CN103508957B - Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof - Google Patents

Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof Download PDF

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CN103508957B
CN103508957B CN201210211667.7A CN201210211667A CN103508957B CN 103508957 B CN103508957 B CN 103508957B CN 201210211667 A CN201210211667 A CN 201210211667A CN 103508957 B CN103508957 B CN 103508957B
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carbonyl
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CN103508957A (en
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沈竞康
李佳
马兰萍
邹贻泉
许磊
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Shanghai Institute of Materia Medica of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention discloses a hydroxyethyl pyrazole compound or aminoethyl pyrazole compound represented by a general formula I, a preparation method and a use thereof. Bioactivity test results demonstrate that the compound has significant beta-secretase inhibition activity, such that the hydroxyethyl pyrazole compound or aminoethyl pyrazole compound can be used as a beta-secretase inhibitor so as to be used for prevention or symptomatic treatment of senile dementia.

Description

Hydroxyethyl pyrazole class compound or aminoethyl pyrazole compound and preparation method thereof and Purposes
Technical field
The invention belongs to pharmaceutical synthesis field.Specifically, the present invention relates to hydroxyethyl pyrazole class compound or aminoethyl Pyrazole compound and preparation method thereof, and it is as beta-secretase inhibitor, preparation be used for preventing, delay or treating by Purposes in the medicine of disease that the deposition of A β causes.
Background technology
Alzheimer (Alzheimer ' s disease, hereinafter referred AD), also known as presenile dementia, is common In a kind of chronic neurodegenerative disease of elderly population, for progressive, the disturbance of intelligence increasing, memory subtract for its clinical manifestation Move back, mental act is abnormal etc..It seriously threatens the health of old people, especially today's society gradually aging, this situation All the more severe, cause the common concern of people.
Acetylcholinesteraseinhibitors inhibitors remain the key agents of clinical treatment AD although choline function can be reversed at present Damage the study leading to, memory impairment, make some patients' symptom mitigation, but can not fundamentally change morbid state (Barril,X.etal Mini Rev.Med.Chem.2001,1,255).
Recent studies indicate that, the product of the amyloid beta (β-amyloidpeptide, hereinafter referred A β) in brain Raw and gathering is considered as a key factor leading to this disease to produce.A β is by amyloid precursor protein (amyloid Precursor protein, hereinafter referred APP) polypeptide of about 4kD that produces of hydrolysis, its end 11-15 aminoacid is located at The transmembrane region of APP.Mainly there are three kinds of secretases to take part in the hydrolytic process to APP, be referred to as α, β and gamma-secretase.α-point The restriction enzyme site secreting enzyme is located in A β sequence, produces solvable α-APP fragment and C83 peptide, C83 peptide can continue after acting on APP Hydrolyzed by gamma-secretase and generate P3 peptide, do not produce A β.And the restriction enzyme site of beta-secretase is located at first aminoacid of A β N-terminal, make For producing β-APP and C99 peptide after APP, C99 peptide acts on through gamma-secretase and produces A β.As can be seen here, beta-secretase is A β Very crucial rate-limiting enzyme in forming process.And the mice knocking out beta-secretase gene shows do not have the generation of A β completely simultaneously The obstacle of no significantly neural and other physiological function aspects, therefore beta-secretase are considered as that treatment AD is safe and effective Novel targets (D.J.Selkoe Science.2002,297,353-356.).And, the inhibitor of beta-secretase compares gamma-secretase Inhibitor is safer, but the synthesis difficulty of the beta-secretase inhibitors of small molecule is far above inhibitors of gamma-secretase.
Content of the invention
Goal of the invention
For solving technical problem present in prior art, the present inventor has designed and synthesized a series of beta-secretase suppression Agent, to reaching the purpose for the treatment of AD.
Therefore, it is an object of the present invention to provide a kind of hydroxyethyl pyrazole class compound or aminoethyl pyrazole compound Or its pharmaceutically acceptable salt.
It is a further object of the present invention to provide such compound is being prepared as the use in the medicine of beta-secretase inhibitor On the way.
A further object of the present invention is to provide to comprise above-mentioned hydroxyethyl pyrazole class compound or aminoethyl pyrazoleses chemical combination The pharmaceutical composition of one or more of thing or its pharmaceutically acceptable salt.
It is also another object of the present invention to provide a kind of prevention, delay or treat by A β deposition cause disease side Method.
Technical scheme
To achieve these goals, the invention provides the hydroxyethyl pyrazole class compound representing as following formula I or ammonia Ethyl pyrazoles compound or its pharmaceutically acceptable salt：
Wherein：
Z is OH or NH2；
Wherein, A is halogen；X is NH or O；Y is carbonyl；R7For H, C1-C6Straight chain alkane Base, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R2ForH、C1-C4Straight chained alkyl, C3-C6Branched alkyl or nitro；Wherein, R8And R9It is identical or different, It is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R3For substituted or unsubstituted phenyl, wherein, described substituent group is C1-C6Straight chained alkyl, C3-C6Branched alkyl or halogen Element；
R4、R5And R6Identical or different, it is each independently H, carboxyl, C1-C6Straight chained alkyl, C3-C6Branched alkyl, C1-C6 Alkoxy carbonyl, hydroxyl C1-C6Alkylidene, substituted or unsubstituted amino carbonyl, substituted or unsubstituted phenyl, naphthyl, replacement Or unsubstituted containing 1-3 heteroatomic 5-7 unit's saturated heterocyclyl carbonyl or containing the insatiable hunger of 1-3 heteroatomic 5-11 unit And heterocyclic radical；
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Directly Alkyl group, C3-C6Branched alkyl, C3-C6Cycloalkyl, C1-C6Alkoxyl, C1-C6Alkoxy C1-C6Alkylidene, hydroxyl C1-C6Alkylene Base, phenyl and C1-C3The benzyl that alkoxyl replaces；
The substituent group of described substituted phenyl is hydroxyl, C1-C6The C of alkoxyl, halogen or halogen substiuted1-C3Alkyl；
Described hetero atom is N, S or O；
The described substituted substituent group containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl is C1-C3Alkyl or C1- C6Alkoxy C1-C6Alkylidene.
Preferably,
When Z is for OH；
R1For Wherein, A is F, Cl or Br；X is NH；Y is carbonyl；R7For H, C1-C6Straight chained alkyl or C3-C6Side chain Alkyl；
R2ForH、C1-C4Straight chained alkyl or nitro；Wherein, R8And R9Identical or different, it is each independently H、C1-C6Straight chained alkyl or C3-C6Branched alkyl；
R3For phenyl；
R4、R5And R6Identical or different, it is each independently H, carboxyl, C1-C6Straight chained alkyl, C3-C6Branched alkyl, C1-C6 Alkoxy carbonyl, hydroxyl C1-C6Alkylidene, substituted or unsubstituted amino carbonyl, substituted or unsubstituted phenyl, naphthyl, replacement Or unsubstituted containing 1-3 heteroatomic 5-7 unit's saturated heterocyclyl carbonyl or containing the insatiable hunger of 1-3 heteroatomic 5-11 unit And heterocyclic radical；
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Directly Alkyl group, C3-C6Branched alkyl, C3-C6Cycloalkyl, C1-C6Alkoxyl, C1-C6Alkoxy C1-C6Alkylidene, hydroxyl C1-C6Alkylene Base, phenyl and C1-C3The benzyl that alkoxyl replaces；
The substituent group of described substituted phenyl is hydroxyl, C1-C6The C of alkoxyl, halogen or halogen substiuted1-C3Alkyl；
Described hetero atom is N, S or O；
The described substituted substituent group containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl is C1-C3Alkyl or C1- C6Alkoxy C1-C6Alkylidene.
When Z is NH2When,
R1ForWherein, X is NH；Y is carbonyl；R7For H, C1-C6Straight chain alkane Base or C3-C6Branched alkyl；
R2ForWherein, R8And R9Identical or different, it is each independently H, C1-C6Straight chained alkyl or C3-C6? Alkyl group；
R3For phenyl；
R4、R5And R6Identical or different, it is each independently C1-C6Alkoxy carbonyl or substituted or unsubstituted amino carbonyl Base；
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Directly Alkyl group and C3-C6Branched alkyl.
It is further preferred that
When Z is for OH；
R1ForWherein, X is NH；Y is carbonyl；R7For H or C1-C4Straight chained alkyl；
R2ForH、C1-C4Straight chained alkyl or nitro；Wherein, R8And R9It is H or C simultaneously1-C4Straight chained alkyl；
R3For phenyl；
R4、R5And R6Identical or different, it is each independently H, carboxyl, C1-C4Straight chained alkyl, C1-C4Alkoxy carbonyl, hydroxyl Base C1-C4Alkylidene, substituted or unsubstituted amino carbonyl, substituted or unsubstituted phenyl, naphthyl, C1-C4Alkoxy C1-C4Sub- The substituted or unsubstituted pyrrolidinylcarbonyl of alkylPiperidino carbonylC1-C3Alkyl replaces Or unsubstituted morpholinyl carbonylCycloheptyl amino-carbonylBenzocyclohepta amino-carbonylFurylThienylOr pyridine radicalsWherein, described substituted amino carbonyl The N atom of base is selected from one of following groups or two replacements：C1-C4Straight chained alkyl, C3-C5Cycloalkyl, C1-C4Alcoxyl Base, C1-C4Alkoxy C1-C4Alkylidene, hydroxyl C1-C4Alkylidene, phenyl and C1-C3The benzyl that alkoxyl replaces；
The substituent group of described substituted phenyl is hydroxyl, C1-C4Alkoxyl, F or trifluoromethyl.
When Z is NH2When,
R1ForWherein, X is NH；Y is carbonyl；R7For H or C1-C4Straight chain Alkyl；
R2ForR8And R9It is H or C simultaneously1-C4Straight chained alkyl
R3For phenyl；
R4、R5And R6Identical or different, it is each independently C1-C4Alkoxy carbonyl or substituted or unsubstituted amino carbonyl Base；Wherein, described substituted aminocarboxy N atom is by one or more C1-C4Straight chained alkyl replaces.
According to hydroxyethyl pyrazole class compound provided by the present invention or aminoethyl pyrazole compound, most preferably as follows One of compound：
Described pharmaceutically acceptable salt is that the described compound being represented by logical formula (I) is formed with mineral acid or organic acid Salt；Wherein, described mineral acid is hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, and described organic acid is citric acid, lactic acid, malic acid, Portugal Saccharic acid, tartaric acid, adipic acid, acetic acid, succinic acid, fumaric acid, ascorbic acid, itaconic acid, methanesulfonic acid or benzenesulfonic acid.
Present invention also offers the preparation method of hydroxyethyl pyrazole class compound, the method use following synthetic route 1,2, 3 or 4：
Synthetic route 1：(corresponding particular compound is 1-9,49,60-63,66-67)
Wherein, R1For Wherein, X is NH or O；Y is carbonyl；R7For H, C1- C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R2ForH、C1-C4Straight chained alkyl, C3-C6Branched alkyl or nitro；Wherein, R8And R9It is identical or different, It is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R3For substituted or unsubstituted phenyl, wherein, described substituent group is C1-C6Straight chained alkyl, C3-C6Branched alkyl or halogen Element；
R4、R5And R6Identical or different, it is each independently H, carboxyl, C1-C6Straight chained alkyl, C3-C6Branched alkyl, C1-C6 Alkoxy carbonyl, hydroxyl C1-C6Alkylidene, unsubstituted containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl；
Described hetero atom is N, S or O.
Reactions steps are as follows：
A) with epoxide A as initiation material, with pyrazole derivatives in the presence of sodium carbonate with DMF for 100 DEG C of solvent Reaction open loop obtains compound B,
B) compound B sloughs Boc protection group in acid condition and obtains compound C,
C) under conditions of in EDCI, HOBt and DIPEA, one or more compound exists, compound C further and Phthalic acid condensation generates compound D-1, obtains target compound by silicagel column or thin plate chromatography method；
Synthetic route 2：(corresponding particular compound is 10-27,58,59,60-63,66-67)
Wherein, R1For Wherein, A is halogen；X is NH or O；Y is carbonyl；R7For H or C1-C6Straight chain alkane Base, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R2ForH、C1-C4Straight chained alkyl, C3-C6Branched alkyl or nitro；Wherein, R8And R9It is identical or different, It is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R3For substituted or unsubstituted phenyl, wherein, described substituent group is C1-C6Straight chained alkyl, C3-C6Branched alkyl or halogen Element；
R4And R6Identical or different, be each independently substituted or unsubstituted amino carbonyl, substituted or unsubstituted containing 1-3 heteroatomic 5-7 unit's saturated heterocyclyl carbonyl or containing 1-3 heteroatomic 5-11 membered unsaturated heterocycle base,
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Directly Alkyl group, C3-C6Branched alkyl, C3-C6Cycloalkyl, C1-C6Alkoxyl, C1-C6Alkoxy C1-C6Alkylidene, hydroxyl C1-C6Alkylene Base, phenyl and C1-C3The benzyl that alkoxyl replaces；
Described hetero atom is N, S or O；
The described substituted substituent group containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl is C1-C3Alkyl, C1- C6Alkoxy C1-C6Alkylidene；
R11And R12Identical or different, it is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl, C3-C6Cycloalkanes Base, C1-C6Alkoxyl, C1-C6Alkoxy C1-C6Alkylidene, hydroxyl C1-C6Alkylidene, phenyl or C1-C3The benzene that alkoxyl replaces Methyl；Or R11And R12Formed substituted or unsubstituted first containing 1-3 heteroatomic 5-7 together with connected N atom Saturated heterocyclyl carbonyl or containing 1-3 heteroatomic 5-11 membered unsaturated heterocycle base,
Described hetero atom is N, S or O；
The described substituted substituent group containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl is C1-C3Alkyl, C1- C6Alkoxy C1-C6Alkylidene.
Wherein, by the reactions steps a) in synthetic route 1, b), c) compound D-2 that R5 be ethoxy carbonyl is obtained, makees Initiation material for synthetic route 2.
Compound D-2 obtains E with THF/ ethanol/water=2/2/1 for aqueous solvent solution, and compound E is in EDCI, HOBt and DIPEA Under conditions of with amine be condensed generate compound F, target compound is obtained by silicagel column or thin plate chromatography method.
Synthetic route 3：(corresponding particular compound is 28-48)
Wherein, R1ForWherein, A is halogen； X is NH or O；Y is carbonyl；R7For H or C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R2ForH、C1-C4Straight chained alkyl, C3-C6Branched alkyl or nitro；Wherein, R8And R9It is identical or different, It is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R3For substituted or unsubstituted phenyl, wherein, described substituent group is C1-C6Straight chained alkyl, C3-C6Branched alkyl or halogen Element；
R4、R5' and R6Identical or different, it is each independently substituted or unsubstituted phenyl, naphthyl or contain 1-3 Heteroatomic 5-11 membered unsaturated heterocycle base,
Wherein, the substituent group of described substituted phenyl is hydroxyl, C1-C6The C of alkoxyl, halogen or halogen substiuted1-C3Alkane Base,
Described hetero atom is N, S or O.
Wherein, by the reactions steps a) in synthetic route 1, R b), c) is obtained5Compound D-3 for Br, as synthesis road The initiation material of line 3.
Compound D-3 is four（Triphenyl phosphorus）Under palladium chtalyst with toluene/ethanol/water=2/2/1 for solvent under microwave reaction Obtain the hydroxyethyl pyrazole class compound G of aryl replacement.
Synthetic route 4：（Corresponding particular compound is 50-57）
Wherein, R1For Wherein, X is NH；Y is carbonyl；R7For H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C3-C6Cycloalkyl；
R2ForWherein, R8And R9Identical or different, it is each independently H, C1-C6Straight chained alkyl, C3-C6? Alkyl group or C3-C6Cycloalkyl；
R3For substituted or unsubstituted phenyl, wherein, described substituent group is C1-C6Straight chained alkyl, C3-C6Branched alkyl or halogen Element；
R4、R5And R6Identical or different, it is each independently C1-C6Alkoxy carbonyl or substituted or unsubstituted amino carbonyl Base,
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Directly Alkyl group and C3-C6Branched alkyl.
Reactions steps are as follows：
A) with epoxide H as initiation material, with pyrazole derivatives in the presence of sodium carbonate with DMF for 100 DEG C of solvent Reaction open loop obtains compound I;
B) compound I and mesyl chloride react and obtain compound J;
C) compound J and Hydrazoic acid,sodium salt react to obtain compound K in 50 DEG C in DMF solvent;
D) compound K is sloughed Boc protection group in acid condition and is obtained compound L;
E) under conditions of in EDCI, HOBt and DIPEA, one or more compound exists, compound K further and Phthalic acid is condensed to obtain compound M;
F) compound M zinc powder reduction obtains compound N.
According to another object of the present invention, the invention provides above-mentioned hydroxyethyl pyrazole class compound or aminoethyl pyrazoleses Compound or its pharmaceutically acceptable salt, as beta-secretase inhibitor, can be used for preparation prevention, delay or treat by A β's The disease that deposition causes, particularly AD medicine.
Another technical scheme of the present invention provides the hydroxyethyl pyrazole that a kind of formula I comprising therapeutically effective amount represents The pharmaceutical composition of one or more of class compound or aminoethyl pyrazole compound or its pharmaceutically acceptable salt, should Compositionss can optionally comprise the excipient allowing on a certain amount of pharmaceuticss, can also optionally comprise a certain amount of odorant agent, fragrance The conventional additives such as agent.
Another technical scheme of the present invention provides prevention, delays or treat the side of the disease being caused by the deposition of A β Method, methods described includes applying hydroxyethyl pyrazole class compound or the aminoethyl pyrazoleses that the formula I of therapeutically effective amount represents One or more of compound or its pharmaceutically acceptable salt, ester, prodrug or solvate or the said medicine of the present invention Compositionss are to patient.
Beneficial effect
Hydroxyethyl pyrazole class compound of the present invention or aminoethyl pyrazole compound, have obvious suppression β-point Secrete the activity of enzyme, this is to study to be likely to be of further to improve cognitive function, and the original new drug simultaneously alleviating AD progression of disease carries Supply valuable information.
Specific embodiment
With reference to embodiment, the present invention is further elaborated, and implementation below only describes this by way of example Bright.It is obvious that those of ordinary skill in the art can be carried out to the present invention various flexible and repair in the scope of the present invention and essence Change.It is to be understood that this invention is intended to covering the accommodation including in the dependent claims and modification.
Experiment and sample analysis instrument：
Mercury-300 the or Mercury-400 type nuclear-magnetism that nuclear magnetic resoance spectrum (1H NMR) is produced by Varian company is altogether Vibration Meter measures.
LC-MS is measured by Thermo Finnigan LCQDECA × p-type mass spectrograph.
HRMS is measured by Finnigan MAT 95 type mass spectrograph.
Sample purity is by high performance liquid chromatograph (306pump, uv/vis-156Detector, 215 of Gilson company Liquid handle) measure.
Optically-active data is measured by PerkinElmer-341 type polariscope.
Column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (200-300 mesh).
TLC silica gel plate is the HSF-254 thin layer chromatography precoated plate of Yantai Chemical Manufacture.
Uviol lamp is Shanghai Gu Cun electric light instrument plant ZF-1 type ultraviolet analysis instrument for three purposed.
Microwave reactor is Biotage Initiator product.
Preparation embodiment
Embodiment 1：
(preparation of compound 1)
Synthetic route 1, reactions steps：
By epoxide (2S, 3S) -1,2- epoxy -3- (N- tert-butoxycarbonylamino) -4- phenylpropyl alcohol alkane (50mg, 0.19mmol) it is dissolved in 2mLDMF, add pyrazoles (13mg, 0.19mmol), catalytic amount sodium carbonate in system.In microwave 110 DEG C reaction 1 hour.Reaction terminates to add 25mL water in system, and ethyl acetate extracts (25mL × 2), merges organic faciess, saturation Sal washes (25mL), anhydrous sodium sulfate drying, filters, and concentrates, obtains white solid (2S, 3S) -1- benzyl -2- hydroxyl -3- pyrrole Oxazolyl t-butyl carbamate 57mg,
Above-mentioned pyrazole compound (57mg, 0.17mmol) is dissolved in 4mL dichloromethane, adds 1mL trifluoro in system Acetic acid, room temperature reaction 2h.Concentrate, the amine obtaining is not treated to be directly entered next step reaction.The amine that obtain upper step and 5- (first Base mesyl) amino -3- ((1R) -1- (4- fluorophenyl)) ethyl aminocarbonyl benzoic acid (68mg, 0.17mmol) is dissolved in 10mL In DCM, add EDCI (38mg, 0.20mmol), HOBt (23mg, 0.17mmol), DIPEA (94 μ l, 0.51mmol), room temperature is stirred Mix overnight.Add 15mL DCM, Diluted Acid Washing (25mL) in reaction system, saturated sodium bicarbonate washes (25mL), saturated aqueous common salt Wash (25mL), anhydrous sodium sulfate drying, filter, concentrate, column chromatography obtain white foam solid N- [(1S, 2S) -1- benzyl - 2- hydroxyl -3- pyrazolyl] -5- [(methyl first sulfo group) amino]-N '-[(1R) -1- (4- fluorophenyl) ethyl] isophtalamide 87mg, yield：79.6%.
1H NMR(300MHz,CD3OD):δ1H NMR(300MHz,CD3OD):δ8.12(s,1H),7.99(s,1H),7.89 (s,1H),7.63(s,1H),7.46-7.39(m,3H),7.26-7.19(m,4H),7.15-7.13(m,1H),7.08-7.02 (t, 2H), 6.24 (s, 1H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.41-4.36 (t, 1H), 4.29-4.23 (t, 1H), 4.15-4.10 (m, 2H), 3.34 (s, 3H), 3.06-2.94 (m, 2H), 2.93 (s, 3H), 1.58-1.55 (d, J=6.9Hz, 3H)
LC-MS:m/z608.1[M+H]+;
Embodiment 2：
(preparation of compound 2)
Synthetic route is with reference to embodiment 1.Replace pyrazoles with 3- methylpyrazole, TLC chromatography obtains white, amorphous solid Compound 2 (19mg, yield：81.2%).
1H NMR(300MHz,CD3OD):δ8.13(s,1H),8.00(s,1H),7.90(s,1H),7.49(m,1H), 7.44-7.39(m,2H),7.26-7.22(m,4H),7.17-7.13(d,1H),7.05-7.02(t,2H),6.01.(s,1H), 5.24-5.21 (q, J=7.2Hz, 1H), 4.39.-4.37 (t, 1H), 4.19.-4.00 (m, 3H), 3.34 (s, 3H), 3.03- 2.96 (m, 2H), 2.94 (s, 3H), 2.18 (s, 3H), 1.58-1.55 (d, J=7.2Hz, 3H)
LC-MS:m/z622.22[M+H]+;
Embodiment 3：
(preparation of compound 3)
Synthetic route, with reference to embodiment 1, replaces pyrazoles with 4-methylpyrazole, and TLC chromatography obtains white, amorphous solid Compound 3 (71mg yield：72.4%).
1H NMR(300MHz,CD3OD):δ8.11(s,1H),7.99(s,1H),7.89(s,1H),7.44-7.38(m, 3H), 7.26-7.17 (m, 5H), 7.16-7.14 (d, 1H), 7.05-7.00 (t, 2H), 5.24-5.20 (q, J=6.6Hz, 1H), 4.39.-4.34(t,1H),4.20-4.16(m,1H),4.08-4.00(m,2H),3.34(s,3H),3.05-3.00(m,2H), 2.98 (s, 3H), 2.02 (s, 3H), 1.58-1.56 (d, J=6.6Hz, 3H)
LC-MS:m/z622.2[M+H]+;
Embodiment 4：
(preparation of compound 4)
Synthetic route is with reference to embodiment 1.Replace pyrazoles with 5- methylpyrazole, TLC chromatography obtains white, amorphous solid Compound 4 (25mg, yield：78.2%).
1H NMR(300MHz,CD3OD):δ8.15(s,1H),7.99(s,1H),7.90(s,1H),7.39-7.29(m, 3H),7.29-7.25(m,3H),7.21-7.19(m,1H),7.06-6.99(t,3H),5.98(s,1H),4.66-4.44(dd,J =7.8Hz, 1H), 4.08.-3.98. (m, 3H), 4.34 (s, 3H), 3.09-3.07 (dd, 2H), 2.86 (s, 3H), 2.19 (s, 3H), 1.62-1.69 (d, J=7.2Hz, 3H)
LC-MS:m/z622.2[M+H]+;
Embodiment 5：
(preparation of compound 5)
Synthetic route, with reference to embodiment 1, replaces pyrazoles, it is solid that TLC chromatography obtains white-amorphous with 3- carbethoxyl group pyrazoles Body compound 5 (33mg, yield：88.7%).
1H NMR(300MHz,CD3OD):δ8.12(s,1H),7.99(s,1H),7.88(s,1H),7.71(s,1H), 7.44-7.40(m,2H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.08-7.02(t,3H),6.73(s,1H), 5.24-5.22 (q, J=6.6Hz, 1H), 4.43-4.15 (m, 6H), 3.34 (s, 3H), 3.05-2.94 (m, 2H), 2.93 (s, 3H), 1.58-1.55 (d, J=6.6Hz, 3H), 1.36-1.31 (t, J=6.9Hz, 3H)
LC-MS:m/z680.1[M+H]+;
Embodiment 6：
(preparation of compound 6)
Synthetic route, with reference to embodiment 1, replaces pyrazoles with 4- carbethoxyl group pyrazoles, column chromatography obtains white, amorphous solid Compound 6 (80mg, yield：76.6%).
1H NMR(300MHz,CD3OD):δ8.11(s,1H),7.98(s,1H),7.88(s,1H),7.84(s,1H), 7.45-7.39(m,2H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.08-7.02(t,3H),5.24-5.22(q,J =6.6Hz, 1H), 4.28.-4.12 (m, 4H), 4.26-4.23 (q, J=6.9Hz, 2H) 3.35 (s, 3H), 3.05-2.98 (m, 2H), 2.95 (s, 3H), 1.58-1.55 (d, J=6.6Hz, 3H), 1.33-1.28 (t, J=6.9Hz, 3H)
LC-MS:m/z608.2[M+H]+;
Embodiment 7：
(preparation of compound 7)
Synthetic route, with reference to embodiment 1, replaces pyrazoles, it is solid that TLC chromatography obtains white-amorphous with 3- carbethoxyl group pyrazoles Body compound 7 (29mg, yield：61.4%).
Yield：78.9%.
1H NMR(300MHz,CD3OD):δ8.44(s,1H),8.24(s,1H),8.09(s,1H),7.48(s,1H), 7.44-7.30 (m, 2H), 7.28-7.18 (m, 5H), 7.08-7.02 (t, 3H), 6.71 (s, 1H), 5.25-5.22 (q, J= 7.2Hz,1H),4.43-4.15(m,6H),3.34(s,3H),3.05-2.94(m,2H),2.93(s,3H),1.58-1.55(d,J =6.6Hz, 3H), 1.36-1.31 (t, J=6.9Hz, 3H)
LC-MS:m/z 608.1[M+H]+;
Embodiment 8：
(preparation of compound 8)
Synthetic route is with reference to embodiment 1, and the compound 6 (80mg, 0.12mmol) that embodiment 6 is obtained is dissolved in 10mL (THF/EtOH/H2O=2/2/1, volume ratio) in solution, add the sodium hydroxide (10mg, 0.24mmol) of two equivalents, room temperature It is stirred overnight.Reactant liquor pH value is adjusted to 4, ethyl acetate (50mL × 2) extracts, saturated aqueous common salt (50mL) washs, anhydrous sulfur Sour sodium is dried, and solvent is recovered by filtration, and TLC chromatography obtains white, amorphous solid compound 105 (62mg, fusing point：122-124 DEG C, Yield：88.8%).
1H NMR(300MHz,CD3OD):δ8.14-8.12(d,2H),7.98(s,1H),7.89(s,1H),7.84(s, 1H),7.44-7.39(m,2H),7.28-7.23(m,4H),7.16-7.14(m,1H),7.08-7.02(m,2H),5.24-5.22 (q, J=6.9Hz, 1H), 4.43-4.42. (m, 1H), 4.28-4.26. (m, 1H), 4.14-4.12 (m, 2H), 3.34 (s, 3H), 3.05-3.01 (m, 2H), 2.95 (s, 3H), 1.58-1.55 (d, J=6.9Hz, 3H)
LC-MS:m/z 652.0[M+H]+;
Embodiment 9：
(preparation of compound 9)
According to synthetic route 1, the compound 6 being obtained with reference to embodiment 1 and by embodiment 6 is obtained final product with Lithium aluminum hydride reduction. Yield：70.0%.
1H NMR(300MHz,CD3OD):δ8.12(s,1H),7.99(s,1H),7.90(s,1H),7.61(s,1H), 7.45-7.40(m,3H),7.27-7.22(m,4H),7.16-7.14(m,1H),7.08-7.03(t,2H),5.24-5.22(q,J =7.2Hz, 1H), 4.46 (s, 2H), 4.38-4.35 (t, 1H), 4.28-4.22 (m, 1H), 4.09-4.06 (m, 2H), 3.35 (s, 3H), 3.03-2.97 (m, 2H), 2.95 (s, 3H), 1.58-1.56 (d, J=7.2Hz, 3H)
LC-MS:m/z 638.0[M+H]+;
Embodiment 10：
(preparation of compound 10)
According to synthetic route 2, yield：71.5%.
Compound 8 (60mg, 0.09mmol) is dissolved in 2mL DMF, adds EDCI (20mg, 0.10mmol), HOBt (10mg, 0.08mmol), ammonium chloride (14mg, 0.2mmol) is stirred at room temperature 10min.Add DIPEA (50 μ L, 0.3mmol), will It is added dropwise to above-mentioned reaction system, then the lower 70 DEG C of reaction 15min of microwave condition.50mL water, ethyl acetate is added in system Extraction (50mL × 2), merges organic faciess, weak acid scrubbing (25mL × 2), saturated sodium bicarbonate washes (25mL × 2), saturated aqueous common salt Washing, anhydrous sodium sulfate drying, filters, concentrates, column chromatography obtains white, amorphous solid compound 10 (41mg, yield： 68.3%).
1H NMR(300MHz,CD3OD):δ8.13(s,1H),8.10(s,1H),7.99(s,1H),
7.89(s,1H),7.88(s,1H),7.44-7.40(m,2H),7.28-7.20(m,4H),7.16-7.14(m, 1H), 7.07-7.02 (t, 2H), 5.24-5.21 (q, J=6.9Hz, 1H), 4.42-4.41 (t, 1H), 4.32-4.28 (m, H), 4.14-4.11 (m, 2H), 3.34 (s, 3H), 3.06-2.98 (m, 2H), 2.95 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H)
LC-MS:m/z651.1[M+H]+;
Embodiment 11：
(preparation of compound 11)
According to synthetic route 2, replace ammonium chloride, yield with the methylamine hydrochloride of two equivalents：74.8%.
1H NMR(300MHz,CD3OD):δ8.14(s,1H),8.06(s,1H),7.99(s,1H),
7.89(s,1H),7.83(s,1H),7.45-7.40(t,2H),7.28-7.20(m,4H),7.16-7.14(m, 1H), 7.08-7.02 (t, 2H), 5.24-5.22 (q, J=7.2Hz, 1H), 4.40-4.38 (t, 1H), 4.31-4.25 (m, 1H), 4.14-4.11(m,2H),3.34(s,3H),3.05-3.01(m,2H),2.82(s,3H),2.98(s,3H),1.58-1.56(d, J=7.2Hz, 3H)
LC-MS:m/z665.2[M+H]+；
Embodiment 12：
(preparation of compound 12)
According to synthetic route 2, replace ammonium chloride, yield with the ethylamine hydrochloride of two equivalents：70.1%.
1H NMR(300MHz,CD3OD):δ8.12(s,1H),8.06(s,1H),7.98(s,1H),
7.88(s,1H),7.85(s,1H),7.44-7.40(m,2H),7.28-7.20(m,4H),7.16-7.14(m, 1H), 7.08-7.02 (t, 2H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.40-4.38 (t, 1H), 4.31-4.25 (m, 1H), 4.14-4.11(m,2H),3.34(s,3H),3.33(q,2H),3.05-2.97(m,2H),2.95(s,3H),1.58-1.56(d, J=6.9Hz, 3H), 1.18-1.14 (t, 3H),
LC-MS:m/z679.3[M+H]+;
Embodiment 13：
(preparation of compound 13)
According to synthetic route 2, replace ammonium chloride, yield with the propylamin hydrochloride of two equivalents：67.1%.
H NMR(300MHz,CD3OD):δ8.13(s,1H),8.06(s,1H),7.98(s,1H),
7.89(s,1H),7.85(s,1H),7.44-7.39(m,2H),7.27-7.19(m,4H),7.15-7.13(m, 1H), 7.07-7.01 (t, 2H), 5.24-5.21 (q, J=6.9Hz, 1H), 4.43-4.38 (t, 1H), 4.30-4.25 (m, 1H), 4.13-4.10(m,2H),3.33(s,3H),3.26-3.22(q,2H),3.09-3.00(m,2H),2.94(s,3H),1.60- 1.50(m,5H),0.95-0.90(t,3H),
LC-MS:m/z693.3[M+H]+；
Embodiment 14：
(preparation of compound 14)
According to synthetic route 2, replace ammonium chloride, yield with the dimethylamine hydrochloride of two equivalents：86.4%.
1H NMR(300MHz,CD3OD):δ8.11(s,1H),8.03(s,1H),7.98(s,1H),
7.89(s,1H),7.77(s,1H),7.45-7.40(q,2H),7.28-7.16(m,4H),7.16-7.14(m, 1H), 7.05-7.03 (t, 2H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.43-4.37 (m, 1H), 4.31-4.25 (m, 1H), 4.15-4.12(m,2H),3.35(s,3H),3.22(s,3H),3.03(s,3H),3.05-2.97(m,2H),2.95(s,3H), 2.98 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H)
LC-MS:m/z679.2[M+H]+;
Embodiment 15：
(preparation of compound 15)
According to synthetic route 2, replace ammonium chloride, yield with the diethylamine hydrochloride of two equivalents：58.8%.
1H NMR(300MHz,CD3OD):δ8.11(s,1H),7.98-7.91(s,2H),
7.90-7.88(s,1H),7.72(s,1H),7.45-7.40(m,2H),7.27-7.17(m,4H),7.16-7.08 (m, 1H), 7.04-7.03 (t, 2H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.40-4.37 (t, 1H), 4.31-4.25 (m, 1H),4.15-4.11(m,2H),3.55-3.51(s,4H),3.35(s,3H),3.22(s,3H),3.05-2.98(m,2H), 2.97 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H), 1.12 (s, 6H)
LC-MS:m/z707.2[M+H]+;
Embodiment 16：
(preparation of compound 16)
According to synthetic route 2, replace ammonium chloride, yield with the dipropyl amine hydrochlorate of two equivalents：86.3%.
1H NMR(300MHz,CD3OD):δ8.12(s,1H),7.98(s,2H),7.95(s,2H),
7.89(s,1H),7.69(s,1H),7.44-7.40(m,2H),7.27-7.20(m,4H),7.16-7.14(m, 1H), 7.08-7.02 (t, 2H), 5.24-5.22 (q, J=6.6Hz, 1H), 4.40-4.37 (t, 1H), 4.31-4.25 (m, 1H), 4.18-4.12(m,2H),3.42(s,4H),3.41(s,3H),3.05-2.98(m,2H),2.95(s,3H),1.68-1.61(m, 4H), 1.58-1.56 (d, J=6.6Hz, 3H), 0.91 (s, 6H)
LC-MS:m/z735.3[M+H]+;
Embodiment 17：
(preparation of compound 17)
According to synthetic route 2, replace ammonium chloride, yield with the N- methoxymethylamine hydrochloride of two equivalents：51.1%.
1H NMR(300MHz,CD3OD):δ8.20(s,1H),8.13(s,2H),7.98(s,1H),
7.91-7.89(m,2H),7.44-7.40(m,2H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.08- 7.02 (t, 2H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.42-4.39 (t, 1H), 4.32-4.26 (m, 1H), 4.16-4.13 (m,2H),3.73(s,3H),3.55(s,3H),3.25(s,3H),3.05-2.96(m,2H),2.95(s,3H),1.58-1.56 (d, J=6.9Hz, 3H)
LC-MS:m/z639.1[M+H]+;
Embodiment 18：
(preparation of compound 18)
According to synthetic route 2, replace ammonium chloride, yield with N- (2- methoxy ethyl) methyl amine of two equivalents： 61.5%.
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.04(s,2H),7.98(s,1H),7.89(s,1H),7.77 (s,1H),7.44-7.40(m,2H),7.27-7.20(m,4H),7.16-7.14(m,1H),7.08-7.02(t,2H),5.24- 5.22 (q, J=6.9Hz, 1H), 4.39-4.137 (m, 4H), 3.67 (s, 2H), 3.60-3.56 (t, 2H), 3.34 (s, 3H), 3.32 (t, 3H), 3.09-2.98 (m, 4H), 2.95 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H);
LC-MS:m/z723.1[M+H]+
Embodiment 19：
(preparation of compound 19)
According to synthetic route 2, replace ammonium chloride, yield with the pyrrolidine of two equivalents：57.8%.
H NMR(300MHz,CD3OD):δ8.11(s,1H),8.10(s,1H),7.99(s,1H),7.89(s,1H),7.85 (s,1H),7.45-7.40(m,2H),7.25-7.20(m,4H),7.15-7.16(q,1H),7.08-7.03(t,2H),5.24- 5.22 (q, J=6.9Hz, 1H), 4.39-4.28 (m, 2H), 4.16-4.13 (m, 2H), 3.69-3.68 (t, 2H), 3.56-3.51 (t, 2H), 3.35 (s, 3H), 3.04-2.98 (m, 2H), 2.95 (s, 3H), 1.99-1.91 (m, 4H), 1.58-1.56 (d, J= 6.9Hz,3H);
LC-MS:m/z705.4[M+H]+;
Embodiment 20：
(preparation of compound 20)
According to synthetic route 2, with (R) of two equivalents-(-) -2- (methoxy) pyrrolidine replaces ammonium chloride, receive Rate：60.9%.
H NMR(300MHz,CD3OD):δ8.11(s,1H),8.09(s,1H),7.98(s,1H),7.89(s,1H),7.83 (s,1H),7.44-7.40(m,2H),7.27-7.20(m,4H),7.16-7.14(m,1H),7.08-7.02(t,2H),5.24- 5.22 (q, J=6.9Hz, 1H), 4.39-4.28 (m, 3H), 4.16-4.13 (m, 2H), 3.71-3.67 (m, 2H), 3.54-3.50 (m, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 3.02-2.98 (m, 2H), 2.00-1.98 (m, 4H), 1.58-1.56 (d, J= 6.9Hz,3H);
LC-MS:m/z749.3[M+H]+
Embodiment 21：
(preparation of compound 21)
According to synthetic route 2, replace ammonium chloride, yield with the piperidines of two equivalents：75.5%
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.98(s,1H),7.95(s,1H),7.89(s,1H),7.68 (s,1H),7.45-7.40(m,2H),7.27-7.20(m,4H),7.16-7.14(q,1H),7.06-7.03(t,2H),5.25- 5.22 (q, J=7.5Hz, 1H), 4.40-4.39 (m, 1H), 4.30-4.24 (m, 1H), 4.15-4.12 (m, 2H), 3.66-3.62 (m, 4H), 3.35 (s, 3H), 3.06-3.01 (m, 2H), 2.95 (s, 3H), 1.70-1.60 (d, 6H), 1.58-1.56 (d, J= 7.5Hz,3H);
LC-MS:m/z719.3[M+H]+;
Embodiment 22：
(preparation of compound 22)
According to synthetic route 2, replace ammonium chloride, yield with the morpholino of two equivalents：54.2%
H NMR(300MHz,CD3OD):δ8.11(s,1H),7.99(s,2H),7.90(s,1H),7.72(s,1H), 7.45-7.40(m,2H),7.25-7.20(m,4H),7.16-7.14(m,1H),7.08-7.03(t,2H),5.24-5.22(q,J =6.9Hz, 1H), 4.38-4.07 (m, 4H), 3.71-3.65 (s, 8H), 3.62-3.58 (t, 2H), 3.35 (s, 3H), 3.04- 2.98 (m, 2H), 2.95 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H);
LC-MS:m/z721.3[M+H]+;
Embodiment 23：
(preparation of compound 23)
According to synthetic route 2, replace ammonium chloride, yield with the cycloheximide of two equivalents：64.8%
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.98(s,2H),7.90(s,1H),7.73(s,1H), 7.45-7.40(m,2H),7.25-7.20(m,4H),7.16-7.14(m,1H),7.08-7.03(t,2H),5.24-5.22(q,J =6.9Hz, 1H), 4.29-4.12 (m, 4H), 3.70-3.66 (t, 2H), 3.62-3.58 (t, 2H), 3.35 (s, 3H), 3.04- (2.98 m, 2H), 2.95 (s, 3H), 1.77 (s, 4H), 1.77 (s, 4H), 1.58 (s, 4H), 1.58-1.56 (d, J=6.9Hz, 3H);
LC-MS:m/z733.4[M+H]+;
Embodiment 24：
(preparation of compound 24)
According to synthetic route 2, replace ammonium chloride, yield with the cyclopropylamine of two equivalents：72.1%
H NMR(300MHz,CD3OD):δ8.11(s,1H),8.06(s,2H),7.99(s,1H),7.89(s,1H),7.84 (s,1H),7.44-7.40(m,2H),7.27-7.20(m,4H),7.16-7.14(m,1H),7.05-7.02(t,2H),5.24- 5.22 (q, J=6.9Hz, 1H), 4.40-4.09 (m, 4H), 3.34 (s, 3H), 3.04-2.95 (m, 4H), 2.94 (s, 3H), 2.75-2.72 (m, 1H), 1.58-1.56 (d, J=6.9Hz, 3H);0.76-0.71(m,2H),0.58-0.54(m,2H)
LC-MS:m/z691.3[M+H]+
Embodiment 25：
(preparation of compound 25)
According to synthetic route 2, replace ammonium chloride, yield with the ethanolamine of two equivalents：63.2%
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.08(s,2H),7.99(s,1H),7.89(s,1H),7.87 (s,1H),7.44-7.39(m,2H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.08-7.02(t,2H),5.24- 5.22 (q, J=7.5Hz, 1H), 4.40-4.12 (m, 4H), 3.66-3.62 (t, 2H), 3.42-3.39 (t, 2H), 3.34 (s, 3H), 3.05-3.00 (m, 4H), 2.95 (s, 3H), 1.58-1.55 (d, J=7.5Hz, 3H);
LC-MS:m/z695.3[M+H]+
Embodiment 26：
(preparation of compound 26)
According to synthetic route 2, replace ammonium chloride, yield with the aniline of two equivalents：53.8%
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.05(s,1H),8.02(s,1H),7.98(s,1H),7.91 (s,1H),7.62(s,1H),7.59(s,1H),7.44-7.40(m,2H),7.34-7.23(m,6H),7.17-7.03(m,4H), 5.23-5.21 (q, J=6.9Hz, 1H), 4.45-4.40 (m, 1H), 4.35-4.29 (m, 1H), 4.20-4.16 (m, 2H), 3.34 (s, 3H), 3.11-3.02 (m, 2H), 2.94 (s, 3H), 1.70-1.60 (d, 6H), 1.58-1.55 (d, J=6.9Hz, 3H)
LC-MS:m/z727.2[M+H]+;
Embodiment 27：
(preparation of compound 27)
According to synthetic route 2, replace ammonium chloride, yield with the 4- methoxybenzylamine of two equivalents：51.5%
H NMR(300MHz,CD3OD):δ8.11(s,1H),8.08(s,1H),7.98(s,1H),7.88-7.87(s, 2H),7.43-7.39(m,2H),7.27-7.20(m,6H),7.15-7.13(m,1H),7.04-7.01(t,2H),6.87-6.82 (d, 2H), 5.23-5.21 (q, J=7.2Hz, 1H), 4.42-4.37 (m, 3H), 4.30-4.24 (m, 1H), 4.13-4.10 (m, 2H), 3.74 (s, 3H), 3.35 (s, 3H), 3.09-2.95 (m, 2H), 2.93 (s, 3H), 1.57-1.55 (d, J=7.2Hz, 3H);
LC-MS:m/z 771.1[M+H]+
Embodiment 28：
(preparation of compound 28)
According to synthetic route 3, yield：45.5%
By compound Ia (68mg, 0.1mmol), FURAN-2-BORONIC ACID (17mg, 0.15mmol), potassium carbonate (30mg, 0.2mmol), lithium chloride monohydrate (20mg, 0.3mmol) sequentially adds 5mL's (toluene/ethanol/water=2/2/1, volume ratio) In mixed solvent, under argon protection, add four (triphenyl phosphorus) palladium (6mg, 0.005mmol).In 120 DEG C under microwave-assisted, Reaction 1 hour.After reaction completely, reactant liquor is poured in 50mL water, ethyl acetate extracts (50mL × 2), merges organic faciess, satisfy And brine It, anhydrous sodium sulfate drying, filter, concentrate, column chromatography obtain white, amorphous solid compound 28 (32mg, Yield：47.0%).
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.99(s,1H),7.89(s,2H),7.68(s,1H), 7.45-7.39(m,3H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.06-7.03(t,2H),6.41-6.36(m, 2H), 5.25-5.22 (q, J=7.2Hz, 1H), 4.45-4.40 (q, 1H), 4.30-4.24 (m, 1H), 4.15-4.11 (m, 2H), 3.34 (s, 3H), 3.10-2.98 (m, 2H), 2.95 (s, 3H), 1.58-1.56 (d, J=7.2Hz, 3H)
LC-MS:m/z674.2[M+H]+;
Embodiment 29：
(preparation of compound 29)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with furan -3- boric acid：49.5%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.99(s,1H),7.90(s,1H),7.79(s,1H),7.66 (s,1H),7.62(s,1H),7.47-7.39(m,3H),7.27-7.20(m,4H),7.16-7.13(m,1H),7.08-7.02 (t, 2H), 6.57 (s, 1H), 5.24-5.22 (q, J=5.7Hz, 1H), 4.44-4.39 (t, 1H), 4.28-4.22 (m, 1H), 4.14-4.09 (m, 2H), 3.33 (s, 3H), 3.07-2.96 (m, 2H), 2.95 (s, 3H), 1.58-1.55 (d, J=5.7Hz, 3H)
LC-MS:m/z674.3[M+H]+;
Embodiment 30：
(preparation of compound 30)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with thiophene -2- boric acid：34.7%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.98(s,1H),7.89(s,1H),7.86(s,1H),7.65 (s,1H),7.43-7.39(m,3H),7.28-7.18(m,5H),7.16-7.13(m,1H),7.04-7.01(t,3H),6.98- 6.95 (m, 1H), 5.24-5.21 (q, J=6.9Hz, 1H), 4.45-4.40 (t, 1H), 4.29-4.23 (q, 1H), 4.15-4.10 (m, 2H), 3.32 (s, 3H), 3.05-2.97 (m, 2H), 2.93 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H)
LC-MS:m/z690.3[M+H]+;
Embodiment 31：
(preparation of compound 31)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with thiophene -3- boric acid：40.2%
H NMR(300MHz,CD3OD):8.12(s,1H),7.98(s,1H),7.89(s,2H),7.72(s,1H),7.44- 7.35 (m, 4H), 7.28-7.20 (m, 5H), 7.16-7.14 (m, 1H), 7.08-7.03 (t, 3H), 5.24-5.22 (q, J= 7.2Hz,1H),4.45-4.40(t,1H),4.29-4.24(q,1H),4.16-4.08(m,2H),3.34(s,3H),3.10- 2.94 (m, 2H), 2.92 (s, 3H), 1.58-1.56 (d, J=7.2.Hz, 3H)
LC-MS:m/z690.1[M+H]+;
Embodiment 32：
(preparation of compound 32)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with pyridine -3- boric acid：45.5%
H NMR(300MHz,CD3OD):δ8.69(s,1H),8.33(s,1H),8.14(s,1H),8.10(s,1H), 7.98-7.89(m,4H),7.61-7.51(m,1H),7.41-7.35(m,3H),7.28-7.13(m,5H),7.07-7.01(t, 2H), 5.23-5.21 (q, J=7.2Hz, 1H), 4.46-4.41 (m, 1H), 4.34-4.28 (m, 1H), 4.20-4.15 (m, 2H), 3.32 (s, 3H), 3.06-3.00 (m, 2H), 2.93 (s, 3H), 1.57-1.54 (d, J=7.2Hz, 3H);
LC-MS:m/z685.3[M+H]+
Embodiment 33：
(preparation of compound 33)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with pyridine -4- boric acid：50.6%
H NMR(300MHz,CD3OD):δ8.43(s,1H),8.41(s,1H),8.23(s,1H),8.12(s,1H),8.00 (s,1H),7.98(s,1H),7.90(s,1H),7.59(s,1H),7.57(s,1H),7.45-7.40(m,2H),7.28-7.20 (m, 4H), 7.16-7.14 (m, 1H), 7.09-7.03 (t, 3H), 5.24-5.22 (q, J=7.2Hz, 1H), 4.45-4.40 (t, 1H),4.34-4.29(m,1H),4.21-4.16(m,2H),3.34(s,3H),3.06-2.98(m,2H),2.95(s,3H), (1.58-1.55 d, J=7.2Hz, 3H);
LC-MS:m/z685.3[M+H]+
Embodiment 34：
(preparation of compound 34)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with phenylboric acid：60.5%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.98(s,2H),7.90(s,1H),7.79(s,1H), 7.50-7.40 (m, 4H), 7.33-7.13 (m, 8H), 7.09-7.03 (t, 3H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.46-4.41(t,1H),4.31-4.25(m,1H),4.18-4.13(m,2H),3.34(s,3H),3.08-2.97(m,2H), 2.95 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H);
LC-MS:m/z684.2[M+H]+
Embodiment 35：
(preparation of compound 35)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 1- naphthalene boronic acids：45.5%
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.09(m,1H),7.98(s,1H),7.90(s,2H), 7.87-7.84(m,2H),7.78-7.75(d,2H),7.71(s,1H),7.45-7.36(m,5H),7.29-7.20(m,4H), 7.16-7.13 (d, 1H), 7.04-6.99 (m, 2H), 5.22-5.19 (q, J=7.2Hz, 1H), 4.49-4.48 (q, 1H), 4.38-4.35(m,1H),4.26-4.21(m,2H),4.09-4.06(m,1H),3.29(s,3H),3.07-3.01(m,2H), 2.89 (s, 3H), 1.55-1.52 (d, J=7.2Hz, 3H)
LC-MS:m/z734.3[M+H]+;
Embodiment 36：
(preparation of compound 36)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2- naphthalene boronic acids：41.9%
H NMR(300MHz,CD3OD):δ8.14-8.10(d,2H),7.98-7.89(m,4H),7.82-7.77(m,3H), 7.65-7.63(d,1H),7.44-7.39(m,4H),7.30-7.21(m,5H),7.16-7.14(m,1H),7.08-7.03(t, 2H), 5.24-5.22 (q, J=7.2Hz, 1H), 4.46 (m, 1H), 4.32 (m, 1H), 4.20-4.17 (m, 2H), 3.31 (s, 3H), 3.07-3.00 (m, 2H), 2.93 (s, 3H), 1.58-1.55 (d, J=7.2Hz, 3H);
LC-MS:m/z734.4[M+H]+
Embodiment 37：
(preparation of compound 37)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2- hydroxyl phenylboric acid：45.5%
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.11(s,1H),7.98(s,1H),7.90(s,2H), 7.44-7.39(m,3H),7.28-7.25(m,4H),7.22-7.20(m,1H),7.07-6.97(m,3H),6.83-6.76(t, 2H), 5.23-5.21 (q, J=6.9Hz, 1H), 4.47-4.42 (t, 1H), 4.32-4.26 (m, 1H), 4.15-4.12 (m, 2H), 3.32 (s, 3H), 3.06-2.97 (m, 2H), 2.93 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H);
LC-MS:m/z700.2[M+H]+
Embodiment 38：
(preparation of compound 38)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 3- hydroxyl phenylboric acid：42.7%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.98(s,1H),7.91(s,1H),7.89(s,1H),7.73 (s,1H),7.44-7.39(m,2H),7.28-7.20(m,4H),7.16-7.02(m,4H),6.96-6.94(d,1H),6.90 (s, 1H), 6.63-6.59 (d, 1H), 5.24-5.22 (q, J=7.2Hz, 1H), 4.46-4.40 (t, 1H), 4.30-4.24 (m, 1H), 4.14-4.11 (m, 2H), 3.32 (s, 3H), 3.05-2.98 (m, 2H), 2.94 (s, 3H), 1.58-1.55 (d, J= 7.2Hz,3H);
LC-MS:m/z700.2[M+H]+
Embodiment 39：
(preparation of compound 39)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 4- hydroxyl phenylboric acid：50.5%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.99(s,1H),7.89(s,1H),7.83(s,1H),7.67 (s,1H),7.43-7.39(m,2H),7.31-7.19(m,6H),7.13-7.08(m,1H),7.07-7.01(t,2H),6.76- 6.73 (d, 2H), 5.23-5.21 (q, J=6.9Hz, 1H), 4.45-4.40 (t, 1H), 4.28-4.22 (m, 1H), 4.15-4.10 (m, 2H), 3.32 (s, 3H), 3.04-2.96 (m, 2H), 2.94 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H);
LC-MS:m/z700.2[M+H]+
Embodiment 40：
(preparation of compound 40)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2- methoxyphenylboronic acid：45.5%
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.13(s,1H),7.98(s,1H),7.90(s,1H),7.87 (s, 1H), 7.45-7.48 (d, 1H), 7.44-7.40 (m, 2H), 7.28-6.88 (m, 10H), 5.24-5.22 (q, J=7.2Hz, 1H),4.47-4.42(t,1H),4.31-4.26(m,1H),4.15-4.12(m,2H),3.33(s,3H),3.08-2.97(m, 2H), 2.93 (s, 3H), 1.58-1.55 (d, J=7.2Hz, 3H);
LC-MS:m/z714.3[M+H]+
Embodiment 41：
(preparation of compound 41)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 3- ethoxybenzene boric acid：55.2%
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.98(s,1H),7.96(s,1H),7.89(s,1H),7.77 (s, 1H), 7.45-7.40 (m, 1H), 7.28-7.03 (m, 10H), 6.75-6.71 (d, 1H), 5.26-5.22 (q, J= 14.4Hz, 1H), 4.45-4.12 (m, 4H), 4.06-4.00 (q, J=6.9Hz, 2H), 3.33 (s, 3H), 3.07-2.97 (m, 2H), 2.96 (s, 3H), 1.58-1.54 (d, J=14.4Hz, 3H);(1.40-1.35 t, J=6.9Hz, 3H);
LC-MS:m/z728.2[M+H]+
Embodiment 42：
(preparation of compound 42)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 4- methoxyphenylboronic acid：65.5%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.98(s,1H),7.89(s,1H),7.87(s,1H),7.70 (s,1H),7.44-7.38(m,4H),7.28-7.20(m,4H),7.16-7.13(d,2H),7.08-7.02(t,3H),6.89- 6.85 (d, 2H), 5.24-5.22 (q, J=6.0Hz, 1H), 4.45-4.11 (m, 4H), 3.77 (s, 3H), 3.33 (s, 3H), 3.05-2.96 (m, 2H), 2.94 (s, 3H), 1.58-1.55 (d, J=6.0Hz, 3H);
LC-MS:m/z714.3[M+H]+
Embodiment 43：
(preparation of compound 43)
According to synthetic route 3,2,6- dimethoxyphenylboronic is used to replace FURAN-2-BORONIC ACID, yield：35.8%
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.10(s,1H),7.98(s,1H),7.93(s,1H),7.90 (s,1H),7.44-7.40(m,2H),7.28-7.12(m,6H),7.04-7.02(t,2H),6.69-6.66(d,2H),5.24- 5.22 (q, J=7.2Hz, 1H), 4.47-4.45 (m, 1H), 4.31-4.25 (m, 1H), 4.15-4.13 (m, 2H), 3.81 (s, 6H), 3.33 (s, 3H), 3.06-2.97 (m, 2H), 2.96 (s, 3H), 1.58-1.56 (d, J=7.2Hz, 3H);
LC-MS:m/z744.3[M+H]+
Embodiment 44：
(preparation of compound 44)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2- fluorobenzoic boric acid：75.8%
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.05(s,1H),7.98(s,1H),7.90(s,1H), 7.62-7.57 (m, 1H), 7.43-7.37 (m, 2H), 7.28-7.02 (m, 10H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.47-4.42(m,1H),4.33-4.28(m,1H),4.20-4.15(m,2H),3.33(s,3H),3.06-3.00(m,2H), 2.96 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H);
LC-MS:m/z702.2[M+H]+
Embodiment 45：
(preparation of compound 45)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 3- fluorobenzoic boric acid：89.5%
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.05(s,1H),7.98(s,1H),7.90(s,1H),7.82 (s,1H),7.44-7.39(m,2H),7.31-7.19(m,7H),7.16-7.14(m,1H),7.08-7.01(t,2H),6.91- 6.88 (s, 1H), 5.25-5.22 (q, J=7.2Hz, 1H), 4.46-4.40 (m, 1H), 4.31-4.25 (m, 1H), 4.16-4.13 (m, 2H), 3.34 (s, 3H), 3.06-3.00 (m, 2H), 2.97 (s, 3H), 1.58-1.56 (d, J=7.2Hz, 3H);
LC-MS:m/z702.2[M+H]+
Embodiment 46：
(preparation of compound 46)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 4- fluorobenzoic boric acid：75.8%
H NMR(300MHz,CD3OD):δ8.13(s,1H),7.98(s,1H),7.94(s,1H),7.90(s,1H),7.76 (s,1H),7.52-7.40(m,4H),7.28-7.20(m,4H),7.16-7.14(m,1H),7.09-7.01(t,2H),5.24- 5.22 (q, J=7.2Hz, 1H), 4.45-4.40 (m, 1H), 4.31-4.25 (m, 1H), 4.15-4.12 (m, 2H), 3.34 (s, 3H), 3.08-2.97 (m, 2H), 2.96 (s, 3H), 1.58-1.56 (d, J=7.2Hz, 3H);
LC-MS:m/z702.2[M+H]+
Embodiment 47：
(preparation of compound 47)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2,4 difluorobenzene boric acid：76.4%
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.02(s,1H),7.99(s,1H),7.90(s,1H),7.83 (s,1H),7.62-7.60(m,1H),7.44-7.39(m,2H),7.28-7.20(m,4H),7.16-7.14(d,1H),7.13- 6.94 (m, 4H), 5.24-5.22 (q, J=6.9Hz, 1H), 4.44-4.14 (m, 4H), 3.33 (s, 3H), 3.06-3.00 (m, 2H), 2.98 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H);
LC-MS:m/z720.1[M+H]+
Embodiment 48：
(preparation of compound 48)
According to synthetic route 3, replace FURAN-2-BORONIC ACID, yield with 2,4 difluorobenzene boric acid：45.9%
H NMR(300MHz,CD3OD):δ8.21(s,1H),8.14(s,1H),8.07(s,2H),8.01(s,1H),7.98 (s,1H),7.73(s,1H),7.44-7.39(m,2H),7.28-7.20(m,4H),7.16-7.14(d,1H),7.07-7.01 (t, 2H), 5.24-5.21 (q, J=6.9Hz, 1H), 4.45-4.29 (m, 2H), 4.20-4.17 (m, 2H), 3.33 (s, 3H), 3.06-3.00 (m, 2H), 2.98 (s, 3H), 1.57-1.55 (d, J=6.9Hz, 3H);
LC-MS:m/z820.2[M+H]+
Embodiment 49：
(preparation of compound 49)
According to synthetic route 1, replaced with 3- (R)-methylbenzylamine formoxyl -5-N- Methanesulfomide yl benzoic acid 3- [(R) - Methyl 4-Fluorobenzylamine formoxyl] -5-N- Methanesulfomide yl benzoic acid, yield：85.5%
H NMR(300MHz,CD3OD):δ8.15(s,1H),8.11(s,1H),7.99(s,1H),7.88(s,1H),7.85 (s,1H),7.42-7.39(m,2H),7.35-7.31(t,2H),7.28-7.20(m,5H),7.16-7.13(d,1H),5.25- 5.23 (q, J=7.2Hz, 1H), 4.41-4.38 (m, 1H), 4.32-4.21 (m, 3H), 4.15-4.12 (m, 2H), 3.35 (s, 3H), 3.05-2.95 (m, 2H), 2.94 (s, 3H), 1.59-1.57 (d, J=7.2Hz, 3H), 1.33-1.28 (t, 3H);
LC-MS:m/z662.2[M+H]+
Embodiment 50：
According to synthetic route 4, yield：25.5%
Epoxide Ib (52mg, 0.2mmol) and pyrazoles -4- ethyl ester (42mg, 0.3mmol) are dissolved in 5mL DMF, plus Enter potassium carbonate (42mg, 0.3mmol).100 DEG C of microwave reaction, 1 hour.Add 50mL water in system, ethyl acetate extracts (50mL × 2), merge organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrate, it is solid that column chromatography obtains white Body Ic (65mg, yield：81.2%, fusing point：102-104℃).Compound Ic (40mg, 0.1mmol) is dissolved in the anhydrous of 10mL In oxolane, add two equivalents triethylamine (40 μ L, 0.2mmol), two equivalents of Deca mesyl chloride (15 μ L, 0.2mmol), two hours are stirred at room temperature.The mesyl chloride of the sterilized amount of Deca methanol, continues stirring half an hour, reclaims molten Agent column chromatography obtains compound Id (39mg, yield：81.3%, fusing point：144-146℃).By compound Id (39mg, 0.08mmol) It is dissolved in 2mL DMF, add the Hydrazoic acid,sodium salt (10mg, 0.16mmol) of 2 equivalents in 60 DEG C of reactions overnight.Add in system Enter 50mL water, ethyl acetate extracts (50mL × 2), merge organic faciess, saturated common salt water washing, anhydrous sodium sulfate drying, filter, Concentrate, column chromatography obtains white solid Ie (30mg, yield：88.2%, fusing point：118-120℃).By compound Ie (30mg, 0.07mmol) it is dissolved in 4mL dichloromethane, add 1mL trifluoroacetic acid, room temperature reaction 2h in system.Concentrate, the amine obtaining is not The treated next step that is directly entered is reacted.Sour (30mg, 0.08mmol) is dissolved in 2mL DMF, addition EDCI (20mg, 0.10mmol), HOBt (10mg, 0.07mmol), is stirred at room temperature 10min.The amine that upper step is obtained is dissolved in the DMF of 2mL, adds DIPEA (50 μ l, 0.3mmol), is added dropwise to above-mentioned reaction system, then the lower 70 DEG C of reaction 15min of microwave condition.To system Middle addition 30mL water, ethyl acetate extracts (50mL × 2), merges organic faciess, Diluted Acid Washing (25mL × 2), saturated sodium bicarbonate is washed (25mL × 2), saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrates, column chromatography obtains compound as white solid If (42mg, yield：85.7%, fusing point：157-159℃).By compound If (42mg, 0.06mmol) be dissolved in 20mL (ethanol/ Water=3/1, volume ratio) mixed solvent in, sequentially add the ammonium chloride (30mg, 0.6mmol) of 10 equivalents, 10 equivalents Zinc powder (40mg, 0.6mmol).It is stirred overnight at room temperature.Kieselguhr filters, absolute ethanol washing, filtrate decompression direct post after reclaiming Chromatography.Obtain compound 50 (32mg.Yield：82.0%).
H NMR(300MHz,CD3OD):δ8.20(s,1H),8.08(s,1H),7.98(s,1H),7.88(s,1H),7.85 (s,1H),7.44-7.39(m,2H),7.23-7.13(m,4H),7.11-7.08(q,1H),7.05-7.02(t,3H),5.24- 5.21 (q, J=7.2Hz, 1H), 4.39-4.33 (m, 2H), 4.28-4.23 (q, J=6.9Hz, 2H), 4.16-4.13 (m, 1H), 3.51-3.47 (s, 1H), 3.33 (s, 3H), 3.04-2.97 (m, 2H), 2.94 (s, 3H), 1.57-1.55 (d, J=7.2Hz, 3H);(1.33-1.28 t, J=6.9Hz, 3H)
LC-MS:m/z679.2[M+H]+;
Embodiment 51：
According to synthetic route 4, with embodiment 50 with simply with 3- (R)-methylbenzylamine formoxyl -5-N- methylsulfonyl amido Benzoic acid replaces 3- [(R)-methyl 4-Fluorobenzylamine formoxyl] -5-N- Methanesulfomide yl benzoic acid, yield：30.9%
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.97(s,1H),7.89(s,1H),7.88(s,1H), 7.41-7.21 (m, 9H), 6.90-6.88 (d, 1H), 5.32-5.30 (q, 1H), 4.72 (q, J=6.6.Hz, 1H), 4.48- 4.45(q,1H),4.30-4.23(m,4H),4.05-4.01(m,1H),3.51-3.48(s,1H),3.34(s,3H),3.02- 2.88 (s, 3H), 2.85 (s, 3H), 1.64-1.62 (d, J=6.6Hz, 3H);(1.35-1.30 t, J=7.2Hz, 3H)
LC-MS:m/z661.1[M+H]+;
Embodiment 52：
According to synthetic route 4, same with embodiment 51, Compound Ig per (42mg, 0.06mmol) is dissolved in the amine of 10mL In methanol solution, 120 DEG C of tube sealing reacts overnight.Water pump recovered under reduced pressure excess of solvent after reaction completely.Crude product is not purified directly Enter the zinc powder reduction of lower step.Column chromatography obtains product 53 (29mg, yield：25.6%).
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.10(s,1H),7.99(s,1H),7.92(s,1H),7.86 (s,1H),7.42-7.40(d,2H),7.36-7.31(t,2H),7.27-7.20(m,5H),7.16-7.14(d,1H),5.25- 5.23 (q, J=6.9Hz 1H), 4.41-4.33 (m, 2H), 4.16-4.11 (d, 1H), 3.49-3.46 (m, 1H), 3.35 (s, 3H), 3.11-2.90 (m, 2H), 2.98 (s, 3H), 1.59-1.57 (d, J=6.9Hz, 3H)
LC-MS:m/z 632.3[M+H]+;
Embodiment 53：
According to synthetic route 4, same with embodiment 51, Compound Ig per (42mg, 0.06mmol) is dissolved in 10mL (THF/ EtOH/H2O=2/2/1) in solution, add the sodium hydroxide (5mg, 0.12mmol) of two equivalents, be stirred overnight at room temperature.Will be anti- Liquid pH value is answered to be adjusted to 4, ethyl acetate extracts, saturated common salt water washing, anhydrous sodium sulfate drying, recycling design, the thick product of gained Thing is not purified to be directly used in the next step.Upper step gained acid is dissolved in 2mL DMF, addition EDCI (20mg, 0.10mmol), HOBt (10mg, 0.08mmol), methylamine hydrochloride (14mg, 0.2mmol) is stirred at room temperature 10min.Upper step is obtained To amine be dissolved in the DMF of 2mL, add DIPEA (50 μ L, 0.3mmol), be added dropwise to above-mentioned reaction system, then micro-strip The lower 70 DEG C of reaction 15min of part.Add 50mL water in system, ethyl acetate extracts (50mL × 2), merges organic faciess, Diluted Acid Washing Wash (25mL × 2), saturated sodium bicarbonate is washed (25mL × 2), saturated common salt water washing, anhydrous sodium sulfate drying, filter, after concentration Directly carry out zinc powder reduction.Column chromatography obtains compound as white solid 53 (24mg, yield：22.9%).
H NMR(300MHz,CD3OD):δ8.14(s,1H),8.02-7.98(d,2H),7.88-7.84(d,2H),7.41- 7.11 (m, 10H), 5.24-5.22 (q, J=6.6Hz 1H), 4.59-4.37 (m, 2H), 4.21-4.16 (m, 1H), 3.58- 3.50 (m, 1H), 3.33 (s, 3H), 3.11-2.96 (m, 2H), 3.06 (s, 3H), 2.98 (s, 3H), 1.58-1.56 (d, J= 6.6Hz,3H)
LC-MS:m/z646.3[M+H]+;
Embodiment 54：
(preparation of compound 54)
According to synthetic route 4, replace methylamine hydrochloride with the hydrochlorate of ethamine.Yield：24.5%
H NMR(300MHz,CD3OD):δ8.10(s,1H),8.07(s,1H),7.98(s,1H),7.90(s,1H),7.85 (s,1H),7.41-7.39(d,2H),7.35-7.30(t,2H),7.26-7.16(m,5H),7.15-7.13(d,1H),5.25- 5.22 (q, J=6.9Hz 1H), 4.41-4.35 (m, 2H), 4.19-4.12 (m, 1H), 3.36 (m, 5H), 3.10-3.04 (m, 2H), 2.90 (s, 3H), 1.58-1.56 (d, J=6.9Hz, 3H), 1.19-1.14 (t, 3H)
LC-MS:m/z660.2[M+H]+;
Embodiment 55：
(preparation of compound 55)
According to synthetic route 4, replace methylamine hydrochloride with the hydrochlorate of dimethylamine.Yield：20.5%
H NMR(300MHz,CD3OD):δ8.12(s,2H),7.98(s,1H),7.85(s,2H),7.42-7.39(d, 2H), 7.34-7.29 (t, 2H), 7.26-7.18 (m, 5H), 7.15-7.13 (d, 1H), 5.23-5.21 (q, J=6.6Hz 1H), 4.53-4.42(m,3H),3.83-3.81(m,1H),3.32(m,5H),3.13(s,3H),3.06(s,3H),3.10-3.04(m, 2H), 2.93 (s, 3H), 1.59-1.57 (d, J=6.6Hz, 3H),
LC-MS:m/z660.3[M+H]+;
Embodiment 56：
(preparation of compound 56)
According to synthetic route 4, replace methylamine hydrochloride with diethylamine.Yield：19.7%
H NMR(300MHz,CD3OD):δ8.12(s,1H),8.03(s,1H),7.91(s,1H),7.85(s,1H), 7.42-7.10 (m, 10H), 5.25-5.21 (q, J=6.6Hz 1H), 4.59-4.35 (m, 3H), 3.80-3.76 (s, 1H), 3.51 (s, 4H), 3.33 (s, 3H), 3.17-3.04 (m, 2H), 2.96 (s, 3H), 1.59-1.57 (d, J=6.6Hz, 3H), 1.22(s,6H),
LC-MS:m/z688.2[M+H]+;
Embodiment 57：
(preparation of compound 57)
According to synthetic route 4, replace methylamine hydrochloride with di-n-propylamine.Yield：20.8%
H NMR(300MHz,CD3OD):δ8.08(s,1H),8.01(s,1H),7.97(s,1H),7.86(s,1H),7.73 (s,2H),7.42-7.39(d,2H),7.35-7.30(t,2H),7.25-7.18(m,5H),7.15-7.13(d,1H),5.24- 5.22 (q, J=6.6Hz 1H), 4.40-4.33 (m, 2H), 4.20-4.13 (m, 1H), 3.52-3.50 (m, 1H), 3.48 (m, 4H), 3.42 (s, 3H), 3.07-2.94 (m, 2H), 2.94 (s, 3H), 1.66-1.62 (m, 4H), 1.59-1.57 (d, J= 6.6Hz,3H),0.90-0.89(m,6H),
LC-MS:m/z716.3[M+H]+;
Embodiment 58：
(preparation of compound 58)
According to synthetic route 2,3,5- thebaine is used to replace ammonium chloride.Yield：70.5%
H NMR(300MHz,CD3OD):δ8.12(s,1H),7.98(s,1H),7.96(s,1H),7.89(s,1H),7.71 (s,2H),7.44-7.39(m,2H),7.27-7.20(m,4H),7.16-7.12(d,1H),7.08-7.02(t,2H),5.24- 5.22 (q, J=6.9Hz 1H), 4.41-4.36 (m, 1H), 4.29-4.24 (m, 1H), 4.18-4.09 (m, 2H), 3.58-3.54 (m,2H),3.34(s,3H),3.06-2.94(m,2H),3.01(s,2H),2.84(s,2H),2.98(s,3H),1.58-1.55 (d, J=6.9Hz, 3H), 1.16-1.14 (m, 6H),
LC-MS:m/z749.3[M+H]+;
Embodiment 59：
(preparation of compound 59)
According to synthetic route 2, use 2,3,4,5- tetrahydrochysene -1H- benzo [D] azatropylidenes（Hydrochlorate）Replace ammonium chloride.Yield： 46.5%
H NMR(300MHz,CD3OD):δ8.14(s,1H),7.99(s,2H),7.92(s,1H),7.71(s,2H), 7.44-7.39(m,2H),7.28-7.21(m,4H),7.17-7.12(m,5H),7.04-7.02(t,2H),5.24-5.22(q,J =7.2Hz 1H), 4.40-4.38 (m, 1H), 4.32-4.26 (m, 1H), 4.17-4.14 (m, 2H), 3.80-3.78 (m, 4H), 3.34(s,3H),3.06-2.94(m,2H),3.01(s,2H),2.99-2.98(m,4H),2.94(s,3H),1.57-1.55(d, J=7.2Hz, 3H)
LC-MS:m/z781.3[M+H]+;
Embodiment 60：
(preparation of compound 60)
According to synthetic route 2, replace 3- [(R)-methyl 4-Fluorobenzylamine first with 3- dipropyl amine formyl -5- ar-Toluic acid Acyl group] -5-N- methanesulfonamido benzoic acid, yield：70.5%
H NMR(300MHz,CD3OD):δ8.00(s,1H),7.74(s,2H),7.65(s,1H),7.48(s,2H),7.31 (s,2H),7.27-7.20(m,4H),7.16-7.14(t,1H),4.41-4.11(m,4H),3.71-3.67(t,2H),3.62- 3.59(t,2H),3.48-3.43(t,2H),3.19-3.14(t,2H),3.04-2.96(m,2H),2.42(s,3H),1.78- 1.49(m,10H),1.01-0.96(t,3H),0.73-0.69(t,3H),
LC-MS:m/z602.4[M+H]+;
Embodiment 61：
(preparation of compound 61)
According to synthetic route 2, with N '-[(R) -2- (methoxy) pyrrolylcarbonyl -5- ar-Toluic acid replaces 3- [(R)-methyl 4-Fluorobenzylamine formoxyl] -5-N- methanesulfonamido benzoic acid, yield：73.8%
H NMR(300MHz,CD3OD):δ8.00(s,1H),7.74(s,2H),7.66(s,1H),7.62(s,1H),7.44 (s,2H),7.27-7.14(m,5H),4.38-4.12(m,4H),3.71-3.67(t,2H),3.62-3.58(m,4H),3.39 (s,3H),3.06-2.98(m,3H),2.42(s,3H),2.08-1.96(m,4H),1.78(s,4H),1.60(s,4H),
LC-MS:m/z616.4[M+H]+;
Embodiment 62：
(preparation of compound 62)
According to synthetic route 2, replace 3- [(R)-methyl 4-Fluorobenzylamine formoxyl] -5- with 3- diethylamine formylbenzoate N- methylsulfonyl ammonia
Yl benzoic acid, yield：80.2%
H NMR(300MHz,CD3OD):δ8.10(s,1H),7.85(s,1H),7.74(s,1H),7.52(s,1H), 7.27-7.14(m,5H),4.31-4.12(m,4H),3.70-3.67(t,2H),3.62-3.54(m,4H),3.28-3.24(m, 2H),3.04-2.98(m,2H),1.77(s,4H),1.59(s,4H),1.27-1.23(t,3H),1.22-1.08(t,3H),
LC-MS:m/z560.3[M+H]+;
Embodiment 63：
(preparation of compound 63)
According to synthetic route 2, replace 3- [(R)-first with 3- [(R)-methyl 4-Fluorobenzylamine formoxyl] -5- nitrobenzoic acid Base 4-Fluorobenzylamine formoxyl] -5-N- methanesulfonamido benzoic acid, yield：78.4%
H NMR(300MHz,CD3OD):δ8.78(s,1H),8.68(s,1H),8.56(s,1H),7.99(s,1H),7.73 (s, 1H), 7.44-7.40 (m, 2H), 7.27-7.02 (m, 7H), 5.25-5.23 (q, J=7.2Hz 1H), 4.11-4.14 (m, 4H),3.70-3.66(t,2H),3.60-3.56(t,2H),3.08-2.95(m,2H),1.76(s,4H),1.59(s,4H), (1.59-1.56 d, J=7.2Hz 3H),
LC-MS:m/z671.3[M+H]+;
Embodiment 66：
(preparation of compound 66)
According to synthetic route 2, [(R)-methyl is to fluorine benzyl to replace 3- with 3- [(R)-methyl 4-Fluorobenzylamine formoxyl] benzoic acid Amine formyl] -5-N- methanesulfonamido benzoic acid yield：73.9%
H NMR(300MHz,CD3OD):δ8.22(s,1H),7.98(s,1H),7.96-7.93(d,1H),7.89-7.87 (d,1H),7.72(s,1H),7.53-7.48(t,1H),7.43-7.39(m,2H),7.27-7.19(m,4H),7.15-7.11 (m, 1H), 7.07-7.01 (t, 2H), 5.23-5.21 (q, J=6.6Hz, 1H), 4.43-4.38 (m, 1H), 4.29-4.24 (m, 1H),4.17-4.11(m,2H),3.68-3.64(m,2H),3.60-3.56(m,2H),3.06-2.98(m,2H),1.75(s, 4H), 1.56 (s, 4H), 1.56-1.54 (d, J=6.6Hz, 3H),
LC-MS:m/z 626.4[M+H]+;
Embodiment 67：
(preparation of compound 67)
According to synthetic route 2, replace 3- [(R)-methyl pair with 3- isobutyl amine formyl -5-N- methanesulfonamido benzoic acid Flunamine formoxyl] -5-N- Methanesulfomide yl benzoic acid, yield：74.7%
H NMR(300MHz,CD3OD):δ8.13(s,1H),δ8.00(s,1H),7.98(s,1H),7.90(s,1H), 7.74(s,1H),7.28-7.21(m,4H),7.16-7.13(m,1H),4.42-4.37(t,1H),4.31-4.25(t,1H), 4.19-4.13(m,2H),3.71-3.66(m,2H),3.62-3.58(m,2H),3.35(s,3H),3.22-3.20(d,2H), 3.07-2.97(m,2H),2.95(s,3H),2.20-1.91(m,1H),1.77(s,4H),1.59(s,4H),0.98-0.96(d, 6H),
LC-MS:m/z 667.4[M+H]+.
EXPERIMENTAL EXAMPLE：Hydroxyethyl pyrazole class compound or the determination of activity of aminoethyl pyrazole compound：
(1) acquisition of beta-secretase albumen：
Using beta-secretase extracellular region protein, (plasmid origin is in Stefan doctor Masure for experiment（List of references： Protein Expression and Purification,2002,26:139-148）), 1-454 aminoacid (hereinafter referred BACE1), be secretory protein, by this albumen gene constructed in pFastBacTMIn 1 carrier (purchased from invitrogen), C-terminal adds Plus 6 histidine.Pass through(Invitrogen) baculovirus expression system obtains destination protein.
First by recombinant plasmid transformed to escherichia coli DH10BacTMIn competent cell (purchased from invitrogen), wherein Contain baculovirus shuttle vector, i.e. rod granule, picking contains pFastBac after indexingTMThe restructuring gram of middle genes of interest section Grand, cultivate and extract restructuring rod granule.Restructuring rod granule is transfected the Sf9 insect cell (purchase of complete TNM-FH culture medium culturing From invitrogen), culture harvested the culture medium containing first generation virus after 3-5 days, continue transfection obtain respectively the second filial generation, the Three generations's virus.Using the culture medium infection Express containing third generation virusThe High of serum-free medium culture FiveTMInsect cell (purchased from invitrogen), express express target protein, collect the culture medium containing destination protein after 72 hours, Need the purification of next step.By the culture medium containing destination protein (25-30mL) 1L level pad (20mM sodium phosphate (sodium phosphate) pH8.0,300mM NaCl, 10mM imidazoles (imidazole)) in dialysed overnight, 12000rpm from The heart 15 minutes, is repeated once, and collects supernatant.By supernatant loading to the metal ion-chelant chromatography through equilibration buffer Post (1mL HiTrapTMChelating HP column (GE Healthcare, Life Sciences), in clean foreign protein Adopt elution buffer (20mM sodium phosphate pH8.0,300mM NaCl, 250mM imidazole) eluting afterwards Obtaining destination protein is beta-secretase extracellular region (BACE1), finally, through 12% polyacrylamide gel electrophoresis (SDS-PAGE) point The albumen obtaining from purification Identification, purity is 90% about.
(2) determination of activity
Experiment uses DABCYL-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS (Synpep, lower letter Claim BS) as substrate, survey reaction of living and carry out in 384 hole microwell plates, reaction volume is 25 μ l, containing 100mM Sodium Acetate Trihydrate (sodium acetate) (pH 4.0)), 20 μM of BS, 50nM BACE-1,2 μ l dimethyl sulfoxide (DMSO) or be dissolved in treating of DMSO Survey compound (50 μ g/ml).Room temperature reaction, in multi-functional read plate instrument EnvisionTM(PerkinElmer) detection fluorescence letter in Number, excite and be respectively 355nm and 460nm with absorbing wavelength, record and be calculated enzyme reaction initial stage unit interval fluorescence signal Increment, enzyme reaction initial velocity is represented with this, with testing compound to beta-secretase activity suppression ratio represent this compound Activity, wherein, suppression ratio (inhibition) calculate sees formula 1.
% Inhibition = ( 1 - v compound v DMSO ) × 100 % Formula 1
υ in formula 1compoundAnd υDMSORepresent the enzyme reaction initial velocity containing compound and DMSO respectively.
If compound to be detected suppression ratio in 20 μ g/mL is more than 50%, further dilutes 7-9 concentration, calculate IC50, the concentration of compound when that is, enzyme initial velocity is suppressed half.Positive inhibitor is that (OM99-2 is with eight to compound OM99-2 Based on peptide [glutamic acid-valine-agedoite-IAA-glutamate-phenylalanine] , the compound of Leu-Ala peptide bond is instead of with the isostere hydroxyalkyl vinyl base of a transitive state).
Gained part of compounds activity is as shown in table 1：
Table 1
By screening on a molecular scale, discovery above-claimed cpd shows has preferable activity to beta-secretase, For further research be likely to be of improve cognitive function, simultaneously alleviate AD progression of disease original new drug provide valuable letter Breath.

Claims (10)

1. a kind of hydroxyethyl pyrazole class compound being represented by formula I or aminoethyl pyrazole compound or it is pharmaceutically acceptable Salt：
Wherein,
Z is OH or NH2；
R1ForWherein, A is halogen；X is NH；Y is carbonyl；R7For C1-C6Straight chained alkyl or C3- C6Branched alkyl；
R2ForWherein, R8And R9Identical or different, it is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkane Base or C3-C6Cycloalkyl；
R3For phenyl；
R4And R6Identical or different, it is each independently H, C1-C6Straight chained alkyl, C3-C6Branched alkyl or C1-C6Alkoxy carbonyl；
R5For H, carboxyl, C1-C6Straight chained alkyl, C3-C6Branched alkyl, C1-C6Alkoxy carbonyl, hydroxyl C1-C6Alkylidene, replacement Or unsubstituted amino carbonyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted containing 1-3 heteroatomic 5-7 First saturated heterocyclyl carbonyl or containing 1-3 heteroatomic 5-11 membered unsaturated heterocycle base；
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Straight chain alkane Base, C3-C6Branched alkyl, C3-C6Cycloalkyl, C1-C6Alkoxyl, C1-C6Alkoxy C1-C6Alkylidene, hydroxyl C1-C6Alkylidene, Phenyl and C1-C3The benzyl that alkoxyl replaces；
The substituent group of described substituted phenyl is hydroxyl, C1-C6The C of alkoxyl, halogen or halogen substiuted1-C3Alkyl；
Described hetero atom is N, S or O；
The described substituted substituent group containing 1-3 heteroatomic 5-7 unit saturated heterocyclyl carbonyl is C1-C3Alkyl or C1-C6Alkane Epoxide C1-C6Alkylidene.
2. hydroxyethyl pyrazole class compound according to claim 1 or aminoethyl pyrazole compound or its pharmaceutically can connect The salt being subject to, wherein,
Z is OH；
R1ForWherein, A is F, Cl or Br；X is NH；Y is carbonyl；R7For C1-C6 Straight chained alkyl or C3-C6Branched alkyl；
R2ForWherein, R8And R9Identical or different, it is each independently H, C1-C6Straight chained alkyl or C3-C6Branched alkane Base.
3. hydroxyethyl pyrazole class compound according to claim 2 or aminoethyl pyrazole compound or its pharmaceutically can connect The salt being subject to, wherein,
Z is OH；
R1ForWherein, R7For C1-C4Straight chained alkyl；
R2ForWherein, R8And R9It is H or C simultaneously1-C4Straight chained alkyl；
R4And R6Identical or different, it is each independently H, C1-C4Straight chained alkyl or C1-C4Alkoxy carbonyl；
R5For H, carboxyl, C1-C4Straight chained alkyl, C1-C4Alkoxy carbonyl, hydroxyl C1-C4Alkylidene, substituted or unsubstituted amino Carbonyl, substituted or unsubstituted phenyl, naphthyl, C1-C4Alkoxy C1-C4Alkylidene substituted or unsubstituted pyrrolidinyl carbonyl BasePiperidino carbonylC1-C3The substituted or unsubstituted morpholinyl carbonyl of alkyl Cycloheptyl amino-carbonylBenzocyclohepta amino-carbonylFurylThienylOr pyridine radicalsWherein, described substituted aminocarboxy N atom be selected from one of following groups or Two replacements：C1-C4Straight chained alkyl, C3-C5Cycloalkyl, C1-C4Alkoxyl, C1-C4Alkoxy C1-C4Alkylidene, hydroxyl C1-C4Sub- Alkyl, phenyl and C1-C3The benzyl that alkoxyl replaces；
The substituent group of described substituted phenyl is hydroxyl, C1-C4Alkoxyl, F or trifluoromethyl.
4. hydroxyethyl pyrazole class compound according to claim 1 or aminoethyl pyrazole compound or its pharmaceutically can connect The salt being subject to, wherein,
Z is NH2；
R1ForWherein, X is NH；Y is carbonyl；R7For C1-C6Straight chained alkyl or C3-C6Side chain Alkyl；
R2ForWherein, R8And R9Identical or different, it is each independently H, C1-C6Straight chained alkyl or C3-C6Branched alkane Base；
R4And R6Identical or different, it is each independently C1-C6Alkoxy carbonyl；
R5For C1-C6Alkoxy carbonyl or substituted or unsubstituted amino carbonyl；
Wherein, described substituted aminocarboxy N atom is selected from one or more of following groups and replaces：C1-C6Straight chain alkane Base and C3-C6Branched alkyl.
5. hydroxyethyl pyrazole class compound according to claim 4 or aminoethyl pyrazole compound or its pharmaceutically can connect The salt being subject to, wherein,
Z is NH2；
R1ForWherein, X is NH；Y is carbonyl；R7For C1-C4Straight chained alkyl；
R2ForWherein, R8And R9It is H or C simultaneously1-C4Straight chained alkyl；
R4And R6Identical or different, it is each independently C1-C4Alkoxy carbonyl；
R5For C1-C4Alkoxy carbonyl or substituted or unsubstituted amino carbonyl；
Wherein, described substituted aminocarboxy N atom is by one or more C1-C4Straight chained alkyl replaces.
6. hydroxyethyl pyrazole class compound according to claim 1 or aminoethyl pyrazole compound or its pharmaceutically can connect The salt being subject to, described compound is selected from following compounds：
7. the hydroxyethyl pyrazole class compound according to any one of claim 1～6 or aminoethyl pyrazole compound or Its pharmaceutically acceptable salt is in preparation as the purposes in the medicine of beta-secretase inhibitor.
8. purposes according to claim 7, wherein, the described medicine as beta-secretase inhibitor is used for preventing, delays Or the disease that treatment is caused by the deposition of A β.
9. purposes according to claim 8, wherein, described is Alzheimer by the disease that the deposition of A β causes.
10. a kind of pharmaceutical composition, it comprises the ethoxy any one of selected from claim 1～6 of therapeutically effective amount One or more of pyrazole compound or aminoethyl pyrazole compound or its pharmaceutically acceptable salt, and optionally One or more excipient allowing on pharmaceuticss.
CN201210211667.7A 2012-06-25 2012-06-25 Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof Expired - Fee Related CN103508957B (en)

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WO2005030709A1 (en) * 2003-10-01 2005-04-07 Lg Life Sciences Ltd. Novel sulfone amide derivatives capable of inhibiting bace
CN1735592A (en) * 2002-12-05 2006-02-15 葛兰素集团有限公司 Hydroxyethylamine derivatives for the treatment of alzheimer's disease
WO2011086098A1 (en) * 2010-01-15 2011-07-21 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Novel substituted bicyclic triazole derivatives as gamma secretase modulators

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WO2005030709A1 (en) * 2003-10-01 2005-04-07 Lg Life Sciences Ltd. Novel sulfone amide derivatives capable of inhibiting bace
WO2011086098A1 (en) * 2010-01-15 2011-07-21 Ortho-Mcneil-Janssen Pharmaceuticals, Inc Novel substituted bicyclic triazole derivatives as gamma secretase modulators

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