram of potassium tert-butoxide, 1.0 milliliters of toluene, tertiary fourth 0.2 milliliter of alcohol, microwave heating is cooled to room temperature after reacting 15 minutes to 160 DEG C, filters to take filtrate, and filter vacuum concentration obtains 0.2 gram of yellow green grease.The yellow oil after further treatment, is not directly transferred to 100 milliliters dry of two-mouth bottle In, 3.0 milliliters of tetrahydrofurans are then added, are stirred at room temperature to dissolution.After being cooled to interior temperature lower than 10 DEG C with ice bath again, dropwise 8.5 milliliters of aqueous hydrochloric acid solution of 6 moles every liter are slowly added to, is stirred overnight at room temperature after being added dropwise to complete.After fully reacting, vacuum is dense Contracting, obtains yellow solid.It is dissolved in 20 milliliters of water, 20%NaOH tune PH to 10, chloroform extraction, organic phase is dry with anhydrous sodium sulfate Dry filtering, vacuum concentration, obtains crude product.Through column chromatography (methylene chloride: methanol=20:1) separation, colorless oil 145.4 is obtained Milligram is target product 1- (2- pyridine) -4- piperidones, yield 84.67%.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.09 (dd, J=6.6,3.3Hz, 1H), 7.55-7.48 (m, 1H), 6.88 (d, J=8.6Hz, 1H), 6.61 (dd, J=6.8,5.2Hz, 1H), 3.74 (m, 4H), 2.68 (m, 4H).
Step 2: preparing 5- (pyridine -2- base) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into 1- (2- pyridine) -4- piperidones, remaining required raw material, reagent and system Preparation Method is with the step 1 in embodiment I-1, and obtaining yellow powder is compound 5- (pyridine -2- base) -4, and 5,6,7- tetrahydro-thiazoles are simultaneously [5,4-c] pyridine -2- amine.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.09 (dd, J=6.6,3.3Hz, 1H), 7.55-7.48 (m, 1H), 6.88 (d, J=8.6Hz, 1H), 6.76 (s, 2H), 6.61 (dd, J=6.8,5.2Hz, 1H), 4.48 (s, 2H), 3.83 (t, J= 5.6Hz, 2H), 2.48 (t, J=5.9Hz, 2H).
Step 4:N- (6- (2- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-34)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- (pyridine -2- base)-into 4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining pale yellow powder is compound N-(6- (2- pyridyl group) -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- Base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-34).
1H NMR (300MHz, d6-DMSO, δ ppm): 12.60 (s, 1H), 8.13 (dd, J=4.2,1.2Hz, 1H), 7.95 (d, J=8.9Hz, 2H), 7.60-7.53 (m, 2H), 7.37 (s, 1H), 7.26 (d, J=8.9Hz, 2H), 7.01-6.94 (m, 2H), 6.66 (dd, J=7.0,4.9Hz, 1H), 4.79 (dd, J=11.2,5.2Hz, 1H), 4.73 (s, 2H), 3.95 (t, J= 5.7Hz, 2H), 3.56-3.45 (m, 2H), 3.29 (s, 3H), 3.22 (s, 3H), 2.75 (t, J=5.0Hz, 2H), 1.25 (d, J =6.2Hz, 3H).
Embodiment 35
N- (6- (3- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (sulfonyloxy methyl Base) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-35)
Step 1: preparation 1- (3- pyridine) -4- piperidones
124.8 milligrams of 3- chloropyridine of the addition into 25 milliliters of microwave reaction bottles, 143.2 milligrams of 4- piperidones condensed ethandiol, Catalytic amount palladium acetate, 2- dicyclohexyl phosphorus -2,4,11.2 milligrams of 6- tri isopropyl biphenyl, 112.2 milligrams of potassium tert-butoxide, toluene 1.0 milliliters, 0.2 milliliter of the tert-butyl alcohol, microwave heating is cooled to room temperature after reacting 15 minutes to 160 DEG C, filters to take filtrate, filtrate is true Sky concentration, obtains 0.2 gram of light yellow oil.The yellow oil after further treatment, is not directly transferred to 100 dry millis In the two-mouth bottle risen, 3.0 milliliters of tetrahydrofurans are then added, are stirred at room temperature to dissolution.Interior temperature is cooled to again with ice bath to be lower than After 10 DEG C, it is slowly added to 8.0 milliliters of aqueous hydrochloric acid solution of 6 moles every liter dropwise, is stirred overnight at room temperature after being added dropwise to complete.It has reacted Quan Hou, vacuum concentration, obtains yellow solid.It is dissolved in 20 milliliters of water, 20%NaOH tune PH to 10, chloroform extraction, organic phase is used Anhydrous sodium sulfate dry filter, vacuum concentration, obtains crude product.Through column chromatography (methylene chloride: methanol=20:1) separation, yellow is obtained 146.6 milligrams of grease, be target product 1- (3- pyridine) -4- piperidones, yield 97.28%.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.40-8.35 (m, 1H), 8.14 (dd, J=4.2,1.4Hz, 1H), 7.22 (ddd, J=11.8,5.1,3.3Hz, 2H), 3.64 (t, J=6.1Hz, 4H), 2.58 (t, J=6.1Hz, 4H).
Step 2: preparing 5- (pyridin-3-yl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into 1- (3- pyridine) -4- piperidones, remaining required raw material, reagent and system Preparation Method is with the step 1 in embodiment I-1, and obtaining yellow powder is compound 5- (pyridin-3-yl) -4, and 5,6,7- tetrahydro-thiazoles are simultaneously [5,4-c] pyridine -2- amine.
1H NMR (300MHz, d6-DMSO, δ ppm): 8.34 (d, J=2.6Hz, 1H), 7.96 (d, J=4.4Hz, 1H), 7.36 (dd, J=8.7,1.4Hz, 1H), 7.24-7.16 (m, 1H), 6.79 (s, 2H), 4.25 (s, 2H), 3.62 (t, J= 5.7Hz, 2H), 2.54 (d, J=5.2Hz, 2H).
Step 4:N- (6- (3- pyridyl group) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- ((4- (first Base sulfonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-35)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- (pyridin-3-yl)-into 4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining pale yellow powder is compound N-(6- (3- pyridyl group) -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- Base) -3- ((4- (methyl sulphonyl) phenyl) oxygroup) benzamido) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-35).
1H NMR (300MHz, d6-DMSO, δ ppm): 8.41 (d, J=1.7Hz, 1H), 7.99 (d, J=5.4Hz, 1H), 7.94 (d, J=8.9Hz, 2H), 7.60-7.56 (m, 1H), 7.48-7.42 (m, 1H), 7.38-7.35 (m, 1H), 7.25 (d, J =8.9Hz, 3H), 7.02-6.98 (m, 1H), 4.83-4.76 (m, 1H), 4.53-4.46 (m, 2H), 3.74 (t, J=4.9Hz, 2H), 3.53-3.47 (m, 2H), 3.29 (s, 3H), 3.21 (s, 3H), 2.81-2.69 (m, 3H), 1.25 (d, J=6.2Hz, 3H)。
Embodiment 36
2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygroup) benzene carbon amide Base) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester (I-36)
Step 1: preparation 2- amino -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into 4- oxocyclohex Ethyl formate, remaining required raw material, reagent and preparation For method with the step 1 in embodiment I-1, obtaining brownish-yellow powder is 2 amino -4,5 of compound, 6,7- tetrahydros-benzo [d] thiazole - 6- carboxylic acid, ethyl ester.
1H NMR(300MHz,d6- DMSO, δ ppm): 6.67 (s, 2H), 4.08 (q, J=7.0Hz, 2H), 2.80-2.62 (m, 3H), 2.42 (d, J=5.4Hz, 2H), 2.10-1.98 (m, 1H), 1.83-1.69 (m, 1H), 1.19 (t, J=7.1Hz, 3H)。
Step 2: preparation 2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygroup) Benzamido) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester (I-36)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -4,5,6,7- into Tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester, remaining required raw material, reagent and preparation method with the step 4 in embodiment I-6, Obtaining pale yellow powder is compound 2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygen Base) benzamido) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester (I-36).
1H NMR(300MHz,CDCl3, δ ppm): 7.90 (d, J=8.2Hz, 2H), 7.12 (d, J=9.5Hz, 2H), 6.94–6.90(m,1H),6.78–6.74(m,1H),6.71–6.67(m,1H),5.30(s,1H),4.59–4.51(m,1H), 3.65-3.53 (m, 3H), 3.50 (d, J=6.1Hz, 3H), 3.40 (s, 4H), 3.06 (s, 3H), 1.92 (dt, J=14.0, 7.4Hz,4H),1.32–1.23(m,6H)。
Embodiment 37
2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygroup) benzene carbon amide Base) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid (I-37)
Step 1: preparation 2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygroup) Benzamido) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid (I-37)
Into 25 milliliters of dry two-mouth bottles, 2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (first is added Base sulfonyl) phenyl oxygroup) benzamido) -4,5,6,7- tetrahydro-benzo [d] thiazole -6- carboxylic acid, ethyl ester (I-36) 58.8 is in the least Gram, 1.0 milliliters of tetrahydrofurans, 0.2 ml methanol, after dissolution is stirred at room temperature, ice bath is cooled to 0 DEG C, and 3N hydroxide is added dropwise It 0.2 milliliter of lithium aqueous solution, is stirred overnight at room temperature after being added dropwise to complete.After fully reacting, be concentrated in vacuo crude product be faint yellow oily Object.After crude product is with 2.0 milli liter of water, slowly adjusting pH value with 1N hydrochloric acid solution is 4, and white precipitate is precipitated.With acetic acid second Ester extraction.Organic phase is dried, filtered with anhydrous sodium sulfate, vacuum concentration, obtains 50.5 milligrams of white powder as compound 2- (3- (2- methoxyl group-(1- Methylethyl) oxygroup) -5- (4- (methyl sulphonyl) phenyl oxygroup) benzamido) -4,5,6,7- four Hydrogen-benzo [d] thiazole -6- carboxylic acid (I-37), yield 90.1%.
1H NMR(300MHz,CDCl3, δ ppm): 7.91 (d, J=8.8Hz, 2H), 7.60-7.56 (m, 1H), 7.48- 7.45 (m, 1H), 7.15 (d, J=8.7Hz, 2H), 6.88 (t, J=2.1Hz, 1H), 4.81-4.72 (m, 1H), 3.63-3.49 (m, 3H), 3.40 (s, 3H), 3.06 (s, 3H), 3.01-2.83 (m, 4H), 2.83-2.62 (m, 3H), 1.35 (dd, J=6.1, 1.7Hz,3H)。
Embodiment 38
N- (7- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-b] pyridine -2- base) -3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-38)
Step 1: preparing 2- amino -6,7- thiazoline simultaneously [5,4-b] pyridine -4 (5H) carboxylic acid tert-butyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into N- tertbutyloxycarbonyl -3- piperidones, remaining required raw material, reagent and Preparation method with the step 1 in embodiment I-1, obtain buff powder be compound 2- amino -6,7- thiazoline simultaneously [5,4-b] Pyridine -4 (5H) carboxylic acid tert-butyl ester.
1H NMR(300MHz,CDCl3, δ ppm): 4.81 (s, 2H), 3.70 (t, 2H), 2.61 (t, J=6.3Hz, 2H), 2.03-1.90(m,2H),1.50(s,9H)。
Step 2: preparation N- (7- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-b] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-38)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -6,7- dihydro into Thiazole simultaneously [5,4-b] pyridine -4 (5H) carboxylic acid tert-butyl ester, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining yellow powder is compound N-(7- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-b] pyridine -2- base) - 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I- 38)。
1H NMR(300MHz,CDCl3, δ ppm): 8.01 (s, 1H), 7.62 (d, J=8.6Hz, 2H), 7.11 (s, 1H), 6.98 (d, J=8.7Hz, 2H), 6.79 (s, 1H), 4.51 (dt, J=9.6,5.1Hz, 1H), 4.39-4.29 (m, 2H), 4.26- 4.17 (m, 2H), 3.74 (dd, J=8.5,6.6Hz, 2H), 3.50 (ddd, J=14.0,10.2,4.9Hz, 2H), 3.37 (s, 3H), 2.59-2.50 (m, 2H), 2.34 (dt, J=14.9,7.5Hz, 2H), 2.00-1.91 (m, 3H), 1.53 (s, 9H), 1.28 (d, J=6.2Hz, 3H).
Embodiment 39
N- (5- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [4,5-c] pyridine -2- base) -3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-39)
Step 1: preparing 2- amino -6,7- thiazoline simultaneously [4,5-c] pyridine -5 (4H) carboxylic acid tert-butyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into N- tertbutyloxycarbonyl -3- piperidones, remaining required raw material, reagent and Preparation method with the step 1 in embodiment I-1, obtain brownish-yellow powder be compound 2- amino -6,7- thiazoline simultaneously [4,5-c] Pyridine -5 (4H) carboxylic acid tert-butyl ester.
1H NMR(300MHz,CDCl3,δppm):5.00(s,2H),4.36(s,2H),3.74-3.64(m,2H),2.70- 2.57(m,2H),1.46(s,9H)。
Step 2: preparation N- (5- tertbutyloxycarbonyl -4,5,6,7- tetrahydro-thiazole simultaneously [4,5-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-39)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -6,7- dihydro into Thiazole simultaneously [4,5-c] pyridine -5 (4H) carboxylic acid tert-butyl ester, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining yellow powder is compound N-(5- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole simultaneously [4,5-c] pyridine -2- base) - 3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I- 39)。
1H NMR(300MHz,CDCl3, δ ppm): 7.64 (d, J=8.7Hz, 2H), 7.28 (s, 1H), 7.14 (s, 1H), 7.01 (d, J=8.6Hz, 2H), 6.81 (s, 1H), 4.64-4.52 (m, 1H), 4.41 (s, 2H), 4.39-4.30 (m, 2H), 4.28-4.18 (m, 2H), 3.77-3.66 (m, 2H), 3.52 (ddd, J=13.9,10.4,7.1Hz, 2H), 3.38 (s, 3H), 2.84-2.73 (m, 2H), 2.42-2.29 (m, 2H), 1.47 (s, 9H), 1.30 (d, J=6.1Hz, 3H).
Embodiment 40
N- (6- carbethoxyl group -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine - 1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-40)
Step 1: preparing 2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid, ethyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into N- carbethoxyl group -4- piperidones, remaining required raw material, reagent and system For Preparation Method with the step 1 in embodiment I-1, obtaining yellow powder is compound 2- amino -6,7- thiazoline simultaneously [5,4-c] pyrrole Pyridine -5 (4H) carboxylic acid, ethyl ester.
1H NMR(300MHz,d6- DMSO, δ ppm): 6.82 (s, 2H), 4.34 (s, 2H), 4.06 (q, J=7.1Hz, 2H), 3.61 (t, J=5.7Hz, 2H), 2.45 (t, J=5.6Hz, 2H), 1.19 (t, J=7.0Hz, 3H).
Step 2: preparation N- (6- carbethoxyl group -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (nitrogen Azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-40)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -6,7- dihydro into Thiazole simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid, ethyl ester, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-1 Rapid 6, obtaining pale yellow powder is compound N-(6- carbethoxyl group -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-40).
1H NMR(300MHz,CDCl3, δ ppm): 7.56 (d, J=8.3Hz, 2H), 7.20 (d, J=2.9Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=8.4Hz, 2H), 6.73 (s, 1H), 4.51 (s, 2H), 4.43 (dd, J=5.6,3.2Hz, 1H), 4.25 (d, J=6.2Hz, 2H), 4.15 (s, 2H), 3.57 (s, 2H), 3.45 (dd, J=16.7,10.7Hz, 2H), 3.30 (s, 3H), 2.45 (t, J=5.6Hz, 2H), 2.37 (s, 2H), 2.32-2.23 (m, 2H), 1.20 (d, J=6.0Hz, 3H), 1.19 (t, J=7.0Hz, 3H).
Embodiment 41
N- (6- methoxycarbonyl group -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine - 1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-41)
Step 1: preparing 2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H) carboxylate methyl ester
Change N- tertbutyloxycarbonyl -4- piperidones into N- methoxycarbonyl group -4- piperidones, remaining required raw material, reagent and system For Preparation Method with the step 1 in embodiment I-1, obtaining pale yellow powder is compound 2- amino -6,7- thiazoline simultaneously [5,4-c] pyrrole Pyridine -5 (4H) carboxylate methyl ester.
1H NMR(300MHz,d6-DMSO,δppm):6.82(s,2H),4.34(s,2H),3.65-3.57(m,5H),2.44 (t, J=8.6Hz, 2H).
Step 2: preparation N- (6- methoxycarbonyl group -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (nitrogen Azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-41)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- amino -6,7- dihydro into Thiazole simultaneously [5,4-c] pyridine -5 (4H) carboxylate methyl ester, remaining required raw material, reagent and preparation method are the same as the step in embodiment I-1 Rapid 6, obtaining pale yellow powder is compound N-(6- methoxycarbonyl group -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-41).
1H NMR(300MHz,CDCl3, δ ppm): 7.56 (d, J=8.3Hz, 2H), 7.20 (d, J=2.9Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=8.4Hz, 2H), 6.73 (s, 1H), 4.51 (s, 2H), 4.43 (dd, J=5.6,3.2Hz, 1H), 4.25 (d, J=6.2Hz, 2H), 4.15 (s, 2H), 3.94 (s, 3H), 3.57 (s, 2H), 3.44 (dd, J=16.7,10.7Hz, 2H), 3.30 (s, 3H), 2.37 (s, 2H), 2.32-2.23 (m, 2H), 1.21 (d, J=6.0Hz, 3H).
Embodiment 42
N- (4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) benzene Oxygroup) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-42)
Prepare N- (4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formyl Base) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-42)
Into 25 milliliters of dry two-mouth bottles, 62.3 milligrams of N- (6- tertbutyloxycarbonyl -4,5,6,7- tetrahydros-thiazole is added And [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- methyl second Base) oxygroup) stir 15 minutes under benzamide (I-13) (0.1 mM) and 2.0 milliliters of methylene chloride, with ice salt bath after, by It is added dropwise to trifluoroacetic acid.After charging, reaction solution is stirred overnight under room temperature environment.After fully reacting, vacuum concentration reaction Liquid obtains yellow oil, and yellow oil is separated through column chromatography (methylene chloride: methanol=50:1), obtains 50.2 milli of white powder Gram for compound N-(4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) Phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-42), yield 100.0%.
1H NMR(300MHz,d6- DMSO, δ ppm): 12.76 (s, 1H), 9.26 (s, 1H), 7.68 (d, J=8.2Hz, 2H), 7.55 (s, 1H), 7.33-7.28 (m, 1H), 7.09 (d, J=8.5Hz, 2H), 6.97-6.91 (m, 1H), 4.85-4.72 (m, 1H), 4.33 (dd, J=10.5,4.5Hz, 4H), 4.08-4.00 (m, 2H), 3.52-3.44 (m, 4H), 3.29 (s, 3H), 2.90 (t, J=5.1Hz, 2H), 2.26 (dt, J=15.3,7.8Hz, 2H), 1.24 (d, J=6.0Hz, 3H).
Embodiment 43
N- (6- (2- hydroxyethyl) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidin Alkane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-43)
Step 1: preparation N, N- bis- (3,3 '-methoxyl groups -3,3 '-oxopropyl) -2 hydroxy ethylamine
Into dry 250 milliliters of single port bottles, 11.2 grams of methyl acrylates (130.0 mMs) and 50.0 ml methanols are added Afterwards, 3.1 grams of (50.0 mMs) 2- ethylaminoethanols are added dropwise.After charging, it is small that reaction solution stirs 15 under the conditions of 40 DEG C When.After fully reacting, vacuum concentration reaction solution obtain 12.2 grams of light yellow oils be N, N- bis- (3,3 '-methoxyl group -3,3 ' - Oxopropyl) -2 hydroxy ethylamine, yield 100.0%.
1H NMR(300MHz,CDCl3, δ ppm): 3.59 (d, J=2.5Hz, 6H), 3.49 (t, 2H), 2.95 (s, 1H), 2.69 (t, 4H), 2.50 (t, 2H), 2.37 (t, J=5.5Hz, 4H).
Step 2: preparation N- (2- hydroxyethyl) -4- piperidones
After 13.4 grams of sodium methoxides (74.0 mMs) and 200 milliliters of toluene are added into dry 500 milliliters of there-necked flasks, dropwise N, 12.0 grams of -2 hydroxy ethylamine of N- bis- (3,3 '-methoxyl groups -3,3 '-oxopropyl) (50.0 mMs) are added.Charging terminates Afterwards, reaction solution stirs 5 hours under the conditions of 115 DEG C.It is slowly added to 120.0 milliliters of concentrated hydrochloric acids into reaction solution and continues stirring 30 It is stood after minute.After reaction liquid layer, water intaking layer simultaneously continues stirring 4 hours to complete acidification under the conditions of 100 DEG C.Sufficiently acidification Afterwards, being slowly added to 40% sodium hydroxide to solution ph into reaction solution under condition of ice bath is 12.It is extracted with dichloromethane.Have Machine is mutually dried, filtered with anhydrous sodium sulfate, vacuum concentration, obtains 0.5 gram of yellow oil as compound N-(2- hydroxyethyl) -4- Piperidones, yield 6.6%.
1H NMR(300MHz,CDCl3, δ ppm): 3.64 (t, J=5.2Hz, 2H), 2.78 (t, 4H), 2.64 (t, J= 6.5Hz, 2H), 2.44 (t, J=5.5Hz, 4H) %.
Step 3: preparation 2- (2- amino -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H) base) ethyl alcohol
Change N- tertbutyloxycarbonyl -4- piperidones into N- (2- hydroxyethyl) -4- piperidones, remaining required raw material, reagent And preparation method, with the step 1 in embodiment I-1, obtaining pale yellow powder is that (2- amino -6,7- thiazoline is simultaneously by compound 2- [5,4-c] pyridine -5 (4H) base) ethyl alcohol.
1H NMR(300MHz,d6- DMSO, δ ppm): 6.68 (s, 2H), 3.60 (t, J=6.3Hz, 2H), 3.52 (t, J= 6.1Hz, 2H), 3.40 (s, 2H), 2.70 (t, J=5.6Hz, 2H), 2.54 (t, J=6.3Hz, 2H), 2.42 (t, J=5.4Hz, 2H)。
Step 4: preparation N- (6- (2- hydroxyethyl) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-43)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 2- (2- amino -6,7- into Thiazoline simultaneously [5,4-c] pyridine -5 (4H) base) ethyl alcohol, remaining required raw material, reagent and preparation method are the same as in embodiment I-1 Step 6, obtaining pale yellow powder is that compound prepares N- (6- (2- hydroxyethyl) -4,5,6,7- tetrahydros-thiazole simultaneously [5,4-c] pyrrole Pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzene first Amide (I-43).
1H NMR(300MHz,CDCl3, δ ppm): 7.62 (d, J=8.5Hz, 2H), 7.40 (s, 1H), 7.20 (s, 1H), 6.99 (d, J=8.5Hz, 2H), 6.84 (s, 1H), 4.64-4.53 (m, 1H), 4.48 (t, J=5.4Hz, 2H), 4.37-4.27 (m, 2H), 4.27-4.17 (m, 2H), 3.64 (s, 2H), 3.58-3.46 (m, 2H), 3.39 (s, 3H), 2.94 (dd, J=12.4, 5.8Hz, 4H), 2.65 (s, 2H), 2.35 (dt, J=15.4,7.7Hz, 2H), 1.31 (d, J=6.2Hz, 3H).
Embodiment 44
N- (6- (2- methoxy ethyl) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azacyclo- Butane -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-44)
Step 1: preparation N, N- bis- (3,3 '-methoxyl groups -3,3 '-oxopropyl) -2- methoxyethyl amine
Change 2- ethylaminoethanol into 2- methoxyethyl amine, remaining required raw material, reagent and preparation method are the same as embodiment I-43 In step 1, obtain light yellow oil be compound N, N- bis- (3,3 '-methoxyl group -3,3 '-oxopropyls) -2- methoxyl group second Amine.
1H NMR(300MHz,CDCl3, δ ppm): 3.63 (s, 6H), 3.40 (t, J=6.0Hz, 2H), 3.30 (s, 3H), 2.80 (t, J=7.2Hz, 4H), 2.61 (t, J=6.0Hz, 2H), 2.42 (t, J=7.2Hz, 4H).
Step 2: preparation N- (2- methoxy ethyl) -4- piperidones
By N, N- bis- (3,3 '-methoxyl groups -3,3 '-oxopropyl) -2 hydroxy ethylamine changes N, (the 3,3 '-methoxyl groups-of N- bis- into 3,3 '-oxopropyls) -2- methoxyethyl amine, remaining required raw material, reagent and preparation method with the step 2 in embodiment I-43, Obtaining yellow oil is compound N-(2- methoxy ethyl) -4- piperidones.
1H NMR(300MHz,CDCl3, δ ppm): 3.48 (t, J=5.4Hz, 2H), 3.31 (s, 3H), 2.74 (t, J= 6.0Hz, 4H), 2.63 (t, J=5.4Hz, 2H), 2.41 (t, J=6.1Hz, 4H).
Step 3: preparing 5- (2- methoxy ethyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine
Change N- tertbutyloxycarbonyl -4- piperidones into N- (2- methoxy ethyl) -4- piperidones, remaining required raw material, examination With the step 1 in embodiment I-1, obtaining brown oil is compound 5- (2- methoxy ethyl) -4,5,6 for agent and preparation method, 7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine.
1H NMR(300MHz,d6- DMSO, δ ppm): 6.69 (s, 2H), 3.46 (t, J=5.4Hz, 2H), 3.41 (s, 2H), 3.23 (s, 3H), 2.72 (t, J=9.7Hz, 2H), 2.63 (t, J=5.2Hz, 2H), 2.40 (t, J=7.4Hz, 2H).
Step 4: preparation N- (6- (2- methoxy ethyl) -4,5,6,7- tetrahydro-thiazole simultaneously [5,4-c] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) benzamide (I-44)
By 2- amino -6,7- thiazoline, simultaneously [5,4-c] pyridine -5 (4H) carboxylic acid tert-butyl ester changes 5- (2- methoxyl group second into Base) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine -2- amine, remaining required raw material, reagent and preparation method are the same as embodiment I-1 In step 6, obtaining yellow powder is that compound prepares N- (6- (2- methoxy ethyl) -4,5,6,7- tetrahydros-thiazole simultaneously [5,4- C] pyridine -2- base) -3- (4- (azetidine -1- formoxyl) phenoxy group) -5- (2- methoxyl group-(1- Methylethyl) oxygroup) Benzamide (I-44).
1H NMR(300MHz,CDCl3, δ ppm): 7.63 (d, J=8.5Hz, 2H), 7.28 (s, 1H), 7.15 (s, 1H), 6.98 (d, J=8.5Hz, 2H), 6.79 (s, 1H), 4.51 (dq, J=11.8,5.9Hz, 1H), 4.33 (t, J=7.0Hz, 2H), 4.27-4.15 (m, 2H), 3.79 (s, 2H), 3.59 (t, J=5.3Hz, 2H), 3.50 (ddd, J=13.6,10.1,3.8Hz, 2H), 3.37 (s, 6H), 2.88 (t, J=5.2Hz, 2H), 2.81 (t, J=5.2Hz, 2H), 2.55-2.43 (m, 2H), 2.39- 2.27 (m, 2H), 1.28 (d, J=6.2Hz, 3H).
Embodiment 45
Influence of the compound of the present invention in molecular level to glucokinase enzyme activity
Step 1: the foundation of glucokinase enzyme activity screening and assessment system
Become under the catalysis of glucokinase based on glucose glucose 6-phosphate (glucose-6-phosphate, G6P), G6P is under the catalysis of glucose-6-phosphate dehydrogenase (glucose-6-phosphate dehydrogenase, G6PD) It is transformed into glucose 6-phosphate lactone, (the 1- naphthaleneacetamide) of an one's share of expenses for a joint undertaking is catalyzed into (β-nicotinoyl simultaneously in this reaction Amine adenine dinucleotide disodium), and NADH has light absorption value at 340nm, can reflect grape by the size of light absorption value The principle of the active size of sugared kinases.Establish the activity screen system of glucokinase agonist shown in table 1.System is total 120 μ L, carry out determination of activity in 96 orifice plates, and every hole includes: the Hepes of 25mmol/L, the KCl of 25mmol/L, 2mmol/L's MgCl2, the G6PD of DTT, 1mmol/LNAD, 0.1%BSA, the 5 μm of ol/mL of the ATP of 1mmol/L, 1mmol/L, the Portugal 5mmol/L The compound of 1.2 μ L respective concentrations is added in grape sugar, the LGK2 albumen of 18.7 μ g/mL, slight to mix, and is placed in 37 degrees Celsius and incubates Educate half an hour.The ATP (1mmol/L) that 12 μ L are added in last every hole starts reaction, dynamics light absorption value is measured at 340nM, most Numerical value of the maximum reaction rate as the flat height of reaction enzymes running water is selected afterwards.
Maximum reaction rate obtains the exciting rate under the concentration compared with DMSO.
The exciting rate of compound is obtained by following formula:
Compound excitement rate %=(compound group OD average value-negative control DMSO group OD average value)/negative control DMSO group OD average value
Exciting rate under various concentration is mapped using Origin8 software, and the concentration-excitement rate S type for obtaining the compound is bent Line.Reach maximum exciting rate of the exciting rate as compound of plateau.Reach compound concentration conduct when 50% exciting rate The EC of compound50。
1 glucokinase agonist of table screens system
Step 2: experimental result
Enzymatic activity test based on the glucokinase enzyme activity screening and assessment system established in step 1 shows the present invention N- substitution -3,5- disubstituted benzenes Carbox amide concentration be micromolar levels when to glucokinase have well swash Dynamic effect, majority of compounds is to the half-maximal effect concentration of glucokinase in 0.04-50 μm of ol/L, and some compounds are to Portugal The half-maximal effect concentration of glucokinase is better than positive reference compound RO28-0450 in every liter or so of 40 nanomole, is a kind of Potent glucokinase agonist (table 2).
The half-maximal effect concentration of 2 compounds on glucose kinases of the embodiment of the present invention of table
aRO28-0450 is as positive control (Grimsby, J. et al. Science.2003；301(5631):370-3.)
Embodiment 46
Influence of the detection compound I-13 and I-20 to ob/ob mouse blood sugar
The present invention measure give I-13 and I-20 respectively in a manner of intraperitoneal injection after diabetes B model mice The fasting blood-glucose of (ob/ob mouse) and glycosylated hemoglobin come study this 2 compounds to the treatment of diabetes B hyperglycemia or Improvement result.The result shows that I-13 and I-20 have good hypoglycemic effect.
1, experimental principle
Ob/ob mouse (leptin (leptin) shortage) belongs to diabetes B animal model.The present invention is with the mouse of the strain Animal model as the evaluation anti-diabetes B of compound.
2, experimental material and method
1) animal origin: diabetic rat model ob/ob mouse is purchased from U.S. Jackson company.
2) animal condition of culture: SPF grades of animal house raisings；Temperature: 22-24 DEG C；Humidity: 45-80%；Illumination: 150- 300Lx, day alternates with night within 12 hours.It is raised, administration, and (including fasting blood-glucose, glycosylated hemoglobin) of every biochemical indicator is surveyed Fixed and execution is in strict accordance with zoopery and the guidance of welfare (referring to Shanghai City management of laboratory animal regulations).
3) animal packet and administration
A, the animal packet and dosage regimen of I-13: ob/ob mouse is raised in SPF grades of animal houses, and adaptability raises and train one Zhou Hou.According to measurement fasting 6 hours after fasting blood-glucose result mean value by mouse be divided into blank control group, positive controls and by Examination object group, every group 8.The daily 10:00-11:00 in morning of each group mouse be injected intraperitoneally respectively give solvent (6%Tween 80, 2%DMSO, solvent group), 5mg/kg positive compound (Rosiglitazone Rosiglitazone, positive compound group), 40mg/kg I-13 (I-13 high dose group), 20mg/kg I-13 (I-13 low dose group).
B, the animal packet and dosage regimen of I-20: ob/ob mouse is raised in SPF grades of animal houses, and adaptability raises and train one Zhou Hou.According to measurement fasting 6 hours after fasting blood-glucose result mean value by mouse be divided into blank control group, positive controls and by Examination object group, every group 8.The daily 10:00-11:00 in morning of each group mouse be injected intraperitoneally respectively give solvent (4%Tween 80, 1%DMSO, solvent group), 5mg/kg positive compound (Rosiglitazone Rosiglitazone, positive compound group), 30mg/kg I-20 (I-20 high dose group), 10mg/kg I-20 (I-20 low dose group).
4) observation index
To the long term of mouse fasting blood-glucose: monitoring that fasting blood-glucose is primary, and fasting blood-glucose is mouse during administration weekly It is deprived of food but not water the rear 6h (blood glucose value after morning 9:30-10:30 to afternoon 3:30-4:30), and count each group average blood sugar.
Effect to mouse glycosylated hemoglobin (HbA1c): experiment terminates to put to death animal, and the side of blood is taken using excision eyeball Method collects blood, takes 100 μ L of whole blood or so, and addition is put well in the EP pipe of anti-coagulants in advance, is centrifugated serum and red blood cell (2000rpm, 2 minutes) collects lower layer's red blood cell and measures for HbA1c.It utilizes automatic clinical chemistry analyzer (7020 type of Hitachi) It detects, reagent uses automatic clinical chemistry analyzer matched glycosylated hemoglobin assay kit.
5) data processing and statistical analysis: data are indicated with means standard deviation (mean ± sem), using one-way ANOVA carries out statistical analysis to data.
3, experimental result:
(1) influence of the I-13 and I-20 to ob/ob mouse fasting blood-glucose (fasting blood glucose, FBG)
A, influence of the I-13 to ob/ob mouse fasting blood-glucose: fasting blood-glucose is tieed up always during blank control group mouse is tested It holds in relatively high level.The fasting blood-glucose of positive controls is constantly in below solvent group, and this phenomenon is continued until reality Test end.The phenomenon that I-13 high and low dose group was also showed below solvent group from first week, wherein high dose group reduces on an empty stomach This phenomenon of blood glucose is continued until that experiment terminates, that is to say, that it is living that I-13 high dose administration group shows good hypoglycemic Property (Fig. 1).
B, influence of the I-20 to ob/ob mouse fasting blood-glucose: fasting blood-glucose is tieed up always during blank control group mouse is tested It holds in relatively high level.The fasting blood-glucose of positive controls is constantly in below solvent group, and this phenomenon is continued until reality Test end.The phenomenon that I-20 high dose group was also showed below solvent group from first week, and this phenomenon is continued until Experiment terminates, that is to say, that I-20 high dose administration group shows good hypoglycemic activity (Fig. 2).
(2) influence of the I-13 and I-20 to ob/ob mouse glycosylated hemoglobin (HbA1c)
After administration, the glycosylated hemoglobin of positive compound group and I-13 high dose group is all dropped than solvent group conspicuousness It is low, illustrate that I-13 administration group has good hypoglycemic activity (Fig. 3).Equally, positive compound group and the high dose group of I-20 Glycosylated hemoglobin is all reduced than solvent group conspicuousness, illustrates that I-20 administration group has good hypoglycemic activity (Fig. 4).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. compound shown in general formula I or its pharmaceutically acceptable salt:
In formula, m 0,1,2 or 3；
X is-O- ,-S- ,-(CH2)nOr-C (O)-, wherein n is 1,2 or 3；
Y is-O- ,-S- ,-N- or-CH-；
R1For substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C6-C10Virtue Base or substituted or unsubstituted 3-8 unit's heteroaryl, wherein the substitution refers to substituent group selected from the group below: C3-C8Cycloalkanes Base, C6-C10Aryl, C1-C6Alkoxy, 3-8 unit's heteroaryl；
R2For substituted or unsubstituted phenyl, wherein the substitution refers to substituent group selected from the group below: halogen, cyano, halogenated C1-C6Alkyl ,-SO2(C1-C6Alkyl) ,-SO2(C3-C8Naphthenic base) ,-SO2(3-8 membered heterocycloalkyl) ,-CO (3-8 circle heterocyclic ring alkane Base)-,-CO (C1-C6Alkyl)-,-CO (C3-C8Naphthenic base)-,-CO2(3-8 membered heterocycloalkyl)-,-CO2(C1-C6Alkyl)-,- CO2(C3-C8Naphthenic base)-,-CONR4R5-、C6-C10Aryl；
R3For nothing, hydrogen, C1-C6Alkyl, C6-C10Aryl, carboxyl ,-COO (C1-C6Alkyl), 3-8 unit's heteroaryl ,-NR4R5-、-CO (C1-C6Alkyl) ,-COO (C6-C10Aryl) ,-COO (3-8 unit's heteroaryl) ,-CO (C6-C10Aryl) ,-CO (3-8 unit's heteroaryl)；
Each R4、R5Independently selected from: C1-C6Alkyl, hydrogen ,-COC1-C6Alkyl.
2. compound shown in general formula I as described in claim 1, which is characterized in that R1For substituted or unsubstituted C1-C6Alkyl, Or substituted or unsubstituted C3-C8Naphthenic base, wherein the substitution refers to substituent group selected from the group below: C3-C8Naphthenic base, C6-C10Aryl, C1-C6Alkoxy.
3. compound shown in general formula I as described in claim 1, which is characterized in that R2For substituted or unsubstituted phenyl, wherein The substitution refers to substituent group selected from the group below: halogen ,-SO2(C1-C4Alkyl) ,-SO2(C3-C6Naphthenic base) ,-SO2(3- 6 membered heterocycloalkyls) ,-CO (3-6 membered heterocycloalkyl)-,-CON (C1-C6Alkyl) (C1-C6Alkyl)-, C6-C10Aryl.
4. compound shown in general formula I as described in claim 1, which is characterized in that m is 0 or 1.
5. compound shown in general formula I as described in claim 1, which is characterized in that R3For nothing, hydrogen, C1-C4Alkyl, carboxyl ,- COO(C1-C6Alkyl), C6-C10Aryl, 3-8 unit's heteroaryl ,-NH (COC1-C6Alkyl)-,-N (C1-C6Alkyl) (COC1-C4Alkane Base)-,-CO (C1-C6Alkyl).
6. compound shown in general formula I as described in claim 1, which is characterized in that compound shown in the general formula I are as follows:
7. the preparation method of compound shown in general formula I as described in claim 1, which is characterized in that the method includes Formula II Compound reacts the step of obtaining compound shown in general formula I with formula III compound,
Wherein, m, X, Y, R1、R2And R3Definition it is as described in claim 1.
8. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes:
(1) compound shown in general formula I described in claim 1 or its pharmaceutically acceptable salt；With
(2) pharmaceutically acceptable carrier.
9. the purposes of compound shown in general formula I as described in claim 1 or pharmaceutical composition according to any one of claims 8, special Sign is, is used for:
(1) drug of glucokinase agonist is prepared；And/or
(2) drug of preparation prevention and/or treatment disease relevant to abnormal glucose metabolism.
10. purposes as claimed in claim 9, which is characterized in that the relevant disease of the abnormal glucose metabolism is and grape Sugared kinase activity lacks relevant disease or disorder.
CN201680004411.5A 2015-01-14 2016-01-14 N- substitution -3,5- disubstituted benzenes Carbox amide and its preparation method and application Expired - Fee Related CN107108656B (en)

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CN1777589A (en) * 2003-02-26 2006-05-24 万有制药株式会社 Heteroarylcarbamoylbenzene derivative
CN101711238A (en) * 2007-06-11 2010-05-19 百时美施贵宝公司 1, 3 - dihydroxy substituted phenylamide glucokinase activators
CN101821276A (en) * 2007-08-13 2010-09-01 症变治疗公司 Novel activators of glucokinase
WO2011095997A1 (en) * 2010-02-08 2011-08-11 Advinus Therapeutics Private Limited Benzamide compounds as glucokinase activators and their pharmaceutical application

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Publication number Priority date Publication date Assignee Title
CN1777589A (en) * 2003-02-26 2006-05-24 万有制药株式会社 Heteroarylcarbamoylbenzene derivative
CN101711238A (en) * 2007-06-11 2010-05-19 百时美施贵宝公司 1, 3 - dihydroxy substituted phenylamide glucokinase activators
CN101821276A (en) * 2007-08-13 2010-09-01 症变治疗公司 Novel activators of glucokinase
WO2011095997A1 (en) * 2010-02-08 2011-08-11 Advinus Therapeutics Private Limited Benzamide compounds as glucokinase activators and their pharmaceutical application

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