CN106632091A - Application of quinazoline compounds in regulation of neural stem cell proliferation and differentiation - Google Patents

Abstract

The invention discloses an application of quinazoline compounds in regulation of neural stem cell proliferation and differentiation and particularly discloses a compound shown in formula I, as well as an optical isomer, a hydrate, a solvate, a prodrug or a pharmaceutically acceptable salt thereof. The compounds can efficiently regulate neural stem cell proliferation and differentiation and are used for repairing nerve injury and treating neurodegenerative diseases and applied to neural stem cell transplantation for treating nervous system diseases.

Description

Application of the quinazoline compound in regulation and control cell proliferation of nerve cord and differentiation

Technical field

The invention belongs to medicinal chemistry art, in particular it relates to quinazoline compound is in regulation and control neural stem cell Application in propagation and differentiation.

Background technology

Neural stem cell (neural stem cells, NSCs) has self renewal and multi-lineage potential, Neuron, oligodendrocyte and astrocyte etc. can be divided into.The differentiation technique of neural stem cell For central nervous system injury, nervous system degeneration disease or inherited metabolic disease, neurodegenerative diseases New therapeutic strategy is provided etc. disease.Therefore the propagation of regulation and control Neural Stem Cells and differentiation becomes The focus of Neuroscience Research.

At present, the method for external evoked differentiation and proliferation of neural stem cells general both at home and abroad is to give mitogen, Such as basic fibroblast growth factor (basic fibroblast growth factor, bFGF) and table Skin growth factor (epidermalgrowth factor, EGF) etc., intervenes the neural stem cell for maintaining culture, Vegetative state is at, mitogen is removed and is added after the culture medium containing hyclone, induction NSCs enters Row differentiation, but this method is relatively complicated, and neural stem cell is difficult to obtain and cultivates, and resulting point Change cell and be mainly glial cell, neuron ratio is relatively low.

Marrow stromal cell (Bone Marrow stroma cells, BMSCs) is that a class has self more The pluripotent stem cell of new ability, can induce be divided into neural stem cell (neural stem under certain condition cells,NSCs).Compare and neural stem cell, marrow stromal cell is more easy to obtain and regulate and control differentiation, group Knit the compatibility good.Both at home and abroad successively report is obtained report using the differentiation of micromolecular compound inducing bone marrow stromal cell Obtain neuronal cell.The small molecule for being used has butylated hydroxyarisol (Butylatedhydroxyarisol, BHA), PI3K (phosphatidylinositol 3-kinase)/AKT inhibitor LY294002 etc..But the inductivity of these derivants need to be improved, and machine Reason is still not clear.

Therefore, this area in the urgent need to develop one kind can high efficiency regulatory cell proliferation of nerve cord, differentiation, use In repairing nerve damage and treatment neurodegenerative diseases and for Neural Stem Cells ' Transplantation nerveous system The medicine of system disease.

The content of the invention

It is an object of the invention to provide one kind can high efficiency regulatory cell proliferation of nerve cord, differentiation, for repairing Multiple nerve injury is with treatment neurodegenerative diseases and for Neural Stem Cells ' Transplantation nervous system disease The medicine of disease.

First aspect present invention provide a kind of compound of formula I, its optical isomer, hydrate, solvate, Its prodrug or its pharmaceutically acceptable salt,

In formula,

R₁And R₂It is each independently selected from the following group：

(i)H；

(i i) substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀Alkenyl, replacement or Unsubstituted C₂-C₁₀Alkynyl group, substituted or unsubstituted C₃-C₁₀Cycloalkyl；Wherein described being substituted by has One or more substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Alkyl halide Base, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro, C₁- C₃Carboxyl ,-R₄-R₅Group ,-NR₆(R₇)、 Unsubstituted phenyl or by C₁-C₃The phenyl of alkyl or halogen substiuted；

(iii) substituted or unsubstituted C₅-C₂₀Aryl, substituted or unsubstituted C₃-C₂₀Heteroaryl, replacement or Unsubstituted 5-20 circle heterocycles base, substituted or unsubstituted C₁₀- C₃₀Condensed ring radical；Wherein, the heteroaryl Base or heterocyclic radical contain 1 to 3 hetero atom selected from N, O, S, and described are substituted by with one Or multiple substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro ,-NR₆(R₇)；

Wherein R₄Selected from unsubstituted or halo C₁- C₈Alkylidene, and R₅Selected from unsubstituted or halo C₅- C₂₀Aryl；R₆And R₇It is each independently hydrogen, unsubstituted or halo C₁-C₁₀Alkyl, it is unsubstituted or The C of halo₂-C₁₀Alkenyl, unsubstituted or halo C₂-C₁₀Alkynyl；

Or, R₁With R₂Containing at least one nitrogen-atoms, replacement can be collectively forming with the N atoms being connected Or in unsubstituted 3-8 circle heterocycles base, and described 3-8 circle heterocycles bases altogether containing 1-3 selected from N, The hetero atom of O, S, wherein described is substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₂-C₁₀Alkenyl, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀ Halogenated alkoxy ,-OH ,-CN, nitro ,-NH₂、C₁- C₃Carboxyl；

And R₃It is selected from the group：H, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀ Alkenyl, substituted or unsubstituted C₂-C₁₀Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl；It is wherein described Be substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN ,-NH₂。

In another preference, described halogen includes F, Cl, Br or I.

In another preference, described halogen is F or Br.

In another preference, the compound has the structure shown in Formulas I a：

In formula, R₁And R₂It is as defined above.

In another preference, R₁、R₂It is each independently selected from the following group：

(i)H；

(ii) substituted or unsubstituted C₂-C₈Alkyl, substituted or unsubstituted C₂- C₈Alkenyl, replacement or not Substituted C₂-C₈Alkynyl, substituted or unsubstituted C₄-C₈Cycloalkyl；Wherein described is substituted by with one Or multiple substituent groups being selected from the group：Halogen, C₁-C₃Alkyl, C₁-C₃Alkoxyl, C₁-C₃Haloalkyl, C₁-C₁₀ Halogenated alkoxy ,-OH ,-CN, nitro, C₁- C₃Carboxyl ,-R₄-R₅Group ,-NR₆(R₇), it is unsubstituted Phenyl or by C₁-C₃The phenyl of alkyl or halogen substiuted；

(iii) substituted or unsubstituted C₅-C₁₀Aryl, substituted or unsubstituted C₃-C₁₀Heteroaryl, replacement or Unsubstituted 5-10 circle heterocycles base, substituted or unsubstituted C₁₀- C₂₀Condensed ring radical；Wherein, the heteroaryl Base or heterocyclic radical contain 1 to 3 hetero atom selected from N, O, S, and described are substituted by with one Or multiple substituent groups being selected from the group：Halogen, C₁-C₃Alkyl, C₁-C₃Alkoxyl, C₁-C₃Haloalkyl, C₁-C₁₀ Halogenated alkoxy ,-OH ,-CN, nitro ,-NR₆(R₇)；

Wherein R₄Selected from unsubstituted or halo C₁- C₆Alkylidene, and R₅Selected from unsubstituted or halo C₅- C₁₀Aryl；R₆And R₇It is each independently hydrogen, unsubstituted or halo C₁-C₆Alkyl, unsubstituted or halogen The C in generation₂-C₆Alkenyl, unsubstituted or halo C₂-C₆Alkynyl；

Or, R₁With R₂Containing at least one nitrogen-atoms, replacement can be collectively forming with the N atoms being connected Or in unsubstituted 3-8 circle heterocycles base, and described 3-8 circle heterocycles bases altogether containing 1-2 selected from N, The hetero atom of O, S, wherein described is substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkoxyl, C₁-C₆Haloalkyl, C₁-C₆Halo Alkoxyl ,-OH ,-CN, nitro ,-NH₂、C₁- C₃Carboxyl.

In another preference, R₁It is selected from the group：H, methyl, ethyl, phenyl or its combination.

In another preference, R₂It is selected from the group：H, methyl, ethyl, propyl group, butyl or its combination.

In another preference, R₁And R₂With the N atoms being connected be collectively forming pyrrolidine, piperidines, piperazine, Morpholine, cycloheximide ring, 1,3- diazepines ring or 1,4- diazepine rings.

In another preference, R₁、R₂、R₃For the corresponding concrete group of each particular compound in embodiment.

In another preference, R₄、R₅、R₆、R₇For the corresponding concrete base of each particular compound in embodiment Group.

In another preference, the compound be embodiment in prepare each particular compound, preferredization Compound is selected from the group：

In another preference, the compound is selected from the group：

Second aspect present invention provides a kind of compound of formula I, its optical isomer, hydrate, solvation The purposes of thing, its prodrug or its pharmaceutically acceptable salt, for preparing medicine or preparation, the medicine or Preparation is used for (i) and treats neurodegenerative diseases；(ii) repairing nerve damage；And/or (iii) promotees Enter cell proliferation of nerve cord.

In another preference, the medicine or preparation can be additionally used in (i) regulation and control (including raise or under Adjust) expression of nestin；And/or (ii) promote Neural Stem Cells and neurogliocyte point Change.

Third aspect present invention provides a kind of pharmaceutical composition, including：

Compound of formula I described in (i) first aspect present invention, its optical isomer, hydrate, solvent Compound, its prodrug or its pharmaceutically acceptable salt；With

(ii) pharmaceutically acceptable carrier.

In another preference, described pharmaceutical composition contains the Formulas I of therapeutically effective amount or safe and effective amount Compound, its optical isomer, hydrate, solvate, its prodrug or its pharmaceutically acceptable salt.

In another preference, the prodrug includes ester type compound.

In another preference, in described pharmaceutical composition, containing 0.0001-99wt% (preferably 0.01-90wt%, More preferably, 0.1-80wt%) component (i), with the gross weight meter of pharmaceutical composition.

In another preference, described pharmaceutical composition is used to prepare the tune of cell proliferation of nerve cord or differentiation Control agent.

In another preference, described pharmaceutical composition is used for (i) repairing nerve damage；(ii) control Treat and/or prevention of neurodegenerative diseases；And/or (iii) promotes cell proliferation of nerve cord.

In another preference, the neurodegenerative diseases are selected from the group：Alzheimer, parkinson Family name's disease, Huntington's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Niu Hai Continuous shape encephalopathy, gram refined Er Shi diseases, cerebral atrophy, multiple sclerosis, primary lateral sclerosiss, spinal cord Property muscular atrophy or its combination.

Fourth aspect present invention provides a kind of compound of formula I or the preparation method of its pharmaceutically acceptable salt, bag Include step：

In atent solvent, in the presence of base, the amine shown in compound 6 and Formula II is reacted, from And obtain compound of formula I；

In various, R₁、R₂And R₃As defined in first aspect present invention.

In another preference, R₃For C₁-C₁₀Alkyl, such as methyl.

In another preference, the atent solvent includes polar solvent.

In another preference, the atent solvent is selected from the group：N,N-dimethylformamide, N, N- diformazans Yl acetamide, dimethyl sulfoxide, N-Methyl pyrrolidone, acetone, tetrahydrofuran or its combination.

In another preference, the alkali is selected from the group：Potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, Sodium hydroxide, sodium hydride, triethylamine, diisopropylamine ethylamine or its combination.

In another preference, the amine is selected from the group：N-butylamine, diethylamide, pyrrolidine, piperidines, Morpholine, benzyl amine, O-substituted aniline, meta substituted aniline, para-orientation aniline or its combination.

In another preference, the compound 6 is prepared by the following method：

A () in the presence of a base, compound 5 and phosphorus oxychloride is reacted, so as to obtain compound 5a；

B () is reacted compound 5a with ammonia, so as to obtain compound 6；

In various, R₃As defined in first aspect present invention.

In another preference, R₃For C₁-C₁₀Alkyl, such as methyl.

In another preference, in step (a), the alkali is selected from the group：N, accelerine.

In another preference, in step (a), reaction temperature 40-150 DEG C, more preferably, 50-140 DEG C, more preferably, 90-110 DEG C.

In another preference, in step (a), the response time 0.1-15h, it is preferred that 1-10h, More preferably, 1-4h.

In another preference, in step (b), 0 DEG C -150 DEG C of the reaction temperature, it is preferred that 10-100 DEG C, more preferably, 15-50 DEG C.

In another preference, in step (b), the response time 0.1-15h, it is preferred that 1-13h, More preferably, 1-10h.

Fifth aspect present invention provides a kind of midbody compound, and the midbody compound is selected from the group：

Sixth aspect present invention provides a kind of method for treating neurodegenerative diseases, methods described bag Include:

Apply described in compound of formula I or third aspect present invention described in first aspect present invention to required object Pharmaceutical composition.

In another preference, the object includes people.

In another preference, the object includes non-human mammal.

In another preference, the non-human mammal includes rodent, such as mice, rat.

In another preference, application dosage is 10-10000mg/kg/ days, it is preferred that 50-10000mg/kg/ My god, more preferably, 100-1000mg/kg/ days.

In another preference, frequency of administration is 1-5 times/day, it is preferred that 1-2 times/day.

In another preference, administration includes one or more cycles, and each cycle is 2-30 days, it is preferred that 3-7 days.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (such as enforcement Example) in can be combined with each other between each technical characteristic for specifically describing, so as to constitute new or preferred skill Art scheme.As space is limited, here is no longer tired out one by one and is stated.

Description of the drawings

Fig. 1 shows the selection result of double reporter gene platforms.

Fig. 2 shows and the result of double reporter gene Screening Platforms screening is verified.

Fig. 3 shows that compound Yhhu-3477, Yhhu-3481 promote Differentiation of Neural Stem Cells, Increase Tuj-1 positive cells ratio.

Fig. 4 shows that compound Yhhu-3477 and Yhhu-3481 can dose-dependently increase the table of Tuj-1 Reach.

Fig. 5 shows that compound Yhhu-3791 and Yhhu-3792 can improve the expression water of Tuj-1 and GFAP It is flat.

Fig. 6 shows that compound Yhhu-3791 and Yhhu-3792 promote the propagation of neural stem cell.

Fig. 7 shows that compound Yhhu-3792 promotes BrdU positive cells ratio to increase.

Fig. 8 shows that compound Yhhu-3792 promotes BrdU+/Tuj-1+ and BrdU+/GFAP+ cell quantities Increase.

Fig. 9 shows that compound Yhhu-3792 promotes Notch-1 expression.

Figure 10 shows that compound Yhhu-3792 increases NICD in core.

Figure 11 shows that compound Yhhu-3792 has no significant effect to SHH signal paths.

Specific embodiment

The present inventor has synthesized a series of quinazoline compound through in-depth study for a long time, described Compound can high efficiency regulatory cell proliferation of nerve cord, differentiation, for repairing nerve damage and treatment nerve move back Row disease and for Neural Stem Cells ' Transplantation nervous system disease.On this basis, the present invention People completes the present invention.

Group definition

As used herein, term " substituted or unsubstituted " refers to that the group can be unsubstituted, or H in the group by one or more (such as 1-10, preferably 1-5, more preferably 1-3, most preferably, 1-2) substituent group replaced.

As used herein, described " replacement " or " substituted " refer to the group have one or more (compared with Good ground 1-6, more preferably 1-3) substituent group that is selected from the group：Halogen, hydroxyl ,-NH₂, nitro ,-CN, C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, C₁-C₃Carboxyl, C₂-C₄Chain Thiazolinyl, C₂-C₄Alkynyl, phenyl, benzyl.

As used herein, term " C₁-C₁₀Alkyl " refers to the straight or branched alkyl with 1-10 carbon atom, Such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar base Group；Wherein, term " C₁-C₃Alkyl " refers to the straight or branched alkyl with 1-3 carbon atom, such as first Base, ethyl, n-pro-pyl, isopropyl or similar group.

As used herein, term " C₃-C₁₀Cycloalkyl " refers to the cyclic alkyl with 3-10 carbon atom, for example Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or similar group.

As used herein, term " C₁-C₁₀Alkylidene " refers to the bivalent hydrocarbon radical with 1-10 carbon atom, e.g., Methylene, ethylidene, propylidene, butylidene or similar group.

As used herein, term " C₂-C₁₀Alkenyl " or " C₂-C₈Alkenyl " refer to respectively with 2-10 or The thiazolinyl of the straight or branched of 2-8 carbon atom, such as vinyl, pi-allyl, 1- acrylic, isopropenyl, 1-butylene base, crotyl or similar group.

As used herein, term " C₂-C₁₀Alkynyl group " refers to the straight or branched with 2-10 carbon atom Alkynyl, such as acetenyl, propinyl or similar group.

As used herein, term " C₂-C₈Alkynyl group " refers to the alkynes of the straight or branched with 2-8 carbon atom Base, such as acetenyl, propinyl or similar group.

As used herein, term " C₅-C₂₀Aryl " refers to the unit price virtue of 5 to 20 (preferable 5-14) carbon atoms Fragrant race's carbon ring group, it has monocyclic (such as phenyl) or condensed ring (such as naphthyl or anthryl), if junction point is in fragrance In carbon original, condensed ring is possibly nonaromatic (such as 2- benzoxazolones, 2H-1,4- benzoxazinyl -3 (4H) -one -7- Base etc.).The substituted or unsubstituted C₅- C₂₀Aryl is selected from the group：Ortho position substituted-phenyl, meta replace Phenyl, para-orientation phenyl.Preferred aryl includes phenyl and naphthyl.The term includes replacing or unsubstituted Form, wherein substituent group is as defined above.The substituent group of the substituted-phenyl is selected from the group：Halogen, hydroxyl Base, methyl, ethyl, isopropyl, the tert-butyl group, methoxyl group, ethyoxyl, tert-butoxy, trifluoromethyl, Or its combination.

As used herein, term " C₅-C₂₀Heteroaryl " refer to 5 to 20 carbon atoms and 1 to 4 selected from oxygen, The heteroatomic aromatic group of nitrogen and sulfur, such heteroaryl can be monocyclic (such as pyridine radicals or furyl) Or condensed ring (such as indolizine base (indolizinyl) or benzothienyl), wherein, the condensed ring can be nonaro-maticity And/or containing a hetero atom, as long as junction point is the atom by armaticity heteroaryl.Preferably heteroaryl Base includes pyridine radicals, pyrrole radicals, indyl, thienyl and furyl.The term includes replacing or unsubstituted Heteroaryl.

As used herein, term " C₅-C₂₀Heterocyclic radical " refers to saturation, fractional saturation or undersaturated base Group's (but not being armaticity), with monocyclic or condensed ring (including bridged-ring system and spiro ring system, with 5 to 20 Individual carbon atom and 1 to 4 hetero atom selected from nitrogen, sulfur or oxygen, in fused ring system, one or more rings can To be cycloalkyl, aryl or heteroaryl, as long as junction point passes through nonaro-maticity ring.The term include replace or Unsubstituted heterocyclic radical.

As used herein, term " halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine and bromine.

As used herein, term " halo " refers to and is taken by the above-mentioned halogen atom of one or more identical or different The group in generation, can with partially halogenated or whole halo, for example trifluoromethyl, pentafluoroethyl group, seven fluorine isopropyls, Or similar group.

As used herein, term " C₁-C₃Haloalkyl " refers to hydrogen by the halogen substiuted of 1 or more than 1 Straight or branched alkyl with 1-3 carbon atom, for example, halogenated methyl, halogenated ethyl, halopropyl, Haloisopropyl or similar group, preferred trifluoromethyl.

The compound of the present invention can contain one or more asymmetric centers, and therefore with raceme, outward disappear The form of rotation mixture, single enantiomer, diastereomeric compound and single diastereomer occurs.Can With the asymmetric center for existing, depending on the property of various substituent groups on molecule.Each this asymmetric center Two optical isomers, and all possible optical isomer and non-enantiomer mixture will independently be produced It is included within the scope of the present invention with pure or partial-purified compound.The present invention is all different including compound Configuration formula.

Herein, term " room temperature " refers to 4-40 DEG C, preferably 20-25 DEG C.

The compound of the present invention

As used herein, term " the compounds of this invention " refers to formula I (or Formulas I a) compounds, its optical siomerism Body, hydrate, solvate, its prodrug or its pharmaceutically acceptable salt.

Typically, the present invention provide compound of Formula I, its optical isomer, hydrate, solvate, its Prodrug or its pharmaceutically acceptable salt.

In formula,

R₁And R₂It is each independently selected from the following group：

(i)H；

(ii) substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀Alkenyl, replacement or Unsubstituted C₂-C₁₀Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl；Wherein described is substituted by with one Individual or multiple substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro, C₁- C₃Carboxyl ,-R₄-R₅Group ,-NR₆(R₇), not Substituted phenyl or by C₁The phenyl of-C3 alkyl or halogen substiuted；

(iii) substituted or unsubstituted C₅-C₂₀Aryl, substituted or unsubstituted C₃-C₂₀Heteroaryl, replacement or Unsubstituted 5-20 circle heterocycles base, substituted or unsubstituted C₁₀- C₃₀Condensed ring radical；Wherein, the heteroaryl Base or heterocyclic radical contain 1 to 3 hetero atom selected from N, O, S, and described are substituted by with one Or multiple substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro ,-NR₆(R₇)；

Wherein R₄Selected from unsubstituted or halo C₁- C₈Alkylidene, and R₅Selected from unsubstituted or halo C₅- C₂₀Aryl；R₆And R₇It is each independently hydrogen, unsubstituted or halo C₁-C₁₀Alkyl, it is unsubstituted or The C of halo₂-C₁₀Alkenyl, unsubstituted or halo C₂-C₁₀Alkynyl；

Or, R₁With R₂Containing at least one nitrogen-atoms, replacement can be collectively forming with the N atoms being connected Or in unsubstituted 3-8 circle heterocycles base, and described 3-8 circle heterocycles bases altogether containing 1-3 selected from N, The hetero atom of O, S, wherein described is substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₂-C₁₀Alkenyl, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀ Halogenated alkoxy ,-OH ,-CN, nitro ,-NH₂、C₁- C₃Carboxyl；

And R₃It is selected from the group：H, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀ Alkenyl, substituted or unsubstituted C₂-C₁₀Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl；It is wherein described Be substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN ,-NH₂。

In another preference, described halogen includes F, Cl or Br.

In another preference, described halogen is F or Br.

In another preference, the compound has the structure shown in Formulas I a：

In formula, R₁And R₂It is as defined above.

In the presence of compound of the present invention has stereoisomer, the present invention includes compound All stereoisomers.

In the presence of compound of the present invention has tautomer, the present invention includes compound All tautomers.

Present invention additionally comprises any one or more hydrogen atoms in the compound are by its stable isotope deuterium The deuterated compound for replacing and producing.

The midbody compound of the present invention

As used herein, term " midbody compound of the present invention " refers to compound 2,3,4,5,5a, 6, It is preferred that following midbody compounds：

The preparation method of the compounds of this invention

The invention provides the preparation method of compound of formula I, the compound in the present invention can be by various conjunctions Prepare into processing ease, these operations are that one of ordinary skill in the art skillfully grasp.These compounds Illustrative preparation method can include but is not limited to flow process hereinafter described.

Generally, in the preparation process in accordance with the present invention, each reaction is mostly in -20 DEG C to 160 DEG C (or backflow temperature Degree) under (it is preferred that -5 DEG C to 100 DEG C, or 0-80 DEG C), carry out a period of time (such as 0.1-72 hours, compared with Good ground 0.5-24 hours).

It is preferred that formula (I) compound of the present invention can be by exemplary described in below scheme and embodiment Related open source literature operation used by method and those skilled in the art is completed.

In specific operation process, as needed the step in method can be extended or be merged.

Scheme (R ₃ =C ₁ -C ₁₀ Alkyl, preferred methyl)

Wherein, R₁And R₂It is defined as in the description.

In step 1, in the presence of alkali (such as potassium carbonate), in polar solvent (such as DMF, DMSO), change Compound 1 carries out one section of nucleophilic substitution (such as 90 DEG C -100 DEG C) at a certain temperature with 3- methoxyphenols Time, form compound 2.

In step 2, in the presence of alkali (such as potassium carbonate), in atent solvent (such as DMSO), compound 2 Reaction a period of time is carried out (such as 20 DEG C -40 DEG C) at a certain temperature with hydrogen peroxide, form compound 3；

In step 3, in the presence of sour (such as hydrochloric acid), in atent solvent (such as THF), compound 3 exists Under uniform temperature (such as 40 DEG C -60 DEG C) through hydrolysis for a period of time, formed compound 4；

In step 4, in atent solvent (such as THF), compound 4 is with triphosgene at a certain temperature (such as 65 DEG C -70 DEG C) carry out ring-closure reaction for a period of time, form compound 5；

In step 5, in the presence of alkali (such as DMA), first compound 5 and phosphorus oxychloride are existed Chlorination is carried out under uniform temperature for a period of time (such as 90 DEG C -110 DEG C), form compound 5a, then will Compound 5a with ammonia room temperature reaction for a period of time, forms compound 6；

In step 6, in atent solvent (such as tetrahydrofuran), compound 6 is with the amine shown in Formula II (one Determine to carry out reaction for a period of time (such as 130 DEG C -160 DEG C) at temperature, form compound of formula I.

The preparation method of compound of formula I disclosed by the invention and compound, medicine are constituted and therapeutic scheme, Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.Specifically It is that all similar replacements and change are apparent to those skilled in the art, and they are all regarded To be included in the present invention.

Pharmaceutical composition

Present invention also offers a kind of pharmaceutical composition, it includes the active component in the range of safe and effective amount, And pharmaceutically acceptable carrier.

" active component " of the present invention refer to compound of Formula I of the present invention, its optical isomer, Hydrate, solvate, its prodrug or its pharmaceutically acceptable salt.

" active component " of the present invention and pharmaceutical composition can be used as cell proliferation of nerve cord, differentiation Adjusting control agent.In another preference, for prepare for repairing nerve damage and treatment neurodegenerative diseases, And for the medicine of Neural Stem Cells ' Transplantation nervous system disease.In another preference, the god Jing degenerative disease is selected from the group：Alzheimer, parkinson, Huntington's disease, amyotrophy Property lateral schlerosis.

" safe and effective amount " is referred to：The amount of active component be enough to be obviously improved the state of an illness, and be unlikely to produce Serious side effect.Generally, pharmaceutical composition contains 1-2000mg active component/agent, more preferably, contains 10-200mg active component/agent.It is preferred that described is " one " for a tablet.

" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solid or liquid filler or solidifying Glue material, they are suitable for people and use and it is necessary to have enough purity and sufficiently low toxicity.It is " compatible In property " referred to herein as compositionss the active component of each component energy and the present invention and they between mutually mix With, and significantly reduce the drug effect of active component.

The compound of the preferred embodiment of the present invention can be administered as independent active agents, it is also possible to one or Multiple other agent combination for being used to treat neurodegenerative diseases are used.The chemical combination of the preferred embodiment of the present invention With known therapeutic combination using being also effective, the compound being currently known and other treatment nerves are moved back thing The combination of the therapeutic agent of row disease is within the scope of preferred embodiment.Special nature based on medicine and involved And disease, those of ordinary skill in the art can distinguish effective pharmaceutical agent combinations.This treatment neurological Property disease therapeutic agent include but is not limited to it is as follows：Alzheimer, parkinson, Heng Tingdunshi Disease, amyotrophic lateral sclerosis etc..The compound of preferred embodiment and treatment neurodegenerative diseases It is also effective when therapeutic agent is administered simultaneously.

Generally, it is preferred to the compound of embodiment is by with therapeutically effective amount, by the medicament with similar effect Any one acceptable pattern is applied.The actual amount root of the compound (i.e. active component) of preferred embodiment Determine according to Multiple factors, such as the order of severity of disease to be treated, the age of patient and relative health, quilt Using the effect of compound, the path applied and form, and other factors.The medicine can be applied many for one day It is secondary, it is preferable that once or twice daily.All of these factors taken together is all in the limit of consideration of the doctor in charge.

The purpose of preferred embodiment, treatment effective dose generally can be that patient's one-time use or gradation are applied Per TDD, for example, about 0.001 to about 1000 mg kg of body weight daily, it is preferable that daily About 1.0 to about 30 mg/kg body weight.Units dosage composition (Dosage unit composition) can include it Dosage factor is forming daily dosage.The selection of dosage form depends on various factors, such as mode of administration and medicine The bioavailability of material.Generally, it is preferred to the compound of embodiment can pass through following as pharmaceutical composition A kind of route of anticipating is administered：Orally, Formulations for systemic administration (such as transdermal, intranasal or by suppository) or parenteral administration is (such as Intramuscular, intravenously or subcutaneously).Preferred administering mode be it is oral, can be according to the degree of hardship day easy to adjust Dosage.The form that compositionss can be taken be tablet, pill, capsule, semisolid, powder, slow releasing preparation, Solution, suspension, elixir, aerosol or any other appropriate compositions.Another kind preferably applies excellent The mode for selecting embodiment compound is suction.This is that a kind of have efficacious prescriptions by what therapeutic agent was shipped directly to respiratory tract Method (referring to, such as U.S. Patent number 5,607,915).

Suitable pharmaceutically acceptable carrier or excipient include：As inorganic agent and medicine transport modifying agent and Accelerator, such as calcium phosphate, magnesium stearate, Talcum, monosaccharide, disaccharide, starch, gelatin, cellulose, Sodium carboxymethylcellulose pyce, carboxymethyl cellulose, glucose, hydroxypropyl-B- cyclodextrin, polyvinylpyrrolidone, Low melt wax, ion exchange resin etc., and its arbitrarily combination of two or more.Liquid and semisolid tax Shape agent can be selected from glycerol, Propylene Glycol, water, ethanol and various oil, including oil, animal oil, vegetable oil Or synthesis source, such as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Oleum sesami.Preferred liquid-carrier, particularly For the carrier of Injectable solution, including water, saline, glucose aqueous solution and ethylene glycol.Other are suitable Pharmaceutically acceptable excipient exist《Remington pharmaceutical science》(Remington’s Pharmaceutical Sciences), Mack Pub.Co., New Jersey (1991) are described, and are totally incorporated herein by reference.

As used herein, term " pharmaceutically acceptable salt " refers to non-toxic acid or the alkaline earth of compound of Formula I Slaine.These salt can be obtained or respectively will be suitable in original position when being finally recovered with purification compound of Formula I Organic or inorganic acid or alkali are obtained with alkalescence or acidic functionality reaction.Representational salt includes, but are not limited to： Acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, Disulfate, butyrate, Camphora hydrochlorate, camsilate, digluconate, cyclopentane propionate, ten Dialkyl sulfate, esilate, flucoheptanoate, glycerophosphate, Hemisulphate, enanthate, Caproate, fumarate, hydrochlorate, hydrobromate, hydriodate, 2- isethionates, lactate, Maleate, mesylate, nicotinate, 2- naphthyl sulphonic acids salt, oxalates, embonate, pectic acid Salt, rhodanate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfur Hydrochlorate, tartrate, rhodanate, tosilate and hendecane hydrochlorate.Additionally, nitrogenous alkalescence Group can be by following reagent quaternization：Alkyl halide, such as methyl, ethyl, propyl group, the chlorination of butyl Thing, bromide and iodide；Dialkyl sulfate, such as dimethyl, diethyl, dibutyl and diamyl sulfur Acid esters；The long chain halide such as chloride of decyl, lauryl, myristyl and stearyl, bromide and iodine Compound；Aralkyl halide such as benzyl and phenylethyl bromide etc..Thus water solublity or oil-soluble or can be obtained Dispersion products.May be used to form the sour example of pharmaceutically acceptable acid-addition salts is included such as hydrochloric acid, sulfur Acid, the mineral acid of phosphoric acid, and such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, the organic acid of citric acid. Base addition salts can be finally recovered and during purification compounds of formula I it is in situ prepared or make carboxylic moiety respectively with Suitable alkali (such as the hydroxide of pharmaceutically acceptable metal cation, carbonate or bicarbonate) or ammonia, Or organic primary, secondary or tertiary amine reaction is obtained.Pharmaceutically acceptable salt includes, but not limited to based on alkali gold The cation of category and alkaline-earth metal, the such as salt of sodium, lithium, potassium, calcium, magnesium, aluminum, and nontoxic ammonium, Quaternary ammonium and amine cation, include, but are not limited to：Ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine, triethylamine, ethamine etc..Other representational organic amines for forming base addition salts include diethyl Amine, ethylenediamine, ethanolamine, diethanolamine, piperazine etc..

As used herein, term " pharmaceutically acceptable prodrug " refers to the compound of those preferred embodiments Prodrug, the compound of the parent compound being quickly converted in vivo shown in above-mentioned formula, for example in blood Hydrolysis.In " T.Higuchi and V.Stella, as prodrug (the Pro-drugs as Novel of new delivery system Delivery Systems), volume 14 of A.C.S.15Symposium Series " and " Edward B.Roche are compiled, Bio-reversible carrier (Bioreversible Carriers in Drug Design) in drug design, American Pharmaceutical association Can and Pergamon publishing houses, 1987 " in provide complete discussion, both of which is hereby incorporated by With reference to.

The significant albumen Nestin of neural stem cell

Present invention also offers application of the compound of formula I in terms of regulation and control Nestin expression.

Nestin is the significant albumen of neural stem cell, closely related with the propagation of neural stem cell, differentiation. Propagation and the differentiation that can affect neural stem cell is lowered in the upper mediation of Nestin.

In the present invention, expression of the most compound to Nestin is acted on rise, only minority Expression of the compound (such as yhhu-3791 and yhhu-3792) to Nestin is acted on downward.

Main advantages of the present invention include：

(1) provide a kind of structure novel compound of Formula I；

(2) compound of the invention can be used as efficient cell proliferation of nerve cord, the adjusting control agent of differentiation；

(3) synthetic method is gentle, and operation is simple, and yield is higher, it is easy to derivatization, and suitable industry is put A large amount of productions；

(4) can be used in repairing nerve damage, treatment neurodegenerative diseases and for neural stem cell Transplantation treatment nervous system disease.

Unless otherwise defined, all specialties used in text are ripe with one skilled in the art institute with scientific words The same meaning known.Additionally, any similar to described content or impartial method and material all can be applicable to In the inventive method.Preferable implementation described in text only presents a demonstration with material and is used.

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition such as Sambrook et al., molecular cloning：Laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) described in condition, or according to institute of manufacturer The condition of suggestion.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.

Prepare embodiment

The preparation of the compound 2 of embodiment 1：

By compound 1 (5g, 28.1mmol), 3- methoxyphenols (3.39mL, 30.9mmol) and carbon Sour potassium (7.74g, 56.1mmol) is placed in stirring in DMF (50mL), and is warming up to 95 DEG C, reaction 12 Hour, reaction is complete.After DMF is evaporated, water (80mL) dilution is added, and with ethyl acetate (80mL × 3) Extraction.After collected organic layer, it is evaporated, and with ether washing, gained solid is compound 15.7g. Yield：72%.¹H NMR(300MHz,CDCl₃)δ2.28(s,3H),3.80(s,3H),6.59 (d, J=8.53Hz, 1H), 6.62-6.69 (m, 2H), 6.72-6.82 (m, 1H), 7.26 - 7.33 (m, 1H), 7.42 (t, J=8.39Hz, 1H), 7.67 (br.s., 1H), 8.10 (d, J=8.25Hz, 1H).

The preparation of the compound 3 of embodiment 2

Compound 2 (5g, 17.7mmol), potassium carbonate (0.37g, 2.64mmol) are added to into 25mL DMSO Middle stirring.Under ice bath, dropwise Deca aqueous hydrogen peroxide solution (30%, 4mL, the 35.4mL) in the mixed liquor, And react at room temperature overnight, that is, react complete.Water (80mL) dilution is added, and with ethyl acetate (100 ML × 3) extract.Collected organic layer, and with saturated sodium sulfite aqueous solution (80mL) washing.It is evaporated organic layer, Obtain compound 35.2g.Solid, yield：98%.¹H NMR(300MHz,CDCl₃)δ2.21(s, 3H), 3.78 (s, 3H), 5.89 (br.s., 1H), 6.73 (ddd, J=9.15,1.44,1.24 Hz, 1H), 7.23-7.31 (m, 2H), 7.35 (t, J=8.39Hz, 1H), 7.61 (br. S., 1H), 8.44 (d, J=8.53Hz, 1H), 11.77 (br.s., 1H).

The preparation of the compound 4 of embodiment 3

3 (5g, 16.6mmol) are dissolved in into tetrahydrofuran (20mL) and aqueous hydrochloric acid solution (3N, 20mL) Mixed solution in, stir 6 hours at 50 DEG C, reaction is complete.The dilution of 60mL water is added, and uses saturation Sodium bicarbonate solution adjusts pH to 9, with dichloromethane (80mL × 3) extraction.Collected organic layer is simultaneously evaporated, and obtains To compound 43.4g.Solid, yield：85%.¹H NMR(300MHz,CDCl₃)δ3.78(s,3H), 5.63 (br.s., 1H), 6.02-6.18 (m, 3H), 6.42 (dd, J=8.25,1.10Hz, 1H), 6.55-6.66 (m, 2H), 6.67-6.75 (m, 1H), 7.04 (t, J=8.11Hz, 1H),7.20-7.29(m,2H),7.49(br.s.,1H).

The preparation of the compound 5 of embodiment 4

Under ice bath, by anhydrous tetrahydrofuran solution (10mL) Deca of triphosgene (2.8g, 9.29mmol) Into the anhydrous tetrahydrofuran solution (20mL) of 4 (3g, 11.6mmol), and 70 DEG C are warming up to, stirring 24 hours, reaction was complete.After being cooled to room temperature, water (20mL) stopped reaction is added.After filtration, with Ethyl acetate (10mL) washs solid, obtains compound 52.5g.Yield：77%.Solid,¹H NMR(300 MHz,DMSO-d₆) δ 3.71 (s, 3H), 6.44 (dd, J=8.06,2.20Hz, 1H), 6.50 (t, J=2.35Hz, 1H), 6.56 (d, J=7.62Hz, 1H), 6.67 (dd, J=7.92, 2.05Hz, 1H), 6.92 (d, J=7.62Hz, 1H), 7.22 (t, J=8.21Hz, 1H), 7.52 (t, J=8.06Hz, 1H), 11.01 (s, 1H), 11.14 (s, 1H).

The preparation of the compound 6 of embodiment 5

5 (2g, 7.04mmol) are added in phosphorus oxychloride (8mL).Under ice bath, then by N, N- dimethyl Aniline (0.45mL, 3.87mmol) is slowly added dropwise into the solution.95 DEG C are warming up to, and it is little to stir 18 When, reaction is complete.After being evaporated phosphorus oxychloride, add frozen water (50mL) dilution, solid to separate out, filter and receive Collection, obtains final product corresponding 2,4- dichloroquinazolines derivant 5a, pulverulent solids, ESI-MS：321.01[M+H]⁺。

The intermediate (5a) is dissolved in tetrahydrofuran (15mL), under ice bath, the Deca ammonia in the solution Aqueous solution (15mL).Stir 5 hours under room temperature, reaction is complete.Water (50mL) dilution is added, with dichloro Methane (50mL × 3) is extracted.Collected organic layer is simultaneously evaporated, and through column chromatography purification, obtains final product target product 61.4 g.Yield：68%.Solid,¹H NMR(400MHz,CDCl₃)δ3.82(s,3H),6.24(br. S., 1H), 6.66-6.71 (m, 2H), 6.72-6.76 (m, 1H), 6.84 (ddd, J= 8.41,2.45,0.88Hz, 1H), 7.36 (t, J=8.22Hz, 1H), 7.44 (dd, J= 8.31,1.08Hz, 1H), 7.55 (t, J=8.22Hz, 1H), 7.64 (br.s., 1H).

The preparation of the compound yhhu-3469 of embodiment 6

Compound 6 (80mg, 0.265mmol) is added in tetrahydrofuran (1.5mL), then the positive fourth of Deca Amine (0.05mL, 0.530mmol) is into the solution.150 DEG C are heated in microwave reactor and 40 are reacted Minute, reaction is complete.Water (30mL) dilution is added, and with ethyl acetate (30mL × 3) extraction.Collection has Machine layer is simultaneously evaporated, Jing column chromatography purification, obtains target product yhhu-346956mg.Yield：62%.It is pale yellow Color solid,¹H NMR(300MHz,CDCl₃) δ 0.93 (t, J=7.29Hz, 3H), 1.34-1.48 (m,2H),1.50-1.65(m,2H),3.40-3.50(m,2H),3.77(s,3H), 5.12 (br.s., 1H), 6.32 (d, J=7.98Hz, 1H), 6.63-6.71 (m, 2H), 6.75 (dd, J=8.25,2.20Hz, 1H), 7.13 (d, J=8.25Hz, 1H), 7.26- 7.29(m,1H),7.29-7.34(m,1H).

The preparation of the compound yhhu-3470 of embodiment 7

Preparation method is with embodiment 6.Yield：51%.Light yellow solid,¹H NMR(300MHz, CDCl₃) δ 1.20 (t, J=6.42Hz, 6H), 3.61-3.75 (m, 4H), 3.79 (s, 3H), 6.29 (d, J=7.70Hz, 1H), 6.62-6.79 (m, 3H), 7.14 (d, J=8.43Hz, 1H),7.23-7.35(m,2H).

The preparation of the compound yhhu-3493 of embodiment 8

Preparation method is with embodiment 6.Yield：75%.White solid,¹H NMR(300MHz,CDCl₃)δ1.89 - 2.02 (m, 4H), 3.64 (t, J=6.60Hz, 4H), 3.79 (s, 3H), 6.31 (d, J=8.07Hz, 1H), 6.63-6.72 (m, 2H), 6.75 (dd, J=8.62,1.65Hz, 1H),7.14-7.22(m,1H),7.27-7.35(m,2H).

The preparation of the compound yhhu-3472 of embodiment 9

Preparation method is with embodiment 6.Yield：71%.Light yellow solid,¹H NMR(300MHz, CDCl₃)δ1.54-1.72(m,6H),3.78(s,3H),3.81-3.88(m,4H),6.31 (d, J=8.07Hz, 1H), 6.62-6.72 (m, 2H), 6.72-6.78 (m, 1H), 7.14 (d, J=8.43Hz, 1H), 7.23-7.34 (m, 2H).

The preparation of the compound yhhu-3473 of embodiment 10

Preparation method is with embodiment 6.Yield：68%.Light yellow solid,¹H NMR(300MHz,CDCl₃) δ1.45-1.55(m,2H),1.90-2.05(m,2H),3.21-3.36(m,2H),3.79 (s, 3H), 3.93 (td, J=8.87,5.09Hz, 1H), 4.56 (ddd, J=13.62,4.81, 4.68Hz, 2H), 6.34 (d, J=7.70Hz, 1H), 6.63-6.73 (m, 2H), 6.76 (dd, J=9.21,1.51Hz, 1H), 7.14 (d, J=9.63Hz, 1H), 7.29 (s, 1 H),7.31-7.36(m,1H).

The preparation of the compound yhhu-3474 of embodiment 11

Preparation method is with embodiment 6.Yield：62%.White solid,¹H NMR(300MHz,CDCl₃)δ1.65 -1.75(m,2H),1.84-1.92(m,2H),3.79(s,3H),3.81-3.95(m, 4H), 3.98-4.06 (m, 1H), 6.34 (d, J=7.98Hz, 1H), 6.64-6.72 (m, 2H), 6.76 (dd, J=8.39,2.34Hz, 1H), 7.15 (d, J=8.25Hz, 1H), 7.29(s,1H),7.31-7.36(m,1H).

The preparation of the compound yhhu-3471 of embodiment 12

Preparation method is with embodiment 6.Yield：68%.White solid,¹H NMR(300MHz,CDCl₃)δ3.73 - 3.79 (m, 4H), 3.80 (s, 3H), 3.87 (t, J=4.40Hz, 4H), 6.36 (d, J=8.07Hz, 1H), 6.65-6.73 (m, 2H), 6.77 (dd, J=8.25,2.38Hz, 1H), 7.15 (d, J=8.80Hz, 1H), 7.27-7.32 (m, 1H), 7.32-7.38 (m, 1H).

The preparation of the compound yhhu-3492 of embodiment 13

Preparation method is with embodiment 6.Yield：60%.Yellow solid,¹H NMR(300MHz,CDCl₃)δ3.79 (s, 3H), 4.71 (d, J=5.87Hz, 2H), 5.43 (br.s., 1H), 6.36 (d, J =8.07Hz, 1H), 6.66-6.75 (m, 2H), 6.78 (dd, J=8.25,2.38Hz, 1 H), 7.16 (d, J=8.43Hz, 1H), 7.23-7.26 (m, 1H), 7.27-7.42 (m, 7H).

The preparation of the compound yhhu-3491 of embodiment 14

Compound 6 (80mg, 0.265mmol) is added in tetrahydrofuran (1.5mL), Deca aniline (0.05 ML, 0.530mmol), then Deca hydrochloric acid solution (0.02mL) is into the solution.Heat in microwave reactor To 120 DEG C and react 40 minutes, reaction is complete.Water (30mL) dilution is added, and with ethyl acetate (30mL × 3) Extraction.Collected organic layer is simultaneously evaporated, Jing column chromatography purification, obtains target product yhhu-349154mg.Produce Rate：57%.Yellow solid, m.p.70-71 DEG C,¹H NMR(300MHz,CDCl₃)δ3.80(s,3 ), H 6.44 (d, J=8.07Hz, 1H), 6.67-6.76 (m, 2H), 6.79 (d, J=7.33 Hz, 1H), 7.00 (t, J=7.33Hz, 1H), 7.31 (t, J=8.07Hz, 4H), 7.39 (t, J=8.25Hz, 1H), 7.72 (d, J=8.43Hz, 2H).

The preparation of the compound yhhu-3477 of embodiment 15

Preparation method is with embodiment 14.Yield：68%.Light yellow solid,¹H NMR(300MHz,CDCl₃) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.42 (d, J=7.70Hz, 1H), 6.66-6.76 (m, 2H), 6.80 (dd, J=8.43,2.57Hz, 1H), 7.01 (t, J=7.52Hz, 1 ), H 7.15-7.25 (m, 2H), 7.33 (t, J=8.25Hz, 1H), 7.39 (t, J=8.25 Hz, 1H), 7.61 (br.s., 1H), 8.05 (d, J=8.06Hz, 1H).

The preparation of the compound yhhu-3487 of embodiment 16

Preparation method is with embodiment 14.Yield：61%.Yellow solid,¹H NMR(300MHz,CDCl₃)δ3.81 (s, 3H), 3.90 (s, 3H), 6.44 (d, J=8.07Hz, 1H), 6.66-6.76 (m, 2H), 6.79 (d, J=8.43Hz, 1H), 6.85-7.06 (m, 3H), 7.28-7.36 (m, 2H), 7.36-7.45 (m, 1H), 7.55 (br.s., 1H), 8.76 (d, J=8.07Hz, 1H).

The preparation of the compound yhhu-3481 of embodiment 17

Preparation method is with embodiment 14.Yield：49%.Yellow solid,¹H NMR(300MHz,CDCl₃)δ3.81 (s, 3H), 6.48 (d, J=7.70Hz, 1H), 6.68-6.77 (m, 2H), 6.77-6.91 (m, 2H), 7.28-7.39 (m, 3H), 7.39-7.46 (m, 1H), 7.54 (dd, J=8.07, 1.47Hz, 1H), 8.80 (d, J=6.97Hz, 1H).

The preparation of the compound yhhu-3478 of embodiment 18

Preparation method is with embodiment 14.Yield：43%.Yellow solid,¹H NMR(300MHz,CDCl₃)δ3.81 (s, 3H), 6.47 (d, J=8.07Hz, 1H), 6.66-6.77 (m, 2H), 6.80 (dd, J=8.43,1.83Hz, 1H), 6.88-6.97 (m, 1H), 7.01-7.20 (m, 3H), 7.27-7.36 (m, 2H), 7.42 (t, J=8.25Hz, 1H), 8.71-8.81 (m, 1H).

The preparation of the compound yhhu-3476 of embodiment 19

Preparation method is with embodiment 14.Yield：59%.Light yellow solid,¹H NMR(400MHz, CDCl₃) δ 2.37 (s, 3H), 3.81 (s, 3H), 6.44 (dd, J=7.96,1.01Hz, 1H), 6.71 (t, J=2.29Hz, 1H), 6.72-6.76 (m, 1H), 6.80 (dd, J=8.42, 2.38Hz, 1H), 6.85 (d, J=7.50Hz, 1H), 7.04 (br.s., 1H), 7.22 (t, J=7.78Hz, 1H), 7.29 (d, J=1.10Hz, 1H), 7.33 (t, J=8.23Hz, 1H), 7.41 (t, J=8.14Hz, 1H), 7.49 (s, 1H), 7.58 (d, J=8.05Hz, 1H).

The preparation of the compound yhhu-3488 of embodiment 20

Preparation method is with embodiment 14.Yield：52%.Dark red solid,¹H NMR(300MHz, CDCl₃) δ 3.80 (s, 3H), 3.84 (s, 3H), 6.44 (d, J=8.07Hz, 1H), 6.57 (d, J=8.07Hz, 1H), 6.68-6.77 (m, 2H), 6.80 (d, J=7.70Hz, 1 ), H 7.16 (t, J=7.52Hz, 1H), 7.20-7.31 (m, 3H), 7.32 (s, 1H), 7.40 (t, J=8.07Hz, 1H), 7.61 (br.s., 1H).

The preparation of the compound yhhu-3479 of embodiment 21

Preparation method is with embodiment 14.Yield：46%.Light yellow solid,¹H NMR(300MHz,CDCl₃) δ 3.81 (s, 3H), 6.46 (d, J=7.70Hz, 1H), 6.62-6.77 (m, 3H), 6.77 -6.85(m,1H),7.16-7.25(m,3H),7.27-7.36(m,2H),7.42(t, J=8.25Hz, 1H), 7.91 (d, J=12.10Hz, 1H).

The preparation of the compound yhhu-3482 of embodiment 22

Preparation method is with embodiment 14.Yield：53%.Light yellow solid,¹H NMR(300MHz, CDCl₃) δ 3.81 (s, 3H), 6.46 (d, J=8.07Hz, 1H), 6.67-6.76 (m, 2H), 6.76-6.83(m,1H),7.07-7.18(m,2H),7.26-7.36(m,2H),7.41 (t, J=8.07Hz, 2H), 7.52 (d, J=7.70Hz, 1H), 8.10 (s, 1H).

The preparation of the compound yhhu-3485 of embodiment 23

Preparation method is with embodiment 14.Yield：49%.Light yellow solid,¹H NMR(300MHz, CDCl₃) δ 3.81 (s, 3H), 6.47 (d, J=7.70Hz, 1H), 6.67-6.77 (m, 2H), 6.80 (d, J=8.43Hz, 1H), 7.19-7.46 (m, 5H), 7.50 (br.s., 1H), 7.81 (d, J=8.07Hz, 1H), 8.18 (br.s., 1H).

The preparation of the compound yhhu-3475 of embodiment 24

Preparation method is with embodiment 14.Yield：65%.White solid, m.p.133-134 DEG C,¹H NMR(300 MHz,CDCl₃) δ 2.32 (s, 3H), 3.80 (s, 3H), 6.42 (d, J=6.97Hz, 1H), 6.66-6.75 (m, 2H), 6.79 (d, J=8.43Hz, 1H), 7.04 (br.s., 1H), 7.13 (d, J=8.43Hz, 2H), 7.20-7.26 (m, 1H), 7.32 (t, J=8.25Hz, 1H), 7.38 (t, J=8.07Hz, 1H), 7.58 (d, J=8.43Hz, 2H).

The preparation of the compound yhhu-3791 of embodiment 25

Preparation method is with embodiment 14.Yield：50%.¹H NMR(400MHz,CDCl₃)δ7.63(d, J=8.8Hz, 2H), 7.39 (t, J=8.4Hz, 1H), 7.36 (d, J=8.8Hz, 2H), 7.32 (t, J=8.0Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.18 (brs, 1H), 6.80 (ddd, J=8.4,2.4,0.8Hz, 1H), 6.74 (ddd, J=8.4,2.4,0.8Hz, 1H), 6.71 (t, J=2.4Hz, 1H), 6.42 (dd, J=8.0,0.8Hz, 1H), 5.88 (brs, 1H),3.81(s,3H),1.32(s,9H).

The preparation of the compound yhhu-3792 of embodiment 26

Preparation method is with embodiment 14.Yield：60%.¹H NMR(400MHz,CDCl₃)δ8.60(brs, 1H), 7.63 (brs, 1H), 7.56 (d, J=8.8Hz, 2H), 7.41 (t, J=8.4Hz, 1H), 7.34 (t, J=8.4Hz, 1H), 7.23 (d, J=8.4Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.82 (dd, J=8.4,2.0Hz, 1H), 6.72 (dd, J=8.4,2.0Hz, 1H), 6.44 (d, J=8.0Hz, 1H), 6.69 (m, 1H), 3.81 (s, 3H), 6.40 (brs, 1H), 2.86 (m, 1H), 1.21 (d, J=6.8Hz, 6H).

The preparation of the compound yhhu-3489 of embodiment 27

Preparation method is with embodiment 14.Yield：55%.White solid,¹H NMR(300MHz,CDCl₃)δ3.80 (s, 6H), 6.41 (d, J=8.07Hz, 1H), 6.68-6.75 (m, 2H), 6.79 (dd, J=8.43,2.20Hz, 1H), 6.89 (m, 2H), 7.23 (d, J=7.70Hz, 1H), 7.32 (t, J=8.07Hz, 1H), 7.38 (t, J=8.25Hz, 1H), 7.59 (m, 2H).

The preparation of the compound yhhu-3480 of embodiment 28

Preparation method is with embodiment 14.Yield：58%.Yellow solid,¹H NMR(300MHz,CDCl₃)δ3.80 (s, 3H), 6.43 (d, J=8.07Hz, 1H), 6.67-6.76 (m, 2H), 6.80 (d, J=8.43Hz, 1H), 6.99 (t, J=8.07Hz, 2H), 7.20-7.28 (m, 1H), 7.32 (t, J=8.25Hz, 1H), 7.39 (t, J=8.07Hz, 1H), 7.64 (dd, J= 8.07,5.13Hz,2H).

The preparation of the compound yhhu-3483 of embodiment 29

Preparation method is with embodiment 14.Yield：50%.White solid,¹H NMR(300MHz,CDCl₃)δ3.81 (s, 3H), 6.46 (d, J=7.70Hz, 1H), 6.68-6.77 (m, 2H), 6.80 (d, J=8.43Hz, 1H), 7.21 (br.s., 1H), 7.27-7.37 (m, 2H), 7.37-7.46 (m, 3H), 7.64 (d, J=8.43Hz, 2H).

The preparation of the compound yhhu-3486 of embodiment 30

Preparation method is with embodiment 14.Yield：56%.Light yellow solid,¹H NMR(300MHz, CDCl₃) δ 3.81 (s, 3H), 6.49 (d, J=8.07Hz, 1H), 6.69-6.77 (m, 2H), 6.80 (d, J=8.43Hz, 1H), 7.27-7.38 (m, 3H), 7.44 (t, J=8.07Hz, 1H),7.56(m,2H),7.86(m,2H).

2- substituted-amino -4- amino -5- (3- the methoxyphenoxies)-quinazolines of the testing example present invention The impact of class compounds on nerve stem cells hyperplasia differentiation

Test method：

The double reporter gene screening techniques of marrow stromal cell

Need to transfect two kinds of plasmids, PGL4 plasmids and pRL-CMV plasmids in this screening system.Wherein PGL4 matter Grain carrier carries LUC Photinus pyralis LUC Photinus pyralis FL (firefly luciferase, FL) sequence, and the Sequences upstream is inserted The special Nestin partial promoter gene orders of central nervous system in rat are entered.Nestin (Nestin) is The intermediate filament protein of specifically expressing in neural stem cell, will start when rMSCs breaks up toward nerve direction Nestin is expressed, and will start the expression of downstream LUC Photinus pyralis LUC Photinus pyralis FL, its expression and neural direction differentiation Ability positive correlation.PRL-CMV plasmids carry renilla luciferase (renillaluciferase, RL) Sequence, the cell after transfection can express the enzyme, used as the Background control of transfection positive cells.By statistics The ratio of FL and RL, filtering out affects the compound of Nestin expression.

Learn from else's experience and the rat marrow stroma cell (rMSCs) in the 3rd generation reached after original cuiture, with pancreatin digestion after, Resuspended counting is centrifuged, above two plasmid is transfected, with α MEM+10%FBS training liquid 1 × 10 is diluted to⁵/ mL is thin Born of the same parents' density, uniformly plants into 96 orifice plates, per the μ L of hole 100, overnight incubation.By the compound stock solution of 10mM, The working concentration for being diluted to 10 μM with culture medium changes liquid entirely.The positive control culture fluid of 20%FBS+ α MEM Beta -mercaptoethanol is configured to into 1mM and changes liquid, blank changes liquid entirely for α MEM culture medium.After culture 24hr, Positive control changes 200 μM of BHA (Butylated hydroxyanisole, Butylated hydroxyanisole) into, Continue to cultivate 5hr, detect FL and RL readings.By comparing Relative Luciferase=RFL/RRL values, Obtaining affects the candidate compound of neural stem cell Nestin expression.

Neural stem cell differentiating experiment

The SD rats of pregnant 13～14 days are put to pre-cooling D-Hanks bufferings with embryo is taken after 10% chloral hydrate anesthesia Take out in liquid and remove under embryo and brain, anatomic microscope clean meninges and isolate hippocampuss, by hippocampal tissue It is cut into 1～2mm³Fritter, the DMEM/F12+1%N2+2%B27 cells training liquid piping and druming with 37 DEG C of preheatings is multiple, obtains To cell suspension, Jing cell sieve filtration cell suspensions obtain unicellular, with 5 × 10⁵Individual cell density kind in Culture dish, adds (20ng/mL) containing EGF, the cell culture fluid of bFGF (20ng/mL) to be placed in titanium dioxide With 5%CO in carbon incubator₂, 95% saturated moist air culture, partly change liquid every other day, cultivate 6 days, centrifugation (1000g, 2 minutes) neural ball is collected, passed on Jing after Accutase digestion is for discrete cellular.

1) the adherent differentiation of neural ball：P1 is taken for more uniform neural ball centrifugation (1000g, 2 minutes) of size, Plant in having overlay in the Tissue Culture Dish of PDL, the compound group for arranging blank control group and each concentration is processed 48hr～72hr carries out subsequent experimental.

2) the adherent differentiation of discrete cellular：Take P1 for size it is more uniform neural ball centrifugation (1000g, 2 points Clock), discrete cellular is digested to Accutase, discrete cellular equably planted after recentrifuge in overlaying In the Tissue Culture Dish of PDL, arrange the compound group process of blank control group and each concentration is carried out for 3 days or 7 days Subsequent experimental.

BrdU mixes experiment

5-Bromo-2-deoxyUridine (BrdU), Chinese name 5- bromodeoxyuridine nucleoside, before being DNA Body thymidine analog, by competition S phase cell single stranded DNA nucleotide sequences are mixed, and substitute thymus Pyrimidine.Using BrdU antibody, by the method for immunocytochemical stain, proliferative cell is can detect.This reality Test with the culture neural molecular biology of 7 days, Jing after Accutase is digested to discrete cellular, use containing BrdU DMEM/F12+1%N2+2%B27 training liquid is diluted to 5 × 10⁵Individual cell density kind is in 24 orifice plates for having overlay PDL In, culture carries out immunofluorescence dyeing after 3 days or 7 days.

Immunofluorescent staining

Cell Jing PBS are washed 2 times, are added after 4% paraformaldehyde fixes 20 minutes, wash 3 times with PBS, every time 5 minutes, with the PBS liquid containing 0.1% TritonX-100 it is penetrating 5～10 minutes after, PBS washs 3 times, every time 5 Minute, 10% hyclone be incubated at room temperature 1 hour close, after with confining liquid prepare an anti-solution overnight incubation. Wash 3 times with PBS again, 5 minutes every time, corresponding two anti-incubation at room temperature 1 hour, PBS is washed 3 times, every time 5 points Clock, mounting.For BrdU immunofluorescence dyeings, cell is also needed with the HCl room temperature treatments of 2N Jing after fixing 30 minutes, make DNA degeneration, then with the sodium tetraborate of 0.1mol/L and 15 minutes, then carry out follow-up reality Test.

Detected by Western blot (Western Blot)

The pre-cooled PBS of cell washes 2 times and adds RIPA lysates (Tris-HCl 50mM, pH7.4, NaCl afterwards 150mM, EDTA 1mM, Na-deoxycholate 0.25%, NP-401%, PMSF 1mM, Na₃VO₄1mM, The μ g/mL of NaF 1mM, Aprotinin 10, Leupeptin 5 μ g/mL, the μ g/mL of Pepstatin 5), Crack 30 minutes on ice.Scraped with cell and scrape lysate, collection lysate to centrifuge tube, 15000g, 4 DEG C centrifugation 15 minutes.Supernatant is drawn, part Coomassie Brilliant Blue is taken and is determined protein concentration, in remaining egg 4 × sample buffer, boiling water bath is added to collect protein sample after 5 minutes in Bai Shangqing.Sample Jing SDS/PAGE It is transferred on pvdf membrane after electrophoretic separation.It is anti-4 DEG C with the one of dilution after 5% defatted milk powder room temperature is closed 1 hour Overnight incubation.Next day, sample strip TBST washes three times, every time 10 minutes.Incubation at room temperature two anti-1～1.5 Hour, sample strip TBST is washed three times, after incubation ECL colour developings, is imaged with ImageQuant LAS 4000 Instrument development is taken pictures.

2- substituted-aminos -4- amino -5- (3- the methoxyphenoxies)-quinoline azoles of the present invention of testing example 1 Quinoline class compound has regulating and controlling effect to nestin expression in SD rat marrow stroma cells

The selection result：

The selection result is shown in Fig. 1.As a result show, compound Yhhu-3469, Yhhu-3479, Yhhu-3491, Yhhu-3492、Yhhu-4282、Yhhu-3472、Yhhu-3476、Yhhu-3477、Yhhu-3478、 Yhhu-3481, Yhhu-3482, Yhhu-3487, Yhhu-3493 make the expression of Nestin significantly raise；Change Compound Yhhu-3791, Yhhu-3792 significantly reduce the expression of Nestin.

The checking of screening：

Using immunofluorescence dyeing method, detect the above-mentioned micromolecular compound for filtering out to marrow stromal cell The expression (Fig. 2) of the significant albumen Nestin of middle neural stem cell.

As a result show, Yhhu-3478, Yhhu-3487, Yhhu-3493 compound makes Nestin positive cells Number increases.

2- substituted-aminos -4- amino -5- (3- the methoxyphenoxies)-quinoline azoles of the present invention of testing example 2 Quinoline class compounds on nerve stem cell differentiation with facilitation

2.1 compound Yhhu-3477, Yhhu-3481 can promote Differentiation of Neural Stem Cells

Compound Yhhu-3477, Yhhu-3481 are with 1 μM of mass action in neural molecular biology and discrete god Jing stem cell, with the method and Western blot of immunofluorescence dyeing, detects neuron-specific labelled protein Tuj-1 (Fig. 3 and Fig. 4).

Statistical result shows that Yhhu-3477, Yhhu-3481 compound can be such that Tuj-1 expressions significantly increase Plus, the neuron ratio of differentiation is dramatically increased.

2.2 compound Yhhu-3791 and Yhhu-3792 can be to Neural Stem Cells and starlike colloid Cell differentiation has facilitation

By Yhhu-3791 and Yhhu-3792 compound effects in neural molecular biology, with immunofluorescence dyeing Method detects the expression feelings of neuron-specific labelled protein Tuj-1 and astrocyte labelled protein GFAP Condition, as a result shows：Compound Yhhu-3791 and Yhhu-3792 can make the expression of Tuj-1 and GFAP Increase (Fig. 5).

As a result show, Yhhu-3791 and Yhhu-3792 has promotion Neural Stem Cells and starlike glue The effect of cell plastid differentiation.

2- substituted-aminos -4- amino -5- (3- the methoxyphenoxies)-quinoline azoles of the present invention of testing example 3 Quinoline class compounds on nerve stem cells hyperplasia has facilitation, and relevant with Notch signal paths.

The present embodiment have studied Nestin and lower compound (such as Yhhu-3791 and Yhhu-3792) to nerve trunk The impact of cell propagation.

3.1 compound Yhhu-3791 and Yhhu-3792 promote the propagation of neural stem cell

As a result it is as shown in Figure 6.Immunofluorescence dyeing result shows that compound Yhhu-3791 and Yhhu-3792 exist When 1 μM of concentration neural molecular biology can increase.As a result show, compound Yhhu-3791 and Yhhu-3792 plays the role of propagation to neural stem cell.

As a result it is as shown in Figure 7.The method mixed using BrdU, is as a result shown, compound Yhhu-3792 can be with Dramatically increase cell BrdU positive rates.As a result show, compound Yhhu-3792 is to cell proliferation of nerve cord With facilitation.

3.2 compound Yhhu-3792 can promote neuron and astrocyte number to increase

As a result it is as shown in Figure 8.By BrdU, altogether calibration method can be true with specific marker proteins' immunofluorescence Determine the type of proliferative cell, as a result show, Yhhu-3792 compounds can promote neuron (BrdU⁺/Tuj-1⁺) and astrocyte (BrdU⁺/GFAP⁺) quantity increase.

3.3Notch signal paths take part in the effect that Yhhu-3792 compounds promote nearly cell proliferation of nerve cord

Notch signal paths are closely related with cell proliferation of nerve cord, detected using Western blot Effect of the Yhhu-3792 compounds to Notch signal paths.

As a result as shown in Figure 9 and Figure 10.As a result show, compound Yhhu-3792 can increase Notch-1 and receive The expression of body expression and endonuclear Notch receptor activated form NICD.As a result show, Notch Signal path take part in the effect that Yhhu-3792 compounds promote cell proliferation of nerve cord.

As a result it is as shown in figure 11.SHH signal paths are closely related with cell proliferation of nerve cord, by Western Blot detects effect of the Yhhu-3792 compounds to SHH signal paths.As a result show, SHH signal path phases Receptor Patched expressions are closed without significant change.As a result show, compound Yhhu-3792 is logical to SHH signals Road has no significant effect.

The all documents referred in the present invention are all incorporated as in this application reference, just as each document It is individually recited as with reference to such.In addition, it is to be understood that after the above-mentioned teachings for having read the present invention, Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen Please appended claims limited range.

Claims (10)

1. a kind of compound of formula I, its optical isomer, hydrate, solvate, its prodrug or its pharmaceutically Acceptable salt,

In formula,

R₁And R₂It is each independently selected from the following group：

(i)H；

(ii) substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀Alkenyl, replacement or Unsubstituted C₂-C₁₀Alkynyl group, substituted or unsubstituted C₃-C₁₀Cycloalkyl；Wherein described being substituted by has One or more substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Alkyl halide Base, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro, C₁- C₃Carboxyl ,-R₄-R₅Group ,-NR₆(R₇)、 Unsubstituted phenyl or by C₁-C₃The phenyl of alkyl or halogen substiuted；

(iii) substituted or unsubstituted C₅-C₂₀Aryl, substituted or unsubstituted C₃-C₂₀Heteroaryl, replacement or Unsubstituted 5-20 circle heterocycles base, substituted or unsubstituted C₁₀- C₃₀Condensed ring radical；Wherein, the heteroaryl Base or heterocyclic radical contain 1 to 3 hetero atom selected from N, O, S, and described are substituted by with one Or multiple substituent groups being selected from the group：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN, nitro ,-NR₆(R₇)；

Wherein R₄Selected from unsubstituted or halo C₁- C₈Alkylidene, and R₅Selected from unsubstituted or halo C₅- C₂₀Aryl；R₆And R₇It is each independently hydrogen, unsubstituted or halo C₁-C₁₀Alkyl, it is unsubstituted or The C of halo₂-C₁₀Alkenyl, unsubstituted or halo C₂-C₁₀Alkynyl；

Or, R₁With R₂Containing at least one nitrogen-atoms, replacement can be collectively forming with the N atoms being connected Or in unsubstituted 3-8 circle heterocycles base, and described 3-8 circle heterocycles bases altogether containing 1-3 selected from N, The hetero atom of O, S, wherein described is substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₂-C₁₀Alkenyl, C₂-C₁₀Alkynyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀ Halogenated alkoxy ,-OH ,-CN, nitro ,-NH₂、C₁- C₃Carboxyl；

And R₃It is selected from the group：H, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₂- C₁₀ Alkenyl, substituted or unsubstituted C₂-C₁₀Alkynyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl；It is wherein described Be substituted by the substituent group being selected from the group with one or more：Halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxyl, C₁-C₁₀Haloalkyl, C₁-C₁₀Halogenated alkoxy ,-OH ,-CN ,-NH₂。

2. compound of formula I as claimed in claim 1, its optical isomer, hydrate, solvate, Its prodrug or its pharmaceutically acceptable salt, it is characterised in that the compound has the knot shown in Formulas I a Structure：

In formula, R₁And R₂Definition it is as claimed in claim 1.

3. compound of formula I as claimed in claim 1, its optical isomer, hydrate, solvate, Its prodrug or its pharmaceutically acceptable salt, it is characterised in that the compound is selected from the group：

4. compound of formula I as claimed in claim 1, its optical isomer, hydrate, solvate, Its prodrug or its pharmaceutically acceptable salt, it is characterised in that the compound is selected from the group：

5. a kind of compound of formula I, its optical isomer, hydrate, solvate, its prodrug or its pharmacy The purposes of upper acceptable salt, it is characterised in that for preparing medicine or preparation, the medicine or preparation are used Neurodegenerative diseases are treated in (i)；(ii) repairing nerve damage；And/or (iii) promotes nerve Stem cells hyperplasia.

6. purposes as claimed in claim 5, it is characterised in that the medicine or preparation can be additionally used in (i) The expression of regulation and control nestin；And/or (ii) promote Neural Stem Cells and neurogliocyte point Change.

7. a kind of pharmaceutical composition, it is characterised in that include：

Compound of formula I described in (i) claim 1, its optical isomer, hydrate, solvate, Its prodrug or its pharmaceutically acceptable salt；With

(ii) pharmaceutically acceptable carrier.

8. pharmaceutical composition as claimed in claim 7, it is characterised in that in described pharmaceutical composition, contain The component (i) of 0.0001-99wt% (preferably 0.01-90wt%, more preferably, 0.1-80wt%), with medicine group The gross weight meter of compound.

9. the preparation method of a kind of compound of formula I or its pharmaceutically acceptable salt, it is characterised in that including step：

In atent solvent, in the presence of base, the amine shown in compound 6 and Formula II is reacted, so as to Obtain compound of formula I；

In various, R₁、R₂And R₃As defined in claim 1.

10. a kind of midbody compound, it is characterised in that the midbody compound is selected from the group：