CN103102359A - Pyrimidine compounds and application thereof - Google Patents
Pyrimidine compounds and application thereof Download PDFInfo
- Publication number
- CN103102359A CN103102359A CN2011103616613A CN201110361661A CN103102359A CN 103102359 A CN103102359 A CN 103102359A CN 2011103616613 A CN2011103616613 A CN 2011103616613A CN 201110361661 A CN201110361661 A CN 201110361661A CN 103102359 A CN103102359 A CN 103102359A
- Authority
- CN
- China
- Prior art keywords
- furo
- piperidines
- pyrimidyl
- replacement
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 238000002360 preparation method Methods 0.000 claims description 141
- 238000006243 chemical reaction Methods 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- -1 Hydrogen Chemical class 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000005936 piperidyl group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of biological medicines, and in particular relates to pyrimidine compounds and application thereof. The pyrimidine compounds are compounds shown by a general formula (I) in the specification and pharmaceutically acceptable equivalents or salts thereof. The pyrimidine compounds can be taken as Janus kinase inhibitors to be applied to various medicine purposes.
Description
Technical field:
The present invention relates to biomedicine field, be specifically related to pyrimidines and pharmaceutically acceptable Equivalent or salt, and preparation method thereof and as the purposes of Janus kinase inhibitor.
Background technology:
Protein kinase is comprised of involved enzyme on a series of structures, mainly is responsible for the control of intracellular signal transduction process.Usually, protein kinase shifts by the phosphoryl of impact from ribonucleoside triphosphote to the protein receptor that participates in signal transduction path, and the mediation intracellular signal.These phosphorylation events play modulation or regulate the molecular switch effect of target protein biological function.A lot of diseases are all relevant with the abnormal cells reaction that causes by above-mentioned protein kinase mediated event.
Janus kinases (JAK) comprises JAK1, JAK2, and JAK3 and TYK2 belong to the cytoplasm protein kinases, with I type and II cytokines receptor acting, regulate cytokine signaling.JAK1, JAK2 and TYK2 can suppress several genes to express, yet JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor is to exist as the heterodimer form, is not therefore a kind of jak kinase and cytokine receptor effect usually.
The downstream substrate of JAK family comprises signal transduction agent and the activator (STAT) of transcription factor.The JAK/STAT signal transduction relates to a lot of abnormal immune reactions, as transformation reactions, and asthma, autoimmune disease such as transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia, lymphoma.
Genetic biology studies show that, JAK1 by with IFNalpha, IFNgamma, IL-2, the cytokine receptor effect such as IL-6 and playing a role, the JAK1 knock-out mice is dead due to LIF receptor signal disappearance.Observe the feature organization of JAK1 knock-out mice, find JAK1 at IFN, IL-10, IL-2/IL-4, and play an important role in the cell pathway such as IL-6.
Genetic biology studies show that, there are contact in JAK2 and strand between IL-3 and interferon-gamma cytokine receptor family.Corresponding, the JAK2 knock-out mice is died from anaemia.Kinase mediated JAK2 variation is disorderly relevant to human bone marrow's hyperplasia, comprises polycythemia vera, hemorrhagic thrombocythemia, the chronic idiopathic myelofibrosis, with the marrow metaplasia of myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia etc.
The specific gamma cells factor acceptor chain that acts on of JAK3, it is at IL-2, IL-4, IL-7, IL-9, IL-15 exists in the cytokine receptors such as IL-21.JAK3 is at lymphocyte growth, and hyperplasia plays an important role in mutation process, and abnormal can cause serious immune deficiency.Regulate lymphocytic effect based on it, the path of JAK3 and JAK3 mediation is used for regulating immunosuppressant indication.JAK3 implication in the mediation that a lot of abnormal immunes are replied, as transformation reactions, asthma, autoimmune disease is as suppressing transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia, lymphoma.
TYK2 acts on I type Interferon, rabbit, IL-6, IL-10, IL-12, the cell factor receptor nanocrystal composition such as IL-23.Consistently with it be, be derived from the people's of TYK2 disappearance primary cell, at I type Interferon, rabbit, IL-6, IL-10, there is obstacle in IL-12 in the signal conduction of IL-23.
In sum, in the urgent need to developing the compound that can be used for kinases inhibitor, definite says, needs exploitation to can be used for the compound of JAK family kinase inhibitors.New compound of the present invention can suppress one or more jak kinases, and therefore expection can be used for treating associated disease.
Summary of the invention:
The object of the present invention is to provide the new pyrimidines of a class.
Purpose of the present invention can reach by following measures:
One class pyrimidines, as general structure (I) compound and pharmaceutically acceptable Equivalent or salt:
Wherein:
R
1Be alkyl, cycloalkyl, acyl group, the alkylsulfonyl that replaces arbitrarily;
R
2Be hydrogen, halogen, C1-C6 straight or branched alkyl, cycloalkyl, halo C1-C6 straight or branched alkyl;
R
3Be hydrogen, halogen;
Perhaps R
2With R
3And form the hetero-aromatic ring of 5 yuan together with the carbon atom that connects them;
Z independently is selected from N, CR
4
N is the 0-3 integer;
R
4Be independently selected from hydrogen, halogen, R
5, OR
5, OH, R
6, CN, CF
3, (CH
2)
nN(R
5)
2, NO
2, R
5R
6, OR
5R
6Perhaps two R
4Saturated or the undersaturated 5 or 6 yuan of heterocyclic radicals of the common formation of the carbon atom that substituting group is connected with them;
R
5Hydrogen, replacement or unsubstituted C1-C4 alkyl or replacement or unsubstituted C1-C4 alkylidene group, wherein two carbon atoms can be randomly by CO, S, SO at the most
2, or O substitute;
R
6NH
2, NHR
5, N (R
5)
2, N (R
4)
2, replacement or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace the De oxazolyl, replace or unsubstituted imidazolyl;
The purposes of the pyrimidines that the present invention also aims to provide new is specifically as the purposes of Janus kinase inhibitor.
Detailed Description Of The Invention
Alkyl represents to have the straight or branched saturated hydrocarbyl that is unsubstituted or is substituted of the carbon atom of described number.Typical alkyl includes, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methylheptyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
Cycloalkyl represent be all carbon monocycle, condense, the ring of volution or bridged ring.Typically be cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, spiral shell [3.4] octane, two ring [3.1.1] hexanes.
Alkylidene group represents itself or as another substituent part, means saturated or unsaturated alkane two bases of the straight chain with two terminal unit price base centers, and its two terminal carbon atoms from the female alkane of straight chain, alkene or alkynes respectively remove a hydrogen atom and get.Typical alkylidene group includes but is not limited to methylene radical, ethylidene, vinylidene, ethynylene, propylidene, butylidene etc.
Saturated heterocyclic radical is Heterocyclylalkyl, and expression contains the heteroatomic monocycle of one or more N, O or S or the ring that condenses.Typically be the heteroatomic 5-6 that contains one or more N, O or S first heterocyclic radical, for example Piperazino, morpholino base, piperidino-(1-position only), pyrrolidyl and derivative thereof.
Piperazino refers to the group with following chemical structure.
The morpholino base refers to the group with following chemical structure.
Piperidino-(1-position only) refers to the group with following chemical structure.
Pyrrolidyl refers to the group with following chemical structure.
Undersaturated heterocyclic radical is heteroaryl, and monocycle or the fused rings group of 5 to 12 annular atomses of expression contain one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have in addition the π-electron system of total conjugated.Typical heteroaryl (but being not limited to) pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, pyridine.
Halogen or halogen group are fluorine, chlorine, bromine or iodine.Be preferably fluorine, chlorine, bromine.The C that is replaced by halogen
1-3Alkyl group represents the alkyl that one or more hydrogen are wherein replaced by halogen, preferably contains one, two or three halogen groups.
In a kind of preferred version, R
1For:
R wherein
7Be C
1-6The straight or branched alkyl ,-CN ,-NHSO
2R
12,-NHOH ,-NHCOR
12,-CON (R
12)
2,-N (R
12)
2,-OR
12,-CF
3,
R
8For C1-6 straight or branched alkyl, C3-C7 cycloalkyl,
R
9, R
10Or R
11Identical or different, independently be selected from separately halogen, hydrogen, C1-C6 straight or branched alkyl, C3-C7 cycloalkyl,
R
12Be selected from hydrogen ,-CN ,-NHSO
2R
5, halogen ,-N (R
5)
2,-OR
5,-CF
3Or C1-C3 straight or branched alkyl; X is selected from S, NH or O; M is the 0-3 integer.
In another kind of preferred version, R
1Be following groups:
R wherein
7For C1-C4 straight or branched alkyl ,-CN,
R
8Be C1-C4 straight or branched alkyl; R
9, R
10Or R
11Identical or different, independently be selected from separately halogen, hydrogen or
R
12Be selected from-CN or hydrogen; X is S; M is 0 or 1.
As a kind of preferred, in such scheme, R
7For-CN,
R
8Be methyl; R
9Or R
10Be hydrogen; R
11For
R
12For-CN or hydrogen; X is S; M is 0 or 1.
In a kind of technical scheme, R
2Be hydrogen, halogen, C1-C4 straight or branched alkyl or halo C1-C4 straight or branched alkyl; R
3Be hydrogen; Perhaps R
2, R
3Form following heterocycle together with the carbon atom that connects them:
As a kind of preferred, structure provided by the invention is suc as formula in the compound shown in (I), R
2For hydrogen ,-F ,-CH
3,-CF
3, R
3Be hydrogen; Perhaps R
2, R
3Form following heterocycle together with the carbon atom that connects them:
In a kind of preferred technical scheme, Z is CR
4
In a kind of preferred technical scheme, R
4For hydrogen, halogen ,-NO
2,-OH, C1-C6 straight or branched alkoxyl group, replacement or non-substituted saturated or undersaturated 5 or 6 yuan of saturated or unsaturated heterocycle bases or-OR
5R
6R
5To replace or unsubstituted C1-C3 alkylidene group; R
6NH
2, C1-C6 straight or branched alkylamino, replacement or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace De oxazolyl, replacement or unsubstituted imidazolyl; R
4, R
5And R
6In substituting group be respectively C1-C6 straight or branched alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkanes formyl radical, dioxan base or the piperidyl of halogen, hydroxyl, C1-C6 straight or branched alkyl, hydroxyl replacement independently.
As a kind of preferred, R
4For hydrogen ,-F ,-NO
2The imidazolyl that the morpholinyl that the piperazinyl that the piperidyl that the pyrrolidyl that ,-OH, C1-C4 straight or branched alkoxyl group, pyrrolidyl, C1-C6 alkyl replace, piperidyl, C1-C6 alkyl replace, piperazinyl, C1-C6 alkyl replace, morpholinyl, C1-C6 alkyl replace, imidazolyl, C1-C6 alkyl replace or-OR
5R
6
As a kind of preferred, R
4Be further hydrogen ,-F ,-N
O2 ,-OH ,-OCH
3,
Or-OR
5R
6
In a kind of preferred technical scheme, R
5For
In a kind of preferred technical scheme, R
6To replace or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace De oxazolyl, replacement or unsubstituted imidazolyl; Described substituting group is C1-C6 straight or branched alkyl, C1-C6 alkyl acyl, C3-C7 cycloalkanes formyl radical or the piperidyl of hydroxyl, C1-C6 straight or branched alkyl, hydroxyl replacement.
As a kind of preferred, R
6Be further
In a kind of preferred technical scheme, n is 0,1 or 2.Wherein preferably when n is 1, R
4Be para-orienting group amino on phenyl ring; When n is 2, R
4Be position and para-orienting group between amino on phenyl ring.
The specific examples of the pyrimidines of formula (I) comprises those compounds that following table is listed:
The present invention also provides a kind of medicinal compositions that is used for the treatment of jak kinase relative disease in organism, comprises above-mentioned each compound provided by the invention and pharmaceutically acceptable carrier, vehicle or thinner.
Pharmacy acceptable salt represents to keep those salt of biological effectiveness and the character of parent compound.Wherein refer to sour salify, the free alkali by parent compound and mineral acid or organic acid reaction get.Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc.Organic acid comprises acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
Medicinal compositions refers to one or more the compounds of this invention or their pharmacy acceptable salt and prodrug and other chemical composition, comprises the mixture of pharmaceutically acceptable carrier and vehicle.The purpose of medicinal compositions is to promote compound to the administration of organism.
Pharmaceutically acceptable carrier refers to organism is not caused obvious pungency and do not disturb carrier or the thinner of biological activity and the character of the compound that gives.
Vehicle refers to and joins in medicinal compositions with the further convenient inert substance that gives compound.The example of vehicle comprises (being not limited to) calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
The invention still further relates to the have general formula preparation method of (I), it is characterized in that, comprise,
1. (a) amine fragment (III) and substituted carboxylic acid (II) are at solvent S
1Middle alkali B
1, catalyzer C
1, condensing agent L
1Under existence in temperature T
1Reacting generating compound under condition (I).
(b) amine fragment (III) and replacement acyl chlorides (II) are at solvent S
2Middle alkali B
2Under existence in temperature T
2Reacting generating compound under condition (I).
In order to prepare the compound described in general formula of the present invention (I), described preparation method is characterized in that, in preparation process, and described solvent S
1Be selected from organic solvent, as methylene dichloride, ethyl acetate, be preferably methylene dichloride; Described alkali B
1Be selected from organic bases, as triethylamine, N-ethyl diisopropylamine, be preferably triethylamine; Described catalyzer C
1Can to Dimethylamino pyridine, 4-pyrrolidyl pyridine, I-hydroxybenzotriazole, tributylphosphine, be preferably I-hydroxybenzotriazole; Condensing agent L
1For phosphinylidyne diimidazole, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide, be preferably 1-ethyl-(3-dimethylaminopropyl) carbodiimide; Temperature T
1For-15-15 ℃, be preferably 0 ℃.
The present invention also provides the purposes of new pyridine derivatives, specifically as the purposes of Janus kinase inhibitor.Comprising but be not limited to polycythemia vera, hemorrhagic thrombocythemia, the chronic idiopathic myelofibrosis, with the marrow metaplasia of myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia, transformation reactions, asthma, autoimmune disease is as suppressing transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia, lymphoma etc.
Invention also provides the application of above-mentioned each compound aspect the illness medicine of preparation treatment JAK2, JAK3 mediation, comprise arbitrary defined compound or its pharmaceutical composition in the system of this type for the treatment of of needs or individual the present invention who uses significant quantity, thereby treat described illness.
In order to check compound provided by the invention for the exposure level of jak kinase, adopt the biochemistry level enzymic activity to test to determine that various compound of the present invention is to activity and the exposure level of one or more PK.The method of knowing in operation is all tested like design class in the same way for any kinases.
In the test of biochemistry level enzymic activity, utilize the activity of HTRF technology for detection Tyrosylprotein kinase, HTRF is a kind of time resolved fluorescence resonance ability transfer techniques.HTRF (homogeneous phase time discrimination fluorescence) is a kind of the most frequently used method that detects determinand in homogeneous system, this technology combines FRET (fluorescence resonance energy transfer) (FRET) and TIME RESOLVED TECHNIQUE (TR), has been widely used in the different steps based on the medicament research and development of cell experiment and biochemical test.measuring principle according to the HTRF method, with pure enzyme JAK2 together with biotinylated substrate and ATP after incubation reaction, add the XL-665 of avidin mark and the antibody of the Eu mark of identification substrate phosphorylation, after substrate is by the JAK2 phosphorylation, the antibody of Eu mark namely can be identified this phosphorylation product, the FRET (fluorescence resonance energy transfer) (FRET) of differentiating with the XL665 formation time of avidin mark, and the substrate that is not phosphorylated is owing to can not being formed the FRET signal by antibody recognition, by the fluorescent signal difference of measuring 665nm and 620nm measure determinand under different concns to JAK2, the kinase whose inhibition of JAK3 is active.Thereby, adopt this method can measure the compounds of this invention to the active function of the biochemistry level of above-mentioned Tyrosylprotein kinase, utilize simultaneously method well known in the art, can use similar measuring method to other protein kinase.
The structure of the present invention's preparation has good restraining effect suc as formula the compound shown in I to multiple kinase activity, and it is to the kinase whose half-inhibition concentration (IC of JAK2, JAK3
50) generally 10
-7Mol.L
-1Below.Know by inference thus, the compound that the present invention has formula I structure can be applicable to prepare the medicine for the treatment of jak kinase relative disease in organism.
Specific implementation method:
The invention discloses intermediate of a kind of compound and preparation method thereof, this compound and preparation method thereof, and this compound is as the application of jak kinase inhibitor, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similarly replace and change apparent to those skilled in the art, and they all are deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change methods and applications as herein described within not breaking away from content of the present invention, spirit and scope or suitably change and combination, realizes and use the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1: the preparation of compound 1
1-benzyl-4-tributyl tin-furo [3,2-c] piperidines
Under nitrogen protection; add 1-benzyl-furo [3 in reaction flask; 2-c] piperidines (11.2mg; 1eq) and dry tetrahydrofuran (150 μ L), drip n-Butyl Lithium (16.05 μ L, 1eq) under condition of ice bath; continue to drip tributyltin chloride (20.8mg; 1.6eq), dropwise, continue reaction 2.5 hours.Stopped reaction adds shrend and goes out, and ethyl acetate (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, and suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-tributyl tin-furo [3,2-c] piperidines (19.25mg).
1-benzyl-4-(3-chloro-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-benzyl-4-tributyl tin-furo [3,2-c] piperidines (3.2mg, 1eq) in reaction flask, 2,4-, two chloro-5-methyl-pyrimidines (0.97mg, 1eq), Pd (PPh
3)
2Cl
2(0.42mg, 0.1eq) and DMF (5mL), 80 degree reacting by heating 5 hours.Stopped reaction adds water (5mL), methylene dichloride (5mL*5) extraction, merge organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-(3-chloro-6-methyl) pyrimidyl-furo [3,2-c] piperidines (0.47mg).
1-benzyl-4-(3-(3,5-, two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 3 in the microwave bottle, 5-two fluoro-4-morpholinyl phenylamine (347.0mg, 1.1eq), 1-benzyl-4-(3-chloro-6-methyl) pyrimidyl-furo [3,2-c] piperidines (500.0mg, 1eq), the hydrochloric acid soln of dioxane (6.6M) (668 μ L), potassiumiodide (97mg, 0.4eq) and trifluoroethanol (5mL) were in the lower 145 ℃ of reactions of microwave 1 hour.Add water (20mL), saturated NaHCO
3The aqueous solution is washed, methylene dichloride (10mL*5) extraction, merge organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-, and (3-(3,5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (723.6mg).
4-(3-(3,5-, two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 to add 1-benzyl-4-in the reaction flask, 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (300.0mg, 1eq), chloroformate-1-chloro-ethyl ester (125 μ L, 2eq), triethylamine (80.75 μ L) and methylene dichloride (9mL), stirring at room 7 hours, concentration of reaction solution, add methyl alcohol (10mL), 60 degree reacting by heating 2 hours, be chilled to room temperature, there is solid to separate out, suction filtration, (3-(3 to get 4-with a small amount of methanol wash, 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (157.9mg).
1-itrile group acyl group-4-(3-(3,5-, two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 4-(3-(3,5-, two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (108mg in reaction flask, 1eq), cyanoacetic acid (42.84mg, 2eq), 1-hydroxyl-benzo-triazole (85.11mg, 2.5eq), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (120.77mg, 2.5eq), the DIPEA of catalytic amount and methylene dichloride (20mL), room temperature reaction 4 hours, induction stirring.Stopped reaction adds water (20mL), saturated NaHCO
3The aqueous solution is washed; methylene dichloride (10mL*5) extraction; merge organic phase; anhydrous sodium sulfate drying; suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-itrile group acyl group-4-, and (3-(3; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (66.0mg).
MS：[M+H]
+＝495.0.
1H-NMR(500M，DMSO-d
6)δ9.85(s，1H)，8.42(s，1H)，7.59-7.62(d，2H)，7.18-7.27(d，1H)，4.54(s，2H)，4.18-4.23(d，2H)，3.70(s，6H)，3.05(s，6H)，2.38(s，3H)ppm。
Embodiment 2: the preparation of compound 2
4-chloro-N-phenyl-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Add 4-chloro-7-to this alkylsulfonyl of first 7H-pyrroles [2,3-d] pyrimidine-2-amine (322.0mg, 1eq), phenyl-iodide (204.1mg, 1eq), Pd (OAC) in reaction flask
2(16.2mg, 0.1eq), Cs
2CO
3(32.5mg, 0.1eq) and dioxan (5mL), 110 degree reactions, induction stirring.Stopped reaction adds water (5mL), methylene dichloride (5mL*5) extraction; merge organic phase, anhydrous sodium sulfate drying, suction filtration; concentrated, the crude product silica gel column chromatography obtains 4-chloro-N-phenyl-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine (367.0mg).
1-benzyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
Add 1-benzyl-4-tributyl tin-furo [3,2-c] piperidines (502.0mg, 1eq) in reaction flask, 4-chloro-N-phenyl-7-tosic acid-7H-pyrroles [2,3-d] pyrimidine-2-amine (398.8mg, 1eq), Pd (PPh
3)
2Cl
2(70.1mg, 0.1eq) and DMF (10mL), 95 degree reacting by heating 2 hours.Stopped reaction; add water (5mL); methylene dichloride (5mL*5) extraction; merge organic phase, anhydrous sodium sulfate drying, suction filtration; concentrated; the crude product silica gel column chromatography obtains 1-benzyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines (532.7mg).
4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
Add 1-benzyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4 in reaction flask; 3-b] pyrimidyl)-furo [3,2-c] piperidines (120mg, 1eq); Mono Chloro Acetic Acid-1-chloroethene ester (34 μ L; 1.5eq), methylene dichloride 5mL, room temperature reaction 1 hour; concentration of reaction solution; add methyl alcohol 5mL, be warming up to back flow reaction 2 hours, induction stirring.Stopped reaction; add water (10mL); methylene dichloride (10mL*5) extraction; merge organic phase, anhydrous sodium sulfate drying, suction filtration; concentrated; the crude product silica gel column chromatography obtains 4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines (43.0mg).
4-(3-anilino pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
Add 4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines (20mg, 1eq) in reaction flask; methyl alcohol 5mL, methylene dichloride 2mL, 2MNaOH1mL; be warming up to backflow, reacted induction stirring 1 hour.Stop stirring, concentration of reaction solution, add water (10mL), methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 4-(3-anilino pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines (6.1mg).
MS：[M+H]
+＝332.1.
1H-NMR(500M，DMSO-d
6)δ11.52(s，1H)，9.20(s，1H)，7.89(d，2H)，7.29-7.19(m，4H)，6.88(t，1H)，6.75(d，1H)，3.71(s，2H)，3.05(t，2H)，2.72(s，2H)ppm。
Embodiment 3: the preparation of compound 3
1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-benzyl-4-(3-chloro-6-methyl) pyrimidyl-furo [3 in the microwave bottle, 2-c] piperidines (2.85g, 1eq), 4-morpholine aniline (1.5g, 1eq), the hydrochloric acid soln of dioxane (6.6M) (2.8mL, 2.2eq), potassiumiodide (0.5g, 0.04eq) and trifluoroethanol (10mL) were in the lower 165 ℃ of reactions of microwave 2 hours.Add water (20mL), saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (3.4g).
4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
add 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (3.35g, 1eq), chloroformate-1-chloro-ethyl ester (1.8mL, 2.5eq), triethylamine (2.4mL) and methylene dichloride (80mL), stirring at room 7 hours, concentration of reaction solution, add methyl alcohol (20mL), 60 degree reacting by heating 2 hours, be chilled to room temperature, there is solid to separate out, suction filtration, get 4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3 with a small amount of methanol wash, 2-c] piperidines (2.34g).
1-itrile group ethanoyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝459.2.
1H-NMR(500M，DMSO-d
6)δ9.21-9.22(d，1H)，8.28(s，1H)，7.64-7.66(d，2H)，7.17(s，1H)，6.88-6.90(d，2H)，4.51(s，1H)，4.43(s，1H)，4.19(s，1H)，4.14(s，1H)，3.85-3.88(t，1H)，3.70-3.74(m，5H)，3.01-3.03(t，3H)，2.91-2.92(m，2H)，2.79-2.81(m，1H)，2.33(s，3H)ppm。
Embodiment 4: the preparation of compound 4
1-benzyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into N methyl piperazine base aniline.
4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group ethanoyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is pyrimidyl-furo [3 with 4-(3-(4-morpholinyl phenylamine base)-6-methyl); 2-c] piperidines changes 4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝472.3.
1H-NMR(400M，DMSO-d
6)δ9.26-9.27(d，1H)，8.30(s，1H)，7.64-7.67(d，2H)，7.16-7.20(d，1H)，6.90-6.92(d，2H)，4.44-4.53(d，2H)，4.17-4.22(d，2H)，3.86-3.89(t，1H)，3.71-3.74(t，1H)，3.11(s，4H)，2.92(s，1H)，2.82(s，1H)，2.64(s，4H)，2.34(s，6H)ppm。
Embodiment 5: the preparation of compound 5
1-benzyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into 2-tetramethyleneimine-1-phenetidine.
4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] the piperidines preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3 into, 2-c] piperidines.
1-itrile group ethanoyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝487.3.
1H-NMR(400M，CDCl
3)δ8.23(s，1H)，7.52-7.54(d，2H)，7.01-7.06(t，2H)，6.93-6.95(d，2H)，4.51-4.64(d，2H)，4.21-4.22(d，2H)，3.81-3.84，4.01-4.04(dt，2H)，3.04(s，2H)，2.82-2.91(d，2H)，2.82(s，4H)，2.40(s，3H)，2.24-2.26(m，2H)，1.90(s，4H)ppm。
Embodiment 6: the preparation of compound 6
1-benzyl-4-(3-chlorine) pyrimidyl-furo [3,2-c] piperidines
Add 1-benzyl-4-tributyl tin-furo [3,2-c] piperidines (1.69g, 1eq) in reaction flask, 2,4-, two chloro-pyrimidines (500.0mg, 1eq), Pd (PPh
3)
2Cl
2(0.24g, 0.1eq) and DMF (15mL), 80 degree reacting by heating 2 hours.Stopped reaction adds water (5mL), methylene dichloride (5mL*5) extraction, merge organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-(3-chlorine) pyrimidyl-furo [3,2-c] piperidines (365.0mg).
1-benzyl-4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines
Add 4-morpholinyl phenylamine (65.0mg in the microwave bottle, 1.1eq), 1-benzyl-4-(3-chloro-) pyrimidyl-furo [3,2-c] piperidines (120.0mg, 1eq), the hydrochloric acid soln of dioxane (6.6M) (184 μ L), potassiumiodide (20.6mg, 0.4eq) and trifluoroethanol (5mL), in the lower 160 ℃ of reactions of microwave 2 hours.Add water (20mL), saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines (127.5mg).
4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines
add 1-benzyl-4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (124.0mg, 1eq), chloroformate-1-chloro-ethyl ester (105 μ L, 2eq), triethylamine (80.75mg) and methylene dichloride (10mL), stirring at room 7 hours, concentration of reaction solution, add methyl alcohol (10mL), 60 degree reacting by heating 2 hours, be chilled to room temperature, there is solid to separate out, suction filtration, get 4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3 with a small amount of methanol wash, 2-c] piperidines (85.6mg).
1-cyano group ethanoyl-4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝445.1.
1H-NMR(400M，CDCl
3)δ8.38-8.40(d，1H)，7.54-7.56(d，2H)，7.23(s，1H)，7.08(s，1H)，6.99(s，1H)，6.96-6.97(d，2H)，4.37(s，2H)，3.90-3.92(t，4H)，3.72-3.75(t，2H)，3.15-3.17(t，4H)，2.95-2.98(t，2H)，2.90(s，2H)ppm。
Embodiment 7: the preparation of compound 7
1-benzyl-4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 6 (3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into N methyl piperazine base aniline.
4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 6 (3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)), 2-c] piperidines changes 1-benzyl-4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group ethanoyl-4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝458.4.
1H-NMR(400M，CDCl
3)δ8.38-8.48(dd，1H)，7.52-7.54(d，2H)，7.06(s，2H)，6.95-6.98(q，3H)，4.48-4.62(d，2H)，3.80-3.83，4.00-4.03(dt，2H)，3.61-3.62(d，2H)，3.22-3.24(t，4H)，2.88-2.91，3.00-3.03(dt，2H)，2.65-2.67(t，4H)，2.41(s，3H)ppm。
Embodiment 8: the preparation of compound 8
2-((furans-3-methyl)-(4-methoxyphenyl) amino) ethanol
Add 1-(furyl-3-)-N-(4-methoxyphenyl) methylamine (65.0mg, 1eq), bromoethanol (74.27mg in reaction flask, 20eq), salt of wormwood (122.21mg, 30eq) and acetonitrile (500 μ L), reflux 12 hours, induction stirring.Stopped reaction, filtering solid, saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, and suction filtration concentrates to get 2-((furans-3-methyl)-(4-methoxyphenyl) amino) ethanol (87.3mg).
2-chloro-N-(furans-3-methyl)-N-(4-methoxyphenyl) ethamine
Add 2-((furans-3-methyl)-(4-methoxyphenyl) amino) ethanol (87.3mg, 1eq) in reaction flask, thionyl chloride (68.38mg, 2eq) and methylene dichloride (500 μ L), under ice bath, reaction is 5 hours.Stopped reaction, saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, and suction filtration concentrates to get 2-chloro-N-(furans-3-methyl)-N-(4-methoxyphenyl) ethamine (63.53mg).
5-(4-p-methoxy-phenyl)-2-tri-n-butyl tin-4,5,6,7-furo [3,2-c] piperidines
Under nitrogen protection; add 2-chloro-N-(furans-3-methyl)-N-(4-methoxyphenyl) ethamine (63.0mg in reaction flask; 1eq) and dry tetrahydrofuran (600 μ L); drip n-Butyl Lithium (108.2 μ L under condition of ice bath; 1.2eq), continue to drip tributyltin chloride (146.77mg, 2eq); dropwise, continue reaction 2.5 hours.Stopped reaction adds shrend and goes out, and ethyl acetate (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, and suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-to methoxybenzyl-4-tributyl tin-furo [3,2-c] piperidines (94.37mg).
2-(4-morpholinyl phenylamine base)--4-chloro-5-trifluoromethyl pyrimidine
Add ether (50 μ L) in reaction flask, the trimethyl carbinol (50 μ L), methylene dichloride (50 μ L) and zinc chloride (9.99mg, 2.2eq) add 2 under condition of ice bath, 4-two chloro-5-trifluoromethyl pyrimidine (7.24mg, 1eq), 4-morpholine aniline (9.66mg, 1.1eq) and triethylamine (6.54mg), reacted induction stirring 2 hours.Stopped reaction, ethyl acetate (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 2-(4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine (12.4mg).
1-is to methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines adds 2-(4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine (22.2mg in reaction flask, 1.5eq), 1-is to methoxybenzyl-4-tributyl tin-furo [3,2-c] piperidines (10.0mg, 1eq), Pd (PPh
3)
2Cl
2(1.95mg, 0.06eq) and DMF (2mL), 90 degree reacting by heating 6 hours, induction stirring.Stopped reaction, ethyl acetate (10mL*5) extraction, merge organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-to methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines (12.6mg).
4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-to methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3 in the microwave bottle, 2-c] piperidines (5.5mg), hydrogen bromide (6 μ L) and trifluoroethanol (2mL), 150 ℃ were reacted 1 hour.Stopped reaction, saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product is crossed post and is got 4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines (0.8mg).
1-cyano group ethanoyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝513.9.
1H-NMR(400M，CDCl
3)δ8.66(s，1H)，7.53-7.55(t，2H)，7.28(s，1H)，7.23-7.24(d，1H)，7.01-7.02(t，2H)，4.52-4.65(d，2H)，4.02-4.05，3.82-3.85(dt，2H)，3.92(s，4H)，3.61-3.63(d，2H)，3.02(s，4H)，3.04-3.07，2.92-2.95(dt，2H)ppm。
Embodiment 9: the preparation of compound 9
1-benzyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into NEP base aniline.
4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group ethanoyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝486.0.
1H-NMR(500M，DMSO-d
6)δ9.21-9.22(d，1H)，8.28(s，1H)，7.61-7.64(d，2H)，7.18(s，1H)，6.87-6.89(d，2H)，5.75(s，1H)，4.51(s，2H)，4.20(d，2H)，3.87(s，2H)，3.69-3.72(m，2H)，3.45(s，2H)，3.04-3.06(m，4H)，2.89-2.92(m，2H)，2.81-2.82(m，1H)，2.33-2.37(m，3H)，1.03(s，3H)ppm。
Embodiment 10: the preparation of compound 10
1-benzyl-4-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into 3,4,5-trimethoxy-aniline.
4-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-into (3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines.
1-itrile group ethanoyl-4-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines changes 4-into (3-(3,4; 5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines.
MS：[M+H]
+＝464.0.
1H-NMR(500M，DMSO-d
6)δ9.37(s，1H)，8.35(s，1H)，7.37-7.38(d，2H)，7.19(s，1H)，5.75(s，1H)，4.51(s，2H)，4.15-4.20(d，2H)，3.80(s，6H)，3.61(s，3H)，2.89-2.92(m，2H)，2.81-2.82(m，1H)，2.35(s，3H)ppm。
Embodiment 11: the preparation of compound 11
1-benzyl-4-(3-anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into aniline.
4-(3-anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-cyano group ethanoyl-4-(3-(anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝374.1.
1H-NMR(500M，DMSO-d
6)δ9.46-9.47(d，1H)，8.34-8.35(d，1H)，7.80-7.82(d，2H)，7.25-7.29(t，2H)，7.17-7.21(d，1H)，6.90-6.93(t，1H)，4.52(s，1H)，4.44(s，1H)，3.86-3.88(t，1H)，3.70-3.73(t，2H)，2.89-2.92(m，2H)，2.81-2.82(m，1H)，2.35(s，3H)ppm。
Embodiment 12: the preparation of compound 12
1-benzyl-4-(3-(4-nitro-anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into the 4-N-methyl-p-nitroaniline.
4-(3-(4-nitro-anilino) 6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-nitro-anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group acyl group-4-(3-(4-oil of mirbane amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-oil of mirbane amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝418.9.
1H-NMR(500M，DMSO-d
6)δ10.39-10.40(d，1H)，8.47-8.48(d，1H)，8.20-8.23(d，2H)，8.06-8.09(d，2H)，7.26-7.33(m，1H)，4.53(s，2H)，4.17-4.21(d，2H)，3.87-3.89(m，2H)，2.83-2.94(m，2H)，2.40(s，3H)ppm。
Embodiment 13: the preparation of compound 13
1-benzyl-4-(3-(4-fluoro-anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into the 4-fluoroaniline.
4-(3-(4-fluoro-anilino) 6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-fluoro-anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group acyl group-4-(3-(4-fluoroanilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-fluoroanilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝392.2.
1H-NMR(500M，CDCl
3)δ8.26(s，1H)，7.58-7.62(m，2H)，7.04-7.08(m，4H)，4.52-4.66(m，2H)，4.02-4.05(m，1H)，3.82-3.85(m，1H)，3.62-3.63(m，2H)，3.04-3.07(m，1H)，2.91-2.94(m，1H)，2.42-2.43(d，3H)ppm。
Embodiment 14: the preparation of compound 14
2-(4-N-Boc-piperazinyl phenyl amido)--4-chloro-5-trifluoromethyl pyrimidine
The preparation method is with 2-in embodiment 8 (4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine, and difference is to change 4-morpholine aniline into N-Boc-piperazinyl aniline.
1-is to methoxy-benzyl-4-(3-(4-N-Boc-piperazinyl phenyl amido)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method with 1-in embodiment 8 to methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, difference is to change 2-(4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine into 2-(4-N-Boc-piperazinyl phenyl amido)--4-chloro-5-trifluoromethyl pyrimidine.
1-is to methoxy-benzyl-4-(3-(4-piperazinyl phenyl amido)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines adds 1-to methoxy-benzyl-4-(3-(4-N-Boc-piperazinyl phenyl amido)-6-trifluoromethyl) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (190mg), trifluoroacetic acid (2mL) and methylene dichloride (10mL), room temperature reaction 2 hours.Stopped reaction, saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated crude product 1-is to methoxy-benzyl-4-(3-(4-piperazinyl phenyl amido)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines (410mg).
1-is to methoxy-benzyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-to methoxy-benzyl-4-(3-(4-piperazinyl phenyl amido)-6-trifluoromethyl) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (2.0mg), monobromethane (0.5mL), salt of wormwood (10mg) and acetone (3mL) are heated to reflux 0.5 hour.Stopped reaction, saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated crude product 1-is to methoxy-benzyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines (2.1mg).
4-(3-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] the piperidines preparation method is with 4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, difference is 1-methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines changes 1-into to methoxy-benzyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines.
1-itrile group ethanoyl-4-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl) pyrimidyl-furo [3, 2-c] (3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the piperidines preparation method, 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3, 2-c] piperidines synthetic, difference is that (3-(3 with 4-, 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3, 2-c] piperidines changes 4-(4-N-ethyl piperazidine base anilino)-6-trifluoromethyl into) pyrimidyl-furo [3, 2-c] piperidines
MS：[M+H]
+＝540.3.
1H-NMR(500M，CDCl
3)δ10.03(s，1H)，8.72(s，1H)，7.61(s，2H)，7.35(s，1H)，6.94-6.96(s，2H)，4.54(s，2H)，4.21(s，2H)，3.13(s，6H)，2.92(s，2H)，2.80(s，2H)，2.57(s，2H)，2.44(s，2H)，1.05-1.08(t，3H)ppm。
Embodiment 15: the preparation of compound 15
2-(4-(2-chloro-1-oxyethyl group) anilino)--4-chloro-5-trifluoromethyl pyrimidine
The preparation method is synthetic with 2-in embodiment 8 (4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine, and difference is to change 4-morpholine aniline into 2-chloro-1-phenetidine.
1-is to methoxy-benzyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method with 1-in embodiment 8 to methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is to change 2-(4-morpholinyl phenylamine base)-4-chloro-5-trifluoromethyl pyrimidine into 2-(4-(2-chloro-1-oxyethyl group) anilino)--4-chloro-5-trifluoromethyl pyrimidine.
4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with the 4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is 1-methoxy-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines changes 1-into to methoxy-benzyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines.
1-itrile group ethanoyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
1-itrile group ethanoyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-itrile group ethanoyl-4-(3-(4-(2-bromo-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3 in reaction flask; 2-c] piperidines (160mg; 1eq); tetramethyleneimine (51.4mg, 3eq), potassiumiodide (9.6mg; 0.054eq) and N; dinethylformamide (10mL), 80 degree reacting by heating 3 hours, induction stirring.Stopped reaction; add water (10mL) and methylene dichloride (10mL) separatory; methylene dichloride (10mL*5) extraction; merge organic phase; anhydrous sodium sulfate drying, suction filtration, concentrated; the crude product silica gel column chromatography obtains 1-itrile group ethanoyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines (62.3mg).
MS：[M+H]
+＝541.3.
1H-NMR(400M，CDCl
3)δ8.60(s，1H)，7.86-7.89(d，1H)，7.46-7.48(d，2H)，7.16(s，1H)，6.91-6.93(t，2H)，4.43-4.58(d，2H)，4.13-4.16(t，2H)，3.95-3.97，3.74-3.76(dt，2H)，3.64-3.65(d，2H)，2.95-2.97(t，3H)，2.84(s，1H)，2.70(s，4H)，1.84(s，4H)ppm。
Embodiment 16: the preparation of compound 16
1-methylsulfonyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
Add 4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4 in reaction flask; 3-b] pyrimidyl)-furo [3; 2-c] piperidines (485.0mg; 1eq); methylsulfonyl chloride (228.7mg, 2eq), the DIPEA of catalytic amount and methylene dichloride (30mL); room temperature reaction 2 hours, induction stirring.Stopped reaction adds water (20mL), saturated NaHCO
3The aqueous solution is washed; methylene dichloride (10mL*5) extraction; merge organic phase; anhydrous sodium sulfate drying; suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-methylsulfonyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4; 3-b] pyrimidyl)-furo [3,2-c] piperidines (485.6mg).
1-methylsulfonyl-4-((3-anilino) pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
Add 1-methylsulfonyl-4-(3-anilino-5-p-toluenesulfonyl pyrrolo-[4 in reaction flask; 3-b] pyrimidyl)-furo [3; 2-c] piperidines (243.0mg; 1eq); saturated sodium carbonate (2M) (10mL), methyl alcohol (10mL) and tetrahydrofuran (THF) (10mL) are warming up to backflow; reacted induction stirring 15 minutes.Stopped reaction adds water (10mL), saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase; anhydrous sodium sulfate drying, suction filtration, concentrated; the crude product silica gel column chromatography obtains 1-methylsulfonyl-4-((3-anilino) pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines (150mg).
MS：[M+H]
+＝410.1.
1H-NMR(500M，DMSO-d
6)δ11.58(s，1H)，9.25(s，1H)，7.89-7.91(dd，2H)，7.32(s，1H)，7.29-7.22(m，3H)，6.92-6.84(m，1H)，6.75-6.77(dd，1H)，4.31(s，2H)，3.62-3.65(t，2H)，2.97(s，3H)，2.96-2.98(t，2H)ppm。
Embodiment 17: the preparation of compound 17
1-methylsulfonyl-4-(3-(anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes into-(3-(anilino-6-methyl) pyrimidyl-furo [3,2-c] piperidines.
MS：[M+H]
+＝385.1.
1H-NMR(500M，DMSO-d
6)δ9.47(s，1H)，8.35(s，1H)，7.82-7.85(d，2H)，7.28-7.31(t，2H)，7.21(s，1H)，6.92-6.95(t，1H)，4.29(s，2H)，3.59-3.62(t，2H)，2.97(s，3H)，2.92-2.95(d，2H)，2.36(s，3H)ppm。
Embodiment 18: the preparation of compound 18
1-methylsulfonyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝470.1.
1H-NMR(500M，DMSO-d
6)δ9.22(s，1H)，8.29(s，1H)，7.65-7.66(d，2H)，7.18(S，1H)，6.90(S，2H)，4.28(s，2H)，3.74(S，4H)，3.58-3.60(t，2H)，3.02(s，4H)，2.97(s，3H)，2.92(s，2H)，2.34(s，3H)ppm
Embodiment 19: the preparation of compound 19
1-methylsulfonyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3; 2-c] the piperidines preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝483.2.
1H-NMR(400M，DMSO-d
6)δ9.26(s，1H)，8.30(s，1H)，7.64-7.66(d，2H)，7.20(S，1H)，6.89-6.91(d，2H)，4.30(s，2H)，3.60(s，3H)，3.07(s，5H)，2.99(s，4H)，2.94(s，3H)，2.35(s，3H)，2.25(s，3H)ppm。
Embodiment 20: the preparation of compound 20
1-methylsulfonyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝498.2.
1H-NMR(400M，CDCl
3)δ8.24(s，1H)，7.52-7.54(d，2H)，7.04(s，1H)，6.93-6.95(t，3H)，4.39(s，2H)，4.20(s，2H)，3.72-3.75(t，2H)，2.97-3.00(t，3H)，2.90-2.91(dt，2H)，2.65-2.67(s，3H)，2.78(s，3H)，2.41(s，3H)，1.90(s，4H)ppm。
Embodiment 21: the preparation of compound 21
1-benzyl-4-(3-(4-imidazoles anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into 4-imidazolyl aniline.
4-(3-(4-imidazoles anilino anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 3 (3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-(4-imidazoles anilino anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
1-methylsulfonyl-4-(3-(4-imidazoles anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 19 (3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines; difference is pyrimidyl-furo [3 with 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl); 2-c] piperidines changes 4-(3-(4-imidazoles anilino anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M-H]
-＝489.3.
1H-NMR(400M，DMSO-d
6)δ8.40(s，1H)，8.18(s，1H)，7.96-7.99(m，2H)，7.54-7.67(m，4H)，7.25(s，1H)，7.11(s，1H)，4.28-4.30(d，2H)，3.58-3.62(m，2H)，3.00(s，3H)，2.92-2.96(m，2H)，2.38(s，3H)ppm。
Embodiment 22: the preparation of compound 22
1-methylsulfonyl-4-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-itrile group ethanoyl-4-in embodiment 10 (3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change cyanoacetic acid into methylsulfonic acid.
MS：[M-H]
-＝475.3.
1H-NMR(400M，DMSO-d
6)δ9.40(s，1H)，8.37(s，1H)，7.40(s，2H)，7.20(s，1H)，4.28(s，2H)，3.81(s，6H)，3.63(s，3H)，3.61-3.62(t，2H)，2.99(s，3H)，2.86-2.89(m，2H)，2.35(s，3H)ppm。
Embodiment 23: the preparation of compound 23
1-benzyl-4-(3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 6 (3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines, and difference is to change the 4-morpholinyl phenylamine into 4-(2-tetramethyleneimine-1-oxyethyl group) aniline.
4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 6 (3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-(4-morpholinyl phenylamine base)), 2-c] piperidines changes 1-benzyl-4-(3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines into.
1-methylsulfonyl-4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 19 (3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines; difference is pyrimidyl-furo [3 with 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl); 2-c] piperidines changes 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝484.1.
1H-NMR(400M，CDCl
3)δ8.40-8.41(d，1H)，7.53-7.55(dd，2H)，7.05-7.06(d，2H)，6.94-6.98(m，3H)，4.37(s，2H)，4.167-4.18(t，2H)，3.12-3.13(t，2H)，2.95-3.00(m，4H)，2.90(s，3H)，2.74(s，4H)，1.86-1.89(m，4H)ppm
Embodiment 24: the preparation of compound 24
1-methylsulfonyl-4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-N-methylpiperazine base anilino)) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝469.2.
1H-NMR(400M，CDCl
3)δ8.39-8.40(d，1H)，7.52-7.54(d，2H)，7.04-7.06(dd，2H)，6.96-6.98(q，3H)，4.37(s，2H)，3.71-3.74(t，2H)，3.21-3.24(t，4H)，2.95-2.98(t，2H)，2.89(s，3H)2.64-2.66(t，4H)，2.41(s，3H)ppm。
Embodiment 25: the preparation of compound 25
1-methylsulfonyl-4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-N-ethyl piperazidine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝497.0.
1H-NMR(500M，DMSO-d
6)δ10.41(s，1H)，8.48(s，1H)，8.20-8.23(d，2H)，8.07-8.09(d，2H)，7.33(s，1H)，5.75(s，3H)，4.30(s，2H)，4.18(s，2H)，3.59-3.61(t，2H)，3.37-3.41(m，2H)，2.95-2.99(m，6H)，2.49-2.50(t，2H)，2.41(s，3H)，1.07-1.11(t，3H)ppm。
Embodiment 26: the preparation of compound 26
(3-(3 for 1-methylsulfonyl-4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] the piperidines preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-into (3-(3; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3,2-c] piperidines.
MS：[M+H]
+＝506.1.
1H-NMR(500M，DMSO-d
6)δ9.86(s，1H)，8.43(s，1H)，7.59-7.64(q，2H)，7.22(s，1H)，5.78(s，3H)，4.32(s，2H)，3.70(s，4H)，3.01-3.05(m，6H)，2.53(s，2H)，2.39(s，3H)ppm。
Embodiment 27: the preparation of compound 27
1-benzyl-4-(3-chloro-6-fluorine) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-benzyl-4-in embodiment 1 (3-chloro-6-methyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change 2,4-, two chloro-5-methyl-pyrimidines into 2,4-two chloro-5-fluoro-pyrimidines.
1-benzyl-4-(3-(3,4,5-trimethoxy-benzene amido)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 1-benzyl-4-in embodiment 10 for the preparation method, 4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is pyrimidyl-furo [3 with 1-benzyl-4-(3-chloro-6-methyl), 2-c] piperidines changes 1-benzyl-4-(3-chloro-6-fluorine) pyrimidyl-furo [3,2-c] piperidines into.
4-(3-(3,4,5-trimethoxy-benzene amido)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines
(3-(3 with 4-in embodiment 10 for the preparation method, 4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines is synthetic, and difference is that (3-(3 with 1-benzyl-4-, 4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines changes 1-benzyl-4-into (3-(3,4,5-trimethoxy-benzene amido)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines.
1-methylsulfonyl-4-(3-(3,4,5-trimethoxy-benzene amido)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 19 (3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines; difference is pyrimidyl-furo [3 with 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-methyl); 2-c] piperidines changes 4-into (3-(3; 4; 5-trimethoxy-benzene amido)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines.
MS：[M+H]
+＝479.0.
1H-NMR(500M，DMSO-d
6)δ9.66(s，1H)，8.57(s，1H)，7.38(s，2H)，7.27(s，1H)，4.28(s，2H)，3.81(s，6H)，3.59-3.62(m，5H)，2.97(s，3H)，2.89(s，2H)ppm。
Embodiment 28: the preparation of compound 28
1-methylsulfonyl-4-(3-(4-oil of mirbane amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-oil of mirbane amido)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝429.9.
1H-NMR(500M，DMSO-d
6)δ10.41(s，1H)，8.48(s，1H)，8.20-8.23(d，2H)，8.07-8.09(d，2H)，7.13(s，1H)，4.18(s，2H)，3.59-3.60(m，2H)，3.39-3.41(m，2H)，2.99(s，3H)，2.41(s，3H)ppm。
Embodiment 29: the preparation of compound 29
1-methylsulfonyl-4-(3-(4-fluoroanilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-fluoroanilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝402.9.
1H-NMR(500M，CDCl
3)δ8.27(s，1H)，7.61(s，2H)，7.07-7.29(m，4H)，4.40(s，2H)，3.75(s，2H)，2.91-3.00(m，2H)，2.88(s，3H)，2.44(s，3H)ppm。
Embodiment 30: the preparation of compound 30
1-methylsulfonyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change cyanoacetic acid into methylsulfonic acid.
1-methylsulfonyl-4-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-pyrrolidyl 1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is pyrimidyl-furo [3 with 1-itrile group ethanoyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl); 2-c] piperidines changes 1-methylsulfonyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝552.2.
1H-NMR(400M，CDCl
3)δ8.64(s，1H)，7.55(s，1H)，7.48-7.50(d，2H)，7.20(s，1H)6.93-6.96(d，2H)，4.36(s，2H)，4.13-4.16(t，2H)，3.70-3.73(t，2H)，2.93-2.96(t，4H)，2.89(s，3H)，2.68(s，4H)，1.84(s，4H)ppm。
Embodiment 31: the preparation of compound 31
1-methylsulfonyl-4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝456.1.
1H-NMR(400M，CDCl
3)δ8.38-8.40(d，1H)，7.54-7.56(d，2H)，7.23(s，1H)，7.08(s，1H)，6.96-6.99(t，3H)，4.37(s，2H)，3.90-3.92(t，4H)，3.72-3.75(t，2H)，3.15-3.17(t，4H)，2.95-2.98(t，2H)，2.90(s，3H)ppm。
Embodiment 32: the preparation of compound 32
1-methylsulfonyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] the piperidines preparation method is with ((3-anilino) pyrrolo-[4 of 1-methylsulfonyl-4-in embodiment 16; 3-b] pyrimidyl)-furo [3; 2-c] piperidines synthetic; difference is ((3-anilino) pyrrolo-[4 with 4-; 3-b] pyrimidyl)-furo [3; 2-c] piperidines changes 4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝524.3.
1H-NMR(400M，DMSO-d
6)δ10.05(s，1H)，8.72(s，1H)，7.61-7.63(d，2H)，7.33(s，1H)，6.93-6.96(d，2H)，4.29(s，2H)，3.73-3.75(t，4H)，3.59(s，2H)，3.05-3.08(t，4H)，2.97(s，3H)，2.91-2.92(d，2H)ppm。
Embodiment 33: the preparation of compound 33
1-benzyl-4-(3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-fluoro-) pyrimidyl-furo [3,2-c] the piperidines preparation method is with (3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3 of 1-benzyl-4-in embodiment 23,2-c] piperidines synthetic, difference is (3-((4-(2-chlorine)-pyrimidyl-furo [3 with 1-benzyl-4-, 2-c] piperidines changes 1-benzyl-4-(3-((4-(2-chloro-6-fluorine)-pyrimidyl-furo [3 into, 2-c] piperidines.
4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 4-in embodiment 23 (3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3,2-c] piperidines synthetic, difference is (3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3 with 1-benzyl-4-, 2-c] piperidines changes 1-benzyl-4-(3-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-fluoro-) pyrimidyl-furo [3,2-c] piperidines into.
1-methylsulfonyl-4-((4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-is fluorine-based for 3-) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 23 (3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is pyrimidyl-furo [3 with 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)); 2-c] piperidines changes 4-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-fluorine) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝502.3.
1H-NMR(400M，CDCl
3)δ8.28-8.29(d，1H)，7.49-7.51(d，2H)，7.15-7.15(d，1H)，7.08(s，1H)，6.93-6.95(d，2H)，4.39-4.41(d，2H)，4.17-4.19(t，2H)，3.73-3.76(t，2H)，3.00-3.04(m，4H)，2.90(s，3H)，2.76(s，4H)，1.88(s，4H)ppm。
Embodiment 34: the preparation of compound 34
1-isobutyryl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-cyano group ethanoyl-4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change itrile group acetic acid into isopropylformic acid.
MS：[M+H]
+＝516.2.
1H-NMR(400M，CDCl
3)δ10.04(s，1H)，8.73(s，1H)，7.63-7.63(d，2H)，7.33(s，1H)，6.96-6.97(d，2H)，4.50-4.59(d，2H)，3.81(s，2H)，3.76(s，4H)，3.08(s，4H)，1.24-1.25(m，3H)，1.03-1.06(m，6H)ppm。
Embodiment 35: the preparation of compound 35
1-(4-itrile group benzoyl)-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-cyano group ethanoyl-4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change itrile group acetic acid into 4-itrile group phenylformic acid.
MS：[M+H]
+＝575.3.
1H-NMR(400M，DMSO-d
6)δ10.02-10.05(d，1H)，8.73(s，1H)，7.95-7.97(d，3H)，7.62-7.71(m，3H)，6.95(s，2H)，4.68(s，2H)，4.38(s，1H)，4.03-4.04(m，2H)，3.74-3.76(m，4H)，3.06-3.08(m，4H)，2.86-2.88(m，2H)ppm。
Embodiment 36: the preparation of compound 36
1-(3-itrile group benzoyl)-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-cyano group ethanoyl-4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change itrile group acetic acid into 3-itrile group phenylformic acid
MS：[M+H]
+＝575.3.
1H-NMR(400M，DMSO-d
6)δ10.05(s，1H)，8.73(s，1H)，8.23-8.28(m，2H)，8.07-8.09(d，2H)，7.97-7.99(d，2H)，7.83(s，1H)，6.96(s，2H)，4.68(s，1H)，4.43(s，1H)，4.03(s，2H)，3.75(s，4H)，3.07(s，4H)，2.90(s，2H)ppm。
Embodiment 37: the preparation of compound 37
1-(thiophene-2-formyl radical)-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-cyano group ethanoyl-4-in embodiment 8 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change itrile group acetic acid into thiophene-2-carboxylic acid
MS：[M+H]
+＝556.0.
1H-NMR(400M，DMSO-d
6)δ10.03(s，1H)，8.71(s，1H)，7.61-7.63(d，2H)，7.30-7.32(d，1H)，6.94-6.96(d，2H)，4.49(s，2H)，3.78-3.79，3.83-3.85(dd，2H)，3.73-3.77(q，4H)，3.05-3.08(t，4H)，2.86-2.75(dd，2H)，2.49-2.52(t，2H)，1.00-1.03(t，3H)ppm。
Embodiment 38: the preparation of compound 38
1-propionyl-4-(3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-methylsulfonyl-4-in embodiment 32 (3-(4-morpholinyl phenylamine base)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change methylsulfonyl chloride into propionyl chloride.
MS：[M+H]
+＝502.3.
1H-NMR(400M，DMSO-d
6)δ10.03(s，1H)，8.71(s，1H)，7.61-7.63(d，2H)，7.30-7.32(d，1H)，6.94-6.96(d，2H)，4.49(s，2H)，3.78-3.79，3.83-3.85(dd，2H)，3.73-3.77(q，4H)，3.05-3.08(t，4H)，2.86-2.75(dd，2H)，2.49-2.51(t，2H)，1.00-1.03(t，3H)ppm。
Embodiment 39: the preparation of compound 39
1-(3-itrile group benzoyl)-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change cyanoacetic acid into 3-itrile group phenylformic acid.1-(3-itrile group benzoyl)-4-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-pyrrolidyl 1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is pyrimidyl-furo [3 with 1-itrile group ethanoyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl); 2-c] piperidines changes 1-(3-itrile group benzoyl)-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝603.3.
1H-NMR(400M，DMSO-d
6)δ10.15(s，1H)，8.75(s，1H)，7.97-7.99(d，2H)，7.82-7.84(d，1H)，7.68-7.72(t，3H)，7.03(s，2H)，4.67(s，2H)，4.42(s，3H)，4.27(s，2H)，2.90(s，4H)，1.95(s，4H)，1.24-1.27(m，4H)ppm。
Embodiment 40: the preparation of compound 40
1-(4-itrile group benzoyl)-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change cyanoacetic acid into 4-itrile group phenylformic acid.1-(4-itrile group benzoyl)-4-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-itrile group ethanoyl-4-in embodiment 15 (3-(4-(2-pyrrolidyl 1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is pyrimidyl-furo [3 with 1-itrile group ethanoyl-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl); 2-c] piperidines changes 1-(4-itrile group benzoyl)-4-(3-(4-(2-chloro-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines into.
MS：[M+H]
+＝603.3.
1H-NMR(400M，DMSO-d
6)δ10.11(s，1H)，8.74(s，1H)，7.95-7.97(d，2H)，7.68(s，4H)，6.96(s，2H)，4.76(s，1H)，4.37(s，1H)，4.03-4.12(m，4H)，3.01-3.03(m，3H)，2.80-2.86(m，2H)，1.78(s，4H)，1.23-1.25(m，4H)ppm。
Embodiment 41: the preparation of compound 41
1-benzyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 1-benzyl-4-(3-chloro-6-methyl) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (2.5g, 1eq), 4-(4-N-methylpiperazine base) aniline (1.4g, 1eq), the hydrochloric acid soln of dioxane (6M) (2.8mL, 2.2eq), potassiumiodide (0.5g, 0.04eq), trifluoroethanol 10mL, 170 ℃ of microwave reactions 1 hour.Stopped reaction adds water (10mL), saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, the crude product silica gel column chromatography obtains 1-benzyl-4-(3-(4-N-methylpiperazine base anilino)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (1.63g).
MS：[M+H]
+＝495.3.
1H-NMR(400M，DMSO-d
6)δ9.22(s，1H)，8.26(s，1H)，7.63-7.66(d，2H)，7.34-7.39(m，4H)，7.26-7.30(m，1H)，7.07(s，1H)，6.87-6.89(d，2H)，3.72(s，2H)，3.40(s，2H)，3.03-3.06(t，4H)，2.82-2.84(d，2H)，2.79-2.80(d，2H)，2.45-2.47(t，4H)，2.32(s，3H)，2.23(s，3H)ppm。
Embodiment 42: the preparation of compound 42
1-isobutyryl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines
Add 4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3 in reaction flask, 2-c] piperidines (70mg, 1eq), isopropylformic acid (15.7mg, 1eq), 1-hydroxyl-benzo-triazole (60.3mg, 2.5eq), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (85.6mg, 2.5eq), the DIPEA of catalytic amount and methylene dichloride (15mL), room temperature reaction 4 hours, induction stirring.Stopped reaction adds water (20mL), saturated NaHCO
3The aqueous solution is washed, and methylene dichloride (10mL*5) extraction merges organic phase; anhydrous sodium sulfate drying, suction filtration, concentrated; the crude product silica gel column chromatography obtains 1-isobutyryl-4-(3-(4-morpholinyl phenylamine base)-6-methyl) pyrimidyl-furo [3,2-c] piperidines (53.7mg).
MS：[M+H]
+＝462.3.
1H-NMR(500M，DMSO-d
6)δ9.26(s，1H)，8.29(s，1H)，7.66-7.68(d，2H)，7.18(s，1H)，6.89-6.92(d，2H)，4.57(s，1H)，4.49(s，1H)，3.85-3.87(t，2H)，3.73-3.76(t，4H)，3.02-3.05(t，4H)，2.88-2.90(m，2H)，2.74-2.79(m，1H)，2.35(s，3H)，0.98-1.07(m，6H)ppm。
Embodiment 43: the preparation of compound 43
1-itrile group ethanoyl-4-((3-anilino) pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines
(3-(3 with 1-itrile group acyl group-4-in embodiment 1 for the preparation method; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is that (3-(3 with 4-; 5-two fluoro-4-morpholinyl phenylamine bases)-6-methyl) pyrimidyl-furo [3; 2-c] piperidines changes 4-((3-anilino) pyrrolo-[4,3-b] pyrimidyl)-furo [3,2-c] piperidines into.
MS：[M+H]
+＝399.1.
1H-NMR(500M，DMSO-d
6)δ11.59(s，1H)，9.24(s，1H)，7.90-7.92(dd，2H)，7.28-7.23(m，4H)，6.89-6.91(t，1H)，6.75-6.77(dd，1H)，4.54(s，2H)，4.18-4.20(d，2H)，3.92-3.70(dt，2H)，2.96-2.82(dt，2H)ppm。
Embodiment 44: the preparation of compound 44
1-methylsulfonyl-4-(3-(4-(2-(N-methyl-piperazinyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into N methyl piperazine.
MS：[M+H]
+＝581.3.
1H-NMR(500M，CDCl
3)δ8.65(s，1H)，7.50-7.52(d，2H)，7.31(s，1H)，7.22(s，1H)，6.94-6.96(d，2H)，4.39(s，2H)，4.13-4.16(t，2H)，3.72-3.75(t，2H)，2.97-3.00(t，2H)，2.91(s，3H)，2.84-2.87(t，2H)，2.59-2.69(m，8H)，2.34(s，3H)ppm。
Embodiment 45: the preparation of compound 45
1-methylsulfonyl-4-(3-(4-(2-(3,5-lupetidine base-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic; difference is to change tetramethyleneimine into 3,5-lupetidine base.
MS：[M+H]
+＝594.1.
1H-NMR(500M，CDCl
3)δ8.66(s，1H)，7.50-7.52(d，2H)，7.29(s，1H)，7.22(s，1H)，6.95-6.97(d，2H)，4.39(s，2H)，4.12-4.15(t，2H)，3.72-3.75(t，2H)，3.01-3.03(t，2H)，2.98-2.99(d，2H)，2.91(s，3H)，2.81-2.84(t，2H)，1.88-1.91(d，2H)，1.61-1.65(m，4H)，0.88-0.90(d，6H)ppm
Embodiment 46: the preparation of compound 46
1-methylsulfonyl-4-(3-(4-(2-(4-cyclopropyl formyl piperidine base-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into 4-cyclopropyl formyl piperidine.
MS：[M+H]
+＝635.2
1H-NMR(500M，CDCl
3)δ8.66(s，1H)，7.53-7.54(d，2H)，7.29(s，1H)，7.22(s，1H)，6.94-6.97(d，2H)，4.38(s，2H)，4.14-4.17(t，2H)，3.64-3.75(m，9H)，3.40-3.41(d，2H)，2.98-3.01(t，2H)，2.91(s，3H)，2.86-2.89(t，2H)，2.59-2.66(d，4H)ppm
Embodiment 47: the preparation of compound 47
1-methylsulfonyl-4-(3-(4-(2-(N-ethyl-piperazinyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into NEP.
MS：[M+H]
+＝595.3
1H-NMR(500M，CDCl
3)δ8.66(s，1H)，7.50-7.52(d，2H)，7.28(s，1H)，7.22(s，1H)，6.94-6.96(d，2H)，4.39(s，2H)，4.13-4.16(t，2H)，3.72-3.75(t，2H)，2.98-3.01(t，2H)，2.91(s，3H)，2.85-2.88(t，2H)，2.70(bs，4H)，2.66(bs，3H)，2.46-2.51(q，3H)，1.11-1.15(t，3H)ppm
Embodiment 48: the preparation of compound 48
1-methylsulfonyl-4-(3-(4-(2-(piperidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is synthetic with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines, and difference is to change tetramethyleneimine into piperidines.
Piperidines.
MS：[M+H]
+＝566.3
1H-NMR(500M，CDCl
3)δ8.65(s，1H)，7.49-7.52(d，2H)，7.29(s，1H)，7.22(s，1H)，6.94-6.96(d，2H)，4.39(s，2H)，4.14-4.17(t，2H)，3.72-3.75(t，2H)，2.98-3.00(t，2H)，2.91(s，3H)，2.82-2.85(t，2H)，2.57(s，4H)，1.63-1.69(q，4H)，1.48-1.51(t，2H)ppm
Embodiment 49: the preparation of compound 49
1-methylsulfonyl-4-(3-(4-(2-(4-hydroxyethyl piperidine base-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into the 4-hydroxyethyl piperidine.
MS：[M+H]
+＝610.3
1H-NMR(500M，CDCl
3)δ8.66(s，1H)，7.49-7.52(d，2H)，7.28(s，1H)，7.21(s，1H)，6.94-6.96(d，2H)，4.39(s，2H)，4.14-4.17(t，2H)，3.71-3.75(m，4H)，3.03-3.06(d，2H)，2.98-3.00(t，3H)，2.91(s，3H)，2.82-2.85(t，2H)，2.15(s，2H)，1.73-1.76(d，3H)，115-1.57(q，4H)ppm
Embodiment 50: the preparation of compound 50
1-methylsulfonyl-4-(3-(4-(2-(4-hydroxy piperidine base-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into the 4-hydroxy piperidine.
MS：[M+H]
+＝582.2
1H-NMR(500M，CDCl
3)δ8.66(s，1H)，7.50-7.52(d，2H)，7.28(s，1H)，7.22(s，1H)，6.94-6.96(d，2H)，4.39(s，2H)，4.13-4.16(t，2H)，3.72-3.75(t，2H)，2.98-3.00(t，2H)，2.93(s，2H)，2.91(s，3H)，2.84-2.87(t，2H)，2.36(s，2H)，1.95-1.97(d，2H)，1.61-1.70(m，4H)ppm
Embodiment 51: the preparation of compound 51
1-methylsulfonyl-4-(3-(4-(2-(4-piperidyl-piperidino-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3,2-c] piperidines
The preparation method is with 1-methylsulfonyl-4-in embodiment 30 (3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [3; 2-c] piperidines synthetic, difference is to change tetramethyleneimine into 4-piperidyl-1-piperidines.
MS：[M+H]
+＝648.2
1H-NMR(500M，CDCl
3)δ8.65(s，1H)，7.50-7.52(d，2H)，7.30(s，1H)，7.21(s，1H)，6.93-6.96(d，2H)，4.38(s，2H)，4.11-4.14(t，2H)，3.72-3.75(t，2H)，3.10-3.12(d，2H)，2.97-2.99(t，2H)，2.91(s，3H)，2.81-2.83(t，2H)，2.63(s，4H)，2.12-2.18(t，2H)，1.88-1.91(d，3H)，1.66-1.74(m，6H)，1.49(m，2H)ppm
Embodiment 52: external biochemistry level suppresses jak kinase (PK) activity experiment
Materials and methods: JAK2, the JAK3 kinases derives from Invitrogen; 384 orifice plates (Greiner company); HTRFKinEASE; MgCl2 (sigma) company; DTT (Sunshine); The multi-functional microplate reader of PHERAstar FS (BMG company); MH-1 type low speed centrifuge (StaiteXiangyi company); TD25-W5 type thermostat container (Binder company); YG020524/ vibrator (Lindberg Optic Design A/S); ATP (sigma company); The positive drug of choosing is CP-690550, and structure is as follows:
Compound dissolution and preservation: with DMSO, test-compound is configured to the mother liquor of 0.5-10mmol/L ,-20 ℃ of preservations after packing;
The preparation of compound working fluid: except CP-690550, all the other compounds are 10uM and play 10 concentration of 3 times of dilutions, then add a full DMSO of zero-dose.
Enzyme reaction step: add the kinases of 4 μ l in each hole of 384 microwell plates, add simultaneously the Enzymaticbuffer of 4 μ L as negative control (Negative); The compound working fluid that adds 2 μ l to the hole, adding simultaneously the damping fluid that does not contain compound of 2 μ L (is positive control, Positive) in contrast; Hatch 5-10min in 25 ℃ (or 30 ℃); Xiang Kongzhong adds 2 μ L ATP and TK Substrate-biotin mixed solution, starts enzyme reaction, in 25 ℃ of (or 30 ℃) oscillatory reaction 15-60min; Xiang Kongzhong adds 4uL TK-Ab-cryptate; Hatch 5-10min in 25 ℃ (or 30 ℃); PHERAstar FS instrument reads the HTRF signal.
For the raw data that read in every hole, ratio=665nm/620nm;
The calculating of inhibiting rate:
Calculate IC50:
Take the log[administration concentration] be that X-coordinate, inhibiting rate are ordinate zou, simulate a dose response curve in Graphpad Prism 5, the drug level when drawing its 50% inhibiting rate, namely for this reason compound at the IC of enzyme level
50Value.
Experimental result: the active half-inhibition concentration (IC of jak kinase
50nM)
The invention provides structure suc as formula the half-inhibition concentration (IC of compound shown in I to the jak kinase activity
50) see Table 1:
Half-inhibition concentration (the IC of table 1 compound to the JAK2 kinase activity
50)
| 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 | CP-690550 | ||||||||
| Activity intensity | +++ | +++ |
+++expression IC
50＜500nM; ++ expression IC
50Scope is 500-5000nM; + expression IC
50Scope is 5000nM-50 μ M;-expression is test not
Half-inhibition concentration (the IC of table 2 compound to the JAK3 kinase activity
50)
+++expression IC
50＜500nM; ++ expression IC
50Scope is 500-5000nM; + expression IC
50Scope is 5000nM-50 μ M;-expression is test not
Experimental result: the compounds of this invention is to JAK2, and the inhibition of JAK3 kinases biochemistry level is active suitable with positive drug CP-690550.
The above is only the preferred embodiment of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (18)
1. structure is suc as formula the compound shown in I, its pharmaceutically acceptable Equivalent or salt:
Wherein:
R
1Be alkyl, cycloalkyl, acyl group, the alkylsulfonyl that replaces arbitrarily;
R
2Be hydrogen, halogen, C1-C6 straight or branched alkyl, cycloalkyl, halo C1-C6 straight or branched alkyl;
R
3Be hydrogen, halogen;
Perhaps R
2With R
3And form the hetero-aromatic ring of 5 yuan together with the carbon atom that connects them;
Z independently is selected from N or CR
4
N is the 0-3 integer;
R
4Be independently selected from hydrogen, halogen, R
5,-OR
5,-OH, R
6,-CN ,-CF
3,-(CH
2)
nN(R
5)
2,-NO
2,-R
5R
6,-OR
5R
6Perhaps two R
4Saturated or the undersaturated 5 or 6 yuan of heterocyclic radicals of the common formation of the carbon atom that substituting group is connected with them;
R
5Hydrogen, replacement or unsubstituted C1-C4 alkyl or replacement or unsubstituted C1-C4 alkylidene group, wherein two carbon atoms can be randomly by CO, S, SO at the most
2, or O substitute;
R
6NH
2, NHR
5, N (R
5)
2, N (R
4)
2, replacement or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace De oxazolyl, replacement or unsubstituted imidazolyl.
2. compound as claimed in claim 1, wherein R
1Be following groups:
Wherein
R
7For C1-6 straight or branched alkyl ,-CN ,-NHSO
2R
12,-NHOH ,-NHCOR
12,-CON (R
12)
2,-N (R
12)
2,-OR
12,-CF
3,
R
8For C1-6 straight or branched alkyl, C3-C7 cycloalkyl,
R
9, R
10Or R
11Identical or different, independently be selected from separately halogen, hydrogen, C1-C6 straight or branched alkyl, C3-C7 cycloalkyl,
R
12Be selected from hydrogen ,-CN ,-NHSO
2R
5, halogen ,-N (R
5)
2,-OR
5,-CF
3Or C1-C3 straight or branched alkyl;
X is selected from S, NH or O;
M is the 0-3 integer.
3. compound as claimed in claim 2, wherein R
1Be following groups:
Wherein
R
7For C1-C4 straight or branched alkyl ,-CN,
R
8Be C1-C4 straight or branched alkyl;
R
9, R
10Or R
11Identical or different, independently be selected from separately halogen, hydrogen or
R
12Be selected from halogen ,-CN or hydrogen;
X is S;
M is 0 or 1.
4. compound as claimed in claim 3, wherein
R
7For-CN,
R
8Be methyl; R
9Or R
10Be hydrogen;
R
11For
R
12For-CN or hydrogen;
X is S;
M is 0 or 1.
5. compound as claimed in claim 1, wherein
R
2Be hydrogen, halogen, C1-C4 straight or branched alkyl or halo C1-C4 straight or branched alkyl;
R
3Be hydrogen;
Perhaps R
2, R
3Form following heterocycle together with the carbon atom that connects them:
6. compound as claimed in claim 5, wherein
R
2For hydrogen ,-F ,-CH
3Or-CF
3R
3Be hydrogen; Or R
2, R
3Form together with the carbon atom that connects them
7. compound as claimed in claim 1, wherein
Z is CR
4
8. compound as described in claim 1 or 7, wherein
R
4For hydrogen, halogen ,-NO
2,-OH, C1-C6 straight or branched alkoxyl group, replacement or non-substituted saturated or undersaturated 5 or 6 yuan of saturated or unsaturated heterocycle bases or-OR
5R
6
R
5To replace or unsubstituted C1-C3 alkylidene group;
R
6NH
2, C1-C6 straight or branched alkylamino, replacement or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace De oxazolyl, replacement or unsubstituted imidazolyl;
R
4, R
5And R
6In substituting group be respectively C1-C6 straight or branched alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkanes formyl radical, dioxan base or the piperidyl of halogen, hydroxyl, C1-C6 straight or branched alkyl, hydroxyl replacement independently.
9. compound as claimed in claim 8, wherein
R
4For hydrogen ,-F ,-NO
2The imidazolyl that the morpholinyl that the piperazinyl that the piperidyl that the pyrrolidyl that ,-OH, C1-C4 straight or branched alkoxyl group, pyrrolidyl, C1-C6 alkyl replace, piperidyl, C1-C6 alkyl replace, piperazinyl, C1-C6 alkyl replace, morpholinyl, C1-C6 alkyl replace, imidazolyl, C1-C6 alkyl replace or-OR
5R
6
10. compound as claimed in claim 9, wherein
R
4For hydrogen ,-F ,-NO
2,-OH ,-OCH
3,
Or-OR
5R
6
11. as claim 8,9 or 10 described compounds, wherein
R
5For
12. as claim 8,9 or 10 described compounds, wherein
R
6To replace or unsubstituted morpholinyl, replacement or unsubstituted thio-morpholinyl, replacement or unsubstituted piperazinyl, replacement or unsubstituted piperidyl, replacement or unsubstituted pyrrolidyl, replacement or unsubstituted pyrryl, replacement or do not replace De oxazolyl, replacement or unsubstituted imidazolyl; Described substituting group is C1-C6 straight or branched alkyl, C1-C6 alkyl acyl, C3-C7 cycloalkanes formyl radical or the piperidyl of hydroxyl, C1-C6 straight or branched alkyl, hydroxyl replacement.
13. compound as claimed in claim 12, wherein
R
6Be
14. compound as claimed in claim 1, wherein
N is 0,1 or 2.
15. compound as claimed in claim 14, wherein
When n is 1, R
4Be para-orienting group amino on phenyl ring;
When n is 2, R
4Be position and para-orienting group between amino on phenyl ring.
16. compound as claimed in claim 1 or its pharmacy acceptable salt, described compound is selected from:
17. a pharmaceutical composition, it comprises pharmaceutically acceptable carrier, vehicle or thinner, and as the described compound of any one in the claim 1 or 16 of activeconstituents.
18. the application of the described compound of any one aspect the illness medicine of preparation treatment JAK mediation in claim 1 or 16, this illness is selected from: polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, the marrow metaplasia with myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia, transformation reactions, asthma, autoimmune disease are as suppressing transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis, multiple sclerosis or entity or hematologic malignancies.
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| WO2008031594A1 (en) * | 2006-09-15 | 2008-03-20 | Novartis Ag | Benzoxazoles and oxazolopyridines being useful as janus kinases inhibitors |
| WO2008109943A1 (en) * | 2007-03-12 | 2008-09-18 | Cytopia Research Pty Ltd | Phenyl amino pyrimidine compounds and uses thereof |
| WO2009064835A1 (en) * | 2007-11-16 | 2009-05-22 | Incyte Corporation | 4-pyrazolyl-n-arylpyrimidin-2-amines and 4-pyrazolyl-n-heteroarylpyrimidin-2-amines as janus kinase inhibitors |
-
2011
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|---|---|---|---|---|
| WO2008031594A1 (en) * | 2006-09-15 | 2008-03-20 | Novartis Ag | Benzoxazoles and oxazolopyridines being useful as janus kinases inhibitors |
| CN101516860A (en) * | 2006-09-15 | 2009-08-26 | 诺瓦提斯公司 | Benzoxazoles and oxazolopyridines being useful as FANUS kinases inhibitors |
| WO2008109943A1 (en) * | 2007-03-12 | 2008-09-18 | Cytopia Research Pty Ltd | Phenyl amino pyrimidine compounds and uses thereof |
| CN101861313A (en) * | 2007-03-12 | 2010-10-13 | 西托匹亚研究有限公司 | Phenyl amino pyrimidine compounds and uses thereof |
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| CN104177363A (en) * | 2013-05-24 | 2014-12-03 | 江苏先声药物研究有限公司 | Bicyclic heterocyclic amine Hedgehog signal pathway inhibitor |
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