CN103709172A - Substituted furan-piperidine derivative and application thereof - Google Patents
Substituted furan-piperidine derivative and application thereof Download PDFInfo
- Publication number
- CN103709172A CN103709172A CN201210369245.2A CN201210369245A CN103709172A CN 103709172 A CN103709172 A CN 103709172A CN 201210369245 A CN201210369245 A CN 201210369245A CN 103709172 A CN103709172 A CN 103709172A
- Authority
- CN
- China
- Prior art keywords
- anilino
- furo
- pyrimidyl
- piperidines
- straight
- 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
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- SOGUBSJEGWOEIU-UHFFFAOYSA-N furan;piperidine Chemical class C=1C=COC=1.C1CCNCC1 SOGUBSJEGWOEIU-UHFFFAOYSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims description 218
- -1 pyrrolidyl Chemical group 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 87
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 39
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 125000005936 piperidyl group Chemical group 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 8
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 8
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 5
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
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- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
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- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001475 halogen functional group Chemical group 0.000 claims 12
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- 150000003053 piperidines Chemical class 0.000 description 421
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 98
- 238000005160 1H NMR spectroscopy Methods 0.000 description 69
- TYCYTQLXAIDJNF-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1 TYCYTQLXAIDJNF-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 30
- 230000000694 effects Effects 0.000 description 28
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
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- 238000000967 suction filtration Methods 0.000 description 15
- 0 CC(C)(C)c1c(*(C)(C)C)cc[o]1 Chemical compound CC(C)(C)c1c(*(C)(C)C)cc[o]1 0.000 description 14
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000006698 induction Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
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- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
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- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CSFAYIHXWKUTHH-UHFFFAOYSA-N n-phenylmorpholin-4-amine Chemical compound C1COCCN1NC1=CC=CC=C1 CSFAYIHXWKUTHH-UHFFFAOYSA-N 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 230000003534 oscillatory effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
The invention relates to the biological medicine field, and specifically relates to a substituted furan-piperidine derivative and an application thereof. The compound has a structure shown as a general formula (I). The invention also provides an application of the substituted furan-piperidine derivative as a Janus kinase inhibitor. The formula (I) is shown in the description.
Description
Technical field:
The present invention relates to biomedicine field, be specifically related to substituted furan piperidine derivative or its pharmacy acceptable salt, and preparation method thereof and as the purposes of Janus kinase inhibitor.
Background technology:
Protein kinase is comprised of involved enzyme in a series of structures, is mainly responsible for the control of intracellular signal transduction process.Conventionally, protein kinase shifts to the phosphoryl that participates in the protein receptor of signal transduction path from ribonucleoside triphosphote by impact, and 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 causing by above-mentioned protein kinase mediated event.
Janus kinases (JAK), comprises JAK1, JAK2, and JAK3 and TYK2 belong to cytoplasm protein kinases, with I type and II cytokines receptor acting, regulate cytokine signaling.JAK1, JAK2 and TYK2 can suppress several genes to express, however JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor is to exist as heterodimer form, is not therefore a kind of jak kinase and cytokine receptor effect conventionally.
The downstream substrate of JAK family comprises signal transduction agent and the activator (STAT) of transcription factor.JAK/STAT signal transduction relates to the reaction of a lot of abnormal immunes, as transformation reactions, and asthma, autoimmune disease is as transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies be as leukemia, lymphoma.
Genetic biology research shows, JAK1 by with IFNalpha, IFNgamma, IL-2, cytokine receptor effects such as IL-6 and playing a role, JAK1 knock-out mice is dead due to LIF receptor signal disappearance.Observe the feature organization of JAK1 knock-out mice, find that JAK1 is at IFN, IL-10, IL-2/IL-4, and play an important role in the cell pathway such as IL-6.
Genetic biology research shows, JAK2 and strand exist contact between IL-3 and interferon-gamma cytokine receptor family.Corresponding, 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, 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, occurs extremely can cause serious immune deficiency.Based on it, regulate lymphocytic effect, the path of JAK3 and JAK3 mediation is used for regulating immunosuppressant indication.Implication in the mediation that JAK3 replys at a lot of abnormal immunes, as transformation reactions, asthma, autoimmune disease is as suppressed transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies be as leukemia, lymphoma.
TYK2 acts on interferon type Ⅰ, IL-6, IL-10, IL-12, the cell factor receptor nanocrystal composition such as IL-23.Consistent with it, be derived from the people's of TYK2 disappearance primary cell, at interferon type Ⅰ, IL-6, IL-10,, in the signal conduction of IL-23, there is obstacle in IL-12.
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 substituted furan piperidine derivative that a class is new.
Another object of the present invention is to provide a kind of above-mentioned substituted furan the purposes of piperidine derivative aspect medicine.
Object of the present invention can reach by following measures:
One class substituted furan piperidine derivative, as general structure (I) compound or its pharmacy acceptable salt:
Wherein:
R
1for alkyl, cycloalkyl, acyl group, alkyl acyl, alkylsulfonyl, the alkyl sulphonyl replacing arbitrarily; Described substituting group is hydrogen, C
1-6the C that straight or branched alkyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
2-6straight or branched thiazolinyl, halogen ,-CN ,-NHSO
2r
12,-NHOH ,-NHCOR
12,-CON (R
12)
2,-CO (CH
2)
mnHC (O) OR
12,-N (R
12)
2,-OR
12,-CF
3,
r
2for hydrogen, halogen, C
1-6straight or branched alkyl, cycloalkyl, halo C
1-6straight or branched alkyl;
R
3for hydrogen, halogen;
Or R
2with R
3and form the hetero-aromatic ring base of 5 yuan together with their carbon atom of connection;
Z is independently selected from N or CR
13;
N or m are independently 0,1,2 or 3;
R
4independently selected from hydrogen, halogen, R
5' ,-OR
5' ,-OH, R
6,-CN ,-CF
3,-N(R
1) R
5r
6, NHSO
2r
6,-N (CH
3) R
5n(R
5')
2,-NHR
5oR
5oH ,-NHR
5r
6,-N (CH
3) R
6,-NHR
5n(R
5')
2,-NHR
6,-OR
5n(R
5')
2,-(CH
2)
pn(R
5)
2,-NO
2,-R
5r
6,-OR
5r
6,
replace or unsubstituted saturated or undersaturated 5 or 6 yuan of heterocyclic radicals, or two adjacent R
4saturated or the undersaturated 5 or 6 yuan of heterocyclic radicals of the common formation of carbon atom that substituting group is connected with them; Described substituting group is hydrogen, halogen, amino ,-CN, C
1-3alkylamino, nitro, C
1-3alkyl sulphonyl, hydroxyl, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
P is 1,2 or 3;
R
5to replace or unsubstituted C
1-4alkylidene group, wherein two carbon atoms can be optionally by CO, S, SO at the most
2, or O substitute; Described substituting group is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C
1-3alkylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3acyloxy, C
1-3the C that alkyl sulphonyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
5' be hydrogen, replacement or unsubstituted C
1-4alkyl, wherein two carbon atoms can be optionally by CO, S, SO at the most
2, or O substitute; Described substituting group is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C
1-3alkylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3acyloxy, C
1-3the C that alkyl sulphonyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
6nH
2, NHR
5', C
1-4alkoxyl group, cyclopropyl, replacement or unsubstituted phenyl, replacement or unsubstituted furyl, 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 oxazolyl, replacement or unsubstituted imidazolyl; Described substituting group is the C of hydrogen, halogen, nitro, halo
1-3alkoxyl group, C
1-3alkane alkylsulfonyl, amino ,-CN, hydroxyl, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
12be selected from hydrogen ,-CN ,-NHSO
2r
5', halogen ,-N (R
5')
2,-OR
5' ,-COOR
5' ,-CF
3or C
1-4straight or branched alkyl, C
3-7cycloalkyl;
R
13be selected from hydrogen, C
1-3alkoxyl group.
The purposes of substituted furan the piperidine derivative that the present invention also aims to provide new, 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 certain number.As clearly limited without other, the alkyl in the present invention is generally to have 1-10 carbonatoms, further can have 1-8 carbonatoms, further can have 1-6 carbonatoms, more further can have 1-4 carbonatoms, most preferably 1-3 carbonatoms.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.
Thiazolinyl represents to have the alkyl of one or more carbon-to-carbon double bonds.Typically include, but is not limited to vinyl, propenyl, cyclohexenyl etc.Connect thiazolinyl and be known as " alkenylene " at this.
Represent-O-of alkoxyl group alkyl, wherein alkyl as defined herein.Typically be C
1-6alkoxyl group, including, but not limited to methoxyl group, oxyethyl group.
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 and has saturated or unsaturated alkane two bases of the straight chain at 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 obtain.Typical alkylidene group includes but is not limited to methylene radical, ethylidene, vinylidene, ethynylene, propylidene, butylidene etc.
Saturated heterocyclic radical is Heterocyclylalkyl, represents containing one or more N, O or the heteroatomic monocycle of S or the ring condensing.Typically be heteroatomic 5-6 first heterocyclic radical, for example Piperazino, morpholino base, piperidino-(1-position only), pyrrolidyl and derivative thereof containing one or more N, O or S.
Piperazino refers to the group with following chemical structure.
Morpholino base refers to the group with following chemical structure.
Thiomorpholine refers to the group with following chemical structure for base.
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, represents monocycle or the fused rings group of 5 to 12 annular atomses, contains 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 being replaced by halogen
1-3alkyl group represents the alkyl that wherein one or more hydrogen are replaced by halogen, preferably containing one, two or three halogen groups.
Acyl group refers to " C (O)-" or " HC (O)-" group, when the carbonatoms of concrete acyl group is greater than 1, refers to alkyl acyl.Alkyl acyl refers to have the acyl group that alkyl replaces, i.e. " alkyl-C (O)-".As clearly limited without other, the alkyl acyl in the present invention refers to C
2-6alkyl acyl, can be further C
2-5alkyl acyl, be further C
2-4alkyl acyl.
Alkylsulfonyl refers to " SO
2-" or " HSO
2-" group, when the carbonatoms of concrete alkylsulfonyl is greater than 1, refer to alkyl sulphonyl.Alkyl sulphonyl refers to have the alkylsulfonyl that alkyl replaces, i.e. " alkyl-SO
2-".As clearly limited without other, the alkyl sulphonyl in the present invention refers to C
2-6alkyl sulphonyl, can be further C
2-5alkyl sulphonyl, be further C
2-4alkyl sulphonyl.
In a kind of preferred version,
R
1for:
R wherein
7for C
1-6straight or branched alkyl, C
2-6straight or branched thiazolinyl ,-CN ,-NHSO
2r
12,-NHOH ,-NHCOR
12,-CON (R
12)
2,-NHC (O) OR
12,-N (R
12)
2,-OR
12,-CF
3,
r
7c more preferably
1-4straight or branched alkyl, C
2-6straight or branched thiazolinyl ,-CN ,-N (R
12)
2,-NHSO
2r
12,-NHC (O) OR
12,
further, R
7can for-CN, NH
2,
-NHC (O) OR
12, methyl, ethyl, allyl group or sec.-propyl;
R
8for C
1-6straight or branched alkyl, C
3-7cycloalkyl,
r
8c more preferably
1-4straight or branched alkyl, C
3-5cycloalkyl,
further, R
8can for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl,
R
9, R
10or R
11identical or different, be independently selected from separately halogen, hydrogen ,-CN, C
1-6straight or branched alkyl, C
3-7cycloalkyl,
r
9, R
10or R
11be preferably selected from independently of one another halogen, hydrogen ,-CN or
further, R
9or R
10for hydrogen, R
11for-CN or
R
12be selected from hydrogen ,-CN ,-NHSO
2r
5, halogen ,-N (R
5)
2,-OR
5,-CF
3or C
1-4straight or branched alkyl; R
12can further be preferably selected from halogen, methyl, the tertiary butyl ,-CN or hydrogen; Further, R
12for-CN, methyl, the tertiary butyl or hydrogen;
X is selected from S, NH or O, more preferably S;
M is 0,1,2 or 3, can be more preferably 0 or 1.
In a kind of preferred version, R
2for hydrogen, halogen, C1-C4 straight or branched alkyl or halo C1-C4 straight or branched alkyl; R
3for hydrogen; Or R
2, R
3form following heterocyclic radical together with their carbon atom of connection:
As a kind of preferred, R
2for hydrogen ,-CH
3or-CF
3; R
3for hydrogen.
In a kind of preferred version, Z is CR
13, R
13be selected from hydrogen, C
1-3alkoxyl group; In a kind of preferred scheme, Z is CR
13, R
13be selected from hydrogen, methoxyl group.
In a kind of preferred version, R
4for hydrogen, halogen ,-NO
2,-OH ,-N(R
1) R
5r
6,-N (CH
3) R
5n(R
5')
2,-NHR
5oR
5oH ,-N (CH
3) R
6,-NHR
6,-NHR
5n(R
5')
2,-NHR
5r
6,-OR
5n(R
5')
2,-(CH
2)
pn(R
5')
2,,
c
1-6straight or branched alkoxyl group, substituted or non-substituted saturated or undersaturated 5 or 6 yuan of heterocyclic radicals ,-OR
5r
6, or two adjacent R
4the common hetero-aromatic ring base that forms 5 yuan of carbon atom that substituting group is connected with them;
Further, R
4can be hydrogen ,-F ,-NO
2,-OH ,-N(R
1) R
5r
6, NHSO
2r
6,-N (CH
3) R
5n(R
5')
2,-N (CH
3) R
6,-NHR
6,-NHR
5r
6,-NHR
5oR
5oH ,-OR
5n(R
5')
2,-NHR
5n(R
5')
2, C
1-4straight or branched alkoxyl group, pyrrolidyl, C
1-6pyrrolidyl, piperidyl, C that the pyrrolidyl that alkyl replaces, pyrrolidinomethyl replace
1-6piperidyl, C that alkyl replaces
1-3the piperidyl that the piperidyl that the piperidyl that alkoxyl group replaces, piperidyl replace, hydroxy piperidine base, dimethylamino replace,, hydroxyl C
1-3piperidyl, C that alkyl replaces
2-4piperidyl, piperazinyl, C that alkyl acyloxy replaces
1-6piperazinyl, morpholinyl, thio-morpholinyl, C that alkyl replaces
1-6morpholinyl, imidazolyl, C that alkyl replaces
1-6the imidazolyl that alkyl replaces,
-OR
5r
6or two R
4together with the carbon atom that substituting group connects with them, form following heterocyclic radical:
Further, R
4can be hydrogen ,-OCH
3,
r
5r
6,-N (CH
3) R
5n(R
5')
2, NHSO
2r
6,-NR
5r
6,-N (CH
3) R
6,-NHR
6,-NHR
5n(R
5')
2,-NR
5oR
5oH ,-OR
5n(R
5')
2,, OR
5r
6or two R
4together with the carbon atom that substituting group connects with them, form
Wherein, R
5can be to replace or unsubstituted C
1-3alkylidene group, it is further
R
5' can be to replace or unsubstituted C
1-3alkyl;
P can be 2 or 3;
R
6can be NH
2, C
1-6straight or branched alkylamino, C
1-3alkoxyl group, replacement or unsubstituted phenyl, replacement or unsubstituted furyl, cyclopropyl, 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 oxazolyl, replacement or unsubstituted imidazolyl; Further, R
6can be C
1-3alkoxyl group, replace unsubstituted phenyl, replacement or unsubstituted furyl, cyclopropyl, 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 oxazolyl, replacement or unsubstituted imidazolyl; Further, R
6can be-OCH
3,
In above-mentioned preferred version, R
4, R
5, R
5' and R
6in substituting group can to distinguish be the C of hydrogen, halogen, hydroxyl, nitro, halo independently
1-3alkoxyl group, methylsulfonyl, cyano group, dimethylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base or piperidyl; Further, each substituting group can be the C of hydroxyl, nitro, halo
1-3alkoxyl group, methylsulfonyl, dimethylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3acyloxy, C
3-4the C that cycloalkyl, hydroxyl replace
1-6straight or branched alkyl, pyrrolidyl, pyrrolidinomethyl, piperidyl.
In a kind of scheme, R
6in substituting group be hydrogen, hydroxyl, C
1-6the C of straight or branched alkyl, cyano group, halogen, halo
1-6the C of straight or branched alkyl, nitro, halo
1-3alkoxyl group, C
1-3the C that alkoxyl group, methylsulfonyl, hydroxyl replace
1-6straight or branched alkyl, piperidyl.
In a kind of preferred version, n is 1,2 or 3; Further, when n is 1, R
13be selected from hydrogen, methoxyl group, R
4for para-orienting group or meta-substituent amino on phenyl ring; When n is 2, R
13be selected from methoxyl group, R
4for position and para-orienting group between amino on phenyl ring; When n is 3, R
13for hydrogen, R
4for amino position and para-orienting group and the R of facing on phenyl ring
4for halogen.
The substituted furan of formula (I) piperidine derivative or its pharmacy acceptable salt, compound wherein can specifically comprise those instantiation compounds that following table is listed:
The present invention also provides a kind of pharmaceutical composition, and the medicinal compositions especially for jak kinase relative disease in treatment organism, comprises that above-mentioned each compound provided by the invention is as activeconstituents, and pharmaceutically acceptable carrier, vehicle or thinner.
Pharmacy acceptable salt represents to retain those salt of biological effectiveness and the character of parent compound.Wherein refer to sour salify, the free alkali by parent compound reacts and obtains with mineral acid or organic acid.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 object of medicinal compositions is to promote the administration of compound to organism.
Pharmaceutically acceptable carrier refers to organism is not caused obvious pungency and do not disturb the biological activity of given compound and the carrier of character or thinner.
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 there is general formula preparation method of (I), it is characterized in that, comprise,
(a) amine fragment (V) and substituted carboxylic acid (VI) 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 (V) and replacement acyl chlorides (VII) are at solvent S
1middle alkali B
1under existence in temperature T
1reacting generating compound under condition (I).
C. the halohydrocarbon (VIII) of amine fragment (V) and replacement is at solvent S
2middle alkali B
2under existence in temperature T
2reacting generating compound under condition (I).
R wherein
1, R
2, R
3, R
4with n as mentioned above.
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, acetonitrile, acetone, be preferably methylene dichloride, acetonitrile; 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 ° C, be preferably 0 ° of C; Described solvent S
2be selected from polar aprotic solvent, as acetonitrile, acetone, DMF, be preferably acetonitrile; Described alkali B
2can think that mineral alkali can be also organic bases, is preferably triethylamine, salt of wormwood; Temperature T
2for 50-100 ° of C, be preferably 70 ° of C.
The present invention also provides the purposes of new substituted furan piperidine derivative, specifically as the purposes of Janus kinase inhibitor, says further the illness medicine aspect that is applied to preparation treatment JAK mediation.Comprising but be not limited to polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with the marrow metaplasia of myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia, transformation reactions, asthma, autoimmune disease is as suppressed transplant rejection, rheumatoid arthritis, psoriatic, lupus erythematosus, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies be 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 present invention who uses significant quantity to system or the individuality of this type for the treatment of of needs, thereby treat described illness.
In order to check compound provided by the invention for the exposure level of jak kinase, adopt biochemistry level enzymic activity to test and determine that various compound of the present invention is to the activity of one or more PK and exposure level.The method of knowing in operation, all tests 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 for detecting a kind of the most frequently used method of 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 of the medicament research and development based on cell experiment and biochemical test.According to the measuring principle of HTRF method, by pure enzyme JAK2 together with biotinylated substrate and ATP after incubation reaction, the antibody that adds the XL-665 of avidin mark and the Eu mark of identification substrate phosphorylation, after substrate is by JAK2 phosphorylation, the antibody of Eu mark can identify this phosphorylation product, the FRET (fluorescence resonance energy transfer) (FRET) of differentiating with the XL665 formation time of avidin mark, and the substrate not being phosphorylated is owing to can not being formed FRET signal by antibody recognition, by measure the fluorescent signal difference of 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 active function of the compounds of this invention to the biochemistry level of above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.
Structure prepared by the present invention 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 the medicine that jak kinase relative disease in organism is treated in preparation.
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 content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1: the preparation of compound 1
6-benzyl-2-tributyl tin-furo [2,3-c] piperidines
Under nitrogen protection; in reaction flask, add 6-benzyl-furo [2; 3-c] piperidines (11.2mg; 1eq) and dry tetrahydrofuran (150 μ L), under condition of ice bath, drip n-Butyl Lithium (16.05 μ L, 1eq); 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, crude product silica gel column chromatography obtains 6-benzyl-2-tributyl tin-furo [2,3-c] piperidines (19.25mg).
2-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
In reaction flask, add ether (50 μ L), 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, the chloro-5-trifluoromethyl pyrimidine of 4-bis-(7.24mg, 1eq), 4-(2-tetramethyleneimine-1-oxyethyl group) aniline (7.57mg, 1.1eq) and triethylamine (6.54mg), react induction stirring 2 hours.Stopped reaction, ethyl acetate (10mL*5) extraction, merges organic phase, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product silica gel column chromatography obtains 2-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-(10.5mg).
6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
(575mg, 1.5eq), 6-benzyl-2-tributyl tin-furo [2,3-c] piperidines (502mg, 1eq), Pd (PPh
3)
2cl
2(42.0mg, 0.06eq) and DMF(9mL), 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, crude product silica gel column chromatography obtains 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines (512.3mg).
2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines adds 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in reaction flask) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines (563mg, 1eq), chloroformate-1-chloro-ethyl ester (0.27mL, 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, by a small amount of methanol wash, obtain 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines (407.2mg).
6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines (119.2mg, 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, crude product silica gel column chromatography obtains 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines (102.0mg).
MS:[M+H]
+=541.1
1H-NMR(400M,DMSO-d
6)δ8.63-8.64(d,1H),7.49-7.52(m,2H),7.22-7.23(m,1H),6.93-6.96(m,2H),4.78(s,2H),4.20(s,2H),3.72-3.75(m,2H),3.62-3.64(m,2H),3.20-3.22(m,2H),2.79-2.80(m,2H),1.89(s,4H),1.47-1.50(m,4H)ppm。
Embodiment 2: the preparation of compound 2
The chloro-6-methyl of 6-benzyl-2-(3-) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 6-benzyl-2-tributyl tin-furo [2,3-c] piperidines (3.2mg, 1eq), the chloro-5-methyl-pyrimidine of 2,4-bis-(0.97mg, 1eq), Pd (PPh3) 2Cl2(0.42mg, 0.1eq) and DMF(5mL), 80 degree reacting by heating 5 hours.Stopped reaction, adds water (5mL), and methylene dichloride (5mL*5) extraction, merges organic phase, anhydrous sodium sulfate drying, and suction filtration, concentrated, crude product silica gel column chromatography obtains the chloro-6-methyl of 6-benzyl-2-(3-) pyrimidyl-furo ［ 2,3-c ］ piperidines (0.47mg).
6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines adds 4-(3-morpholinyl-1-propoxy-in microwave bottle) aniline (382.4mg, 1.1eq), the chloro-6-methyl of 6-benzyl-2-(3-) pyrimidyl-furo ［ 2,3-c ］ piperidines (500.0mg, 1eq), the hydrochloric acid soln of dioxane (6.6M) (668 μ L), potassiumiodide (97mg, 0.4eq) and trifluoroethanol (5mL), in the lower 145 ° of C reaction of microwave 1 hour.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, crude product silica gel column chromatography obtains 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (723.6mg).
2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (449.5mg, 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, crude product silica gel column chromatography obtains 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (503.6mg).
MS:[M+2]
+=264.5
1H-NMR(400M,DMSO-d
6)δ9.36(s,1H),8.31(s,1H),7.70-7.72(d,2H),7.19(s,1H),6.89-6.91(d,2H),4.43(s,2H),4.02-4.03(m,2H),3.79-3.81(m,4H),3.47-3.50(m,3H),3.08(s,4H),2.94(s,4H),2.69(s,2H),2.50(s,3H),2.13-2.15(m,2H)ppm。
Embodiment 3: the preparation of compound 3
2-(4-(2-morpholinyl-1-oxyethyl group) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-(2-morpholinyl-1-oxyethyl group into) aniline.
6-benzyl-2-(3-(4-(2-morpholinyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(2-morpholinyl-1-oxyethyl group into) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-.
2-(3-(4-(2-morpholinyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(2-morpholinyl-1-oxyethyl group into) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(2-morpholinyl-1-oxyethyl group) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-morpholinyl-1-oxyethyl group into) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=557.1
1H-NMR(400M,DMSO-d
6)δ10.12(s,1H),8.74(s,1H),7.64-7.65(d,2H),7.29-7.31(d,1H),6.94-6.96(d,2H),4.60-4.66(d,2H),4.22(s,2H),4.05-4.08(t,2H),3.76(s,2H),3.57-3.59(m,4H),2.67-2.69(m,2H),2.58(s,2H),2.47-2.50(m,4H)ppm。
Embodiment 4: the preparation of compound 4
6-benzyl-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-methoxyl group-piperidino into) aniline.
2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-methoxyl group-piperidino into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-(thiophene-2-formyl radical)-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (419.5mg, 1eq), thiophene-2-carboxylic acid (256.3mg, 2eq), 1-hydroxyl-benzo-triazole (337.7mg, 2.5eq), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (477.5mg, 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, crude product silica gel column chromatography obtains 6-(thiophene-2-formyl radical)-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (487.6mg).
MS:[M+H]
+=530.1
1H-NMR(400M,DMSO-d
6)δ9.25(s,1H),8.30(s,1H),7.83-7.84(m,1H),7.58-7.64(m,3H),7.19(s,2H),6.90-6.92(d,2H),4.84(s,2H),3.91(s,2H),3.28(s,3H),2.73-2.81(m,4H),2.51(s,3H),2.34(s,3H),1.93-1.95(m,2H),1.53-1.55(m,2H)ppm。
Embodiment 5: the preparation of compound 5
6-cyano group ethanoyl-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3-morpholinyl-1-propoxy-into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=517.1
1H-NMR(400M,CDCl
3)δ8.22(s,1H),7.59(s,2H),7.03(s,1H),6.90(s,2H),4.61-4.78(d,2H),4.02(s,2H),3.91(s,2H),3.61(s,4H),2.79(s,2H),2.38(s,4H),1.97(s,3H),1.72(s,4H),1.25(s,2H)ppm。
Embodiment 6: the preparation of compound 6
6-(4-cyano group benzoyl)-2-(3-(4-(3-morpholinyl-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 5) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change cyanoacetic acid into 4-cyanobenzoic acid.
MS:[M+H]
+=579.1
1H-NMR(400M,DMSO-d
6)δ9.34(s,1H),8.32(s,1H),7.97-7.99(d,2H),7.19(s,1H),7.67-7.69(d,4H),6.86-6.88(m,2H),4.81(s,2H),3.94-3.97(m,4H),3.56-3.58(m,4H),2.67-2.68(m,2H),2.50(s,3H),2.36-2.38(m,4H),2.30-2.32(m,2H),1.83-1.87(m,2H)ppm。
Embodiment 7: the preparation of compound 7
6-benzyl-2-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(2-pyrrolidyl-1-oxyethyl group into) aniline.
2-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method
With 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(2-pyrrolidyl-1-oxyethyl group into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(2-pyrrolidyl-1-oxyethyl group) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-pyrrolidyl-1-oxyethyl group into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=486.8
1H-NMR(400M,DMSO-d
6)δ8.22-8.23(d,1H),7.49-7.52(m,2H),7.03-7.04(m,1H),6.91-6.93(m,2H),4.78(s,2H),4.13-4.16(m,2H),3.71-3.74(m,2H),3.60-3.61(m,2H),2.93-2.95(m,2H),2.78-2.80(m,2H),2.68-2.69(m,4H),2.35(s,3H),1.84(s,4H)ppm。
Embodiment 8: the preparation of compound 8
6-benzyl-2-(3-(4-(3,5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(3 into, 5-dimethyl-piperidino) aniline.
2-(3-(4-(3,5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method
With 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(3 into, 5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(3,5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3 into; 5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=485.2
1H-NMR(400M,DMSO-d
6)δ9.22(s,1H),8.29(s,1H),7.60-7.63(d,2H),7.16-7.17(d,1H),6.87-6.89(d,2H),4.43(s,2H),4.48-3.53(m,4H),3.01(s,3H),2.69(s,3H),2.34(s,3H),2.04-2.10(t,2H),1.70-1.73(m,2H),0.89-0.90(m,6H)ppm。
Embodiment 9: the preparation of compound 9
6-methylsulfonyl-2-(3-(4-(3,5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3 into; 5-dimethyl-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=496.0
1H-NMR(400M,DMSO-d
6)δ9.22(s,1H),8.29(s,1H),7.60-7.63(d,2H),7.17(s,1H),6.87-6.89(d,2H),4.43(s,2H),4.48-3.53(m,5H),3.01(s,3H),2.69(s,3H),2.34(s,3H),2.04-2.10(t,2H),1.70-1.73(m,2H),0.89-0.90(m,6H)ppm。
Embodiment 10: the preparation of compound 10
4-(4-acetoxyl group-piperidino) oil of mirbane
In reaction flask, add p-fluoronitrobenzene (141.0mg, 1eq), 4-acetoxyl group-1-piperidines (186.9mg, 1.3eq), salt of wormwood (552.9mg, 4eq) and DMF(15mL), 80 degree reactions 6 hours, induction stirring.Stopped reaction, adds water (50mL), separates out solid, and suction filtration is dry, obtains 4-(4-acetoxyl group-piperidino) oil of mirbane (236.6mg).
4-(4-acetoxyl group-piperidino) aniline
In reaction flask, add 4-(4-acetoxyl group-piperidino) oil of mirbane (132.1mg, 1eq), Pd/C(13.2mg, 10%) and methyl alcohol (10mL), pass into H2, stirring at room 3 hours.Stopped reaction, suction filtration, filtrate is concentrated, is dried to obtain 4-(4-acetoxyl group-piperidino) aniline (97.3mg)
6-benzyl-2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-acetoxyl group-piperidino into) aniline.
2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method
With 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-acetoxyl group-piperidino into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-methylsulfonyl-2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-acetoxyl group-piperidino into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=527.0
1H-NMR(400M,DMSO-d
6)δ9.29(s,1H),8.32(s,1H),7.67(s,2H),7.67(s,1H),6.94(s,2H),4.82(s,1H),4.46(s,3H),3.04(s,3H),2.93(s,3H),2.72(s,3H),2.36(s,4H),2.05(s,3H),1.97(s,2H),1.70(s,2H)ppm。
Embodiment 11: the preparation of compound 11
6-benzyl-2-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 3,4,5-trimethoxy-aniline into.
2-(3-(3,4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(3 into, 4,5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-methylsulfonyl-2-(3-(3,4,5-trimethoxy-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(3 into; 4; 5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=475.3
1H-NMR(400M,DMSO-d
6)δ9.39(s,1H),8.36(s,1H),7.36(s,2H),7.18(s,1H),4.39(s,2H),3.79(s,6H),3.61(s,3H),3.47-3.50(m,2H),3.01(s,3H),2.67(s,2H),2.34(s,3H)ppm。
Embodiment 12: the preparation of compound 12
6-cyano group ethanoyl-2-(3-(3, 4, 5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines synthetic, difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines changes 2-(3-(3 into, 4, 5-trimethoxy-benzene amido)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines.
MS:[M+H]
+=464.0
1H-NMR(400M,DMSO-d
6)δ9.39(s,1H),8.36(s,1H),7.36-7.39(d,2H),7.17(s,1H),4.57-4.63(d,2H),4.21(s,2H),3.77-3.81(m,6H),3.62(s,5H),2.67(s,2H),2.33(s,3H)ppm。
Embodiment 13: the preparation of compound 13
6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-ethyl-1-piperazinyl into) aniline.
2-(3-(4-(4-ethyl-1-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-ethyl-1-piperazinyl into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=486.1
1H-NMR(400M,CDCl
3)δ8.23(s,1H),7.51-7.54(m,2H),6.98(s,1H),7.03(s,1H),6.94-6.96(m,2H),4.78(s,2H),3.60-3.61(m,2H),3.37-3.39(m,4H),2.92-2.93(m,4H),2.78-2.80(m,4H),
2.38(s,3H),1.31-1.32(m,3H),1.25-1.26(m,2H)ppm。
Embodiment 14: the preparation of compound 14
6-methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-ethyl-1-piperazinyl into) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=497.1
1H-NMR(400M,DMSO-d
6)δ9.24(s,1H),8.29(s,1H),7.63-7.65(d,2H),7.17(s,1H),6.88-6.90(d,2H),4.43(s,2H),3.47-3.50(m,3H),3.06(s,4H),3.01(s,4H),2.50-2.54(m,3H),2.41(s,2H),2.33(s,4H),1.02-1.06(m,3H)ppm。
Embodiment 15: the preparation of compound 15
6-(3-cyano group-benzoyl)-2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (223.7mg, 1eq), 3-cyano group-phenylformic acid (147.1mg, 2eq), 1-hydroxyl-benzo-triazole (169.2mg, 2.5eq), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (239.6mg, 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, crude product silica gel column chromatography obtains 6-(3-cyano group-benzoyl)-2-(3-(4-(4-acetoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (265.3mg).
MS:[M+H]
+=577.1
1H-NMR(400M,DMSO-d
6)δ9.25(s,1H),7.98(s,2H),7.81-7.83(d,1H),7.63-7.70(m,3H),7.17(s,1H),6.90-6.92(m,2H),5.75(s,1H),4.80(s,2H),3.95(s,1H),3.54(s,2H),2.90-2.92(m,2H),2.65-2.66(m,2H),2.35(s,3H),2.02(s,3H),1.93-1.94(m,2H),1.23-1.25(m,2H),
1.66-1.68(m,2H)ppm。
Embodiment 16: the preparation of compound 16
6-benzyl-2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(3-(4-methyl-piperazinyl into)-1-propoxy-) aniline.
2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(3-(4-methyl-piperazinyl into)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl into)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=531.0
1H-NMR(400M,DMSO-d
6)δ9.31(s,1H),8.30(s,1H),7.67-7.69(d,2H),7.17(s,1H),6.85-6.87(d,2H),4.61-4.67(d,2H),4.20-4.22(d,2H),3.94-3.97(t,2H),3.63-3.65(m,2H),2.65-2.68(m,4H),2.57-2.59(m,4H),2.33(s,3H),2.29-2.30(m,4H),1.85-1.87(m,3H),1.23-1.25(m,2H)ppm。
Embodiment 17: the preparation of compound 17
6-isobutyryl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 13) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change cyanoacetic acid into isopropylformic acid.
MS:[M+H]
+=489.2
1H-NMR(400M,DMSO-d
6)δ9.30(s,1H),8.30(s,1H),7.68-7.70(d,2H),7.15(s,1H),6.94-6.96(d,2H),4.63(s,2H),3.76-3.77(m,2H),3.01-3.08(m,10H),2.50-2.51(m,2H),2.33-2.35(s,1H),2.69(m,3H),1.06-1.11(m,6H),1.02-1.04(m,3H)ppm。
Embodiment 18: the preparation of compound 18
6-methylsulfonyl-2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3-(4-methyl isophthalic acid-piperazinyl into)-1-propoxy-) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=542.1
1H-NMR(400M,DMSO-d
6)δ9.31(s,1H),8.31(s,1H),7.67-7.69(d,2H),7.17(s,1H),6.85-6.88(d,2H),4.43(s,2H),3.94-3.97(t,2H),3.47-3.50(t,2H),3.32(s,2H),3.01(s,3H),2.69(s,3H),2.29-2.34(m,7H),1.84-1.87(m,3H),1.23-1.28(m,5H)ppm。
Embodiment 19: the preparation of compound 19
6-benzyl-2-(3-(indoles-5-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes indoles-5-aniline into.
2-(3-(indoles-5-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(indoles-5-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(indoles-5-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(indoles-5-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=413.0
1H-NMR(400M,DMSO-d
6)δ10.86(s,1H),9.20(s,1H),8.30(s,1H),8.06(s,1H),7.15-7.36(m,4H),6.36(s,1H),4.62-4.68(d,2H),4.22(s,2H),3.77(s,1H),3.63(s,1H),2.69(s,2H),2.34(s,3H)ppm。
Embodiment 20: the preparation of compound 20
6-cyano group ethanoyl-2-(3-(4-(4-methoxyl group-piperidyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-(thiophene-2-formyl radical in embodiment 4)-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change thiophene-2-carboxylic acid into cyanoacetic acid.
MS:[M+H]
+=487.1
1H-NMR(400M,DMSO-d
6)δ9.22(s,1H),8.29(s,1H),7.63-7.65(m,2H),7.17(s,1H),6.88-6.90(m,2H),4.61-4.67(d,2H),4.19-4.21(d,2H),3.63-3.77(m,4H),3.45-3.48(m,2H),2.68(s,2H),2.57(s,1H),2.50(s,3H),2.33(s,3H),2.16-2.22(m,2H),1.14-1.15(m,2H)ppm。
Embodiment 21: the preparation of compound 21
6-(3-cyano group-benzoyl)-2-(3-(4-(4-methoxyl group-piperidyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-(thiophene-2-formyl radical in embodiment 4)-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic, difference is to change thiophene-2-carboxylic acid into 3-cyano group-phenylformic acid.
MS:[M+H]
+=549.2
1H-NMR(400M,DMSO-d
6)δ9.27(s,1H),8.30(s,1H),7.98-8.00(m,2H),7.82-7.86(m,1H),7.69-7.73(m,3H),7.17(s,1H),6.89-6.91(m,2H),4.81(s,2H),3.55(s,2H),3.27(s,3H),2.78-2.80(m,2H),2.65(s,2H),2.35(s,3H),1.99(s,3H),1.52-1.54(m,2H),1.16-1.23(m,2H)ppm。
Embodiment 22: the preparation of compound 22
6-(4-cyano group-benzoyl)-2-(3-(4-(4-methoxyl group-piperidyl) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-(thiophene-2-formyl radical in embodiment 4)-2-(3-(4-(4-methoxyl group-piperidino) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic, difference is to change thiophene-2-carboxylic acid into 4-cyano group-phenylformic acid.
MS:[M+H]
+=549.2
1H-NMR(400M,DMSO-d
6)δ9.27(s,1H),8.30(s,1H),7.97-7.99(m,2H),7.63-7.69(m,4H),7.17(s,1H),6.89-6.91(m,2H),4.82(s,2H),3.52(s,2H),3.27(s,3H),2.78-2.81(m,2H),2.68-2.69(m,2H),2.51(s,3H),2.36(s,2H),2.28-2.30(m,1H),1.93-1.95(m,2H),1.52-1.57(m,2H)ppm。
Embodiment 23: the preparation of compound 23
6-benzyl-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-morpholinyl phenylamine into.
2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-morpholinyl-1-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-(4-cyano group-benzoyl)-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-(4-cyano group-benzoyl in embodiment 22)-2-(3-(4-(4-methoxyl group-piperazinyl) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is methoxyl group-piperazinyl by 2-(3-(4-(4-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=521.1
1H-NMR(400M,DMSO-d
6)δ9.29(s,1H),8.31(s,1H),7.87-7.98(m,2H),7.66-7.68(m,4H),7.18(s,1H),6.89-6.91(m,2H),4.81(s,2H),3.73(s,4H),3.52(s,2H),3.02(s,4H),2.62(s,2H),2.35(s,3H)ppm。
Embodiment 24: the preparation of compound 24
6-(3-cyano group-benzoyl)-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-(4-cyano group-benzoyl in embodiment 23)-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic, difference is to change 4-cyano group-phenylformic acid into 3-cyano group-phenylformic acid.
MS:[M+H]
+=521.1
1H-NMR(400M,DMSO-d
6)δ9.29(s,1H),8.30(s,1H),7.89(s,2H),7.81-7.83(m,1H),7.67-7.70(m,3H),7.18(s,1H),6.89(s,2H),4.81(s,2H),3.73(s,4H),3.54(s,2H),3.02(m,4H),2.65(m,2H),2.35(s,3H)ppm。
Embodiment 25: the preparation of compound 25
6-methylsulfonyl-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=470.0
1H-NMR(400M,DMSO-d
6)δ9.30(s,1H),8.30(s,1H),7.65-7.77(m,2H),7.17(s,1H),6.89-6.91(d,2H),4.43(s,2H),3.72-3.74(m,4H),3.47-3.49(m,2H),3.02-3.03(m,7H),2.69-2.71(m,2H),2.34(s,3H)ppm。
Embodiment 26: the preparation of compound 26
2-(4-morpholinyl-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-morpholinyl phenylamine into.
6-benzyl-2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-changes 2-(4-morpholinyl-1-anilino into) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-methylsulfonyl-2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=524.2
1H-NMR(400M,DMSO-d
6)δ10.08(s,1H),8.74(s,1H),7.61(s,2H),7.30(s,1H),6.94-6.97(d,2H),4.41(s,2H),3.73-3.75(m,4H),3.46-3.49(m,2H),3.05-3.08(m,4H),3.03(s,3H),2.70(s,2H)ppm。
Embodiment 27: the preparation of compound 27
6-cyano group ethanoyl-2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines synthetic, difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines.
MS:[M+H]
+=513.0
1H-NMR(400M,DMSO-d
6)δ10.07(s,1H),8.73(s,1H),7.61(s,2H),7.92-7.31(m,1H),6.94-6.96(m,2H),4.60-4.66(m,2H),4.22(s,2H),3.74-3.78(m,6H),3.05-3.08(m,4H),2.67-2.69(m,2H)ppm。
Embodiment 28: the preparation of compound 28
6-cyano group ethanoyl-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-(4-cyano group-benzoyl in embodiment 23)-2-(3-(4-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change 4-cyano group-phenylformic acid into cyanoacetic acid.
MS:[M+H]
+=459.1
1H-NMR(400M,DMSO-d
6)δ9.29(s,1H),8.30(s,1H),7.65-7.67(d,2H),7.16-7.17(d,1H),6.89-6.91(d,2H),4.61-4.67(m,2H),4.21-4.23(m,2H),3.72-3.77(m,4H),3.62-3.63(m,2H),3.01-3.03(m,4H),2.67-2.69(m,2H),2.33(s,3H)ppm。
Embodiment 29: the preparation of compound 29
2-(4-(4-methyl isophthalic acid-piperazinyl) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-(4-methyl isophthalic acid-piperazinyl into) aniline.
6-benzyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-changes 2-(4-(4-methyl isophthalic acid-piperazinyl into) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-morpholinyl-1-anilino in embodiment 23)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the anilino by 2-(3-(4-morpholinyl-1-)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-methyl isophthalic acid-piperazinyl into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=526.0
1H-NMR(400M,DMSO-d
6)δ8.62-8.63(d,1H),7.46-7.50(m,2H),7.30(s,1H),7.22-7.23(m,1H),6.95-6.97(m,2H),4.78(s,2H),3.90-3.93(m,2H),3.61(s,2H),3.20-3.22(m,4H),2.78-2.81(m,2H),2.66-2.67(m,4H),2.37(s,3H)ppm。
Embodiment 30: the preparation of compound 30
6-benzyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-methyl isophthalic acid-piperazinyl into) aniline.
2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(4-methyl isophthalic acid-piperazinyl)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-morpholinyl-1-anilino in embodiment 23)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the anilino by 2-(3-(4-morpholinyl-1-)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-methyl isophthalic acid-piperazinyl into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=471.8
1H-NMR(400M,DMSO-d
6)δ8.21-8.23(d,1H),7.48-7.52(m,2H),7.03-7.04(m,1H),6.92-6.96(m,3H),4.78(s,2H),3.71-3.74(m,2H),3.60-3.61(m,2H),3.17-3.19(m,4H),2.78-2.81(m,2H),2.60-2.63(m,3H),2.37(s,4H),1.65(s,3H)ppm。
Embodiment 31: the preparation of compound 31
2-(4-(4-ethyl-1-piperazinyl) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-(4-ethyl-1-piperazinyl into) aniline.
6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-changes 2-(4-(4-ethyl-1-piperazinyl into) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-morpholinyl-1-anilino in embodiment 23)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the anilino by 2-(3-(4-morpholinyl-1-)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-ethyl-1-piperazinyl into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=540.0
1H-NMR(400M,CDCl3)δ8.26(s,1H),7.48(s,2H),7.39(s,1H),6.95-6.97(d,2H),4.77(s,2H),3.91(s,2H),3.60-3.62(d,2H),3.29(s,4H),2.76(s,4H),2.61-2.62(m,4H),1.21-1.25(t,3H)ppm。
Embodiment 32: the preparation of compound 32
6-methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the propoxy-by 2-(3-(4-(3-morpholinyl-1-) anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 22-(3-(4-(4-ethyl-1-piperazinyl into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=551.0
1H-NMR(400M,CDCl3)δ8.62(s,1H),7.49(s,2H),7.26(s,2H),6.97(s,2H),4.50(s,2H),3.61(s,2H),3.27(s,3H),2.89(s,2H),2.65(s,8H),2.58(s,2H),1.25(s,3H)ppm。
Embodiment 33: the preparation of compound 33
6-ethylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 32)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change methylsulfonyl chloride into ethyl sulfonyl chloride.
MS:[M+H]
+=565.0
1H-NMR(400M,CDCl3)δ8.62(s,1H),7.47-7.49(d,2H),7.22(s,1H),6.95-6.97(d,2H),4.53(s,2H),3.63(s,2H),3.22(s,4H),3.04-3.05(d,2H),2.72(s,2H),2.64(s,4H),2.48-2.50(d,2H),1.38(s,3H),1.25(s,3H)ppm。
Embodiment 34: the preparation of compound 34
6-(thiophene-2-formyl radical)-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 31)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change cyanoacetic acid into thiophene-2-carboxylic acid.
MS:[M+H]
+=530.0.
1H-NMR(400M,DMSO-d
6)δ9.26(s,1H),8.29(s,1H),8.16(s,1H),7.82-7.83(d,1H),7.64-7.67(d,2H),7.56-7.57(d,1H),7.18-7.19(d,1H),6.90-6.92(d,2H),4.83(s,2H),3.15-3.17(m,2H),3.01-3.06(m,8H),2.72-2.74(m,2H),2.66-2.68(m,2H),2.34(s,3H),1.20-1.23(m,3H)ppm。
Embodiment 35: the preparation of compound 35
6-the third alkylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 32)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change methylsulfonyl chloride into third SULPHURYL CHLORIDE.
MS:[M+H]
+=536.0.
1H-NMR(400M,DMSO-d
6)δ9.23(s,1H),8.29(s,1H),7.63-7.65(d,2H),7.16(s,1H),6.87-6.89(d,2H),4.46(s,2H),3.51-3.54(t,2H),3.13-3.17(m,6H),3.05(s,4H),2.66(s,2H),2.33-2.39(m,5H),1.67-1.73(m,2H),1.00-1.02(m,3H),1.03-1.05(m,3H)ppm。
Embodiment 36: the preparation of compound 36
6-encircles the third methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-methylsulfonyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 32)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change methylsulfonyl chloride into ring the third methylsulfonyl chloride.
MS:[M+H]
+=578.0
1H-NMR(400M,CDCl
3)δ8.62(s,1H),7.47-7.49(d,2H),7.22(s,1H),6.95-6.97(d,2H),4.54(s,2H),3.63-3.66(t,2H),3.22-3.24(m,4H),2.75-2.76(m,2H),2.53-2.64(m,4H),2.49-2.51(m,2H),2.29-2.32(m,1H),1.16-1.18(m,3H),0.98-0.99(m,2H),0.86-0.89(m,2H)ppm。
Embodiment 37: the preparation of compound 37
6-benzyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-piperidyl-piperidino into)-1-aniline.
2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-piperidyl-piperidino into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-the third alkylsulfonyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-the third alkylsulfonyl in embodiment 35-2-(3-(4-(4-ethyl-1-piperazinyl)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the piperazinyl by 2-(3-(4-(4-ethyl-1-)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-piperidyl-piperidino into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+2]
+=290.2
1H-NMR(400M,DMSO-d
6)δ9.27(s,1H),8.30(s,1H),7.64-7.66(d,2H),7.17(s,1H),6.92-6.94(d,2H),4.46(s,2H),3.70-3.73(m,2H),3.53(s,2H),3.14-3.17(m,2H),3.03-3.07(m,5H),2.62-2.66(m,4H),2.33(s,3H),2.13-2.16(m,2H),1.81-1.82(m,6H),1.68-1.73(m,4H),0.97-1.00(t,3H)ppm。
Embodiment 38: the preparation of compound 38
6-cyano group ethanoyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 31)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the piperazinyl by 2-(3-(4-(4-ethyl-1-)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-piperidyl-piperidino into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=541.2
1H-NMR(400M,CDCl3)δ8.21-8.22(d,1H),7.50-7.53(m,2H),7.04-7.07(m,1H),6.91-6.93(d,2H),4.77(s,2H),3.91(s,1H),3.70-3.73(m,4H),3.60-3.63(m,2H),3.06-3.15(m,4H),2.72-2.78(m,4H),2.67(s,1H),2.38(s,3H),1.95-1.98(m,2H),1.38-1.42(t,2H),1.19-1.25(m,6H)ppm。
Embodiment 39: the preparation of compound 39
6-methylsulfonyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-the third alkylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 37)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change the third SULPHURYL CHLORIDE into methylsulfonyl chloride.
MS:[M+H]
+=552.1
1H-NMR(400M,CDCl
3)δ8.22(s,1H),7.51-7.53(d,2H),7.03(s,1H),6.92-6.97(m,3H),4.51(s,2H),3.71-3.73(m,2H),3.62-3.63(m,2H),3.45-3.48(m,2H),3.18(s,1H),2.89(s,3H),2.76-2.79(m,6H),1.99-2.02(m,3H),1.86-1.89(m,2H),1.63(s,6H),1.41-1.43(m,2H)ppm。
Embodiment 40: the preparation of compound 40
6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-the third alkylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 37)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change the third SULPHURYL CHLORIDE into ethyl sulfonyl chloride.
MS:[M+H]
+=565.1
1H-NMR(400M,CDCl
3)δ8.21(s,1H),7.51-7.53(d,2H),7.04(s,1H),6.98(s,1H),6.91-6.93(d,2H),4.54(s,2H),3.70-3.73(m,2H),3.62-3.65(m,2H),3.43(s,1H),3.02-3.05(m,2H),2.73-2.79(m,6H),2.37(s,6H),1.95-2.01(m,3H),1.65(s,4H),1.36-1.43(m,5H)ppm。
Embodiment 41: the preparation of compound 41
6-fourth alkylsulfonyl-2-(3-(4-(4-piperidyl-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-the third alkylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 37)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change the third SULPHURYL CHLORIDE into fourth SULPHURYL CHLORIDE.
MS:[M+H]
+=594.2.
1H-NMR(400M,DMSO-d
6)δ9.26(s,1H),8.30(s,1H),7.64-7.66(d,2H),7.17(s,1H),6.91-6.93(d,2H),4.47(s,2H),3.69-3.70(m,2H),3.34(s,2H),3.15-3.19(m,4H),3.03-3.06(s,3H),2.60-2.66(m,4H),2.33(s,3H),2.01-2.13(m,2H),1.79-1.81(m,6H),1.65(s,2H),1.38-1.40(m,2H),1.19-1.23(m,2H),0.84-0.88(m,3H)ppm。
Embodiment 42: the preparation of compound 42
6-benzyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-thio-morpholinyl-1-aniline into.
2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-thio-morpholinyl-1-anilino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines preparation method is with 6-cyano group ethanoyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 38)-1-anilino)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines synthetic, difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-anilino)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines changes 2-(3-(4-thio-morpholinyl-1-anilino into)-6-methyl) pyrimidyl-furo [2, 3-c] piperidines.
MS:[M+H]
+=476.1.
1H-NMR(400M,DMSO-d
6)δ9.25(s,1H),8.29(s,1H),7.64-7.66(d,2H),7.16-7.17(d,1H),6.88-6.90(d,2H),4.61-4.67(m,2H),4.19-4.21(d,2H),3.62-3.64(m,2H),3.38-3.39(m,4H),3.31-3.32(m,2H),2.68-2.70(m,4H),2.33(s,3H)ppm。
Embodiment 43: the preparation of compound 43
6-propionyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-cyano group ethanoyl-2-(3-(4-thio-morpholinyl-1-anilino in embodiment 42)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic, difference is to change cyanoacetic acid into propionic acid.
MS:[M+H]
+=464.1
1H-NMR(400M,CDCl
3)δ8.19-8.21(m,1H),7.51-7.53(m,2H),7.01-7.03(m,1H),6.91-6.93(m,2H),4.76(s,2H),3.69-3.72(m,2H),3.44-3.50(m,4H),2.77-2.79(m,4H),2.62-2.67(m,2H),2.42-2.49(m,2H),2.38(s,3H),1.17-1.25(m,3H)ppm。
Embodiment 44: the preparation of compound 44
6-ethanoyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-thio-morpholinyl-1-anilino in embodiment 42)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change cyanoacetic acid into acetic acid.
MS:[M+H]
+=450.0
1H-NMR(400M,CDCl
3)δ8.19-8.21(m,1H),7.50-7.54(m,2H),7.04(s,1H),6.91-6.93(m,2H),4.76(s,2H),3.69-3.71(m,2H),3.44-3.46(m,4H),2.77-2.79(m,4H),2.63-2.68(m,2H),2.38(s,3H),2.19-2.21(m,3H)ppm。
Embodiment 45: the preparation of compound 45
6-cyanogen methyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines adds 2-(3-(4-thio-morpholinyl-1-anilino in reaction flask)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (203.5mg, 1eq), bromoacetonitrile (119.5mg, 2eq), salt of wormwood (207.1mg, 3eq) and acetonitrile (10mL), 60 degree reactions 3 hours, induction stirring.Stopped reaction, suction filtration, filtrate is concentrated, crude product silica gel column chromatography obtains 6-cyanogen methyl-2-(3-(4-thio-morpholinyl-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (198.2mg).
MS:[M+H]
+=447.0
1H-NMR(400M,CDCl
3)δ8.20(s,1H),7.50-7.52(m,2H),7.03(s,1H),6.91-6.94(m,3H),3.81(s,2H),3.76(s,2H),3.43-3.46(m,4H),2.88-2.91(m,2H),2.76-2.79(m,4H),2.69-2.71(m,2H),2.37(s,3H)ppm。
Embodiment 46: the preparation of compound 46
6-benzyl-2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-methoxyl group-piperidino into)-1-aniline.
2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-methoxyl group-piperidino into)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
6-p-toluenesulfonyl-2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
In reaction flask, add 2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (419.5mg, 1eq), tolysulfonyl rate (381.3mg, 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, crude product silica gel column chromatography obtains 6-p-toluenesulfonyl-2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines (435.6mg).
1H-NMR(400M,CDCl
3)δ8.15(s,1H),7.84-7.92(m,2H),7.39-7.52(m,4H),7.26(s,1H),6.92-6.99(m,2H),4.34(s,2H),3.83(s,2H),3.42(s,4H),3.38(s,3H),2.65(s,2H),2.35(s,5H),1.26(s,6H)ppm。
Embodiment 47: the preparation of compound 47
6-methylsulfonyl-2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-p-toluenesulfonyl-2-(3-(4-(4-methoxyl group-piperidino in embodiment 46)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change tolysulfonyl rate into methylsulfonyl chloride.
MS:[M+H]
+=499.0
1H-NMR(400M,CDCl
3)δ8.21(s,1H),7.50-7.52(d,2H),7.04(s,1H),6.91-6.93(m,3H),4.51(s,2H),3.81-3.84(m,2H),3.60-3.63(m,2H),3.38-3.41(m,2H),2.89(s,3H),2.73-2.76(m,2H),2.40-2.42(m,1H),2.37(s,3H),1.59(s,3H),1.25-1.27(m,4H)ppm。
Embodiment 48: the preparation of compound 48
6-benzenesulfonyl-2-(3-(4-(4-methoxyl group-piperidino)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-p-toluenesulfonyl-2-(3-(4-(4-methoxyl group-piperidino in embodiment 46)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change tolysulfonyl rate into benzene sulfonyl chloride.
1H-NMR(400M,CDCl
3)δ8.18(s,1H),7.71-7.73(d,2H),7.48-7.50(d,2H),7.31-7.33(d,2H),6.96-6.98(m,2H),6.90-6.92(d,2H),4.31(s,2H),3.80-3.84(m,2H),3.37(m,3H),2.65-2.66(m,2H),2.34-2.42(m,8H),1.25-1.26(m,4H)ppm。
Embodiment 49: the preparation of compound 49
6-benzyl-2-(3-(4-(4-methyl isophthalic acid-piperidyl)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(4-methyl isophthalic acid-piperidyl into)-1-aniline.
MS:[M+H]
+=494.2
1H-NMR(400M,DMSO-d
6)δ8.09(s,1H),7.39-7.41(d,2H),7.22-7.39(m,4H),7.19-7.22(m,1H),6.95(s,1H),6.86-6.89(m,3H),3.69(s,2H),3.66(s,2H),3.47-3.50(m,2H),2.72-2.75(m,2H),2.54-2.60(m,4H),2.27(s,3H),1.65-1.68(m,2H),1.32-1.35(m,1H),1.28-1.29(m,2H),0.89-0.91(m,3H)ppm。
Embodiment 50: the preparation of compound 50
6-benzyl-2-(3-(4-(3,5-dimethyl-1-morpholinyl)-1-anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-benzyl-2-(3-(4-(3-morpholinyl-1-propoxy-in embodiment 2) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the propoxy-by 4-(3-morpholinyl-1-) aniline changes 4-(3 into, 5-dimethyl-1-morpholinyl)-1-aniline.
MS:[M+H]
+=510.1
1H-NMR(400M,DMSO-d
6)δ8.09(s,1H),7.42-7.44(d,2H),7.23-7.32(m,4H),7.19(s,1H),6.95(s,1H),6.89(s,1H),6.83-6.85(d,2H),3.73-3.78(m,2H),3.69(s,2H),3.56(s,2H),2.29-2.32(d,2H),2.72-2.75(m,2H),2.55-2.57(m,2H),2.27-2.34(m,5H),1.18-1.20(m,6H)ppm。
Embodiment 51: the preparation of compound 51
6-benzyl-2-(3-chlorine) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with the chloro-6-methyl of 6-benzyl-2-(3-in embodiment 2) pyrimidyl-furo ［ 2,3-c ］ piperidines synthetic, difference is to change the chloro-5-methyl-pyrimidine of 2,4-bis-into 2,4-bis-chloro-pyrimidine.
6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 13) anilino)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the chloro-6-methyl by 6-benzyl-2-(3-) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-chlorine into) pyrimidyl-furo [2,3-c] piperidines.
2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-ethyl-1-piperazinyl into) anilino)) pyrimidyl-furo [2,3-c] piperidines.
6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2, 3-c] piperidines preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines synthetic, difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2, 3-c] piperidines changes 2-(3-(4-(4-ethyl-1-piperazinyl into) anilino)) pyrimidyl-furo [2, 3-c] piperidines.
MS:[M+H]
+=472.3
1H-NMR(400M,CDCl
3)δ8.37-8.38(m,1H),7.83-7.85(d,1H),7.61-7.63(d,1H),7.53-7.55(d,2H),6.91-6.97(m,2H),4.61-4.75(m,2H),3.70-3.73(m,2H),3.59-3.61(m,2H),3.07-3.15(m,4H),2.97-2.99(m,4H),2.81-2.84(m,4H),1.34-1.37(t,3H)ppm。
Embodiment 52: the preparation of compound 52
6-(N-Boc-glycyl)-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 51) anilino)) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is to change cyanoacetic acid into N-Boc-Padil.
MS:[M+2]
+=281.6
1H-NMR(400M,CDCl3)δ8.36-8.38(m,1H),7.49-7.52(d,2H),7.00-7.04(m,1H),6.96(s,1H),6.91-6.94(m,3H),5.53(s,1H),4.75(s,2H),4.08-4.09(m,2H),3.62-3.64(m,2H),3.18-3.20(m,4H),2.62-2.64(m,6H),2.46-2.49(m,2H),1.46(s,9H),1.12-1.15(t,3H)ppm。
Embodiment 53: the preparation of compound 53
6-allyl acyl group-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2; 3-c] under 0 ℃ of condition of piperidines; in reaction flask, add 2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2; 3-c] piperidines (50.0mg, 1eq), triethylamine (15.43mg; 1.25eq) and tetrahydrofuran (THF) (5mL); drip the mixing solutions of acrylate chloride (11.10mg, 1eq) and tetrahydrofuran (THF), induction stirring 3h.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; crude product silica gel column chromatography obtains 6-allyl acyl group-2-(3-(4-(4-ethyl-1-piperazinyl) anilino)) pyrimidyl-furo [2,3-c] piperidines (43.7mg).
MS:[M+H]
+=459.1
1H-NMR(400M,DMSO-d
6)δ9.45(s,1H),8.41-8.43(d,1H),7.67-7.69(d,2H),7.22(s,1H),6.91-7.01(m,4H),6.15-6.19(m,1H),5.74-5.76(m,1H),4.70(s,2H),3.82(s,2H),3.03-3.08(m,4H),2.65(s,2H),1.17-1.28(m,9H)ppm。
Embodiment 54: the preparation of compound 54
6-allyl acyl group-2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-allyl acyl group-2-(3-(4-(4-ethyl-1-piperazinyl in embodiment 53) anilino)) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the piperazinyl by 2-(3-(4-(4-ethyl-1-) anilino)) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=500.0
1H-NMR(400M,DMSO-d
6)δ10.04(s,1H),8.72(s,1H),7.61-7.62(d,2H),6.89-6.96(m,3H),6.15-6.19(d,1H),5.74-5.77(d,1H),5.36-5.38(d,1H),4.70-4.79(m,2H),3.73-3.79(m,4H),3.80-3.83(m,4H),3.06-3.07(m,4H)ppm。
Embodiment 55: the preparation of compound 55
6-ethylsulfonyl-2-(3-(4-morpholinyl-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-phenylamino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=538.2
1H-NMR(400M,DMSO-d
6)δ8.73(s,1H),7.62(d,2H),7.29(s,1H),6.95(d,2H),4.46(s,2H),3.74(t,4H),3.55(t,2H),3.20(q,2H),3.07(t,4H),2.68(t,2H),1.21(t,3H)
Embodiment 56: the preparation of compound 56
6-ethylsulfonyl-2-(3-(4-morpholinyl-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-morpholinyl-1-phenylamino into)-6-methyl) pyrimidyl-furo [2,3-c] piperidines.
[M+H]
+=484.2
1H-NMR(400M,DMSO-d
6)δ9.24(s,1H),8.29(s,1H),7.67(d,2H),7.16(s,1H),6.90(d,2H),4.47(s,2H),3.74(t,4H),3.54(t,2H),3.19(q,2H),3.03(t,4H),2.66(t,2H),2.33(s,1H),1.22(t,3H)
Embodiment 57: the preparation of compound 57
2-(4-piperidyl-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-piperidyl-1-aniline into.
6-benzyl-2-(3-(4-piperidyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-piperidyl-1-anilino into)--the chloro-5-trifluoromethyl pyrimidine of 4-.
2-(3-(4-piperidyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-piperidyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-piperidyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-piperidyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
[M+H]
+=536.2
1H-NMR(400M,DMSO-d
6)δ10.01(s,1H),8.72(s,1H),7.57(d,2H),7.29(s,1H),6.93(d,2H),4.46(s,2H),3.55(t,2H),3.20(q,2H),3.08(t,4H),2.67(t,2H),1.63(m,4H),1.53-1.52(m,2H),1.21(t,3H)
Embodiment 58: the preparation of compound 58
2-(4-piperazinyl-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-tetramethyleneimine-1-) aniline changes 4-piperazinyl-1-aniline into.
6-benzyl-2-(3-(4-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-piperazinyl-1-anilino into) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-piperazinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-piperazinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=537.2
1H-NMR(400M,CDCl
3))δ8.63(s,1H),7.49(d,2H),7.22(s,1H),6.95(d,2H),4.53(s,2H),3.63(t,2H),3.15(t,4H),3.05(m,6H),2.72(t,2H),1.69(t,3H)
Embodiment 59: the preparation of compound 59
2-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 4-(2-piperidyl-1-oxyethyl group into) aniline.6-benzyl-2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=580.2
1H-NMR(400M,DMSO-d
6)δ10.17(s,1H),8.76(s,1H),7.71(d,2H),7.30(s,1H),7.04(d,2H),4.46(s,2H),4.31(t,2H),3.55(t,2H),3.51(t,2H),3.20(q,2H),3.10-3.08(m,4H),2.67(t,2H),1.90-1.85(m,2H),1.76-1.70(m,2H),1.23-1.20(m,5H)
Embodiment 60: the preparation of compound 60
2-(3-(2-morpholinyl-1-oxyethyl group)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 3-(2-morpholinyl-1-oxyethyl group into) aniline.
6-benzyl-2-(3-(3-(2-morpholinyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(3-(2-morpholinyl-1-oxyethyl group into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(3-(2-morpholinyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(3-(2-morpholinyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(3-(2-morpholinyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=582.2
1H-NMR(400M,CDCl
3)δ8.68(s,1H),7.48(s,1H),7.42(s,1H),7.26(m,1H),7.14(d,1H),6.67(d,1H),4.54(s,2H),4.16(t,2H),3.75(t,4H),3.64-3.59(t,2H),3.05(q,2H),2.84(t,2H),2.73(t,2H),2.61(t,4H),1.39(t,3H)
Embodiment 61: the preparation of compound 61
6-ethylsulfonyl-2-(3-(4-(2-pyrrolidyl-1-oxyethyl group)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-pyrrolidyl-1-oxyethyl group into)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=595.1
1H-NMR(400M,CDCl3)δ8.64(s,1H),7.54(d,2H),7.32(s,1H),7.22(s,1H),6.96-6.94(d,2H),4.53(s,2H),4.25(t,2H),3.83(t,2H),3.63(t,2H),3.06-3.04(m,2H),2.72(t,2H),1.59(t,4H),1.40-1.37(t,3H),1.26(m,4H)
Embodiment 62: the preparation of compound 62
6-ethylsulfonyl-2-(3-(4-(2-morpholinyl-1-oxyethyl group)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-morpholinyl-1-oxyethyl group into)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=582.1
1H-NMR(400M,CDCl3)δ8.63(s,1H),7.54-7.51(d,2H),7.39(s,1H),7.22(s,1H),6.96-6.94(d,2H),4.53(s,2H),4.26-4.24(t,2H),3.84-3.81(t,2H),3.64-3.62（t,2H),3.08-3.02(m,2H),2.72(t,2H),1.61(t,4H),1.42-1.37(t,4H),1.26(t,3H)
Embodiment 63: the preparation of compound 63
2-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group into) aniline.
6-benzyl-2-(3-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-N-methyl isophthalic acid-piperazinyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=595.1
1H-NMR(400M,CDCl3)δ8.63(s,1H),7.54-7.52(d,2H),7.40(s,1H),7.23(s,1H),6.93-6.91(d,2H),4.53(s,2H),4,15(t,2H),3.65(t,2H),3.09-2.86(m,10H),2.74(t,4H),1.38(t,3H)
Embodiment 64: the preparation of compound 64
2-(4-(4-hydroxy piperidine base)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 4-(4-hydroxy piperidine base into) aniline.
6-benzyl-2-(3-(4-(4-hydroxy piperidine base)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(4-hydroxy piperidine base into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(4-hydroxy piperidine base)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(4-hydroxy piperidine base into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(4-hydroxy piperidine base)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(4-hydroxy piperidine base into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=552.1
1H-NMR(400M,DMSO-d
6)δ10.02(s,1H),8.72(s,1H),7.58-7.57(d,2H),7.29(s,1H),6.95-6.93(d,2H),4.67(s,1H),4.46(d,2H),3.63-3.46(m,5H),3.23-3.19(t,2H),2.81-2.76(t,2H),2.68(t,2H),1.83-1.81(m,2H),1.52-1.47(m,2H),1.22(t,3H)
Embodiment 65: the preparation of compound 65
2-(4-(3-pyrrolidyl-1-propoxy-)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 4-(3-pyrrolidyl-1-propoxy-into) aniline.
6-benzyl-2-(3-(4-(3-pyrrolidyl-1-propoxy-)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(3-pyrrolidyl-1-propoxy-into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(3-pyrrolidyl-1-propoxy-)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(3-pyrrolidyl-1-propoxy-into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(3-pyrrolidyl-1-propoxy-)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(3-pyrrolidyl-1-propoxy-into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=580.3
1H-NMR(400M,DMSO-d
6)δ8.62(s,1H),7.52(d,3H),7.25(d,1H),6.90(d,2H),5.54(brs,1H),4.52(s,2H),4.10(t,2H),3.63(t,2H),3.32(t,2H),3.06(q,2H),2.72(t,2H),2.44(q,2H),
2.22-2.00(m,4H),1.47-1.42(m,4H),0.92-0.83(m,3H)ppm
Embodiment 66: the preparation of compound 66
6-cyanogen methyl-2-(3-(4-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines preparation method is with 6-cyanogen methyl-2-(3-(4-thio-morpholinyl-1-anilino in embodiment 45)-6-methyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the anilino by 2-(3-(4-thio-morpholinyl-1-)-6-methyl) pyrimidyl-furo [2,3-c] piperidines changes 2-(3-(4-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=485.1
Embodiment 67: the preparation of compound 67
2-(3-morpholinyl-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes morpholinyl aniline into.
6-benzyl-2-(3-(3-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(3-morpholinyl-1-anilino into) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(3-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(3-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(3-morpholinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(3-morpholinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+Na]
+=560.2
1H-NMR(400M,DMSO-d
6)δ10.13(s,1H),8.79(s,1H),7.51(s,1H),7.31(s,1H),7.20(q,2H),6.66(d,1H),4.46(s,2H),3.76(t,4H),3.55(t,2H),3.20(q,4H),3.11(t,4H),2.68(t,2H),1.22(t,3H)
Embodiment 68: the preparation of compound 68
6-cyano group ethanoyl-2-(3-(4-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-cyano group ethanoyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is the oxyethyl group by 2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-piperazinyl-1-anilino into)) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=512.2
1H-NMR(400M,DMSO-d
6)δ10.04(s,1H),8.73(s,1H),7.59(s,2H),7.29(s,1H),6.93(d,2H),4.64(d,2H),4.22(s,2H),3.77(s,1H),3.64(s,1H),3.03(d,4H),2.87(s,4H),2.69(s,1H),2.58(s,1H)ppm
Embodiment 69: the preparation of compound 69
6-ethylsulfonyl-2-(3-(4-(N-methylpiperazine base)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(N-methylpiperazine base into)-1-phenylamino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=551.3
1H-NMR(400M,DMSO-d
6)δ10.04(s,1H),8.73(s,1H),7.59(d,2H),7.30(s,1H),6.94(d,2H),4.46(s,2H),3.55(t,2H),3.20(q,2H),3.09(t,4H),2.68(t,2H),2.46(t,4H),2.22(s,3H),1.21(t,3H)
Embodiment 70: the preparation of compound 70
2-(3-piperazinyl-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 3-piperazinyl aniline into.
6-benzyl-2-(3-(3-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(3-piperazinyl-1-anilino into) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(3-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(3-piperazinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(3-piperazinyl-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2; 3-c] piperidines preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(3-piperazinyl-1-anilino into)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=537.2
1H-NMR(400M,DMSO-d
6)δ10.19(s,1H),8.81(m,2H),7.51(s,1H),7.32(m,2H),7.24(q,1H),6.73(d,1H),4.47(s,2H),3.56(t,2H),3.37(m,6H),3.23(m,4H),2.69(t,2H),1.23(t,3H)
Embodiment 71: the preparation of compound 71
2-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-
Preparation method is with 2-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino) the chloro-5-trifluoromethyl pyrimidine of-4-synthetic, difference is the oxyethyl group by 4-(2-pyrrolidyl-1-) aniline changes 4-(2-piperidyl-1-oxyethyl group into) aniline.
6-benzyl-2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 2-(4-(2-tetramethyleneimine-1-) anilino)--the chloro-5-trifluoromethyl pyrimidine of 4-changes 2-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino) the chloro-5-trifluoromethyl pyrimidine of-4-.
2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 2-(3-(4-(2-tetramethyleneimine-1-oxyethyl group in embodiment 1) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines synthetic, difference is the oxyethyl group by 6-benzyl-2-(3-(4-(2-tetramethyleneimine-1-) anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines changes 6-benzyl-2-(3-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
6-ethylsulfonyl-2-(3-(4-(2-piperidyl-1-oxyethyl group)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines
Preparation method is with 6-ethylsulfonyl-2-(3-(4-(4-piperidyl-piperidino in embodiment 40)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines synthetic; difference is piperidyl-piperidino by 2-(3-(4-(4-)-1-phenylamino)-6-methyl) pyrimidyl-furo [2; 3-c] piperidines changes 2-(3-(4-(2-piperidyl-1-oxyethyl group into)-1-anilino)-6-trifluoromethyl) pyrimidyl-furo [2,3-c] piperidines.
MS:[M+H]
+=580.2
Embodiment 72: external biochemistry level suppresses jak kinase (PK) activity experiment
Materials and methods: JAK2, JAK3 kinases, derives from Invitrogen; 384 orifice plates (Greiner company); HTRFKinEASE; MgCl
2(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: the kinases to adding 4 μ l in each hole of 384 microwell plates adds the Enzymatic buffer of 4 μ L as negative control (Negative) simultaneously; The compound working fluid that adds 2 μ l to hole, add the damping fluid that does not contain compound of 2 μ L (is positive control, Positive) simultaneously in contrast; In 25 ℃ (or 30 ℃), hatch 5-10min; 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; In 25 ℃ (or 30 ℃), hatch 5-10min;
PHERAstar FS instrument reads HTRF signal.
The raw data of reading for every hole, ratio=665nm/620nm;
The calculating of inhibiting rate:
Calculate IC50:
Take log[administration concentration] be X-coordinate, inhibiting rate is ordinate zou, simulates a dose response curve in Graphpad Prism 5, the drug level while drawing its 50% inhibiting rate, 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 compound shown in I the half-inhibition concentration (IC to jak kinase activity
50) in Table 1:
Half-inhibition concentration (the IC of table 1 compound to 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 | 52 | 53 | 54 | 55 | 56 | 57 | 58 | 59 | 60 |
| Activity intensity | +++ | ++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ |
| Compound | 61 | 62 | 63 | 64 | 65 | 66 | 67 | 68 | 69 | 70 |
| Activity intensity | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ |
| Compound | 71 | CP-690550 | ||||||||
| Activity intensity | +++ | +++ |
+++ represent IC
50<500nM; ++ represent IC
50scope is 500-5000nM; + expression IC
50scope is 5000nM-50 μ M;-represent not test
Half-inhibition concentration (the IC of table 2 compound to JAK3 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 | 52 | 53 | 54 | 55 | 56 | 57 | 58 | 59 | 60 |
| Activity intensity | +++ | ++ | +++ | +++ | +++ | +++ | +++ | +++ | + | + |
| Compound | 61 | 62 | 63 | 64 | 65 | 66 | 67 | 68 | 69 | 70 |
| Activity intensity | +++ | + | + | +++ | +++ | +++ | +++ | +++ | +++ | +++ |
| Compound | 71 | CP-690550 | ||||||||
| Activity intensity | + | +++ |
+++ represent IC
50<500nM; ++ represent IC
50scope is 500-5000nM; + expression IC
50scope is 5000nM-50 μ M;-represent not test
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; it should be pointed out that for those skilled in the art, under the premise without departing from the principles 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 (17)
1. structure is suc as formula the compound shown in I or its pharmacy acceptable salt:
Wherein:
R
1for alkyl, cycloalkyl, acyl group, alkyl acyl, alkylsulfonyl, the alkyl sulphonyl replacing arbitrarily; Described substituting group is hydrogen, C
1-6the C that straight or branched alkyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
2-6straight or branched thiazolinyl, halogen ,-CN ,-NHSO
2r
12,-NHOH ,-NHCOR
12,-CON (R
12)
2,-CO (CH
2)
mnHC (O) OR
12,-N (R
12)
2,-OR
12,-CF
3,
r
2for hydrogen, halogen, C
1-6straight or branched alkyl, cycloalkyl, halo C
1-6straight or branched alkyl;
R
3for hydrogen, halogen;
Or R
2with R
3and form the hetero-aromatic ring base of 5 yuan together with their carbon atom of connection;
Z is independently selected from N or CR
13;
N or m are independently 0,1,2 or 3;
R
4independently selected from hydrogen, halogen, R
5' ,-OR
5' ,-OH, R
6,-CN ,-CF
3,-N (CH
3) R
5n(R
5')
2,-NHR
5r
6,-NHR
5n(R
5')
2, NHSO
2r
6,-N(R
1) R
5r
6,-N (CH
3) R
6,-NHR
6,-NHR
5oR
5oH ,-OR
5n(R
5')
2,
-(CH
2)
pn(R
5')
2,-NO
2,-R
5r
6,-OR
5r
6, replacement or unsubstituted saturated or undersaturated 5 or 6 yuan of heterocyclic radicals, or two adjacent R
4saturated or the undersaturated 5 or 6 yuan of heterocyclic radicals of the common formation of carbon atom that substituting group is connected with them; Described substituting group is hydrogen, halogen, amino ,-CN, hydroxyl, C
1-3alkylamino, nitro, C
1-3alkyl sulphonyl, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
P is 1,2 or 3;
R
5to replace or unsubstituted C
1-4alkylidene group, wherein two carbon atoms can be optionally by CO, S, SO at the most
2, or O substitute; Described substituting group is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C
1-3alkylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3acyloxy, C
1-3the C that alkyl sulphonyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
5' be hydrogen, replacement or unsubstituted C
1-4alkyl, wherein two carbon atoms can be optionally by CO, S, SO at the most
2, or O substitute; Described substituting group is hydrogen, halogen, amino ,-CN, hydroxyl, nitro, C
1-3alkylamino, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3acyloxy, C
1-3the C that alkyl sulphonyl, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
6nH
2, NHR
5', C
1-4alkoxyl group, cyclopropyl, replacement or unsubstituted phenyl, replacement or unsubstituted furyl, 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 oxazolyl, replacement or unsubstituted imidazolyl; Described substituting group is hydrogen, halogen, amino, nitro, C
1-3the C of alkylamino, halo
1-3alkoxyl group, C
1-3alkane alkylsulfonyl ,-CN, hydroxyl, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl;
R
12be selected from hydrogen ,-CN ,-NHSO
2r
5', halogen ,-N (R
5')
2,-OR
5' ,-COOR
5' ,-CF
3or C
1-4straight or branched alkyl, C
3-7cycloalkyl;
R
13be selected from hydrogen, C
1-3alkoxyl group.
2. compound as claimed in claim 1, wherein R
1for following groups:
Wherein:
R
7for C
1-6straight or branched alkyl, C
2-6straight or branched thiazolinyl ,-CN ,-NHSO
2r
12,-NHOH ,-NHC (O) OR
12,-NHCOR
12,-CON (R
12)
2,-N (R
12)
2,-OR
12,-CF
3,
r
8for C
1-6straight or branched alkyl, C
3-7cycloalkyl,
R
9, R
10or R
11identical or different, be independently selected from separately halogen, hydrogen ,-CN, C
1-6straight or branched alkyl, C
3-7cycloalkyl,
R
12be selected from hydrogen ,-CN ,-NHSO
2r
5, halogen ,-N (R
5)
2,-OR
5,-CF
3or C
1-4straight or branched alkyl;
X is selected from S, NH or O;
M is 0,1,2 or 3.
3. compound as claimed in claim 2, wherein R
1for following groups:
Wherein:
R
7for C
1-4straight or branched alkyl, C
2-6straight or branched thiazolinyl ,-CN ,-N (R
12)
2,-NHSO
2r
12,-NHC (O) OR
12,
R
8for C
1-4straight or branched alkyl, C
3-5cycloalkyl,
R
9, R
10or R
11identical or different, be independently selected from separately halogen, hydrogen ,-CN or
R
12be selected from halogen, methyl, the tertiary butyl ,-CN or hydrogen;
X is S;
M is 0 or 1.
4. compound as claimed in claim 3, wherein
R
7for-CN, NH
2,
-NHC (O) OR
12, methyl, ethyl, allyl group or sec.-propyl;
R
8for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl,
r
9or R
10for hydrogen;
R
11for-CN or
R
12for-CN, methyl, the tertiary butyl or hydrogen;
X is S;
M is 0 or 1.
5. compound as claimed in claim 1, wherein
R
2for hydrogen, halogen, C
1-4straight or branched alkyl or halo C
1-4straight or branched alkyl;
R
3for hydrogen;
Or R
2, R
3form following heterocyclic radical together with their carbon atom of connection:
6. compound as claimed in claim 5, wherein
R
2for hydrogen ,-CH
3or-CF
3; R
3for hydrogen.
7. compound as claimed in claim 1, wherein
Z is CR
13;
R
13be selected from hydrogen, methoxyl group.
8. the compound as described in claim 1 or 7, wherein
R
4for hydrogen, halogen ,-NO
2,-OH ,-(CH
2)
pn(R
5')
2,-N(R
1) R
5r
6, NHSO
2r
6,-N (CH
3) R
5n(R
5')
2,-N (CH
3) R
6,-NHR
5n(R
5')
2,-NHR
6,-NHR
5oR
5oH ,-NHR
5r
6,-OR
5n(R
5')
2,
c
1-6straight or branched alkoxyl group, substituted or non-substituted saturated or undersaturated 5 or 6 yuan of heterocyclic radicals ,-OR
5r
6or two adjacent R
4the common hetero-aromatic ring base that forms 5 yuan of carbon atom that substituting group is connected with them;
R
5to replace or unsubstituted C
1-3alkylidene group, R
5' be to replace or unsubstituted C
1-3alkyl;
P is 2 or 3;
R
6nH
2, C
1-6straight or branched alkylamino, C
1-3alkoxyl group, cyclopropyl, replacement or unsubstituted phenyl, replacement or unsubstituted furyl, 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 oxazolyl, replacement or unsubstituted imidazolyl;
R
4, R
5, R
5' and R
6in substituting group be respectively the C of hydrogen, halogen, hydroxyl, cyano group, dimethylamino, nitro, halo independently
1-3alkoxyl group, methylsulfonyl, C
1-6straight or branched alkyl, C
1-3alkoxyl group, C
1-3the C that acyloxy, hydroxyl replace
1-6the C of straight or branched alkyl, halo
1-6straight or branched alkyl, C
3-7cycloalkyl, C
3-7cycloalkanes formyl radical, dioxan base, pyrrolidyl, pyrrolidinomethyl or piperidyl.
9. compound as claimed in claim 8, wherein
R
4for hydrogen ,-F ,-NO
2,-OH ,-N(R
1) R
5r
6,-N (CH
3) R
5n(R
5')
2,-NHR
5n(R
5')
2, NHSO
2r
6,-NHR
5oR
5oH ,-N (CH
3) R
6,-NHR
6,-NHR
5r
6,-OR
5n(R
5')
2, C
1-4straight or branched alkoxyl group, pyrrolidyl, C
1-6pyrrolidyl, piperidyl, C that the pyrrolidyl that alkyl replaces, pyrrolidinomethyl replace
1-6piperidyl, C that alkyl replaces
1-3piperidyl, hydroxyl C that the piperidyl that the piperidyl that alkoxyl group replaces, piperidyl replace, hydroxy piperidine base, dimethylamino replace
1-3piperidyl, C that alkyl replaces
2-4piperidyl, piperazinyl, C that alkyl acyloxy replaces
1-6piperazinyl, morpholinyl, thio-morpholinyl, C that alkyl replaces
1-6morpholinyl, imidazolyl, C that alkyl replaces
1-6the imidazolyl that alkyl replaces,
-OR
5r
6or two R
4together with the carbon atom that substituting group connects with them, form following heterocyclic radical:
10. compound as claimed in claim 9, wherein
R
4for hydrogen ,-OCH
3,
-N(R
1) R
5r
6,-N (CH
3) R
5n(R
5')
2,-NHR
5n(R
5')
2,-NHR
5r
6,-NR
5oR
5oH ,-N (CH
3) R
6,-NHR
6,-NHR
5n(R
5')
2,-OR
5n(R
5')
2, OR
5r
6or two R
4together with the carbon atom that substituting group connects with them, form
11. compounds as claimed in claim 10, wherein
12. compounds as claimed in claim 10, wherein
R
6c
1-3alkoxyl group, cyclopropyl, replacement or unsubstituted phenyl, replacement or unsubstituted furyl, 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 oxazolyl, replacement or unsubstituted imidazolyl; Described substituting group is hydrogen, hydroxyl, C
1-6the C of straight or branched alkyl, cyano group, halogen, halo
1-6the C of straight or branched alkyl, nitro, halo
1-3alkoxyl group, C
1-3the C that alkoxyl group, methylsulfonyl, hydroxyl replace
1-6straight or branched alkyl, piperidyl.
13. compounds as claimed in claim 12, wherein
R
6be-OCH
3,
14. compounds as claimed in claim 1, wherein
N is 1,2 or 3;
When n is 1, R
13for hydrogen or methoxyl group, R
4for para-orienting group or meta-substituent amino on phenyl ring;
When n is 2, R
13for methoxyl group, R
4for position and para-orienting group between amino on phenyl ring;
When n is 3, R
13for hydrogen, R
4for amino position and para-orienting group and the R of facing on phenyl ring
4for halogen.
15. compounds or its pharmacy acceptable salt, described compound is selected from:
16. 1 kinds of pharmaceutical compositions, it comprises pharmaceutically acceptable carrier, vehicle or thinner, and as the compound described in any one in the claim 1 or 15 of activeconstituents.
The application of compound in 17. claims 1 or 15 described in any one aspect the illness medicine of preparation treatment JAK mediation, 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 suppressed transplant rejection, rheumatoid arthritis, psoriatic, lupus erythematosus, muscle contracting lateral sclerosis, multiple sclerosis or entity or hematologic malignancies.
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|---|---|---|---|---|
| US20090048282A1 (en) * | 2007-08-14 | 2009-02-19 | Wyeth | Pyrimidine sulfonamide analogs and their use as agonists of the wnt-beta-catenin cellular messaging system |
| WO2009046416A1 (en) * | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| WO2009049028A1 (en) * | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
| CN101568342A (en) * | 2006-11-27 | 2009-10-28 | 阿雷斯贸易股份有限公司 | Treatment for multiple myeloma |
| WO2010038081A2 (en) * | 2008-10-03 | 2010-04-08 | Astrazeneca Ab | Heterocyclic derivatives and methods of use thereof |
| CN102007124A (en) * | 2008-02-15 | 2011-04-06 | 里格尔制药公司 | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
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2012
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101568342A (en) * | 2006-11-27 | 2009-10-28 | 阿雷斯贸易股份有限公司 | Treatment for multiple myeloma |
| US20090048282A1 (en) * | 2007-08-14 | 2009-02-19 | Wyeth | Pyrimidine sulfonamide analogs and their use as agonists of the wnt-beta-catenin cellular messaging system |
| WO2009046416A1 (en) * | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| WO2009049028A1 (en) * | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
| CN102007124A (en) * | 2008-02-15 | 2011-04-06 | 里格尔制药公司 | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
| WO2010038081A2 (en) * | 2008-10-03 | 2010-04-08 | Astrazeneca Ab | Heterocyclic derivatives and methods of use thereof |
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