CN103709172B - Substituted furan and piperidine derivative and its application - Google Patents

Substituted furan and piperidine derivative and its application Download PDF

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Publication number
CN103709172B
CN103709172B CN201210369245.2A CN201210369245A CN103709172B CN 103709172 B CN103709172 B CN 103709172B CN 201210369245 A CN201210369245 A CN 201210369245A CN 103709172 B CN103709172 B CN 103709172B
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piperidines
anilino
pyrimidine radicals
furans
methyl
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CN103709172A (en
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刘飞
陈盼
赵鑫鑫
桂力
王佳
朱新荣
王亚洲
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Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Abstract

The present invention relates to biomedicine field, and in particular to substituted furan and piperidine derivative and its application, such compound have formula（I）Structure.Present invention also offers such substituted furan and purposes of the piperidine derivative as Janus kinase inhibitors.

Description

Substituted furan and piperidine derivative and its application
Technical field：
The present invention relates to biomedicine field, and in particular to substituted furan and piperidine derivative or its is pharmaceutically acceptable Salt, and preparation method thereof and the purposes as Janus kinase inhibitors.
Background technology：
Protein kinase is made up of a series of enzyme related in structures, the control of main responsible intracellular signal transduction process. Generally, protein kinase by influence from ribonucleoside triphosphote to participate in signal transduction path protein receptor phosphinylidyne group-transfer, and Mediate intracellular signal.These phosphorylation events play modulation or the molecular switch effect of regulation target protein biological function.A lot Disease is all relevant with the abnormal cell reaction triggered by above-mentioned protein kinase mediated event.
Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2 belong to cytoplasm protein kinases, with I type and II type Cytokine receptor acts on, and adjusts cytokine signaling.JAK1, JAK2 and TYK2 can suppress several genes expression, so And JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor are present as heterodimer form, therefore Not usually a kind of jak kinase acts on cytokine receptor.
The stream substrates of JAK families include signal transduction agent and the activator (STAT) of transcription factor.JAK/STAT signals Transduction is related to many abnormal immunes and reacted, such as allergy, asthma, autoimmunity disease such as graft rejection, rheumatoid arthritis, Muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukaemia, lymthoma.
Genetic biology research shows, JAK1 by with the cell factor receptor such as IFNalpha, IFNgamma, IL-2, IL-6 Body is acted on and played a role, and JAK1 knock-out mices are dead because LIF receptor signals lack.Observe the feature of JAK1 knock-out mices Tissue, it is found that JAK1 plays an important role in the cell pathways such as IFN, IL-10, IL-2/IL-4, and IL-6.
Genetic biology research shows that JAK2 exists with single-stranded between IL-3 and interferon gamma cytokine receptor family Contact.Corresponding, JAK2 knock-out mices die from anaemia.Kinase mediated JAK2 variations and human bone marrow's proliferative disorder phase Close, including polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with myelofibrosis Myeloide metaplasia, chronic special myelomatosis, chronic myelomonocytic leukemia etc..
JAK3 is specific to act on gamma cells factor acceptor chain, and it is in IL-2, IL-4, IL-7, IL-9, IL-15, IL- Exist in 21 grade cytokine receptors.JAK3 is in lymphocyte growth, hyperplasia, is played an important role in mutation process, occurs different Serious immune deficiency can often be caused.The effect of lymphocyte is adjusted based on it, the path that JAK3 and JAK3 are mediated is used for Adjust immunosuppressive indication.JAK3 implications in the mediation of many abnormal immune responses, such as allergy, asthma, from Body immunological diseases such as suppress graft rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity With hematologic malignancies such as leukaemia, lymthoma.
TYK2 acts on the cytokine receptor complex such as interferon type Ⅰ, IL-6, IL-10, IL-12, IL-23.Phase therewith It is consistent, the primary cell of the people derived from TYK2 missings, in interferon type Ⅰ, IL-6, IL-10, IL-12, IL-23 letter Number conduction in obstacle be present.
In summary, there is an urgent need to develop the compound available for kinases inhibitor, specifically, it is necessary to develop Compound available for JAK family kinase inhibitors.Novel compound of present invention can suppress one or more jak kinases, because This is expected to can be used for treating associated disease.
The content of the invention：
It is an object of the invention to provide a kind of new substituted furan and piperidine derivative.
Another object of the present invention is to provide a kind of above-mentioned substituted furan and purposes of the piperidine derivative in terms of medicine.
The purpose of the present invention can be reached by following measures：
A kind of substituted furan and piperidine derivative, such as general structure（I）Compound or its pharmaceutically acceptable salt：
Wherein：
R1For alkyl, cycloalkyl, acyl group, alkyl acyl, sulfonyl, the alkyl sulphonyl arbitrarily substituted；The substituent For hydrogen, C1-6Straight or branched alkyl, the C of hydroxyl substitution1-6The C of straight or branched alkyl, halo1-6Straight or branched alkyl, C3-7Cycloalkyl, C2-6Straight or branched alkenyl, halogen ,-CN ,-NHSO2R12、-NHOH、-NHCOR12、-CON(R12)2、-CO (CH2)mNHC(O)OR12、-N(R12)2、-OR12、-CF3、R2For hydrogen, halogen, C1-6Straight chain or branch Alkyl group, cycloalkyl, halo C1-6Straight or branched alkyl；
R3For hydrogen, halogen；
Or R2With R3And one 5 yuan of heteroaryl ring group is formed together with connecting their carbon atom；
Z independences are selected from N or CR13；
N or m is independently 0,1,2 or 3；
R4Independently selected from hydrogen, halogen, R5’、-OR5’、-OH、R6、-CN、-CF3、-N（R1）R5R6、NHSO2R6、-N(CH3) R5N(R5’)2、-NHR5OR5OH、-NHR5R6、-N(CH3)R6、-NHR5N(R5’)2、-NHR6、-OR5N(R5’)2、-(CH2)pN (R5)2、-NO2、-R5R6、-OR5R6、Substituted or unsubstituted saturation or undersaturated 5 or 6 circle heterocycles Base, or adjacent two R4Substituent carbon atom in connection is collectively forming saturation or undersaturated 5 or 6 circle heterocycles Base；The substituent is hydrogen, halogen, amino ,-CN, C1-3Alkylamino, nitro, C1-3Alkyl sulphonyl, hydroxyl, C1-6Straight chain or branch Alkyl group, C1-3Alkoxy, C1-3Acyloxy, the C of hydroxyl substitution1-6The C of straight or branched alkyl, halo1-6Straight or branched alkane Base, C3-7Cycloalkyl, C3-7Cycloalkanes formoxyl, dioxanes base, pyrrolidinyl, pyrrolidinomethyl or piperidyl；
P is 1,2 or 3；
R5It is substituted or unsubstituted C1-4Alkylidene, wherein at most two carbon atoms can be optionally by CO, S, SO2Or O Substitute；The substituent is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C1-3Alkylamino, C1-6Straight or branched alkyl, C1-3Alkane Epoxide, C1-3Acyloxy, C1-3Alkyl sulphonyl, the C of hydroxyl substitution1-6The C of straight or branched alkyl, halo1-6Straight or branched Alkyl, C3-7Cycloalkyl, C3-7Cycloalkanes formoxyl, dioxanes base, pyrrolidinyl, pyrrolidinomethyl or piperidyl；
R5' it is hydrogen, substituted or unsubstituted C1-4Alkyl, wherein at most two carbon atoms can be optionally by CO, S, SO2、 Or O is substituted；The substituent is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C1-3Alkylamino, C1-6Straight or branched alkyl, C1-3Alkoxy, C1-3Acyloxy, C1-3Alkyl sulphonyl, the C of hydroxyl substitution1-6The C of straight or branched alkyl, halo1-6Straight chain or Branched alkyl, C3-7Cycloalkyl, C3-7Cycloalkanes formoxyl, dioxanes base, pyrrolidinyl, pyrrolidinomethyl or piperidyl；
R6It is NH2、NHR5’、C1-4Alkoxy, cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted furans Base, substituted or unsubstituted morpholinyl, substituted or unsubstituted thio-morpholinyl, substituted or unsubstituted piperazinyl, substitution or In unsubstituted piperidyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrole radicals, Qu generations, do not substitute oxazoles Base, substituted or unsubstituted imidazole radicals；The substituent is hydrogen, halogen, nitro, the C of halo1-3Alkoxy, C1-3Alkane sulfonyl, Amino ,-CN, hydroxyl, C1-6Straight or branched alkyl, C1-3Alkoxy, C1-3Acyloxy, the C of hydroxyl substitution1-6Straight or branched alkane The C of base, halo1-6Straight or branched alkyl, C3-7Cycloalkyl, C3-7Cycloalkanes formoxyl, dioxanes base, pyrrolidinyl, pyrrolidines first Base or piperidyl；
R12Selected from hydrogen ,-CN ,-NHSO2R5', halogen ,-N (R5’)2、-OR5’、-COOR5’、-CF3Or C1-4Straight or branched Alkyl, C3-7Cycloalkyl；
R13Selected from hydrogen, C1-3Alkoxy.
The present invention also aims to provide the purposes of new substituted furan and piperidine derivative, specifically conduct The purposes of Janus kinase inhibitors.
Detailed description of the invention
Alkyl represents the straight or branched saturated hydrocarbyl for being unsubstituted or being substituted of the carbon atom with certain amount.Such as Clearly limited without other, the alkyl in the present invention is usually to have 1-10 carbon number, can further have 1-8 carbon atom Number, can further have 1-6 carbon number, can further have 1-4 carbon number, most preferably 1-3 carbon atom Number.Typical alkyl includes（But it is not limited to）Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, positive penta Base, isopentyl, neopentyl, n-hexyl, isohesyl, 3- methylheptyls, 2,2- dimethylbutyls and 2,3- dimethylbutyls.
Alkenyl represents the alkyl with one or more carbon-to-carbon double bonds.It is typically include（But it is not limited to）Vinyl, propylene Base, cyclohexenyl group etc..Connection alkenyl is known as " alkenylene " herein.
Alcoxyl basis representation-O- alkyl, wherein alkyl are as defined herein.Typically C1-6Alkoxy, including but not limited to Methoxyl group, ethyoxyl.
The monocyclic of all carbon of cycloalkanes basis representation, fusion, the ring of loop coil or bridged ring.Typically cyclopropane, cyclobutane, ring Pentane, cyclopentene, hexamethylene, spiral shell [3.4] octane, two rings [3.1.1] hexane.
Alkylene basis representation in itself or the part as another substituent, means the straight chain with two terminal monovalent radical centers Saturation or unsaturated alkane diyl, it respectively removes a hydrogen atom from two terminal carbon atoms of straight chain mother alkane, alkene or alkynes and obtained.Allusion quotation The alkylidene of type includes（But it is not limited to）Methylene, ethylidene, ethenylidene, ethynylene, propylidene, butylidene etc..
The heterocyclic radical of saturation is Heterocyclylalkyl, represents heteroatomic monocyclic or fusion the ring containing one or more N, O or S. Heteroatomic 5-6 circle heterocycles base typically containing one or more N, O or S, such as Piperazino, morpholino base, piperidines Base, pyrrolidinyl and its derivative.
Piperazino refers to the group with following chemical constitution.
Morpholino base refers to the group with following chemical constitution.
Thiomorpholine refers to the group with following chemical constitution for base.
Piperidino refers to the group with following chemical constitution.
Pyrrolidinyl refers to the group with following chemical constitution.
Undersaturated heterocyclic radical is heteroaryl, represent 5 to 12 annular atoms monocyclic or fused ring group, containing one, Two, three or four ring hetero atoms for being selected from N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated System.Typical heteroaryl（But it is not limited to）Pyrroles, furans, thiophene, imidazoles, oxazoles, thiazole, pyrazoles, pyrimidine, pyridine.
Halogen or halogen group are fluorine, chlorine, bromine or iodine.Preferably fluorine, chlorine, bromine.The C being optionally substituted by halogen1-3Alkyl group table Show that wherein one or more hydrogen are by the alkyl of halogen displacement, preferably halogen group containing one, two or three.
Acyl group refers to "-C (O)-" or " HC (O)-" group, when the carbon number of specific acyl group is more than 1, refers to alkyl acyl Base.Alkyl acyl refers to there is alkyl-substituted acyl group, i.e. " alkyl-C (O)-".Such as clearly limited without other, in the present invention Alkyl acyl refers to C2-6Alkyl acyl, can be further C2-5Alkyl acyl, be further C2-4Alkyl acyl.
Sulfonyl refers to "-SO2- " or " HSO2- " group, when the carbon number of specific sulfonyl is more than 1, refer to alkyl Sulfonyl.Alkyl sulphonyl refers to there is alkyl-substituted sulfonyl, i.e. " alkyl-SO2-”.Such as clearly limited without other, this hair Alkyl sulphonyl in bright refers to C2-6Alkyl sulphonyl, can be further C2-5Alkyl sulphonyl, be further C2-4 Alkyl sulphonyl.
In a kind of preferred scheme,
R1For：
Wherein R7For C1-6Straight or branched alkyl, C2-6Straight or branched alkenyl ,-CN ,-NHSO2R12、-NHOH、- NHCOR12、-CON(R12)2、-NHC(O)OR12、-N(R12)2、-OR12、-CF3、R7Can be further Preferably C1-4Straight or branched alkyl, C2-6Straight or branched alkenyl ,-CN ,-N (R12)2、-NHSO2R12、-NHC(O)OR12、Further, R7Can be-CN, NH2、 -NHC(O) OR12, methyl, ethyl, pi-allyl or isopropyl；
R8For C1-6Straight or branched alkyl, C3-7Cycloalkyl,R8Can be more preferably C1-4Straight or branched alkyl, C3-5Cycloalkyl,Further, R8Can be methyl, ethyl, n-propyl, different Propyl group, normal-butyl,
R9、R10Or R11It is identical or different, it is each independently selected from halogen, hydrogen ,-CN, C1-6Straight or branched alkyl, C3-7Cycloalkanes Base,R9、R10Or R11Be preferably selected from independently of one another halogen, hydrogen ,-CN orMore Further, R9Or R10For hydrogen, R11For-CN or
R12Selected from hydrogen ,-CN ,-NHSO2R5, halogen ,-N (R5)2、-OR5、-CF3Or C1-4Straight or branched alkyl；R12It can enter One step is preferably selected from halogen, methyl, the tert-butyl group ,-CN or hydrogen；Further, R12For-CN, methyl, the tert-butyl group or hydrogen；
X is selected from S, NH or O, can be more preferably S；
M is 0,1,2 or 3, can be more preferably 0 or 1.
In a kind of preferred scheme, R2For hydrogen, halogen, C1-C4 straight or branched alkyls or halo C1-C4 straight or brancheds Alkyl；R3For hydrogen；Or R2、R3Following heterocyclic radical is formed together with connecting their carbon atom：
As a preferred embodiment, R2For hydrogen ,-CH3Or-CF3；R3For hydrogen.
In a kind of preferred scheme, Z CR13, R13Selected from hydrogen, C1-3Alkoxy；In a kind of preferred scheme, Z is CR13, R13Selected from hydrogen, methoxyl group.
In a kind of preferred scheme, R4For hydrogen, halogen ,-NO2、-OH、-N（R1）R5R6、-N(CH3)R5N(R5’)2、- NHR5OR5OH、-N(CH3)R6、-NHR6、-NHR5N(R5’)2、-NHR5R6、-OR5N(R5’)2、-(CH2)pN(R5’)2、、C1-6Straight or branched alkoxyl, substituted or non-substituted saturation or undersaturated 5 or 6 circle heterocycles Base ,-OR5R6, or adjacent two R4Substituent carbon atom in connection is collectively forming 5 yuan of heteroaryl ring group；
Further, R4Can be hydrogen ,-F ,-NO2、-OH、-N（R1）R5R6、NHSO2R6、-N(CH3)R5N(R5’)2、-N (CH3)R6、-NHR6、-NHR5R6、-NHR5OR5OH、-OR5N(R5’)2、-NHR5N(R5’)2、C1-4Straight or branched alkoxyl, pyrrole Cough up alkyl, C1-6Alkyl-substituted pyrrolidinyl, pyrrolidinyl, piperidyl, the C of pyrrolidinomethyl substitution1-6Alkyl-substituted piperazine Piperidinyl, C1-3The piperidyl of alkoxy substitution, the piperidyl of piperidyl substitution, hydroxy piperidine base, the piperidines of dimethylamino substitution Base, hydroxyl C1-3Alkyl-substituted piperidyl, C2-4Piperidyl, piperazinyl, the C of alkyl acyloxy substitution1-6Alkyl-substituted piperazine Piperazine base, morpholinyl, thio-morpholinyl, C1-6Alkyl-substituted morpholinyl, imidazole radicals, C1-6Alkyl-substituted imidazole radicals,-OR5R6Or two R4Substituent carbon atom in connection forms together Following heterocyclic radical：
Further, R4Can be hydrogen ,-OCH3、 R5R6、-N(CH3)R5N(R5’)2、NHSO2R6、-NR5R6、-N(CH3)R6、-NHR6、-NHR5N(R5’)2、-NR5OR5OH、-OR5N (R5’)2、、OR5R6Or two R4Substituent carbon atom in connection forms together
Wherein, R5Can be substituted or unsubstituted C1-3Alkylidene, it is further
R5' can be substituted or unsubstituted C1-3Alkyl；
P can be 2 or 3；
R6Can be NH2、C1-6Straight or branched alkylamino, C1-3Alkoxy, substituted or unsubstituted phenyl, substitution or not Substituted furyl, cyclopropyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thio-morpholinyl, substitution do not take The piperazinyl in generation, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrole radicals, In Qu generations, do not substitute oxazolyls, substituted or unsubstituted imidazole radicals；Further, R6Can be C1-3Alkoxy, substitution do not take It is the phenyl in generation, substituted or unsubstituted furyl, cyclopropyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thio Morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidinyl, substitution Or unsubstituted pyrrole radicals, Qu generation or do not substitute oxazolyls, substituted or unsubstituted imidazole radicals；Further, R6Can be with It is-OCH3、
In above-mentioned preferred scheme, R4、R5、R5' and R6In substituent can be separately hydrogen, halogen, hydroxyl, nitre The C of base, halo1-3Alkoxy, mesyl, cyano group, dimethylamino, C1-6Straight or branched alkyl, C1-3Alkoxy, C1-3Acyl-oxygen Base, the C of hydroxyl substitution1-6Straight or branched alkyl, C3-7Cycloalkyl, C3-7Cycloalkanes formoxyl, dioxanes base or piperidyl；Enter one Step ground, each substituent can be hydroxyl, nitro, the C of halo1-3Alkoxy, mesyl, dimethylamino, C1-6Straight or branched Alkyl, C1-3Alkoxy, C1-3Acyloxy, C3-4Cycloalkyl, the C of hydroxyl substitution1-6Straight or branched alkyl, pyrrolidinyl, pyrroles Alkane methyl, piperidyl.
In a kind of scheme, R6In substituent for hydrogen, hydroxyl, C1-6Straight or branched alkyl, cyano group, halogen, halo C1-6Straight or branched alkyl, nitro, the C of halo1-3Alkoxy, C1-3Alkoxy, mesyl, the C of hydroxyl substitution1-6Straight chain or Branched alkyl, piperidyl.
In a kind of preferred scheme, n 1,2 or 3；Further, when n is 1, R13Selected from hydrogen, methoxyl group, R4For phenyl ring The para-orientating group or meta-substituent of upper amino；When n is 2, R13Selected from methoxyl group, R4Meta for amino on phenyl ring and right Bit substituent；When n is 3, R13For hydrogen, R4Face position and para-orientating group, and R for amino on phenyl ring4For halogen.
Formula（I）Substituted furan and piperidine derivative or its pharmaceutically acceptable salt, compound therein can be specific Including those Compound of Example listed in Table：
Present invention also offers a kind of pharmaceutical composition, is particularly used to treat jak kinase relevant disease in organism Pharmaceutical composition, including above-mentioned each compound provided by the invention is as active component, and pharmaceutically acceptable carrier, figuration Agent or diluent.
Pharmaceutically acceptable salt represents to retain the biological effectiveness of parent compound and those salt of property.Wherein with acid Refer into salt, obtained by the free alkali of parent compound with the reaction of inorganic acid or organic acid.Inorganic acid includes hydrochloric acid, hydrogen bromine Acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc..Organic acid include acetic acid, propionic acid, acrylic acid, oxalic acid,（D） Or（L）Malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, first sulphur Acid, ethyl sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, amber Amber acid or malonic acid etc..
Pharmaceutical composition refers to one or more the compounds of this invention or their pharmaceutically acceptable salt with before Medicine and other chemical compositions, including the mixture of pharmaceutically acceptable carrier and excipient.The purpose of Pharmaceutical composition is Promote the administration of compound on organism body.
Pharmaceutically acceptable carrier refers to not causing obvious excitant to organism and does not disturb given chemical combination The bioactivity of thing and the carrier of property or diluent.
Excipient is referred to being added in Pharmaceutical composition with the further convenient inert substance for giving compound.Figuration The example of agent includes（It is not limited to）It is calcium carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, bright Glue, vegetable oil and polyethylene glycol.
The invention further relates to formula（I）Preparation method, it is characterised in that including,
（a）Amine fragment（V）With substituted carboxylic acid（VI）In solvent S1Middle alkali B1, catalyst C1, condensing agent L1In the presence of in temperature T1Under the conditions of reaction generation compound（I）.
B. amine fragment（V）With substituting acyl chlorides（Ⅶ）In solvent S1Middle alkali B1In the presence of in temperature T1Under the conditions of react generationization Compound（I）.
C. amine fragment（V）With substituted halogenated hydrocarbons（Ⅷ）In solvent S2Middle alkali B2In the presence of in temperature T2Under the conditions of react life Into compound（I）.
Wherein R1、R2、R3、R4It is as described above with n.
In order to prepare formula of the present invention（I）Described in compound, described preparation method, it is characterised in that preparing During, described solvent S1Selected from organic solvent, such as dichloromethane, ethyl acetate, acetonitrile, acetone, preferably dichloromethane, Acetonitrile；Described alkali B1Selected from organic base, such as triethylamine, preferably N- ethyl diisopropylamines, triethylamine；Described catalyst C1 Can be to dimethylamino naphthyridine, 4- pyrollidinopyridines, I-hydroxybenzotriazole, tributylphosphine, preferably 1- hydroxy benzos three Azoles；Condensing agent L1For phosphinylidyne diimidazole, dicyclohexylcarbodiimide, 1- ethyls-（3- dimethylaminopropyls）Carbodiimide, it is excellent Elect as 1- ethyls-（3- dimethylaminopropyls）Carbodiimide；Temperature T1For -15-15 °C, preferably 0 °C；Described solvent S2 Selected from polar non-solute, such as acetonitrile, acetone, DMF, preferably acetonitrile；Described alkali B2It can think that inorganic base can also For organic base, preferably triethylamine, potassium carbonate；Temperature T2For 50-100 °C, preferably 70 °C.
Present invention also offers the purposes of new substituted furan and piperidine derivative, specifically as Janus kinases The purposes of inhibitor, further say it is the disorder agent aspect for being applied to prepare treatment JAK mediations.Including but do not limit to In, polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with the marrow of myelofibrosis Property metaplasia, chronic special myelomatosis, chronic myelomonocytic leukemia, allergy, asthma, autoimmunity Disease such as suppresses graft rejection, rheumatoid arthritis, psoriasis, lupus erythematosus, muscle contracting lateral sclerosis and multiple hard Change and entity and hematologic malignancies such as leukaemia, lymthoma etc..
Invention additionally provides application of the above-mentioned each compound in terms of the disorder agent for the treatment of JAK2, JAK3 mediation is prepared, Any defined compound or its medicine in the present invention including applying effective dose to the system or individual that need such treatment Composition, so as to treat the illness.
In order to examine exposure level of the compound provided by the invention for jak kinase, surveyed using biochemistry level enzymatic activity Try to determine activity and exposure level of the various compounds of the present invention to one or more PK.Use well known side in technique Method, similar experiment can be designed in the same way for any kinases.
In the test of biochemistry level enzymatic activity, using the activity of HTRF technology for detection EGFR-TKs, when HTRF is a kind of Between resolved fluorescent resonance ability transfer techniques.HTRF (homogeneous phase time discrimination fluorescence) is for detecting determinand in homogeneous system A kind of the most frequently used method, this technology combine FRET (FRET) and TIME RESOLVED TECHNIQUE (TR), It is widely used in the different phase of the medicament research and development based on cell experiment and biochemical test.According to the measuring principle of HTRF methods, Pure enzyme JAK2 after incubation reaction, is added into XL-665 and the identification of Avidin mark together with biotinylated substrate and ATP The antibody of the Eu marks of substrate phosphorylation, after substrate is by JAK2 phosphorylations, the antibody of Eu marks can identify the phosphorylation Product, time-resolved FRET is formed with the XL665 of Avidin mark（FRET）, and the bottom not being phosphorylated Thing can not form FRET signals due to that can not be identified by antibody, be determined by the fluorescence signal difference for determining 665nm and 620nm Determinand is under various concentrations to the inhibitory activity of JAK2, JAK3 kinases.Thus, the compounds of this invention pair can be determined using this method The active function of the biochemistry level of above-mentioned EGFR-TK, while method well known in the art is utilized, other albumen can be swashed Enzyme uses similar assay method.
The compound of structure prepared by the present invention shown in formula I has good inhibiting effect to a variety of kinase activities, its To the half-inhibition concentration of JAK2, JAK3 kinases（IC50）Generally 10-7mol.L-1Below.Thus deduce, the present invention has Formulas I The compound of structure can be applied to prepare the medicine of jak kinase relevant disease in treatment organism.
Specific implementation method：
The invention discloses the intermediate and preparation method thereof of a kind of compound and preparation method thereof, the compound, and its Application of the compound as jak kinase inhibitor, those skilled in the art can use for reference present disclosure, be suitably modified technique ginseng Number is realized.In particular, all similar replacements and change are apparent to those skilled in the art, They are considered as being included in the present invention.The method of the present invention and application are described by preferred embodiment, related Personnel can substantially not depart from present invention, method described herein and application are being modified in spirit and scope or suitably Change is with combining, to realize and using the technology of the present invention.
With reference to embodiment, the present invention is expanded on further：
Embodiment 1：The preparation of compound 1
6- benzyls -2- tributyl tins-furans simultaneously [2,3-c] piperidines
Under nitrogen protection, 6- benzyls-furans simultaneously [2,3-c] piperidines is added into reaction bulb（11.2mg 1eq）With dry four Hydrogen furans（150μL）, n-BuLi is added dropwise under condition of ice bath（16.05 μ L, 1eq）, continue that tributyltin chloride is added dropwise （20.8mg 1.6eq）, it is added dropwise, continues reaction 2.5 hours.Stop reaction, add water quenching to go out, ethyl acetate（10mL*5）Extraction Take, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- benzyls -2- tributyl tins-furan Mutter simultaneously [2,3-c] piperidines（19.25mg）.
2-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Ether is added into reaction bulb（50μL）, the tert-butyl alcohol（50μL）, dichloromethane（50μL）And zinc chloride（9.99mg 2.2eq）, the chloro- 5- trifluoromethyl pyrimidines of 2,4- bis- are added under condition of ice bath（7.24mg 1eq）, 4-（2- pyrrolidines -1- ethoxies Base）Aniline（7.57mg 1.1eq）And triethylamine（6.54mg）, react 2 hours, electromagnetic agitation.Stop reaction, ethyl acetate （10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 2-（4-（2- pyrroles Cough up alkane -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyl pyrimidines of -4-（10.5mg）.
6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
2- is added into reaction bulb（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
（575mg, 1.5eq）, 6- benzyls -2- tributyl tins-furans simultaneously [2,3-c] piperidines（502mg, 1eq）, Pd (PPh3)2Cl2（42.0mg 0.06eq）And DMF（9mL）, 90 degree of heating responses 6 hours, electromagnetic agitation.Stop reaction, ethyl acetate （10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- benzyls -2- （3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines （512.3mg）.
2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine adds 6- benzyls -2- into reaction bulb（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines（563mg, 1eq）, chloroformate -1-chloro-ethyl ester（0.27mL, 2.5eq）, triethylamine（2.4mL）With two Chloromethanes（80mL）, it is stirred at room temperature 7 hours, concentration of reaction solution, adds methanol（20mL）, 60 degree of heating responses 2 hours, it is cooled to room Temperature, there is solid precipitation, filter, 2- is washed to obtain with a small amount of methanol（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoros Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines (407.2mg).
6- Cyanoacetyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
2- is added into reaction bulb（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines（119.2mg, 1eq）, cyanoacetic acid（42.84mg 2eq）, 1- hydroxyls-benzo-triazole （85.11mg 2.5eq）, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride（120.77mg, 2.5eq）, catalytic amount DIPEA and dichloromethane（20mL）, react at room temperature 4 hours, electromagnetic agitation.Stop reaction, add water（20mL）, saturation NaHCO3 The aqueous solution is washed, dichloromethane（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silicagel column Chromatography obtains 6- Cyanoacetyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines（102.0mg）.
MS:[M+H]+=541.1
1H-NMR(400M,DMSO-d6)δ8.63-8.64(d,1H),7.49-7.52(m,2H),7.22-7.23(m,1H), 6.93-6.96(m,2H),4.78(s,2H),4.20(s,2H),3.72-3.75(m,2H),3.62-3.64(m,2H),3.20- 3.22(m,2H),2.79-2.80(m,2H),1.89(s,4H),1.47-1.50(m,4H)ppm。
Embodiment 2：The preparation of compound 2
6- benzyls -2-（The chloro- 6- methyl of 3-）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
6- benzyls -2- tributyl tins-furans simultaneously [2,3-c] piperidines is added into reaction bulb（3.2mg, 1eq）, 2,4- bis- Chloro- 5- methyl-pvrimidines（0.97mg, 1eq）, Pd (PPh3) 2Cl2（0.42mg, 0.1eq）And DMF（5mL）, 80 degree of heating responses 5 Hour.Stop reaction, add water（5mL）, dichloromethane（5mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, it is dense Contracting, crude product silica gel column chromatography obtain 6- benzyls -2-（The chloro- 6- methyl of 3-）Pyrimidine radicals-furans simultaneously ［ 2,3-c ］ piperidines（0.47mg）.
6- benzyls -2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines adds 4- into microwave bottle（Morpholinyl -1- propoxyl group）Aniline（382.4mg, 1.1eq）, 6- benzyls -2-（The chloro- 6- of 3- Methyl）Pyrimidine radicals-furans simultaneously ［ 2,3-c ］ piperidines（500.0mg, 1eq）, the hydrochloric acid solution of dioxane（6.6M）（668μL）, iodine Change potassium（97mg, 0.4eq）And trifluoroethanol（5mL）, in microwave, lower 145 °C are reacted 1 hour.Add water（20mL）, saturation NaHCO3 The aqueous solution is washed, dichloromethane（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silicagel column Chromatography obtains 6- benzyls -2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines（723.6mg）.
2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（The oxygen of morpholinyl -1- third Base）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- mesyls -2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
2- is added into reaction bulb（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines（449.5mg, 1eq）, mesyl chloride（228.7mg, 2eq）, the DIPEA and dichloromethane of catalytic amount（30mL）, Room temperature reaction 2 hours, electromagnetic agitation.Stop reaction, add water（20mL）, saturation NaHCO3The aqueous solution is washed, dichloromethane（10mL* 5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- mesyls -2-（3- （4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines（503.6mg）.
MS:[M+2]+=264.5
1H-NMR(400M,DMSO-d6)δ9.36(s,1H),8.31(s,1H),7.70-7.72(d,2H),7.19(s,1H), 6.89-6.91(d,2H),4.43(s,2H),4.02-4.03(m,2H),3.79-3.81(m,4H),3.47-3.50(m,3H), 3.08(s,4H),2.94(s,4H),2.69(s,2H),2.50(s,3H),2.13-2.15(m,2H)ppm。
Embodiment 3：The preparation of compound 3
2-（4-（2- morpholinyl -1- ethyoxyls）Anilino-）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4-（2- morpholinyl -1- ethyoxyls）Benzene Amine.
6- benzyls -2-（3-（4-（2- morpholinyl -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（2- morpholinyl -1- ethyoxyls）Anilino-）-- the chloro- 5- trifluoromethyls of 4- Pyrimidine.
2-（3-（4-（2- morpholinyl -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（2- morpholinyl -1- ethoxies Base）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（2- morpholinyl -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- morpholinyl -1- ethoxies Base）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=557.1
1H-NMR(400M,DMSO-d6)δ10.12(s,1H),8.74(s,1H),7.64-7.65(d,2H),7.29-7.31 (d,1H),6.94-6.96(d,2H),4.60-4.66(d,2H),4.22(s,2H),4.05-4.08(t,2H),3.76(s,2H), 3.57-3.59(m,4H),2.67-2.69(m,2H),2.58(s,2H),2.47-2.50(m,4H)ppm。
Embodiment 4：The preparation of compound 4
6- benzyls -2-（3-（4-（4- methoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （4- methoxyl group -1- piperidyls）Aniline.
2-（3-（4-（4- methoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- methoxyl group -1- piperidines Base）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6-（Thiophene -2- formoxyls）-2-（3-（4-（4- methoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
2- is added into reaction bulb（3-（4-（4- methoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines（419.5mg, 1eq）, thiophene -2-carboxylic acid（256.3mg, 2eq）, 1- hydroxyls-benzo-triazole（337.7mg 2.5eq）, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride（477.5mg, 2.5eq）, the DIPEA of catalytic amount and two Chloromethanes（20mL）, react at room temperature 4 hours, electromagnetic agitation.Stop reaction, add water（20mL）, saturation NaHCO3The aqueous solution is washed, and two Chloromethanes（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- （Thiophene -2- formoxyls）-2-（3-（4-（4- methoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines（487.6mg）.
MS:[M+H]+=530.1
1H-NMR(400M,DMSO-d6)δ9.25(s,1H),8.30(s,1H),7.83-7.84(m,1H),7.58-7.64 (m,3H),7.19(s,2H),6.90-6.92(d,2H),4.84(s,2H),3.91(s,2H),3.28(s,3H),2.73-2.81 (m,4H),2.51(s,3H),2.34(s,3H),1.93-1.95(m,2H),1.53-1.55(m,2H)ppm。
Embodiment 5：The preparation of compound 5
6- Cyanoacetyls -2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（The oxygen of morpholinyl -1- third Base）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=517.1
1H-NMR(400M,CDCl3)δ8.22(s,1H),7.59(s,2H),7.03(s,1H),6.90(s,2H),4.61- 4.78(d,2H),4.02(s,2H),3.91(s,2H),3.61(s,4H),2.79(s,2H),2.38(s,4H),1.97(s,3H), 1.72(s,4H),1.25(s,2H)ppm。
Embodiment 6：The preparation of compound 6
6-（4- cyanobenzoyls）-2-（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 5（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）-6- Methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to 4- cyanobenzoic acids.
MS:[M+H]+=579.1
1H-NMR(400M,DMSO-d6)δ9.34(s,1H),8.32(s,1H),7.97-7.99(d,2H),7.19(s,1H), 7.67-7.69(d,4H),6.86-6.88(m,2H),4.81(s,2H),3.94-3.97(m,4H),3.56-3.58(m,4H), 2.67-2.68(m,2H),2.50(s,3H),2.36-2.38(m,4H),2.30-2.32(m,2H),1.83-1.87(m,2H) ppm。
Embodiment 7：The preparation of compound 7
6- benzyls -2-（3-（4-（2- pyrrolidinyl -1- ethyoxyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （2- pyrrolidinyl -1- ethyoxyls）Aniline.
2-（3-（4-（2- pyrrolidinyl -1- ethyoxyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines Preparation method
With 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（2- pyrrolidinyl -1- ethyoxyls）Benzene Amido）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（2- pyrrolidinyl -1- ethyoxyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- pyrrolidinyl -1- second Epoxide）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=486.8
1H-NMR(400M,DMSO-d6)δ8.22-8.23(d,1H),7.49-7.52(m,2H),7.03-7.04(m,1H), 6.91-6.93(m,2H),4.78(s,2H),4.13-4.16(m,2H),3.71-3.74(m,2H),3.60-3.61(m,2H), 2.93-2.95(m,2H),2.78-2.80(m,2H),2.68-2.69(m,4H),2.35(s,3H),1.84(s,4H)ppm。
Embodiment 8：The preparation of compound 8
6- benzyls -2-（3-（4-（3,5- dimethyl -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （3,5- dimethyl -1- piperidyls）Aniline.
2-（3-（4-（3,5- dimethyl -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines Preparation method
With 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（3,5- dimethyl -1- piperidyls）Benzene Amido）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（3,5- dimethyl -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（3,5- dimethyl -1- piperazines Piperidinyl）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=485.2
1H-NMR(400M,DMSO-d6)δ9.22(s,1H),8.29(s,1H),7.60-7.63(d,2H),7.16-7.17 (d,1H),6.87-6.89(d,2H),4.43(s,2H),4.48-3.53(m,4H),3.01(s,3H),2.69(s,3H),2.34 (s,3H),2.04-2.10(t,2H),1.70-1.73(m,2H),0.89-0.90(m,6H)ppm。
Embodiment 9：The preparation of compound 9
6- mesyls -2-（3-（4-（3,5- dimethyl -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（3,5- dimethyl -1- piperidyls）Aniline Base）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=496.0
1H-NMR(400M,DMSO-d6)δ9.22(s,1H),8.29(s,1H),7.60-7.63(d,2H),7.17(s,1H), 6.87-6.89(d,2H),4.43(s,2H),4.48-3.53(m,5H),3.01(s,3H),2.69(s,3H),2.34(s,3H), 2.04-2.10(t,2H),1.70-1.73(m,2H),0.89-0.90(m,6H)ppm。
Embodiment 10：The preparation of compound 10
4-（4- acetoxyl group -1- piperidyls）Nitrobenzene
P-fluoronitrobenzene is added into reaction bulb（141.0mg, 1eq）, 4- acetoxyl group -1- piperidines（186.9mg 1.3eq）, potassium carbonate（552.9mg, 4eq）And DMF（15mL）, 80 degree are reacted 6 hours, electromagnetic agitation.Stop reaction, add water （50mL）, solid is separated out, is filtered, dries, obtains 4-（4- acetoxyl group -1- piperidyls）Nitrobenzene（236.6mg）.
4-（4- acetoxyl group -1- piperidyls）Aniline
4- is added into reaction bulb（4- acetoxyl group -1- piperidyls）Nitrobenzene（132.1mg, 1eq）, Pd/C（13.2mg, 10%）And methanol（10mL）, H2 is passed through, is stirred at room temperature 3 hours.Stop reaction, filter, filtrate concentration, dry 4-（4- acetyl Oxy-1-piperidyl）Aniline（97.3mg）
6- benzyls -2-（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （4- acetoxyl group -1- piperidyls）Aniline.
2-（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines Preparation method
With 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- acetoxyl group -1- piperidyls）Benzene Amido）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- mesyls -2-（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- acetoxyl group -1- piperidyls）Aniline Base）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=527.0
1H-NMR(400M,DMSO-d6)δ9.29(s,1H),8.32(s,1H),7.67(s,2H),7.67(s,1H),6.94 (s,2H),4.82(s,1H),4.46(s,3H),3.04(s,3H),2.93(s,3H),2.72(s,3H),2.36(s,4H),2.05 (s,3H),1.97(s,2H),1.70(s,2H)ppm。
Embodiment 11：The preparation of compound 11
6- benzyls -2-（3-（3,4,5- trimethoxy-benzene amidos）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines system Preparation Method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 3,4,5- trimethoxies Aniline.
2-（3-（3,4,5- trimethoxy-benzene amidos）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（3,4,5- trimethoxy-anilines Base）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- mesyls -2-（3-（3,4,5- trimethoxies-anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（3,4,5- trimethoxy-benzene amidos）- 6- methyl） Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=475.3
1H-NMR(400M,DMSO-d6)δ9.39(s,1H),8.36(s,1H),7.36(s,2H),7.18(s,1H),4.39 (s,2H),3.79(s,6H),3.61(s,3H),3.47-3.50(m,2H),3.01(s,3H),2.67(s,2H),2.34(s,3H) ppm。
Embodiment 12：The preparation of compound 12
6- Cyanoacetyls -2-（3-（3,4,5- trimethoxy-benzene amidos）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoros Methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- ethyoxyls） Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（3,4,5- trimethoxy-benzene amidos）-6- Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=464.0
1H-NMR(400M,DMSO-d6)δ9.39(s,1H),8.36(s,1H),7.36-7.39(d,2H),7.17(s,1H), 4.57-4.63(d,2H),4.21(s,2H),3.77-3.81(m,6H),3.62(s,5H),2.67(s,2H),2.33(s,3H) ppm。
Embodiment 13：The preparation of compound 13
6- benzyls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （4- ethyl -1- piperazinyls）Aniline.
2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls） Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls） Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=486.1
1H-NMR(400M,CDCl3)δ8.23(s,1H),7.51-7.54(m,2H),6.98(s,1H),7.03(s,1H), 6.94-6.96(m,2H),4.78(s,2H),3.60-3.61(m,2H),3.37-3.39(m,4H),2.92-2.93(m,4H), 2.78-2.80(m,4H),
2.38(s,3H),1.31-1.32(m,3H),1.25-1.26(m,2H)ppm。
Embodiment 14：The preparation of compound 14
6- mesyls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls）Anilino-）-6- Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=497.1
1H-NMR(400M,DMSO-d6)δ9.24(s,1H),8.29(s,1H),7.63-7.65(d,2H),7.17(s,1H), 6.88-6.90(d,2H),4.43(s,2H),3.47-3.50(m,3H),3.06(s,4H),3.01(s,4H),2.50-2.54(m, 3H),2.41(s,2H),2.33(s,4H),1.02-1.06(m,3H)ppm。
Embodiment 15：The preparation of compound 15
6-（3- cyano-benzoyls）-2-（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine Base-furans simultaneously [2,3-c] piperidines
2- is added into reaction bulb（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans And [2,3-c] piperidines（223.7mg, 1eq）, 3- cyano-benzoic acids（147.1mg, 2eq）, 1- hydroxyls-benzo-triazole （169.2mg, 2.5eq）, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride（239.6mg, 2.5eq）, catalytic amount DIPEA and dichloromethane（20mL）, react at room temperature 4 hours, electromagnetic agitation.Stop reaction, add water（20mL）, saturation NaHCO3Water Solution is washed, dichloromethane（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column layer Analysis obtains 6-（3- cyano-benzoyls）-2-（3-（4-（4- acetoxyl group -1- piperidyls）Anilino-）- 6- methyl）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines（265.3mg）.
MS:[M+H]+=577.1
1H-NMR(400M,DMSO-d6)δ9.25(s,1H),7.98(s,2H),7.81-7.83(d,1H),7.63-7.70 (m,3H),7.17(s,1H),6.90-6.92(m,2H),5.75(s,1H),4.80(s,2H),3.95(s,1H),3.54(s, 2H),2.90-2.92(m,2H),2.65-2.66(m,2H),2.35(s,3H),2.02(s,3H),1.93-1.94(m,2H), 1.23-1.25(m,2H),
1.66-1.68(m,2H)ppm。
Embodiment 16：The preparation of compound 16
6- benzyls -2-（3-（4-（3-（4- methyl isophthalic acids-piperazinyl）- 1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （3-（4- methyl-piperazinyl groups）- 1- propoxyl group）Aniline.
2-（3-（4-（3-（4- methyl isophthalic acids-piperazinyl）- 1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（3-（4- thyl-piperazins Base）- 1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（3-（4- methyl isophthalic acids-piperazinyl）- 1- propoxyl group）Anilino-）- 6- methyl）It is phonetic Piperidinyl-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（3-（4- methyl isophthalic acids-piperazine Base）- 1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=531.0
1H-NMR(400M,DMSO-d6)δ9.31(s,1H),8.30(s,1H),7.67-7.69(d,2H),7.17(s,1H), 6.85-6.87(d,2H),4.61-4.67(d,2H),4.20-4.22(d,2H),3.94-3.97(t,2H),3.63-3.65(m, 2H),2.65-2.68(m,4H),2.57-2.59(m,4H),2.33(s,3H),2.29-2.30(m,4H),1.85-1.87(m, 3H),1.23-1.25(m,2H)ppm。
Embodiment 17：The preparation of compound 17
6- isobutyryls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 13（3-（4-（4- ethyl -1- piperazinyls）Anilino-）-6- Methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to isobutyric acid.
MS:[M+H]+=489.2
1H-NMR(400M,DMSO-d6)δ9.30(s,1H),8.30(s,1H),7.68-7.70(d,2H),7.15(s,1H), 6.94-6.96(d,2H),4.63(s,2H),3.76-3.77(m,2H),3.01-3.08(m,10H),2.50-2.51(m,2H), 2.33-2.35(s,1H),2.69(m,3H),1.06-1.11(m,6H),1.02-1.04(m,3H)ppm。
Embodiment 18：The preparation of compound 18
6- mesyls -2-（3-（4-（3-（4- methyl isophthalic acids-piperazinyl）- 1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine Base-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（3-（4- methyl isophthalic acids-piperazinyl）The oxygen of -1- third Base）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=542.1
1H-NMR(400M,DMSO-d6)δ9.31(s,1H),8.31(s,1H),7.67-7.69(d,2H),7.17(s,1H), 6.85-6.88(d,2H),4.43(s,2H),3.94-3.97(t,2H),3.47-3.50(t,2H),3.32(s,2H),3.01(s, 3H),2.69(s,3H),2.29-2.34(m,7H),1.84-1.87(m,3H),1.23-1.28(m,5H)ppm。
Embodiment 19：The preparation of compound 19
6- benzyls -2-（3-（Indoles -5- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to Yin Diindyl -5- aniline.
2-（3-（Indoles -5- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（Indoles -5- anilino-s）- 6- first Base）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（Indoles -5- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（Indoles -5- anilino-s）- 6- first Base）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=413.0
1H-NMR(400M,DMSO-d6)δ10.86(s,1H),9.20(s,1H),8.30(s,1H),8.06(s,1H), 7.15-7.36(m,4H),6.36(s,1H),4.62-4.68(d,2H),4.22(s,2H),3.77(s,1H),3.63(s,1H), 2.69(s,2H),2.34(s,3H)ppm。
Embodiment 20：The preparation of compound 20
6- Cyanoacetyls -2-（3-（4-（4- Methoxy-piperidin bases）Anilino-）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
Preparation method is the same as 6- in embodiment 4（Thiophene -2- formoxyls）-2-（3-（4-（4- methoxyl group -1- piperidyls）Aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are thiophene -2-carboxylic acid being changed to cyano group second Acid.
MS:[M+H]+=487.1
1H-NMR(400M,DMSO-d6)δ9.22(s,1H),8.29(s,1H),7.63-7.65(m,2H),7.17(s,1H), 6.88-6.90(m,2H),4.61-4.67(d,2H),4.19-4.21(d,2H),3.63-3.77(m,4H),3.45-3.48(m, 2H),2.68(s,2H),2.57(s,1H),2.50(s,3H),2.33(s,3H),2.16-2.22(m,2H),1.14-1.15(m, 2H)ppm。
Embodiment 21：The preparation of compound 21
6-（3- cyano-benzoyls）-2-（3-（4-（4- Methoxy-piperidin bases）Anilino-）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- in embodiment 4（Thiophene -2- formoxyls）-2-（3-（4-（4- methoxyl group -1- piperidyls）Aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are thiophene -2-carboxylic acid being changed to 3- cyanogen Base-benzoic acid.
MS:[M+H]+=549.2
1H-NMR(400M,DMSO-d6)δ9.27(s,1H),8.30(s,1H),7.98-8.00(m,2H),7.82-7.86 (m,1H),7.69-7.73(m,3H),7.17(s,1H),6.89-6.91(m,2H),4.81(s,2H),3.55(s,2H),3.27 (s,3H),2.78-2.80(m,2H),2.65(s,2H),2.35(s,3H),1.99(s,3H),1.52-1.54(m,2H),1.16- 1.23(m,2H)ppm。
Embodiment 22：The preparation of compound 22
6-（4- cyano-benzoyls）-2-（3-（4-（4- Methoxy-piperidin bases）Anilino-）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- in embodiment 4（Thiophene -2- formoxyls）-2-（3-（4-（4- methoxyl group -1- piperidyls）Aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are thiophene -2-carboxylic acid being changed to 4- cyanogen Base-benzoic acid.
MS:[M+H]+=549.2
1H-NMR(400M,DMSO-d6)δ9.27(s,1H),8.30(s,1H),7.97-7.99(m,2H),7.63-7.69 (m,4H),7.17(s,1H),6.89-6.91(m,2H),4.82(s,2H),3.52(s,2H),3.27(s,3H),2.78-2.81 (m,2H),2.68-2.69(m,2H),2.51(s,3H),2.36(s,2H),2.28-2.30(m,1H),1.93-1.95(m,2H), 1.52-1.57(m,2H)ppm。
Embodiment 23：The preparation of compound 23
6- benzyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- Morpholinyl phenylamine.
2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6-（4- cyano-benzoyls）-2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines
Preparation method is the same as 6- in embodiment 22（4- cyano-benzoyls）-2-（3-（4-（4- methoxyl groups-piperazinyl）Aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- methoxyl groups-piperazine Piperazine base）Anilino-）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- first Base）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=521.1
1H-NMR(400M,DMSO-d6)δ9.29(s,1H),8.31(s,1H),7.87-7.98(m,2H),7.66-7.68 (m,4H),7.18(s,1H),6.89-6.91(m,2H),4.81(s,2H),3.73(s,4H),3.52(s,2H),3.02(s, 4H),2.62(s,2H),2.35(s,3H)ppm。
Embodiment 24：The preparation of compound 24
6-（3- cyano-benzoyls）-2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines preparation method is the same as 6- in embodiment 23（4- cyano-benzoyls）-2-（3-（4- morpholinyl -1- anilino-s）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4- cyano-benzoic acids being changed to 3- cyano group-benzene first Acid.
MS:[M+H]+=521.1
1H-NMR(400M,DMSO-d6)δ9.29(s,1H),8.30(s,1H),7.89(s,2H),7.81-7.83(m,1H), 7.67-7.70(m,3H),7.18(s,1H),6.89(s,2H),4.81(s,2H),3.73(s,4H),3.54(s,2H),3.02 (m,4H),2.65(m,2H),2.35(s,3H)ppm。
Embodiment 25：The preparation of compound 25
6- mesyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine Base-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=470.0
1H-NMR(400M,DMSO-d6)δ9.30(s,1H),8.30(s,1H),7.65-7.77(m,2H),7.17(s,1H), 6.89-6.91(d,2H),4.43(s,2H),3.72-3.74(m,4H),3.47-3.49(m,2H),3.02-3.03(m,7H), 2.69-2.71(m,2H),2.34(s,3H)ppm。
Embodiment 26：The preparation of compound 26
2-（4- morpholinyl -1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4- morpholinyl phenylamines.
6- benzyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）The chloro- 5- trifluoromethyl pyrimidines of -4- are changed to 2-（4- morpholinyl -1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- mesyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls） Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=524.2
1H-NMR(400M,DMSO-d6)δ10.08(s,1H),8.74(s,1H),7.61(s,2H),7.30(s,1H), 6.94-6.97(d,2H),4.41(s,2H),3.73-3.75(m,4H),3.46-3.49(m,2H),3.05-3.08(m,4H), 3.03(s,3H),2.70(s,2H)ppm。
Embodiment 27：The preparation of compound 27
6- Cyanoacetyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoros Methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- ethyoxyls） Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- anilino-s）- 6- three Methyl fluoride）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=513.0
1H-NMR(400M,DMSO-d6)δ10.07(s,1H),8.73(s,1H),7.61(s,2H),7.92-7.31(m, 1H),6.94-6.96(m,2H),4.60-4.66(m,2H),4.22(s,2H),3.74-3.78(m,6H),3.05-3.08(m, 4H),2.67-2.69(m,2H)ppm。
Embodiment 28：The preparation of compound 28
6- Cyanoacetyls -2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- in embodiment 23（4- cyano-benzoyls）-2-（3-（4- morpholinyl -1- anilino-s）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4- cyano-benzoic acids being changed to cyanoacetic acid.
MS:[M+H]+=459.1
1H-NMR(400M,DMSO-d6)δ9.29(s,1H),8.30(s,1H),7.65-7.67(d,2H),7.16-7.17 (d,1H),6.89-6.91(d,2H),4.61-4.67(m,2H),4.21-4.23(m,2H),3.72-3.77(m,4H),3.62- 3.63(m,2H),3.01-3.03(m,4H),2.67-2.69(m,2H),2.33(s,3H)ppm。
Embodiment 29：The preparation of compound 29
2-（4-（4- methyl isophthalic acids-piperazinyl）Anilino-）The chloro- 5- trifluoromethyl pyrimidines of -4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4-（4- methyl isophthalic acids-piperazinyl）Aniline.
6- benzyls -2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）The chloro- 5- trifluoromethyl pyrimidines of -4- are changed to 2-（4-（4- methyl isophthalic acids-piperazinyl）Anilino-）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- methyl isophthalic acids-piperazine Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 23（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine Simultaneously [2,3-c] piperidines is changed to 2- to base-furans（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine Base-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=526.0
1H-NMR(400M,DMSO-d6)δ8.62-8.63(d,1H),7.46-7.50(m,2H),7.30(s,1H),7.22- 7.23(m,1H),6.95-6.97(m,2H),4.78(s,2H),3.90-3.93(m,2H),3.61(s,2H),3.20-3.22(m, 4H),2.78-2.81(m,2H),2.66-2.67(m,4H),2.37(s,3H)ppm。
Embodiment 30：The preparation of compound 30
6- benzyls -2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）It is phonetic The synthesis of piperidinyl-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4-（4- Methyl isophthalic acid-piperazinyl）Aniline.
2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- methyl isophthalic acids-piperazine Base）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 23（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine Simultaneously [2,3-c] piperidines is changed to 2- to base-furans（3-（4-（4- methyl isophthalic acids-piperazinyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines.
MS:[M+H]+=471.8
1H-NMR(400M,DMSO-d6)δ8.21-8.23(d,1H),7.48-7.52(m,2H),7.03-7.04(m,1H), 6.92-6.96(m,3H),4.78(s,2H),3.71-3.74(m,2H),3.60-3.61(m,2H),3.17-3.19(m,4H), 2.78-2.81(m,2H),2.60-2.63(m,3H),2.37(s,4H),1.65(s,3H)ppm。
Embodiment 31：The preparation of compound 31
2-（4-（4- ethyl -1- piperazinyls）Anilino-）The chloro- 5- trifluoromethyl pyrimidines of -4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4-（4- ethyl -1- piperazinyls）Aniline.
6- benzyls -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）The chloro- 5- trifluoromethyl pyrimidines of -4- are changed to 2-（4-（4- ethyl -1- piperazinyls）Anilino-）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazines Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 23（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4- morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine Simultaneously [2,3-c] piperidines is changed to 2- to base-furans（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine Base-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=540.0
1H-NMR(400M,CDCl3)δ8.26(s,1H),7.48(s,2H),7.39(s,1H),6.95-6.97(d,2H), 4.77(s,2H),3.91(s,2H),3.60-3.62(d,2H),3.29(s,4H),2.76(s,4H),2.61-2.62(m,4H), 1.21-1.25(t,3H)ppm。
Embodiment 32：The preparation of compound 32
6- mesyls -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（Morpholinyl -1- propoxyl group）Benzene Amido）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 22- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls）- 1- aniline Base）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=551.0
1H-NMR(400M,CDCl3)δ8.62(s,1H),7.49(s,2H),7.26(s,2H),6.97(s,2H),4.50 (s,2H),3.61(s,2H),3.27(s,3H),2.89(s,2H),2.65(s,8H),2.58(s,2H),1.25(s,3H)ppm。
Embodiment 33：The preparation of compound 33
6- ethylsulfonyls -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 32（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are mesyl chloride being changed to ethyl sulfonic chloride.
MS:[M+H]+=565.0
1H-NMR(400M,CDCl3)δ8.62(s,1H),7.47-7.49(d,2H),7.22(s,1H),6.95-6.97(d, 2H),4.53(s,2H),3.63(s,2H),3.22(s,4H),3.04-3.05(d,2H),2.72(s,2H),2.64(s,4H), 2.48-2.50(d,2H),1.38(s,3H),1.25(s,3H)ppm。
Embodiment 34：The preparation of compound 34
6-（Thiophene -2- formoxyls）-2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine Base-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 31（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to thiophene -2- first Acid.
MS:[M+H]+=530.0.
1H-NMR(400M,DMSO-d6)δ9.26(s,1H),8.29(s,1H),8.16(s,1H),7.82-7.83(d,1H), 7.64-7.67(d,2H),7.56-7.57(d,1H),7.18-7.19(d,1H),6.90-6.92(d,2H),4.83(s,2H), 3.15-3.17(m,2H),3.01-3.06(m,8H),2.72-2.74(m,2H),2.66-2.68(m,2H),2.34(s,3H), 1.20-1.23(m,3H)ppm。
Embodiment 35：The preparation of compound 35
The third sulfonyls of 6- -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 32（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are mesyl chloride being changed to the third sulfonic acid chloride.
MS:[M+H]+=536.0.
1H-NMR(400M,DMSO-d6)δ9.23(s,1H),8.29(s,1H),7.63-7.65(d,2H),7.16(s,1H), 6.87-6.89(d,2H),4.46(s,2H),3.51-3.54(t,2H),3.13-3.17(m,6H),3.05(s,4H),2.66(s, 2H),2.33-2.39(m,5H),1.67-1.73(m,2H),1.00-1.02(m,3H),1.03-1.05(m,3H)ppm。
Embodiment 36：The preparation of compound 36
The third mesyl of 6- rings -2-（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- mesyls -2- in embodiment 32（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are mesyl chloride being changed to the methylsulfonyl of ring third Chlorine.
MS:[M+H]+=578.0
1H-NMR(400M,CDCl3)δ8.62(s,1H),7.47-7.49(d,2H),7.22(s,1H),6.95-6.97(d, 2H),4.54(s,2H),3.63-3.66(t,2H),3.22-3.24(m,4H),2.75-2.76(m,2H),2.53-2.64(m, 4H),2.49-2.51(m,2H),2.29-2.32(m,1H),1.16-1.18(m,3H),0.98-0.99(m,2H),0.86-0.89 (m,2H)ppm。
Embodiment 37：The preparation of compound 37
6- benzyls -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （4- piperidyl -1- piperidyls）- 1- aniline.
2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- piperidyl -1- piperidines Base）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
The third sulfonyls of 6- -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as the third sulfonyls of 6- -2- in embodiment 35（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- ethyl -1- piperazines Base）- 1- anilino-s）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- piperidyl -1- piperidines Base）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+2]+=290.2
1H-NMR(400M,DMSO-d6)δ9.27(s,1H),8.30(s,1H),7.64-7.66(d,2H),7.17(s,1H), 6.92-6.94(d,2H),4.46(s,2H),3.70-3.73(m,2H),3.53(s,2H),3.14-3.17(m,2H),3.03- 3.07(m,5H),2.62-2.66(m,4H),2.33(s,3H),2.13-2.16(m,2H),1.81-1.82(m,6H),1.68- 1.73(m,4H),0.97-1.00(t,3H)ppm。
Embodiment 38：The preparation of compound 38
6- Cyanoacetyls -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 31（3-（4-（4- ethyl -1- piperazinyls）- 1- anilino-s）- 6- trifluoromethyls）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- ethyl -1- piperazines Piperazine base）- 1- anilino-s）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- piperidyl -1- piperazines Piperidinyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=541.2
1H-NMR(400M,CDCl3)δ8.21-8.22(d,1H),7.50-7.53(m,2H),7.04-7.07(m,1H), 6.91-6.93(d,2H),4.77(s,2H),3.91(s,1H),3.70-3.73(m,4H),3.60-3.63(m,2H),3.06- 3.15(m,4H),2.72-2.78(m,4H),2.67(s,1H),2.38(s,3H),1.95-1.98(m,2H),1.38-1.42(t, 2H),1.19-1.25(m,6H)ppm。
Embodiment 39：The preparation of compound 39
6- mesyls -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as the third sulfonyls of 6- -2- in embodiment 37（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are the third sulfonic acid chloride being changed to mesyl chloride.
MS:[M+H]+=552.1
1H-NMR(400M,CDCl3)δ8.22(s,1H),7.51-7.53(d,2H),7.03(s,1H),6.92-6.97(m, 3H),4.51(s,2H),3.71-3.73(m,2H),3.62-3.63(m,2H),3.45-3.48(m,2H),3.18(s,1H), 2.89(s,3H),2.76-2.79(m,6H),1.99-2.02(m,3H),1.86-1.89(m,2H),1.63(s,6H),1.41- 1.43(m,2H)ppm。
Embodiment 40：The preparation of compound 40
6- ethylsulfonyls -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as the third sulfonyls of 6- -2- in embodiment 37（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are the third sulfonic acid chloride being changed to ethyl sulfonic chloride.
MS:[M+H]+=565.1
1H-NMR(400M,CDCl3)δ8.21(s,1H),7.51-7.53(d,2H),7.04(s,1H),6.98(s,1H), 6.91-6.93(d,2H),4.54(s,2H),3.70-3.73(m,2H),3.62-3.65(m,2H),3.43(s,1H),3.02- 3.05(m,2H),2.73-2.79(m,6H),2.37(s,6H),1.95-2.01(m,3H),1.65(s,4H),1.36-1.43(m, 5H)ppm。
Embodiment 41：The preparation of compound 41
6- fourth sulfonyls -2-（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as the third sulfonyls of 6- -2- in embodiment 37（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are the third sulfonic acid chloride being changed to fourth sulfonic acid chloride.
MS:[M+H]+=594.2.
1H-NMR(400M,DMSO-d6)δ9.26(s,1H),8.30(s,1H),7.64-7.66(d,2H),7.17(s,1H), 6.91-6.93(d,2H),4.47(s,2H),3.69-3.70(m,2H),3.34(s,2H),3.15-3.19(m,4H),3.03- 3.06(s,3H),2.60-2.66(m,4H),2.33(s,3H),2.01-2.13(m,2H),1.79-1.81(m,6H),1.65(s, 2H),1.38-1.40(m,2H),1.19-1.23(m,2H),0.84-0.88(m,3H)ppm。
Embodiment 42：The preparation of compound 42
6- benzyls -2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines system Preparation Method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline be changed to 4- thio-morpholinyls- 1- aniline.
2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4- thio-morpholinyl -1- aniline Base）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines preparation method is the same as 6- Cyanoacetyls -2- in embodiment 38（3-（4-（4- piperidyl -1- piperidyls）- 1- anilino-s）-6- Methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- anilino-s）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- thio-morpholinyl -1- aniline Base）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=476.1.
1H-NMR(400M,DMSO-d6)δ9.25(s,1H),8.29(s,1H),7.64-7.66(d,2H),7.16-7.17 (d,1H),6.88-6.90(d,2H),4.61-4.67(m,2H),4.19-4.21(d,2H),3.62-3.64(m,2H),3.38- 3.39(m,4H),3.31-3.32(m,2H),2.68-2.70(m,4H),2.33(s,3H)ppm。
Embodiment 43：The preparation of compound 43
6- propionos -2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 42（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals- The synthesis of furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to propionic acid.
MS:[M+H]+=464.1
1H-NMR(400M,CDCl3)δ8.19-8.21(m,1H),7.51-7.53(m,2H),7.01-7.03(m,1H), 6.91-6.93(m,2H),4.76(s,2H),3.69-3.72(m,2H),3.44-3.50(m,4H),2.77-2.79(m,4H), 2.62-2.67(m,2H),2.42-2.49(m,2H),2.38(s,3H),1.17-1.25(m,3H)ppm。
Embodiment 44：The preparation of compound 44
6- acetyl group -2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 42（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to acetic acid.
MS:[M+H]+=450.0
1H-NMR(400M,CDCl3)δ8.19-8.21(m,1H),7.50-7.54(m,2H),7.04(s,1H),6.91- 6.93(m,2H),4.76(s,2H),3.69-3.71(m,2H),3.44-3.46(m,4H),2.77-2.79(m,4H),2.63- 2.68(m,2H),2.38(s,3H),2.19-2.21(m,3H)ppm。
Embodiment 45：The preparation of compound 45
6- cyanogen methyl -2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines 2- is added into reaction bulb（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines （203.5mg, 1eq）, bromoacetonitrile（119.5mg, 2eq）, potassium carbonate（207.1mg, 3eq）And acetonitrile（10mL）, 60 degree of reactions are 3 small When, electromagnetic agitation.Stop reaction, filter, filtrate concentration, crude product silica gel column chromatography obtains 6- cyanogen methyl -2-（3-（4- thiomorpholines Base -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines（198.2mg）.
MS:[M+H]+=447.0
1H-NMR(400M,CDCl3)δ8.20(s,1H),7.50-7.52(m,2H),7.03(s,1H),6.91-6.94(m, 3H),3.81(s,2H),3.76(s,2H),3.43-3.46(m,4H),2.88-2.91(m,2H),2.76-2.79(m,4H), 2.69-2.71(m,2H),2.37(s,3H)ppm。
Embodiment 46：The preparation of compound 46
6- benzyls -2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2, 3-c] piperidines preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl） The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4- （4- methoxyl group -1- piperidyls）- 1- aniline.
2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- methoxyl group -1- piperidines Base）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- p-toluenesulfonyls -2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
2- is added into reaction bulb（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines（419.5mg, 1eq）, tolysulfonyl rate（381.3mg, 2eq）, the DIPEA and dichloromethane of catalytic amount Alkane（30mL）, react at room temperature 2 hours, electromagnetic agitation.Stop reaction, add water（20mL）, saturation NaHCO3The aqueous solution is washed, dichloromethane Alkane（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- to toluene Sulfonyl -2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines （435.6mg）.
1H-NMR(400M,CDCl3)δ8.15(s,1H),7.84-7.92(m,2H),7.39-7.52(m,4H),7.26(s, 1H),6.92-6.99(m,2H),4.34(s,2H),3.83(s,2H),3.42(s,4H),3.38(s,3H),2.65(s,2H), 2.35(s,5H),1.26(s,6H)ppm。
Embodiment 47：The preparation of compound 47
6- mesyls -2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- p-toluenesulfonyls -2- in embodiment 46（3-（4-（4- methoxyl group -1- piperidyls）- 1- aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are tolysulfonyl rate being changed to first sulphur Acyl chlorides.
MS:[M+H]+=499.0
1H-NMR(400M,CDCl3)δ8.21(s,1H),7.50-7.52(d,2H),7.04(s,1H),6.91-6.93(m, 3H),4.51(s,2H),3.81-3.84(m,2H),3.60-3.63(m,2H),3.38-3.41(m,2H),2.89(s,3H), 2.73-2.76(m,2H),2.40-2.42(m,1H),2.37(s,3H),1.59(s,3H),1.25-1.27(m,4H)ppm。
Embodiment 48：The preparation of compound 48
6- benzenesulfonyls -2-（3-（4-（4- methoxyl group -1- piperidyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- p-toluenesulfonyls -2- in embodiment 46（3-（4-（4- methoxyl group -1- piperidyls）- 1- aniline Base）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are tolysulfonyl rate being changed to benzene sulphur Acyl chlorides.
1H-NMR(400M,CDCl3)δ8.18(s,1H),7.71-7.73(d,2H),7.48-7.50(d,2H),7.31- 7.33(d,2H),6.96-6.98(m,2H),6.90-6.92(d,2H),4.31(s,2H),3.80-3.84(m,2H),3.37(m, 3H),2.65-2.66(m,2H),2.34-2.42(m,8H),1.25-1.26(m,4H)ppm。
Embodiment 49：The preparation of compound 49
6- benzyls -2-（3-（4-（4- methyl isophthalic acids-piperidyl）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- methyl）It is phonetic The synthesis of piperidinyl-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4-（4- Methyl isophthalic acid-piperidyl）- 1- aniline.
MS:[M+H]+=494.2
1H-NMR(400M,DMSO-d6)δ8.09(s,1H),7.39-7.41(d,2H),7.22-7.39(m,4H),7.19- 7.22(m,1H),6.95(s,1H),6.86-6.89(m,3H),3.69(s,2H),3.66(s,2H),3.47-3.50(m,2H), 2.72-2.75(m,2H),2.54-2.60(m,4H),2.27(s,3H),1.65-1.68(m,2H),1.32-1.35(m,1H), 1.28-1.29(m,2H),0.89-0.91(m,3H)ppm。
Embodiment 50：The preparation of compound 50
6- benzyls -2-（3-（4-（3,5- dimethyl -1- morpholinyls）- 1- anilino-s）- 6- methyl）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines preparation method is the same as 6- benzyls -2- in embodiment 2（3-（4-（Morpholinyl -1- propoxyl group）Anilino-）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 4-（Morpholinyl -1- propoxyl group）Aniline is changed to 4-（3,5- dimethyl -1- morpholinyls）- 1- aniline.
MS:[M+H]+=510.1
1H-NMR(400M,DMSO-d6)δ8.09(s,1H),7.42-7.44(d,2H),7.23-7.32(m,4H),7.19 (s,1H),6.95(s,1H),6.89(s,1H),6.83-6.85(d,2H),3.73-3.78(m,2H),3.69(s,2H),3.56 (s,2H),2.29-2.32(d,2H),2.72-2.75(m,2H),2.55-2.57(m,2H),2.27-2.34(m,5H),1.18- 1.20(m,6H)ppm。
Embodiment 51：The preparation of compound 51
6- benzyls -2-（3- chlorine）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 2（The chloro- 6- methyl of 3-）The conjunction of pyrimidine radicals-furans simultaneously ［ 2,3-c ］ piperidines Into difference is the chloro- 5- methyl-pvrimidines of 2,4- bis- being changed to 2,4- Dichloro-pyrimidins.
6- benzyls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 13（3-（4-（4- ethyl -1- piperazinyls）Anilino-）- 6- methyl）It is phonetic The synthesis of piperidinyl-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（The chloro- 6- methyl of 3-）Pyrimidine radicals-furans And [2,3-c] piperidines is changed to 6- benzyls -2-（3- chlorine）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls） Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- Cyanoacetyls -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- ethyl -1- piperazinyls）Aniline Base））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=472.3
1H-NMR(400M,CDCl3)δ8.37-8.38(m,1H),7.83-7.85(d,1H),7.61-7.63(d,1H), 7.53-7.55(d,2H),6.91-6.97(m,2H),4.61-4.75(m,2H),3.70-3.73(m,2H),3.59-3.61(m, 2H),3.07-3.15(m,4H),2.97-2.99(m,4H),2.81-2.84(m,4H),1.34-1.37(t,3H)ppm。
Embodiment 52：The preparation of compound 52
6-（N-Boc- glycyls）-2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 51（3-（4-（4- ethyl -1- piperazinyls）Anilino-））It is phonetic The synthesis of piperidinyl-furans simultaneously [2,3-c] piperidines, difference are cyanoacetic acid being changed to N-Boc- amion acetic acids.
MS:[M+2]+=281.6
1H-NMR(400M,CDCl3)δ8.36-8.38(m,1H),7.49-7.52(d,2H),7.00-7.04(m,1H), 6.96(s,1H),6.91-6.94(m,3H),5.53(s,1H),4.75(s,2H),4.08-4.09(m,2H),3.62-3.64(m, 2H),3.18-3.20(m,4H),2.62-2.64(m,6H),2.46-2.49(m,2H),1.46(s,9H),1.12-1.15(t, 3H)ppm。
Embodiment 53：The preparation of compound 53
6- allyl acyl groups -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines 0 Under the conditions of DEG C, 2- is added into reaction bulb（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines（50.0mg 1eq）, triethylamine（15.43mg 1.25eq）And tetrahydrofuran（5mL）, acryloyl chloride is added dropwise（11.10mg, 1eq）With the mixed solution of tetrahydrofuran, electromagnetic agitation 3h.Stop reaction, add water（20mL）, saturation NaHCO3The aqueous solution is washed, and two Chloromethanes（10mL*5）Extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentration, crude product silica gel column chromatography obtains 6- alkene Propiono -2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans simultaneously [2,3-c] piperidines（43.7mg）.
MS:[M+H]+=459.1
1H-NMR(400M,DMSO-d6)δ9.45(s,1H),8.41-8.43(d,1H),7.67-7.69(d,2H),7.22 (s,1H),6.91-7.01(m,4H),6.15-6.19(m,1H),5.74-5.76(m,1H),4.70(s,2H),3.82(s,2H), 3.03-3.08(m,4H),2.65(s,2H),1.17-1.28(m,9H)ppm。
Embodiment 54：The preparation of compound 54
6- allyl acyl groups -2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine preparation method is the same as 6- allyl acyl groups -2- in embodiment 53（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 2-（3-（4-（4- ethyl -1- piperazinyls）Anilino-））Pyrimidine radicals-furan Simultaneously [2,3-c] piperidines of muttering is changed to 2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine.
MS:[M+H]+=500.0
1H-NMR(400M,DMSO-d6)δ10.04(s,1H),8.72(s,1H),7.61-7.62(d,2H),6.89-6.96 (m,3H),6.15-6.19(d,1H),5.74-5.77(d,1H),5.36-5.38(d,1H),4.70-4.79(m,2H),3.73- 3.79(m,4H),3.80-3.83(m,4H),3.06-3.07(m,4H)ppm。
Embodiment 55：The preparation of compound 55
6- ethylsulfonyls -2-（3-（4- morpholinyl -1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- phenylaminos）- 6- trifluoros Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=538.2
1H-NMR(400M,DMSO-d6)δ8.73(s,1H),7.62(d,2H),7.29(s,1H),6.95(d,2H),4.46 (s,2H),3.74(t,4H),3.55(t,2H),3.20(q,2H),3.07(t,4H),2.68(t,2H),1.21(t,3H)
Embodiment 56：The preparation of compound 56
6- ethylsulfonyls -2-（3-（4- morpholinyl -1- phenylaminos）- 6- methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines system Preparation Method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）It is phonetic The synthesis of piperidinyl-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos Base）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- morpholinyl -1- phenylaminos）- 6- methyl）Pyrimidine Base-furans simultaneously [2,3-c] piperidines.
[M+H]+=484.2
1H-NMR(400M,DMSO-d6)δ9.24(s,1H),8.29(s,1H),7.67(d,2H),7.16(s,1H),6.90 (d,2H),4.47(s,2H),3.74(t,4H),3.54(t,2H),3.19(q,2H),3.03(t,4H),2.66(t,2H),2.33 (s,1H),1.22(t,3H)
Embodiment 57：The preparation of compound 57
2-（4- piperidyl -1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4- piperidyl -1- aniline.
6- benzyls -2-（3-（4- piperidyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4- piperidyl -1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-.
2-（3-（4- piperidyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4- piperidyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4- piperidyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- piperidyl -1- anilino-s）-6- Trifluoromethyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
[M+H]+=536.2
1H-NMR(400M,DMSO-d6)δ10.01(s,1H),8.72(s,1H),7.57(d,2H),7.29(s,1H),6.93 (d,2H),4.46(s,2H),3.55(t,2H),3.20(q,2H),3.08(t,4H),2.67(t,2H),1.63(m,4H), 1.53-1.52(m,2H),1.21(t,3H)
Embodiment 58：The preparation of compound 58
2-（4- piperazinyl -1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidines -1- ethyoxyls）Aniline is changed to 4- piperazinyl -1- aniline.
6- benzyls -2-（3-（4- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4- piperazinyl -1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（4- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- piperazinyl -1- anilino-s）- 6- trifluoros Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=537.2
1H-NMR(400M,CDCl3))δ8.63(s,1H),7.49(d,2H),7.22(s,1H),6.95(d,2H),4.53 (s,2H),3.63(t,2H),3.15(t,4H),3.05(m,6H),2.72(t,2H),1.69(t,3H)
Embodiment 59：The preparation of compound 59
2-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 4-（2- piperidyl -1- ethyoxyls）Benzene Amine.6- benzyls -2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）The chloro- 5- fluoroforms of -4- Yl pyrimidines.
2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（2- piperidyl -1- ethoxies Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=580.2
1H-NMR(400M,DMSO-d6)δ10.17(s,1H),8.76(s,1H),7.71(d,2H),7.30(s,1H),7.04 (d,2H),4.46(s,2H),4.31(t,2H),3.55(t,2H),3.51(t,2H),3.20(q,2H),3.10-3.08(m, 4H),2.67(t,2H),1.90-1.85(m,2H),1.76-1.70(m,2H),1.23-1.20(m,5H)
Embodiment 60：The preparation of compound 60
2-（3-（2- morpholinyl -1- ethyoxyls）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 3-（2- morpholinyl -1- ethyoxyls）Benzene Amine.
6- benzyls -2-（3-（3-（2- morpholinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（3-（2- morpholinyl -1- ethyoxyls）- 1- anilino-s）The chloro- 5- fluoroforms of -4- Yl pyrimidines.
2-（3-（3-（2- morpholinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（3-（2- morpholinyl -1- ethoxies Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（3-（2- morpholinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=582.2
1H-NMR(400M,CDCl3)δ8.68(s,1H),7.48(s,1H),7.42(s,1H),7.26(m,1H),7.14(d, 1H),6.67(d,1H),4.54(s,2H),4.16(t,2H),3.75(t,4H),3.64-3.59(t,2H),3.05(q,2H), 2.84(t,2H),2.73(t,2H),2.61(t,4H),1.39(t,3H)
Embodiment 61：The preparation of compound 61
6- ethylsulfonyls -2-（3-（4-（2- pyrrolidinyl -1- ethyoxyls）- 1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- pyrrolidinyl -1- ethoxies Base）- 1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=595.1
1H-NMR(400M,CDCl3)δ8.64(s,1H),7.54(d,2H),7.32(s,1H),7.22(s,1H),6.96- 6.94(d,2H),4.53(s,2H),4.25(t,2H),3.83(t,2H),3.63(t,2H),3.06-3.04(m,2H),2.72 (t,2H),1.59(t,4H),1.40-1.37(t,3H),1.26(m,4H)
Embodiment 62：The preparation of compound 62
6- ethylsulfonyls -2-（3-（4-（2- morpholinyl -1- ethyoxyls）- 1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- morpholinyl -1- ethyoxyls）- 1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=582.1
1H-NMR(400M,CDCl3)δ8.63(s,1H),7.54-7.51(d,2H),7.39(s,1H),7.22(s,1H), 6.96-6.94(d,2H),4.53(s,2H),4.26-4.24(t,2H),3.84-3.81(t,2H),3.64-3.62（t,2H), 3.08-3.02(m,2H),2.72(t,2H),1.61(t,4H),1.42-1.37(t,4H),1.26(t,3H)
Embodiment 63：The preparation of compound 63
2-（4-（2-N- methyl isophthalic acids-piperazinyl -1- ethyoxyls）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 4-（2-N- methyl isophthalic acids-piperazinyl -1- Ethyoxyl）Aniline.
6- benzyls -2-（3-（4-（2-N- methyl isophthalic acids-piperazinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine Base-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（2-N- methyl isophthalic acids-piperazinyl -1- ethyoxyls）- 1- anilino-s）- 4- is chloro- 5- trifluoromethyl pyrimidines.
2-（3-（4-（2-N- methyl isophthalic acids-piperazinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（2-N- methyl isophthalic acids-piperazine Base -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（2-N- methyl isophthalic acids-piperazinyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls） Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2-N- methyl isophthalic acid-piperazinyls- 1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=595.1
1H-NMR(400M,CDCl3)δ8.63(s,1H),7.54-7.52(d,2H),7.40(s,1H),7.23(s,1H), 6.93-6.91(d,2H),4.53(s,2H),4,15(t,2H),3.65(t,2H),3.09-2.86(m,10H),2.74(t,4H), 1.38(t,3H)
Embodiment 64：The preparation of compound 64
2-（4-（4- hydroxy piperidine bases）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 4-（4- hydroxy piperidine bases）Aniline.
6- benzyls -2-（3-（4-（4- hydroxy piperidine bases）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（4- hydroxy piperidine bases）- 1- anilino-s）The chloro- 5- trifluoromethyls of -4- are phonetic Pyridine.
2-（3-（4-（4- hydroxy piperidine bases）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（4- hydroxy piperidine bases）-1- Anilino-）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（4- hydroxy piperidine bases）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（4- hydroxy piperidine bases）- 1- benzene Amido）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=552.1
1H-NMR(400M,DMSO-d6)δ10.02(s,1H),8.72(s,1H),7.58-7.57(d,2H),7.29(s, 1H),6.95-6.93(d,2H),4.67(s,1H),4.46(d,2H),3.63-3.46(m,5H),3.23-3.19(t,2H), 2.81-2.76(t,2H),2.68(t,2H),1.83-1.81(m,2H),1.52-1.47(m,2H),1.22(t,3H)
Embodiment 65：The preparation of compound 65
2-（4-（3- pyrrolidinyl -1- propoxyl group）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 4-（3- pyrrolidinyl -1- propoxyl group） Aniline.
6- benzyls -2-（3-（4-（3- pyrrolidinyl -1- propoxyl group）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans And [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（3- pyrrolidinyl -1- propoxyl group）- 1- anilino-s）The chloro- 5- trifluoros of -4- Methylpyrimidine.
2-（3-（4-（3- pyrrolidinyl -1- propoxyl group）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3- C] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（3- pyrrolidinyls -1- third Epoxide）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（3- pyrrolidinyl -1- propoxyl group）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals- Furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（3- pyrrolidinyls the third oxygen of -1- Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=580.3
1H-NMR(400M,DMSO-d6)δ8.62(s,1H),7.52(d,3H),7.25(d,1H),6.90(d,2H),5.54 (brs,1H),4.52(s,2H),4.10(t,2H),3.63(t,2H),3.32(t,2H),3.06(q,2H),2.72(t,2H), 2.44(q,2H),
2.22-2.00(m,4H),1.47-1.42(m,4H),0.92-0.83(m,3H)ppm
Embodiment 66：The preparation of compound 66
6- cyanogen methyl -2-（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines Preparation method is the same as 6- cyanogen methyl -2- in embodiment 45（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals-furans And the synthesis of [2,3-c] piperidines, difference are 2-（3-（4- thio-morpholinyl -1- anilino-s）- 6- methyl）Pyrimidine radicals- Simultaneously [2,3-c] piperidines is changed to 2- to furans（3-（4- morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines.
MS:[M+H]+=485.1
Embodiment 67：The preparation of compound 67
2-（Morpholinyl -1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to morpholinyl aniline.
6- benzyls -2-（3-（Morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（Morpholinyl -1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（Morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（Morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（Morpholinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（Morpholinyl -1- anilino-s）-6- Trifluoromethyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+Na]+=560.2
1H-NMR(400M,DMSO-d6)δ10.13(s,1H),8.79(s,1H),7.51(s,1H),7.31(s,1H),7.20 (q,2H),6.66(d,1H),4.46(s,2H),3.76(t,4H),3.55(t,2H),3.20(q,4H),3.11(t,4H),2.68 (t,2H),1.22(t,3H)
Embodiment 68：The preparation of compound 68
6- Cyanoacetyls -2-（3-（4- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines
Preparation method is the same as 6- Cyanoacetyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-6- Trifluoromethyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（2- pyrrolidines -1- second Epoxide）Anilino-）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4- piperazinyl -1- anilino-s）） Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=512.2
1H-NMR(400M,DMSO-d6)δ10.04(s,1H),8.73(s,1H),7.59(s,2H),7.29(s,1H),6.93 (d,2H),4.64(d,2H),4.22(s,2H),3.77(s,1H),3.64(s,1H),3.03(d,4H),2.87(s,4H),2.69 (s,1H),2.58(s,1H)ppm
Embodiment 69：The preparation of compound 69
6- ethylsulfonyls -2-（3-（4-（N methyl piperazine base）- 1- phenylaminos）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（N methyl piperazine base）- 1- benzene Amino）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=551.3
1H-NMR(400M,DMSO-d6)δ10.04(s,1H),8.73(s,1H),7.59(d,2H),7.30(s,1H),6.94 (d,2H),4.46(s,2H),3.55(t,2H),3.20(q,2H),3.09(t,4H),2.68(t,2H),2.46(t,4H),2.22 (s,3H),1.21(t,3H)
Embodiment 70：The preparation of compound 70
2-（3- piperazinyl -1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 3- piperazinyl aniline.
6- benzyls -2-（3-（3- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Aniline Base）-- the chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（3- piperazinyl -1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（3- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（3- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（3- piperazinyl -1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperazine Pyridine preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- first Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（3- piperazinyl -1- anilino-s）- 6- trifluoros Methyl）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=537.2
1H-NMR(400M,DMSO-d6)δ10.19(s,1H),8.81(m,2H),7.51(s,1H),7.32(m,2H),7.24 (q,1H),6.73(d,1H),4.47(s,2H),3.56(t,2H),3.37(m,6H),3.23(m,4H),2.69(t,2H),1.23 (t,3H)
Embodiment 71：The preparation of compound 71
2-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）-- the chloro- 5- trifluoromethyl pyrimidines of 4-
Preparation method is the same as 2- in embodiment 1（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）The chloro- 5- trifluoromethyls of -4- are phonetic The synthesis of pyridine, difference are 4-（2- pyrrolidinyl -1- ethyoxyls）Aniline is changed to 4-（2- piperidyl -1- ethyoxyls）Aniline.
6- benzyls -2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] piperidines
Preparation method is the same as 6- benzyls -2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- fluoroforms Base）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）-- The chloro- 5- trifluoromethyl pyrimidines of 4- are changed to 2-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）The chloro- 5- trifluoromethyl pyrimidines of -4-.
2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans is simultaneously [2,3-c] Piperidines
Preparation method is the same as 2- in embodiment 1（3-（4-（2- pyrrolidines -1- ethyoxyls）Anilino-）- 6- trifluoromethyls）Pyrimidine The synthesis of base-furans simultaneously [2,3-c] piperidines, difference are 6- benzyls -2-（3-（4-（2- pyrrolidines -1- ethyoxyls）Benzene Amido）- 6- trifluoromethyls）Simultaneously [2,3-c] piperidines is changed to 6- benzyls -2- to pyrimidine radicals-furans（3-（4-（2- piperidyl -1- ethoxies Base）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
6- ethylsulfonyls -2-（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furan Mutter simultaneously [2,3-c] piperidines
Preparation method is the same as 6- ethylsulfonyls -2- in embodiment 40（3-（4-（4- piperidyl -1- piperidyls）- 1- phenylaminos）- 6- methyl）The synthesis of pyrimidine radicals-furans simultaneously [2,3-c] piperidines, difference are 2-（3-（4-（4- piperidyl -1- piperidines Base）- 1- phenylaminos）- 6- methyl）Simultaneously [2,3-c] piperidines is changed to 2- to pyrimidine radicals-furans（3-（4-（2- piperidyl -1- ethyoxyls）- 1- anilino-s）- 6- trifluoromethyls）Pyrimidine radicals-furans simultaneously [2,3-c] piperidines.
MS:[M+H]+=580.2
Embodiment 72：External biochemistry level suppresses jak kinase（PK）Activity experiment
Materials and methods：JAK2, JAK3 kinases, from Invitrogen；384 orifice plates（Greiner companies）； HTRFKinEASE；MgCl2（sigma）Company；DTT（Sunshine）；PHERAstar FS multi-function microplate readers（BMG companies）； MH-1 type low speed centrifuges（StaiteXiangyi companies）；TD25-W5 type insulating boxs（Binder companies）；YG020524/ vibrates Device（Lindberg Optic Design A/S）；ATP（Sigma companies）；The positive drug of selection is CP-690550, and structure is as follows：
Compound dissolves and preserved：Test-compound is configured to 0.5-10mmol/L mother liquor with DMSO, -20 after packing DEG C preserve；
The preparation of compound working solutions：In addition to CP-690550, remaining compound is that 10uM plays 3 times of dilutions, 10 concentration, Again plus a full DMSO of zero-dose.
Enzyme reaction step：4 μ l kinases is added into each hole of 384 microwell plates, while adds 4 μ L Enzymatic Buffer is as negative control（Negative）；2 μ l compound working solutions are added to hole, while adds 2 μ L and is free of chemical combination The buffer solution of thing is as control（That is positive control, Positive）；In 25 DEG C（Or 30 DEG C）It is incubated 5-10min；Xiang Kongzhong adds 2 μ L ATP and TK Substrate-biotin mixed liquors, start enzyme reaction, in 25 DEG C（Or 30 DEG C）Oscillating reactions 15-60min； Xiang Kongzhong adds 4uL TK-Ab-cryptate；In 25 DEG C（Or 30 DEG C）It is incubated 5-10min；
PHERAstar FS instruments read HTRF signals.
The initial data read for every hole, ratio=665nm/620nm；
The calculating of inhibiting rate：
Calculate IC50：
With log [administration concentration] for abscissa, inhibiting rate is ordinate, and one is fitted in Graphpad Prism 5 Dose-effect curve, drug concentration during its 50% inhibiting rate is drawn, be IC of this compound in enzyme level50Value.
Experimental result：Jak kinase activity half-inhibition concentration（IC50nM）
The present invention provides the structure half-inhibition concentration of compound to jak kinase activity as shown in formula I（IC50）It is shown in Table 1：
Half-inhibition concentration of the compound of table 1 to JAK2 kinase activities（IC50）
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity +++ +++ +++ +++ +++ +++ +++ ++ +++ +++
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity +++ ++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 61 62 63 64 65 66 67 68 69 70
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 71 CP-690550
Activity intensity +++ +++
+++ represent IC50<500nM;++ represent IC50Scope is 500-5000nM;+ represent IC50Scope is 5000nM-50 μ M；- represent not test
Half-inhibition concentration of the compound of table 2 to JAK3 kinase activities（IC50）
Compound 1 2 3 4 5 6 7 8 9 10
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ ++ +++
Compound 11 12 13 14 15 16 17 18 19 20
Activity intensity +++ +++ +++ +++ ++ +++ +++ +++ +++ +++
Compound 21 22 23 24 25 26 27 28 29 30
Activity intensity ++ +++ +++ +++ ++ +++ +++ +++ +++ +++
Compound 31 32 33 34 35 36 37 38 39 40
Activity intensity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound 41 42 43 44 45 46 47 48 49 50
Activity intensity +++ +++ +++ +++ +++ ++ +++ ++ +++ +++
Compound 51 52 53 54 55 56 57 58 59 60
Activity intensity +++ ++ +++ +++ +++ +++ +++ +++ + +
Compound 61 62 63 64 65 66 67 68 69 70
Activity intensity +++ + + +++ +++ +++ +++ +++ +++ +++
Compound 71 CP-690550
Activity intensity + +++
+++ represent IC50<500nM;++ represent IC50Scope is 500-5000nM;+ represent IC50Scope is 5000nM-50 μ M；- represent not test
Experimental result：The compounds of this invention is to JAK2, inhibitory activity and the positive drug CP- of JAK3 kinases biochemistry levels 690550 suitable
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (16)

1. structure compound shown in formula I or its pharmaceutically acceptable salt：
Wherein：
R1For following groups：
R7For C1‐6Straight or branched alkyl, C2‐6Straight or branched alkenyl ,-CN ,-NHSO2R12、‐NHOH、‐NHC(O)OR12、‐ NHCOR12、‐CON(R12)2、‐N(R12)2、‐OR12、‐CF3、
R8For C1‐6Straight or branched alkyl, C3‐7Cycloalkyl,
R9、R10Or R11It is identical or different, be each independently selected from hydrogen ,-CN or
R12Selected from hydrogen ,-CN ,-NHSO2R5’, halogen ,-N (R5’)2、‐OR5’、‐CF3Or C1‐4Straight or branched alkyl；
X is selected from S, NH or O；
R2For hydrogen, halogen, C1‐6Straight or branched alkyl, cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, halo C1‐6 Straight or branched alkyl；
R3For hydrogen, halogen；
Or R2、R3Following heterocyclic radical is formed together with connecting their carbon atom：
Z independences are selected from N or CR13；
N or m is independently 0,1,2 or 3；
R4For hydrogen, halogen ,-NO2、‐OH、‐(CH2)pN(R5’)2、‐N(R1)R5R6、NHSO2R6、‐N(CH3)R5N(R5’)2、‐N(CH3) R6、‐NHR5N(R5’)2、‐NHR6、‐NHR5OR5OH、‐NHR5R6、‐OR5N(R5’)2、 C1‐6Straight chain or branch Chain alkoxy, substituted or non-substituted saturation or undersaturated 5 or 6 circle heterocycles bases ,-OR5R6Or two adjacent R4Substituent Carbon atom in connection is collectively forming 5 yuan of heteroaryl ring group；
R5It is substituted or unsubstituted C1‐3Alkylidene, R5’It is substituted or unsubstituted C1‐3Alkyl；
P is 2 or 3；
R6It is NH2、C1‐6Straight or branched alkylamino, C1‐3Alkoxy, cyclopropyl, substituted or unsubstituted phenyl, substitution do not take The furyl in generation, substituted or unsubstituted morpholinyl, substituted or unsubstituted thio-morpholinyl, substituted or unsubstituted piperazine Base, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrole radicals, substitution or not Substituted oxazolyls, substituted or unsubstituted imidazole radicals；
R4、R5、R5’And R6In substituent be separately hydrogen, halogen, hydroxyl, cyano group, dimethylamino, nitro, halo C1‐3Alkoxy, mesyl, C1‐6Straight or branched alkyl, C1‐3Alkoxy, C1‐3Acyloxy, the C of hydroxyl substitution1‐6Straight chain or The C of branched alkyl, halo1‐6Straight or branched alkyl, C3‐7Cycloalkyl, C3‐7Cycloalkanes formoxyl, dioxanes base, pyrrolidinyl, pyrrole Cough up alkane methyl or piperidyl；
R13Selected from hydrogen, C1‐3Alkoxy.
2. compound as claimed in claim 1, wherein：
R7For C1‐4Straight or branched alkyl, C2‐6Straight or branched alkenyl ,-CN ,-N (R12)2、‐NHSO2R12、‐NHC(O)OR12、
R8For C1‐4Straight or branched alkyl, C3‐5Cycloalkyl,
R9、R10Or R11It is identical or different, be each independently selected from halogen, hydrogen ,-CN or
R12Selected from halogen, methyl, the tert-butyl group ,-CN or hydrogen；
X is S；
M is 0 or 1.
3. compound as claimed in claim 2, wherein
R7For-CN, NH2、‐NHC(O)OR12, methyl, ethyl, pi-allyl or isopropyl；
R8For methyl, ethyl, n-propyl, isopropyl, normal-butyl,R9Or R10For hydrogen；
R11For-CN or
R12For-CN, methyl, the tert-butyl group or hydrogen；
X is S；
M is 0 or 1.
4. compound as claimed in claim 1, wherein
R2For hydrogen, halogen, C1‐4Straight or branched alkyl or halo C1‐4Straight or branched alkyl；
R3For hydrogen；
Or R2、R3Following heterocyclic radical is formed together with connecting their carbon atom：
5. compound as claimed in claim 4, wherein
R2For hydrogen ,-CH3Or-CF3；R3For hydrogen.
6. compound as claimed in claim 1, wherein
Z is CR13；
R13Selected from hydrogen, methoxyl group.
7. compound as claimed in claim 1, wherein
R4For hydrogen ,-F ,-NO2、‐OH、‐N(R1)R5R6、‐N(CH3)R5N(R5’)2、‐NHR5N(R5’)2、NHSO2R6、‐ NHR5OR5OH、‐N(CH3)R6、‐NHR6、‐NHR5R6、‐OR5N(R5’)2、C1‐4Straight or branched alkoxyl, pyrrolidinyl, C1‐6Alkane Pyrrolidinyl, pyrrolidinyl, piperidyl, the C of pyrrolidinomethyl substitution of base substitution1‐6Alkyl-substituted piperidyl, C1‐3Alcoxyl The piperidyl of base substitution, the piperidyl of piperidyl substitution, hydroxy piperidine base, piperidyl, the hydroxyl C of dimethylamino substitution1‐3Alkyl takes Piperidyl, the C in generation2‐4Piperidyl, piperazinyl, the C of alkyl acyloxy substitution1‐6Alkyl-substituted piperazinyl, morpholinyl, thiomorpholine Base, C1‐6Alkyl-substituted morpholinyl, imidazole radicals, C1‐6Alkyl-substituted imidazole radicals, ‐OR5R6Or two R4Substituent carbon atom in connection forms following heterocyclic radical together：
8. compound as claimed in claim 7, wherein
R4For hydrogen ,-OCH3、 ‐N(R1)R5R6、‐N (CH3)R5N(R5’)2、‐NHR5N(R5’)2、‐NHR5R6、‐NR5OR5OH、‐N(CH3)R6、‐NHR6、‐NHR5N(R5’)2、‐OR5N (R5’)2、OR5R6Or two R4Substituent carbon atom in connection forms together
9. compound as claimed in claim 8, wherein
R5For
10. compound as claimed in claim 8, wherein
R6It is C1‐3Alkoxy, cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substitution or unsubstituted Morpholinyl, substituted or unsubstituted thio-morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidyl, In substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrole radicals, Qu generations, do not substitute oxazolyls, substitution or unsubstituted Imidazole radicals；The substituent is hydrogen, hydroxyl, C1‐6Straight or branched alkyl, cyano group, halogen, the C of halo1‐6Straight or branched Alkyl, nitro, the C of halo1‐3Alkoxy, C1‐3Alkoxy, mesyl, the C of hydroxyl substitution1‐6Straight or branched alkyl, piperidines Base.
11. compound as claimed in claim 10, wherein
R6It is-OCH3、
12. compound as claimed in claim 1, wherein
N is 1,2 or 3；
When n is 1, R13For hydrogen or methoxyl group, R4For the para-orientating group or meta-substituent of amino on phenyl ring；
When n is 2, R13For methoxyl group, R4For the meta and para-orientating group of amino on phenyl ring；
When n is 3, R13For hydrogen, R4Face position and para-orientating group, and R for amino on phenyl ring4For halogen.
13. compound or its pharmaceutically acceptable salt, the compound are selected from：
14. a kind of pharmaceutical composition, it includes pharmaceutically acceptable carrier, excipient or diluent, and as activity into The compound any one of claim 1 to 13 divided.
15. compound the answering in terms of the disorder agent for the treatment of JAK mediations is prepared any one of claim 1 to 13 With the illness is selected from：It is polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, fine with marrow Myeloide metaplasia, allergy, autoimmune disease or the entity or hematologic malignancies of dimensionization.
16. application as claimed in claim 15, wherein the illness is selected from：Chronic special myelomatosis, Chronic Myeloid list Monocytic leukemia, asthma, suppress graft rejection, rheumatoid arthritis, psoriasis, lupus erythematosus, muscle contracting funiculus lateralis Hardening, multiple sclerosis.
CN201210369245.2A 2012-09-28 2012-09-28 Substituted furan and piperidine derivative and its application Active CN103709172B (en)

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Citations (6)

* Cited by examiner, † Cited by third party
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US20090048282A1 (en) * 2007-08-14 2009-02-19 Wyeth Pyrimidine sulfonamide analogs and their use as agonists of the wnt-beta-catenin cellular messaging system
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