CN103508957A - 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 PDFInfo
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- CN103508957A CN103508957A CN201210211667.7A CN201210211667A CN103508957A CN 103508957 A CN103508957 A CN 103508957A CN 201210211667 A CN201210211667 A CN 201210211667A CN 103508957 A CN103508957 A CN 103508957A
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- 0 C**C(*1CC1)C1=CCCC=C1 Chemical compound C**C(*1CC1)C1=CCCC=C1 0.000 description 4
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N NC(N1CCOCC1)=O Chemical compound NC(N1CCOCC1)=O ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D231/12—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
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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
- C07D231/14—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
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- 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
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- 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
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- 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
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
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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
Technical field
The invention belongs to the synthetic field of medicine.Particularly, the present invention relates to hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound and preparation method thereof, using and as beta-secretase inhibitor, for the preparation of prevention, delay or treat the purposes in the medicine of the disease of the deposition initiation of A β.
Background technology
Alzheimer (Alzheimer ' s disease, hereinafter referred AD), claiming again presenile dementia, is a kind of chronic nerve degenerative diseases that is common in elderly population, and its clinical manifestation is that carrying out the property disturbance of intelligence, hypomnesis, the mental act that increase the weight of are abnormal etc.The elderly's health in its serious threat, especially society aging gradually, and this situation is all the more severe, has caused people's common concern.
Acetylcholinesterase depressant remains the main medicine of clinical treatment AD at present, although can reverse study, memory impairment that choline function damage causes, part patient symptom is alleviated, but can not fundamentally change morbid state (Barril, X.etal Mini Rev.Med.Chem.2001,1,255).
Research in recent years shows, the generation of the amyloid beta in brain (β-amyloidpeptide, hereinafter referred A β) and gathering are considered to an important factor that causes this disease to produce.A β is that 11-15 amino acid of its end is positioned at APP cross-film district by the polypeptide of the approximately 4kD of amyloid precursor protein (amyloid precursor protein, hereinafter referred APP) hydrolysis generation.Mainly contain three kinds of Secretasess and participated in the hydrolytic process to APP, be called α, β and gamma-secretase.The restriction enzyme site of alpha-secretase enzyme is positioned at A β sequence, produces soluble α-APP fragment and C83 peptide after acting on APP, and C83 peptide can continue to be generated P3 peptide by gamma-secretase hydrolysis, does not produce A β.And the restriction enzyme site of beta-secretase is positioned at A β N and holds first amino acid, produce β-APP and C99 peptide after acting on APP, C99 peptide produces A β through gamma-secretase effect again.As can be seen here, beta-secretase is very crucial rate-limiting enzyme in A β forming process.And the mouse that knocks out beta-secretase gene shows there is no the generation of the A β while completely without the obstacle of obvious nerve and other physiological function aspect, therefore beta-secretase is considered to treat the safe and effective novel targets of AD (D.J.Selkoe Science.2002,297,353-356.).And the inhibitor of beta-secretase is more safer than inhibitors of gamma-secretase, but the synthetic difficulty of micromolecular beta-secretase inhibitors is far above inhibitors of gamma-secretase.
Summary of the invention
Goal of the invention
For solving the technical problem existing in prior art, the inventor has designed and synthesized a series of beta-secretase inhibitors, to reaching the object for the treatment of AD.
Therefore, an object of the present invention is to provide a kind of hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound or its pharmacy acceptable salt.
Another object of the present invention is to provide this compounds and is preparing as the purposes in the medicine of beta-secretase inhibitor.
Another object of the present invention is to provide one or more the pharmaceutical composition comprising in above-mentioned hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound or its pharmacy acceptable salt.
A further object of the present invention is to provide a kind of prevention, delays or treats the method by the disease of the deposition initiation of A β.
Technical scheme
To achieve these goals, the invention provides hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound or its pharmacy acceptable salt representing as following general formula I:
Wherein:
Z is OH or NH
2;
R
2for
h, C
1-C
4straight chained alkyl, C
3-C
6branched-chain alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
1-C
6alkoxy carbonyl, hydroxyl C
1-C
6the heteroatomic 5-7 unit's saturated heterocyclyl carbonyl of alkylidene group, replacement or unsubstituted aminocarboxyl, replacement or unsubstituted phenyl, naphthyl, replacement or the unsubstituted 1-3 of containing or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base;
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl group, C
1-C
6alkoxy C
1-C
6alkylidene group, hydroxyl C
1-C
6alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
The substituting group of the phenyl of described replacement is hydroxyl, C
1-C
6the C that alkoxyl group, halogen or halogen replace
1-C
3alkyl;
Described heteroatoms is N, S or O;
The substituting group that contains 1-3 the first saturated heterocyclyl carbonyl of heteroatomic 5-7 of described replacement is C
1-C
3alkyl or C
1-C
6alkoxy C
1-C
6alkylidene group.
Preferably,
When Z is OH;
R
1for
wherein, A is F, Cl or Br; X is NH; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
2for
h, C
1-C
4straight chained alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
3for phenyl;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
1-C
6alkoxy carbonyl, hydroxyl C
1-C
6the heteroatomic 5-7 unit's saturated heterocyclyl carbonyl of alkylidene group, replacement or unsubstituted aminocarboxyl, replacement or unsubstituted phenyl, naphthyl, replacement or the unsubstituted 1-3 of containing or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base;
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl group, C
1-C
6alkoxy C
1-C
6alkylidene group, hydroxyl C
1-C
6alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
The substituting group of the phenyl of described replacement is hydroxyl, C
1-C
6the C that alkoxyl group, halogen or halogen replace
1-C
3alkyl;
Described heteroatoms is N, S or O;
The substituting group that contains 1-3 the first saturated heterocyclyl carbonyl of heteroatomic 5-7 of described replacement is C
1-C
3alkyl or C
1-C
6alkoxy C
1-C
6alkylidene group.
When Z is NH
2time,
R
1for
wherein, X is NH; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
2for
wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
3for phenyl;
R
4, R
5and R
6identical or different, be C independently of one another
1-C
6alkoxy carbonyl or replacement or unsubstituted aminocarboxyl;
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl and C
3-C
6branched-chain alkyl.
More preferably,
When Z is OH;
R
1for
wherein, X is NH; Y is carbonyl; R
7for H or C
1-C
4straight chained alkyl;
R
2for
h, C
1-C
4straight chained alkyl or nitro; Wherein, R
8and R
9be H or C simultaneously
1-C
4straight chained alkyl;
R
3for phenyl;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
4straight chained alkyl, C
1-C
4alkoxy carbonyl, hydroxyl C
1-C
4alkylidene group, replacement or unsubstituted aminocarboxyl, replacement or unsubstituted phenyl, naphthyl, C
1-C
4alkoxy C
1-C
4that replace or the unsubstituted pyrrolidyl carbonyl of alkylidene group
piperidino carbonyl
c
1-C
3that replace or the unsubstituted morpholinyl carbonyl of alkyl
cycloheptylamine base carbonyl
benzocyclohepta amido carbonyl
furyl
thienyl
or pyridyl
wherein, the aminocarboxy N atom of described replacement is selected from one or two replacement in following groups: C
1-C
4straight chained alkyl, C
3-C
5cycloalkyl, C
1-C
4alkoxyl group, C
1-C
4alkoxy C
1-C
4alkylidene group, hydroxyl C
1-C
4alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
The substituting group of the phenyl of described replacement is hydroxyl, C
1-C
4alkoxyl group, F or trifluoromethyl.
When Z is NH
2time,
R
1for
wherein, X is NH; Y is carbonyl; R
7for H or C
1-C
4straight chained alkyl;
R
2for
r
8and R
9be H or C simultaneously
1-C
4straight chained alkyl
R
3for phenyl;
R
4, R
5and R
6identical or different, be C independently of one another
1-C
4alkoxy carbonyl or replacement or unsubstituted aminocarboxyl; Wherein, the aminocarboxy N atom of described replacement is by one or more C
1-C
4straight chained alkyl replaces.
According to hydroxyethyl pyrazole compounds provided by the present invention or aminoethyl pyrazole compound, most preferably be one of following compound:
Described pharmacy acceptable salt is the salt that the described compound being represented by general formula (I) and mineral acid or organic acid form; Wherein, described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid, and described organic acid is citric acid, lactic acid, oxysuccinic acid, glyconic acid, tartrate, hexanodioic acid, acetic acid, succsinic acid, fumaric acid, xitix, methylene-succinic acid, methylsulfonic acid or Phenylsulfonic acid.
The present invention also provides the preparation method of hydroxyethyl pyrazole compounds, and the method is used following synthetic route 1,2,3 or 4:
The particular compound that synthetic route 1:(is corresponding is 1-9,49, and 60-63,66-67)
Wherein, R
1for
wherein, X is NH or O; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
2for
h, C
1-C
4straight chained alkyl, C
3-C
6branched-chain alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
1-C
6alkoxy carbonyl, hydroxyl C
1-C
6alkylidene group, the unsubstituted first saturated heterocyclyl carbonyl of the individual heteroatomic 5-7 of 1-3 that contains;
Described heteroatoms is N, S or O.
Reactions steps is as follows:
A) take epoxy compounds A as starting raw material, the DMF of take under sodium carbonate exists with pyrazole derivatives obtains compd B as 100 ℃ of solvents react open loop,
B) compd B is sloughed Boc protecting group and is obtained Compound C under acidic conditions,
C), under the condition that one or more compounds exist in EDCI, HOBt and DIPEA, Compound C further generates Compound D-1 with m-phthalic acid condensation, by silicagel column or thin plate layer analysis method, obtains target compound;
The particular compound that synthetic route 2:(is corresponding is 10-27,58,59, and 60-63,66-67)
Wherein, R
1for
wherein, A is halogen; X is NH or O; Y is carbonyl; R
7for H or C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
2for
h, C
1-C
4straight chained alkyl, C
3-C
6branched-chain alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4and R
6identical or different, independently of one another for replacing or unsubstituted aminocarboxyl, replacement or the unsubstituted 1-3 of containing heteroatomic 5-7 unit's saturated heterocyclyl carbonyl or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base,
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl group, C
1-C
6alkoxy C
1-C
6alkylidene group, hydroxyl C
1-C
6alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
Described heteroatoms is N, S or O;
The substituting group that contains 1-3 the first saturated heterocyclyl carbonyl of heteroatomic 5-7 of described replacement is C
1-C
3alkyl, C
1-C
6alkoxy C
1-C
6alkylidene group;
R
11and R
12identical or different, be H independently of one another, C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl group, C
1-C
6alkoxy C
1-C
6alkylidene group, hydroxyl C
1-C
6alkylidene group, phenyl or C
1-C
3the phenmethyl that alkoxyl group replaces; Or R
11and R
12with connected N atom, form together replacement or the unsubstituted 1-3 of containing heteroatomic 5-7 unit's saturated heterocyclyl carbonyl or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base,
Described heteroatoms is N, S or O;
The substituting group that contains 1-3 the first saturated heterocyclyl carbonyl of heteroatomic 5-7 of described replacement is C
1-C
3alkyl, C
1-C
6alkoxy C
1-C
6alkylidene group.
Wherein, by the reactions steps in synthetic route 1 a), b), c) make Compound D-2 that R5 is ethoxy carbonyl, as the starting raw material of synthetic route 2.
Take THF/ ethanol/water=2/2/1 and obtain E as aqueous solvent solution in Compound D-2, compd E generates compound F 17-hydroxy-corticosterone with amine condensation under the condition of EDCI, HOBt and DIPEA, by silicagel column or thin plate layer analysis method, obtains target compound.
The particular compound that synthetic route 3:(is corresponding is 28-48)
Wherein, R
1for
wherein, A is halogen; X is NH or O; Y is carbonyl; R
7for H or C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
2for
h, C
1-C
4straight chained alkyl, C
3-C
6branched-chain alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4, R
5' and R
6identical or different, independently of one another for replacing or unsubstituted phenyl, naphthyl or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base,
Wherein, the substituting group of the phenyl of described replacement is hydroxyl, C
1-C
6the C that alkoxyl group, halogen or halogen replace
1-C
3alkyl,
Described heteroatoms is N, S or O.
Wherein, by the reactions steps in synthetic route 1 a), b), c) make R
5for Compound D-3 of Br, as the starting raw material of synthetic route 3.
Take toluene/ethanol/water=2/2/1 and under microwave reaction, obtain the hydroxyethyl pyrazole compounds G that aryl replaces as solvent in Compound D-3 under the catalysis of four (triphenyl phosphorus) palladium.
The particular compound that synthetic route 4:(is corresponding is 50-57)
Wherein, R
1for
wherein, X is NH; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
2for
wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4, R
5and R
6identical or different, be C independently of one another
1-C
6alkoxy carbonyl or replacement or unsubstituted aminocarboxyl,
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl and C
3-C
6branched-chain alkyl.
Reactions steps is as follows:
A) take epoxy compounds H as starting raw material, the DMF of take under sodium carbonate exists with pyrazole derivatives obtains Compound I as 100 ℃ of solvents react open loop;
B) Compound I is reacted with methylsulfonyl chloride and is obtained compound J;
C) compound J reacts to obtain compound K in 50 ℃ with sodiumazide in DMF solvent;
D) compound K is sloughed Boc protecting group and is obtained compound L under acidic conditions;
E), under the condition that one or more compounds exist in EDCI, HOBt and DIPEA, compound K further obtains compound M with m-phthalic acid condensation;
F) compound M obtains compound N with zinc powder reduction.
According to a further object of the present invention, the invention provides above-mentioned hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound or its pharmacy acceptable salt as beta-secretase inhibitor, can be used for preparation prevention, delay or treat disease, particularly AD medicine by the deposition initiation of A β.
Another technical scheme of the present invention provides treat hydroxyethyl pyrazole compounds that the general formula I of significant quantity represents or one or more the pharmaceutical composition in aminoethyl pyrazole compound or its pharmacy acceptable salt a kind of comprising, said composition can optionally comprise the vehicle allowing in a certain amount of pharmaceutics, can also optionally comprise the conventional additives such as a certain amount of odorant agent, flavouring agent.
Another technical scheme of the present invention provides prevention, delayed or has treated the method for the disease being caused by the deposition of A β, and described method comprises that hydroxyethyl pyrazole compounds that the general formula I of administering therapeutic significant quantity represents or one or more or aforementioned pharmaceutical compositions of the present invention in aminoethyl pyrazole compound or its pharmacy acceptable salt, ester, prodrug or solvate are to patient.
Beneficial effect
Hydroxyethyl pyrazole compounds of the present invention or aminoethyl pyrazole compound, the activity with obvious inhibition beta-secretase, this may have for further research the cognitive function of improvement, and the original new drug of simultaneously alleviating AD progression of disease provides valuable information.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, and following embodiment is only described the present invention by way of example.Clearly, those of ordinary skills can, in scope of the present invention and essence, carry out various accommodations and modification to the present invention.Need to be appreciated that, this invention is intended to be encompassed in the flexible and modification that appended claims comprises.
Experiment and sample analysis instrument:
The Mercury-300 that nuclear magnetic resonance spectrum (1H NMR) is produced by Varian company or Mercury-400 type nmr determination.
LC-MS is measured by Thermo Finnigan LCQDECA * P type mass spectrograph.
HRMS is measured by Finnigan MAT 95 type mass spectrographs.
Sample purity is measured by the high performance liquid chromatograph (306pump, uv/vis-156Detector, 215 liquid handle) of Gilson company.
Optically-active data are measured by PerkinElmer-341 type polarimeter.
Column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (200-300 order).
TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture.
Ultraviolet lamp is the Shanghai ZF-1 of Gu Cun electric light instrument plant type ultraviolet analysis instrument for three purposed.
Microwave reactor is Biotage Initiator product.
Preparation Example
Embodiment 1:
(preparation of compound 1)
Synthetic route 1, reactions steps:
By epoxy compounds (2S, 3S)-1,2-epoxy-3-(N-tertiary butyloxycarbonyl is amino)-4-phenylpropyl alcohol alkane (50mg, 0.19mmol) is dissolved in 2mLDMF, in system, adds pyrazoles (13mg, 0.19mmol), catalytic amount sodium carbonate.In 110 ℃ of reactions of microwave 1 hour.Reaction finishes to add 25mL water in system, and ethyl acetate extraction (25mL * 2) merges organic phase, saturated common salt washing (25mL), anhydrous sodium sulfate drying, filters, concentrated, obtain white solid (2S, 3S)-1-benzyl-2-hydroxyl-3-pyrazolyl t-butyl carbamate 57mg
Above-mentioned pyrazole compound (57mg, 0.17mmol) is dissolved in 4mL methylene dichloride, in system, adds 1mL trifluoroacetic acid, room temperature reaction 2h.Concentrated, the amine obtaining is not treated directly enters next step reaction.The amine that upper step is obtained and 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl)) ethyl aminocarbonyl phenylformic acid (68mg; 0.17mmol) be dissolved in 10mL DCM; add EDCI (38mg; 0.20mmol), HOBt (23mg; 0.17mmol); DIPEA (94 μ l, 0.51mmol), stirred overnight at room temperature.In reaction system, add 15mL DCM, Diluted Acid Washing (25mL), saturated sodium bicarbonate is washed (25mL), saturated common salt washing (25mL), anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtains white foam shape solid N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-pyrazolyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine 87mg, yield: 79.6%.
1H NMR(300MHz,CD
3OD):δ
1H NMR(300MHz,CD
3OD):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:
Synthetic route is with reference to embodiment 1.With 3-methylpyrazole, replace pyrazoles, TLC chromatography obtains white amorphous solid compound 2 (19mg, yield: 81.2%).
1H NMR(300MHz,CD
3OD):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:
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,CD
3OD):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:
Synthetic route is with reference to embodiment 1.With 5-methylpyrazole, replace pyrazoles, TLC chromatography obtains white amorphous solid compound 4 (25mg, yield: 78.2%).
1H NMR(300MHz,CD
3OD):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:
Synthetic route, with reference to embodiment 1, replaces pyrazoles with 3-ethoxycarbonyl pyrazoles, and TLC chromatography obtains white amorphous solid compound 5 (33mg, yield: 88.7%).
1H NMR (300MHz,CD
3OD):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:
Synthetic route, with reference to embodiment 1, replaces pyrazoles with 4-ethoxycarbonyl pyrazoles, and column chromatography obtains white amorphous solid compound 6 (80mg, yield: 76.6%).
1H NMR(300MHz,CD
3OD):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:
Synthetic route, with reference to embodiment 1, replaces pyrazoles with 3-ethoxycarbonyl pyrazoles, and TLC chromatography obtains white amorphous solid compound 7 (29mg, yield: 61.4%).
Yield: 78.9%.
1H NMR(300MHz,CD
3OD):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:
Synthetic route is with reference to embodiment 1, and the compound 6 (80mg, 0.12mmol) that embodiment 6 is made is dissolved in 10mL (THF/EtOH/H
2o=2/2/1, volume ratio), in solution, add the sodium hydroxide (10mg, 0.24mmol) of two equivalents, stirred overnight at room temperature.Reaction solution pH value is adjusted to 4, ethyl acetate (50mL * 2) extraction, saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying, filtered and recycled solvent, TLC chromatography obtains white amorphous solid compound 105 (62mg, fusing point: 122-124 ℃, yield: 88.8%).
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 1, with reference to embodiment 1 compound 6 use lithium aluminium hydride that embodiment 6 is made, reduce and get final product.Yield: 70.0%.
1H NMR(300MHz,CD
3OD):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:
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) stirring at room 10min.Add DIPEA (50 μ L, 0.3mmol), splashed into above-mentioned reaction system, then the lower 70 ℃ of reaction 15min of microwave condition.In system, add 50mL water, ethyl acetate extraction (50mL * 2), merge organic phase, weak acid scrubbing (25mL * 2), saturated sodium bicarbonate is washed (25mL * 2), saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtains white amorphous solid compound 10 (41mg, yield: 68.3%).
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the methylamine hydrochloride of two equivalents, replace ammonium chloride, yield: 74.8%.
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the ethylamine hydrochloride of two equivalents, replace ammonium chloride, yield: 70.1%.
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the propylamin hydrochloride of two equivalents, replace ammonium chloride, yield: 67.1%.
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the dimethylamine hydrochloride of two equivalents, replace ammonium chloride, yield: 86.4%.
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the diethylamine hydrochloride of two equivalents, replace ammonium chloride, yield: 58.8%.
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the dipropyl amine hydrochloride of two equivalents, replace ammonium chloride, yield: 86.3%.
1H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the N-methoxy methyl amine hydrochlorate of two equivalents, replace ammonium chloride, yield: 51.1%.
1H NMR (300MHz,CD
3OD):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, by N-(2-methoxy ethyl) methylamine of two equivalents, replace ammonium chloride, yield: 61.5%.
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the tetramethyleneimine of two equivalents, replace ammonium chloride, yield: 57.8%.
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with (R)-(-)-2-(methoxymethyl) tetramethyleneimine of two equivalents, replace ammonium chloride, yield: 60.9%.
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the piperidines of two equivalents, replace ammonium chloride, yield: 75.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the morpholino of two equivalents, replace ammonium chloride, yield: 54.2%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the U-4527 of two equivalents, replace ammonium chloride, yield: 64.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the cyclopropylamine of two equivalents, replace ammonium chloride, yield: 72.1%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the thanomin of two equivalents, replace ammonium chloride, yield: 63.2%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the aniline of two equivalents, replace ammonium chloride, yield: 53.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with the 4-methoxybenzylamine of two equivalents, replace ammonium chloride, yield: 51.5%
H NMR(300MHz,CD
3OD):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 I a (68mg; 0.1mmol); FURAN-2-BORONIC ACID (17mg, 0.15mmol), salt of wormwood (30mg; 0.2mmol); lithium chloride monohydrate (20mg, 0.3mmol) adds in the mixed solvent of 5mL (toluene/ethanol/water=2/2/1, volume ratio) successively; under argon shield, add four (triphenyl phosphorus) palladiums (6mg, 0.005mmol).Under microwave-assisted, in 120 ℃, react 1 hour.After reacting completely, by reaction solution impouring 50mL water, ethyl acetate extraction (50mL * 2), merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtains white amorphous solid compound 28 (32mg, yield: 47.0%).
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with furans-3-boric acid, replace FURAN-2-BORONIC ACID, yield: 49.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with thiophene-2-boric acid, replace FURAN-2-BORONIC ACID, yield: 34.7%
H NMR(300MHz,CD
3OD):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, with thiophene-3-boric acid, replace FURAN-2-BORONIC ACID, yield: 40.2%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with pyridine-3-boric acid, replace FURAN-2-BORONIC ACID, yield: 45.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with pyridine-4-boric acid, replace FURAN-2-BORONIC ACID, yield: 50.6%
H NMR(300MHz,CD
3OD):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, with phenylo boric acid, replace FURAN-2-BORONIC ACID, yield: 60.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 1-naphthalene boronic acids, replace FURAN-2-BORONIC ACID, yield: 45.5%
H NMR(300MHz,CD
3OD):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, with 2-naphthalene boronic acids, replace FURAN-2-BORONIC ACID, yield: 41.9%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 2-hydroxybenzene boric acid, replace FURAN-2-BORONIC ACID, yield: 45.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 3-hydroxybenzene boric acid, replace FURAN-2-BORONIC ACID, yield: 42.7%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 4-hydroxybenzene boric acid, replace FURAN-2-BORONIC ACID, yield: 50.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 2-methoxyphenylboronic acid, replace FURAN-2-BORONIC ACID, yield: 45.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 3-phenetole boric acid, replace FURAN-2-BORONIC ACID, yield: 55.2%
H NMR(300MHz,CD
3OD):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, with 4-methoxyphenylboronic acid, replace FURAN-2-BORONIC ACID, yield: 65.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 2,6-dimethoxy phenylo boric acid, replace FURAN-2-BORONIC ACID, yield: 35.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 2-fluorobenzoic boric acid, replace FURAN-2-BORONIC ACID, yield: 75.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 3-fluorobenzoic boric acid, replace FURAN-2-BORONIC ACID, yield: 89.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 4-fluorobenzoic boric acid, replace FURAN-2-BORONIC ACID, yield: 75.8%
H NMR(300MHz,CD
3OD):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, with 2,4 difluorobenzene boric acid, replace FURAN-2-BORONIC ACID, yield: 76.4%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 3, with 2,4 difluorobenzene boric acid, replace FURAN-2-BORONIC ACID, yield: 45.9%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 1, with 3-(R)-methylbenzylamine formyl radical-5-N-Toluidrin yl benzoic acid, replace 3-[(R)-methyl NSC 158269 formyl radical]-5-N-Toluidrin yl benzoic acid, yield: 85.5%
H NMR(300MHz,CD
3OD):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, add salt of wormwood (42mg, 0.3mmol).100 ℃ of microwave reactions, 1 hour.In system, add 50mL water, ethyl acetate extraction (50mL * 2), merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtain white solid Ic (65mg, yield: 81.2%, fusing point: 102-104 ℃).Compound I c (40mg, 0.1mmol) is dissolved in the anhydrous tetrahydro furan of 10mL, adds the triethylamine (40 μ L, 0.2mmol) of two equivalents, drip the methylsulfonyl chloride (15 μ L, 0.2mmol) of two equivalents, stirring at room two hours.Drip the Jia Chun temper excessive methylsulfonyl chloride that goes out, continue to stir half hour, reclaim solvent column chromatography obtain Compound I d (39mg, yield: 81.3%, fusing point: 144-146 ℃).Compound I d (39mg, 0.08mmol) is dissolved in 2mL DMF, adds the sodiumazide (10mg, 0.16mmol) of 2 equivalents to spend the night in 60 ℃ of reactions.In system, add 50mL water, ethyl acetate extraction (50mL * 2), merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtain white solid Ie (30mg, yield: 88.2%, fusing point: 118-120 ℃).Compound I e (30mg, 0.07mmol) is dissolved in 4mL methylene dichloride, in system, adds 1mL trifluoroacetic acid, room temperature reaction 2h.Concentrated, the amine that obtains is unprocessed directly enters next step reaction.Acid (30mg, 0.08mmol) is dissolved in 2mL DMF, adds EDCI (20mg, 0.10mmol), HOBt (10mg, 0.07mmol), stirring at room 10min.The amine that upper step is obtained is dissolved in the DMF of 2mL, adds DIPEA (50 μ l, 0.3mmol), is splashed into above-mentioned reaction system, then the lower 70 ℃ of reaction 15min of microwave condition.In system, add 30mL water, ethyl acetate extraction (50mL * 2), merges organic phase, Diluted Acid Washing (25mL * 2), saturated sodium bicarbonate is washed (25mL * 2), saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, column chromatography obtain white solid Compound I f (42mg, yield: 85.7%, fusing point: 157-159 ℃).Compound I f (42mg, 0.06mmol) is dissolved in the mixed solvent of (ethanol/water=3/1, volume ratio) of 20mL, adds successively the ammonium chloride (30mg, 0.6mmol) of 10 equivalents, the zinc powder (40mg, 0.6mmol) of 10 equivalents.Stirred overnight at room temperature.Diatomite filtration, absolute ethanol washing, direct column chromatography after filtrate decompression reclaims.Obtain compound 50 (32mg.Yield: 82.0%).
H NMR(300MHz,CD
3OD):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, same with embodiment 50, just with 3-(R)-methylbenzylamine formyl radical-5-N-Toluidrin yl benzoic acid, replace 3-[(R)-methyl NSC 158269 formyl radical] and-5-N-Toluidrin yl benzoic acid, yield: 30.9%
H NMR(300MHz,CD
3OD):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, with embodiment 51 with, Compound I g (42mg, 0.06mmol) is dissolved in to 120 ℃ of reactions of tube sealing in the methanol solution of amine of 10mL and spends the night.The unnecessary solvent of water pump reclaim under reduced pressure after reacting completely.Crude product is not purified directly enters lower step zinc powder reduction.Column chromatography obtains product 53 (29mg, yield: 25.6%).
H NMR(300MHz,CD
3OD):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 I g (42mg, 0.06mmol) is dissolved in to 10mL (THF/EtOH/H
2o=2/2/1), in solution, add the sodium hydroxide (5mg, 0.12mmol) of two equivalents, stirred overnight at room temperature.Reaction solution pH value is adjusted to 4, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, reclaims solvent, the not purified the next step that is directly used in of the crude product of gained.The acid of upper step gained is dissolved in 2mL DMF, adds EDCI (20mg, 0.10mmol), HOBt (10mg, 0.08mmol), methylamine hydrochloride (14mg, 0.2mmol) stirring at room 10min.The amine that upper step is obtained is dissolved in the DMF of 2mL, adds DIPEA (50 μ L, 0.3mmol), is splashed into above-mentioned reaction system, then the lower 70 ℃ of reaction 15min of microwave condition.In system, add 50mL water, ethyl acetate extraction (50mL * 2), merges organic phase, weak acid scrubbing (25mL * 2), saturated sodium bicarbonate is washed (25mL * 2), saturated common salt water washing, anhydrous sodium sulfate drying, filters, and after concentrating, directly carries out zinc powder reduction.Column chromatography obtains white solid compound 53 (24mg, yield: 22.9%).
H NMR(300MHz,CD
3OD):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, with the hydrochloride of ethamine, replace methylamine hydrochloride.Yield: 24.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 4, with the hydrochloride of dimethylamine, replace methylamine hydrochloride.Yield: 20.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 4, with diethylamine, replace methylamine hydrochloride.Yield: 19.7%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 4, with dipropyl amine, replace methylamine hydrochloride.Yield: 20.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 3,5-thebaine, replace ammonium chloride.Yield: 70.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 2,3,4,5-tetrahydrochysene-1H-benzo [D] azatropylidene (hydrochloride), replace ammonium chloride.Yield: 46.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 3-dipropyl amine formyl radical-5-tolyl acid, replace 3-[(R)-methyl NSC 158269 formyl radical]-5-N-methanesulfonamido phenylformic acid, yield: 70.5%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, use N '-[(R)-2-(methoxymethyl) pyrroyl-5-tolyl acid replaces 3-[(R)-methyl NSC 158269 formyl radical]-5-N-methanesulfonamido phenylformic acid, yield: 73.8%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 3-diethylamine formyl radical phenylformic acid, replace 3-[(R)-methyl NSC 158269 formyl radical]-5-N-methylsulfonyl ammonia
Yl benzoic acid, yield: 80.2%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 3-[(R)-methyl NSC 158269 formyl radical]-5-nitrobenzoyl acid substitution 3-[(R)-methyl NSC 158269 formyl radical]-5-N-methanesulfonamido phenylformic acid, yield: 78.4%
H NMR(300MHz,CD
3OD):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, with 3-[(R)-methyl NSC 158269 formyl radical] phenylformic acid replacement 3-[(R)-methyl NSC 158269 formyl radical]-5-N-methanesulfonamido phenylformic acid yield: 73.9%
H NMR(300MHz,CD
3OD):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:
According to synthetic route 2, with 3-isobutylamine formyl radical-5-N-methanesulfonamido phenylformic acid, replace 3-[(R)-methyl NSC 158269 formyl radical]-5-N-Toluidrin yl benzoic acid, yield: 74.7%
H NMR(300MHz,CD
3OD):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: the determination of activity of hydroxyethyl pyrazole compounds or aminoethyl pyrazole compound:
(1) acquisition of beta-secretase albumen:
Experiment adopts beta-secretase extracellular region protein, and (plasmid derives from Stefan doctor Masure (reference: Protein Expression and Purification, 2002,26:139-148)), 1-454 amino acid (hereinafter referred BACE1), for secretory protein, gene constructed in pFastBac by this albumen
tMin 1 carrier (purchased from invitrogen), C end adds 6 Histidines.By
(Invitrogen) baculovirus expression system obtains target protein.
First recombinant plasmid transformed is arrived to intestinal bacteria DH10Bac
tMin competent cell (purchased from invitrogen), wherein comprised baculovirus shuttle vectors, i.e. rod granule, picking contains pFastBac after transposition
tMthe recombinant clone of middle goal gene section, cultivates and extracting restructuring rod granule.By the Sf9 insect cell (purchased from invitrogen) of restructuring rod granule transfection complete TNM-FH culture medium culturing, cultivate and within 3-5 days, gather in the crops afterwards the substratum that contains first-generation virus, continue transfection and obtain respectively the s-generation, third generation virus.The substratum that employing contains third generation virus infects Express
the High Five that serum free medium is cultivated
tMinsect cell (purchased from invitrogen), expresses target protein, collects the substratum that contains target protein after 72 hours, needs next step purifying.Level pad (20mM sodium phosphate (sodium phosphate) pH8.0 by the substratum that contains target protein (25-30mL) at 1L, 300mM NaCl, 10mM imidazoles (imidazole)) dialysed overnight in, centrifugal 15 minutes of 12000rpm, repeat once, collect supernatant liquor.By supernatant liquor loading to through metal ion-chelant chromatography column (the 1mL HiTrap of level pad balance
tMchelating HP column (GE Healthcare, Life Sciences), after cleaning foreign protein, adopt elution buffer (20mM sodium phosphate pH8.0,300mM NaCl, 250mM imidazole) to obtain target protein be beta-secretase extracellular region (BACE1) to wash-out, finally, the albumen obtaining through 12% polyacrylamide gel electrophoresis (SDS-PAGE) isolation identification purifying, purity is 90% left and right.
(2) determination of activity
DABCYL-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS (Synpep is used in experiment, lower abbreviation BS) as substrate, survey in the reaction 384 hole microwell plate of living and carry out, reaction volume is 25 μ l, contains 100mM sodium-acetate (sodium acetate) (pH 4.0)), 20 μ MBS, 50nM BACE-1,2 μ l methyl-sulphoxides (DMSO) or be dissolved in the testing compound (50 μ g/ml) of DMSO.Room temperature reaction, at the multi-functional plate instrument Envision that reads
tM(PerkinElmer) in, detect fluorescent signal, excite with absorbing wavelength and be respectively 355nm and 460nm, record and calculate the increment of enzyme reaction initial stage unit time fluorescent signal, with this, represent enzyme reaction initial velocity, with testing compound, the inhibiting rate of beta-secretase activity is represented the activity of this compound, wherein, inhibiting rate (inhibition) calculates and sees formula 1.
υ in formula 1
compoundand υ
dMSOthe enzyme reaction initial velocity that representative contains compound and DMSO respectively.
If compound to be detected inhibiting rate when 20 μ g/mL is greater than 50%, more further dilutes 7-9 concentration, calculate IC
50, i.e. the concentration of the suppressed half compound of enzyme initial velocity.Positive inhibitor is compound OM99-2 (OM99-2 be take octapeptide [L-glutamic acid-OMR99-1] as basis, has replaced the compound of Leu-Ala peptide bond with the isostere hydroxyalkyl vinyl base of a transition state).
Gained part of compounds activity is as shown in table 1:
Table 1
By the screening on molecular level, discovery above-claimed cpd shows has good activity to beta-secretase, for further research may have the original new drug that improves cognitive function, alleviates AD progression of disease simultaneously, provides valuable information.
Claims (10)
1. the hydroxyethyl pyrazole compounds being represented by general formula I or aminoethyl pyrazole compound or its pharmacy acceptable salt:
General formula I
Wherein,
Z is OH or NH
2;
R
1for
wherein, A is halogen; X is NH or O; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
2for
h, C
1-C
4straight chained alkyl, C
3-C
6branched-chain alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or C
3-C
6cycloalkyl;
R
3for replacing or unsubstituted phenyl, wherein, described substituting group is C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl or halogen;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
1-C
6alkoxy carbonyl, hydroxyl C
1-C
6the heteroatomic 5-7 unit's saturated heterocyclyl carbonyl of alkylidene group, replacement or unsubstituted aminocarboxyl, replacement or unsubstituted phenyl, naphthyl, replacement or the unsubstituted 1-3 of containing or contain 1-3 heteroatomic 5-11 membered unsaturated heterocycle base;
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl, C
3-C
6branched-chain alkyl, C
3-C
6cycloalkyl, C
1-C
6alkoxyl group, C
1-C
6alkoxy C
1-C
6alkylidene group, hydroxyl C
1-C
6alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
The substituting group of the phenyl of described replacement is hydroxyl, C
1-C
6the C that alkoxyl group, halogen or halogen replace
1-C
3alkyl;
Described heteroatoms is N, S or O;
The substituting group that contains 1-3 the first saturated heterocyclyl carbonyl of heteroatomic 5-7 of described replacement is C
1-C
3alkyl or C
1-C
6alkoxy C
1-C
6alkylidene group.
2. hydroxyethyl pyrazole compounds according to claim 1 or aminoethyl pyrazole compound or its pharmacy acceptable salt, wherein,
Z is OH;
R
1for
wherein, A is F, Cl or Br; X is NH; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
2for
h, C
1-C
4straight chained alkyl or nitro; Wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
3for phenyl.
3. hydroxyethyl pyrazole compounds according to claim 2 or aminoethyl pyrazole compound or its pharmacy acceptable salt, wherein,
Z is OH;
R
1for
wherein, R
7for H or C
1-C
4straight chained alkyl;
R
2for
h, C
1-C
4straight chained alkyl or nitro; Wherein, R
8and R
9be H or C simultaneously
1-C
4straight chained alkyl;
R
4, R
5and R
6identical or different, be H, carboxyl, C independently of one another
1-C
4straight chained alkyl, C
1-C
4alkoxy carbonyl, hydroxyl C
1-C
4alkylidene group, replacement or unsubstituted aminocarboxyl, replacement or unsubstituted phenyl, naphthyl, C
1-C
4alkoxy C
1-C
4that replace or the unsubstituted pyrrolidyl carbonyl of alkylidene group
piperidino carbonyl
c
1-C
3that replace or the unsubstituted morpholinyl carbonyl of alkyl
cycloheptylamine base carbonyl
benzocyclohepta amido carbonyl
furyl
thienyl
or pyridyl
wherein, the aminocarboxy N atom of described replacement is selected from one or two replacement in following groups: C
1-C
4straight chained alkyl, C
3-C
5cycloalkyl, C
1-C
4alkoxyl group, C
1-C
4alkoxy C
1-C
4alkylidene group, hydroxyl C
1-C
4alkylidene group, phenyl and C
1-C
3the phenmethyl that alkoxyl group replaces;
The substituting group of the phenyl of described replacement is hydroxyl, C
1-C
4alkoxyl group, F or trifluoromethyl.
4. hydroxyethyl pyrazole compounds according to claim 1 or aminoethyl pyrazole compound or its pharmacy acceptable salt, wherein,
Z is NH
2;
R
1for
wherein, X is NH; Y is carbonyl; R
7for H, C
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
2for
wherein, R
8and R
9identical or different, be H, C independently of one another
1-C
6straight chained alkyl or C
3-C
6branched-chain alkyl;
R
3for phenyl;
R
4, R
5and R
6identical or different, be C independently of one another
1-C
6alkoxy carbonyl or replacement or unsubstituted aminocarboxyl;
Wherein, the aminocarboxy N atom of described replacement is selected from the one or more replacements in following groups: C
1-C
6straight chained alkyl and C
3-C
6branched-chain alkyl.
5. hydroxyethyl pyrazole compounds according to claim 4 or aminoethyl pyrazole compound or its pharmacy acceptable salt, wherein,
Z is NH
2;
R
1for
wherein, X is NH; Y is carbonyl; R
7for H or C
1-C
4straight chained alkyl;
R
2for
wherein, R
8and R
9be H or C simultaneously
1-C
4straight chained alkyl;
R
4, R
5and R
6identical or different, be C independently of one another
1-C
4alkoxy carbonyl or replacement or unsubstituted aminocarboxyl;
Wherein, the aminocarboxy N atom of described replacement is by one or more C
1-C
4straight chained alkyl replaces.
6. hydroxyethyl pyrazole compounds according to claim 1 or aminoethyl pyrazole compound or its pharmacy acceptable salt, described compound is selected from following compounds:
According to the hydroxyethyl pyrazole compounds described in any one in claim 1 ~ 6 or aminoethyl pyrazole compound or its pharmacy acceptable salt 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 for preventing, delay or treat the disease by the deposition initiation of A β.
9. purposes according to claim 8, wherein, the disease that the described deposition by A β causes is Alzheimer.
10. a pharmaceutical composition, one or more in the hydroxyethyl pyrazole compounds described in any one in claim 1 ~ 6 or aminoethyl pyrazole compound or its pharmacy acceptable salt of being selected from that it comprises treatment significant quantity, and one or more vehicle that optionally allow in pharmaceutics.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017068089A2 (en) | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
| WO2018192973A1 (en) | 2017-04-18 | 2018-10-25 | Vifor (International) Ag | Ferroportin-inhibitor salts |
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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 |
-
2012
- 2012-06-25 CN CN201210211667.7A patent/CN103508957B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017068089A2 (en) | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
| WO2017068089A3 (en) * | 2015-10-23 | 2017-07-27 | Vifor (International) Ag | Ferroportin inhibitors |
| US10364239B2 (en) | 2015-10-23 | 2019-07-30 | Vifor (International) Ag | Ferroportin inhibitors |
| US10738041B2 (en) | 2015-10-23 | 2020-08-11 | Vifor (International) Ag | Ferroportin inhibitors |
| US11001579B2 (en) | 2015-10-23 | 2021-05-11 | Vifor (International) Ag | Ferroportin inhibitors |
| US11066399B2 (en) | 2015-10-23 | 2021-07-20 | Vifor (International) Ag | Ferroportin inhibitors |
| WO2018192973A1 (en) | 2017-04-18 | 2018-10-25 | Vifor (International) Ag | Ferroportin-inhibitor salts |
| US11129820B2 (en) | 2017-04-18 | 2021-09-28 | Vifor (International) Ag | Ferroportin-inhibitor salts |
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|---|---|
| CN103508957B (en) | 2017-02-08 |
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