CN105712998A - Azaindole derivatives, preparation method and applications thereof in medicine - Google Patents
Azaindole derivatives, preparation method and applications thereof in medicine Download PDFInfo
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- CN105712998A CN105712998A CN201410732591.1A CN201410732591A CN105712998A CN 105712998 A CN105712998 A CN 105712998A CN 201410732591 A CN201410732591 A CN 201410732591A CN 105712998 A CN105712998 A CN 105712998A
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- 0 *[C@](C(*)NC1=N*)C1=** Chemical compound *[C@](C(*)NC1=N*)C1=** 0.000 description 13
- SLCAVPTUVCCIIB-UHFFFAOYSA-N C(C1)C2C1C=CC2 Chemical compound C(C1)C2C1C=CC2 SLCAVPTUVCCIIB-UHFFFAOYSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N C1Nc(cccc2)c2NC1 Chemical compound C1Nc(cccc2)c2NC1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- XITDNIVCLVPERU-UHFFFAOYSA-N C=CC(NC(CCC1)CN1c1cnc2[nH]ccc2n1)=O Chemical compound C=CC(NC(CCC1)CN1c1cnc2[nH]ccc2n1)=O XITDNIVCLVPERU-UHFFFAOYSA-N 0.000 description 1
- XLPRLPJJWLOYGN-UHFFFAOYSA-N CN(C1CNCCC1)c1ncnc2c1cc[nH]2 Chemical compound CN(C1CNCCC1)c1ncnc2c1cc[nH]2 XLPRLPJJWLOYGN-UHFFFAOYSA-N 0.000 description 1
- FJRLRPPDJXKKDZ-UHFFFAOYSA-O C[NH2+]c(cc1)ccc1-c1c(ccn2)c2ncn1 Chemical compound C[NH2+]c(cc1)ccc1-c1c(ccn2)c2ncn1 FJRLRPPDJXKKDZ-UHFFFAOYSA-O 0.000 description 1
- ZZEPEBHNDAKZSM-UHFFFAOYSA-N C[n]1c2ncnc(-c(cc3)ccc3NC(C=C)=O)c2cc1 Chemical compound C[n]1c2ncnc(-c(cc3)ccc3NC(C=C)=O)c2cc1 ZZEPEBHNDAKZSM-UHFFFAOYSA-N 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N Clc1ncnc2c1cc[nH]2 Chemical compound Clc1ncnc2c1cc[nH]2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- WXWURRYQZAORJB-UHFFFAOYSA-N NC(CCC1)CN1c1cc(cc[nH]2)c2nc1 Chemical compound NC(CCC1)CN1c1cc(cc[nH]2)c2nc1 WXWURRYQZAORJB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to azaindole derivatives, a preparation method and applications thereof in medicine. Specifically, the invention relates to novel derivatives represented by the formula (I), pharmaceutically acceptable salts thereof, pharmaceutical composition containing the derivatives, and a preparation method of the derivatives. The invention also discloses an application of the derivatives, pharmaceutically acceptable salts thereof, or pharmaceutical composition containing the derivative in the preparation of drugs for treating and/or preventing inflammation related diseases, especially Janus kinase 3 (JAK3) inhibitor. The definitions of each substituent in the formula (I) are the same as the definitions in the description.
Description
Technical field
The present invention relates to a kind of new azaindole analog derivative and pharmaceutically useful salt thereof or containing its pharmaceutical composition, and preparation method thereof.The invention still further relates to described analog derivative and pharmaceutically useful salt thereof or the pharmaceutical composition containing it is preparing therapeutic agent, JAK3 inhibitor, and the purposes in the medicine of preparation treatment and/or prevention of inflammation relevant disease.
Background technology
Janus kinases signal conduction and activating transcription factor (Janus-activatedkinasesingaltransducersandactivatorsoftra nscriprion, JAK/STAT) be one of discovered in recent years with the closely-related Cellular Signaling Transduction Mediated path of cytokine.Work as cytokine, such as interferon, growth hormone, white born of the same parents' interleukin etc., with its receptor in conjunction with time, JAK can by cytokine receptor phosphorylation, and further phosphorylation activate the stat protein by the recruitment of phosphorylation cytokine receptor.After the STAT being activated leaves receptor and forms dimer, it is then transferred in nucleus and is attached on DNA and causes genetic transcription, thus realizing intracellular signal transduction.Leukocyte have expressed multiple JAK/STAT path, participate in many important biological processes such as the propagation of cell, differentiation, apoptosis and immunomodulating, if its function is disturbed or lacks of proper care (usually hereditary or acquired genetic flaw), it will cause immunodeficiency syndrome and cancer.Therefore, it is the effective means treating this kind of disease with the assembly in JAK/STAT for target.
Janus kinases (JAK) is a kind of non-receptor type tyrosine protein kinase, its inhibitor can be used for prevention and treats the disease mediated by JAK, such as disease in the blood system, tumor (breast carcinoma, cancer of pancreas, small cell lung cancer etc.), rheumatoid arthritis and psoriasis etc..Janus kinases has 4 family members, JAK1, JAK2, TYK2 and JAK3, and front 3 are widely present in various tissue and cell, and JAK3 exists only in bone marrow and lymphsystem.Therefore, JAK3 is an immunoreactive target of the suppression had a great attraction.
Tofacitinib (CP-690550) is the currently the only a kind of new oral JAK3 inhibitor ratified by FDA of Pfizer's research and development, is used for treating rheumatoid arthritis.But, tofacitinib can cause some untoward reaction, the risk of such as serious infection and increase cancer and heart failure clinically.These untoward reaction are likely due to tofacitinib all to be had very high inhibition effect and is caused JAK1, JAK2 and JAK3.It addition, the half-life that tofacitinib is in human body is shorter, it is necessary to day takes twice.Therefore, develop more effective and there is the JAK3 inhibitor of more high specific, better Therapeutic Method being provided by the patient of the JAK3 disease regulated and controled for suffering from inflammation and other.Through being continually striving to, present invention design has the compound of the structure shown in formula (I), and finds that the compound with this class formation shows excellent effect and effect.
Summary of the invention
It is an object of the invention to provide the compound shown in a kind of formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein:
A1、A2And A3It is each independently selected from N or CR3, but be asynchronously N；
R1And R2Be each independently selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
R3Selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl, heteroaryl or substituent group (W):
L is independently selected from chemical bond ,-CH2-、-CH(CH3)-、-C(CH3)2-、-CH(OH)-、-C(O)-、-CH2O-、-OCH2-、-SCH2-、-CH2S-、-N(R5)-、-N(R5)C(O)-、-C(O)N(R5)-、-N(R5)CON(R6)-、-O-、-S(O)m-、-N(R5)S(O)2-or-S (O)2N(R5)-；
Ring B independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from hydrogen, halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
Z is independently selected from H, NHR7CN、
Ra、RbAnd RcBe each independently selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
RaAnd RbChemical bond can be formed；
R4、R5And R6It is each independently selected from H, C1-C8 alkyl, the assorted alkyl of C1-C8, C3-C8 cyclic hydrocarbon radical, 3-8 unit monocyclic heterocycles base, bicyclic heteroaryl or monocyclic aryl；
R7Independently selected from H or C0-C3 alkyl；And
M is 0,1 or 2.
In one embodiment of the invention, compound shown in a kind of formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the compound described in formula (II) or (III) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein:
R1、R2And R3Definition as described in the appended claim 1.
In another embodiment of the invention, compound shown in a kind of formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the compound described in formula (IV) or (V) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein R3Definition as described in the appended claim 1.
The typical compound of the present invention includes, but is not limited to:
Or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.
The invention further relates to a kind of pharmaceutical composition, its compound shown in formula (I) containing therapeutically effective amount or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof and pharmaceutically acceptable carrier, diluent and excipient.
Another aspect of the present invention relates to the compound shown in formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof or the purposes that the pharmaceutical composition comprising it is in preparing JAK3 inhibitor.
Another aspect of the present invention relates to the compound shown in formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof or the purposes that the pharmaceutical composition comprising it is in preparing the medicine for the treatment of and/or prevention of inflammation relevant disease.
A kind of method that the invention still further relates to treatment and/or prevention of inflammation relevant disease, the method includes the compound shown in formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and the pharmaceutically useful salt thereof that give the bacterium of needs treatment, or comprises its pharmaceutical composition.
Another aspect of the present invention relates to the compound shown in the formula (I) as treatment and/or the medicine of prevention of inflammation relevant disease or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.
Detailed description of the invention
Unless stated to the contrary, otherwise following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, including straight chain and the branched group of 1 to 20 carbon atom, for instance can be straight chain and the branched group of 1 to 18 carbon atom, 1 to 12 carbon atom, 1 to 8 carbon atom, 1 to 6 carbon atom or 1 to 4 carbon atom.Non-limiting example include methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl and various branched chain isomers thereof etc..Alkyl can be optionally substituted or unsubstituted.Carbon number range also can represent in the way of " Cx-Cy ", and wherein x and y is integer, for instance C1-C8 represent in carbochain can contain 1 to 8 in any number of carbon atom.X can be 0, for instance C0 alkyl, and it represents chemical bond.This carbon number range method for expressing is also applied for other carbon containing substituent groups in this specification.
" cyclic hydrocarbon radical " refers to the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon substituent.It includes 3 to 20 annular atomses, for instance can be 3 to 16,3 to 12,3 to 10,3 to 8 or 3 to 6 annular atomses,.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc..Cyclic hydrocarbon radical can be optionally substituted or unsubstituted.
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon substituent, it includes 3 to 20 annular atomses, can being such as 3 to 16,3 to 12,3 to 10,3 to 8 or 3 to 6 annular atomses, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon.Preferably including 3 to 12 annular atomses, wherein 1～4 is hetero atom, and more preferably heterocyclic ring comprises 3 to 10 annular atomses, it is most preferred that 5 rings or 6 rings, and wherein 1～4 is hetero atom, and more preferably 1～3 is hetero atom, it is most preferred that 1～2 is hetero atom..The non-limiting example of monocyclic heterocycles base comprises pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base and azetidinyl etc..Multiring heterocyclic includes the heterocyclic radical of volution, condensed ring and bridged ring.
" spiro heterocyclic radical " refers to 5 to 20 yuan, shares the polycyclic heterocyclic group of an atom (title spiro-atom) between monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system gripped altogether completely.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double; two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to spiro-atom shared between ring and ring, it is preferred to single spiro heterocyclic radical and double; two spiro heterocyclic radicals.It is more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical comprises
" condensed hetero ring base " refers to 5 to 20 yuan, each ring in system shares the polycyclic heterocyclic group of a pair atom adjoined with other rings in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system gripped altogether completely, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), all the other annular atomses are carbon.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring condensed hetero ring base, it is preferred to dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of condensed hetero ring base comprises
Described heterocyclic ring can condense on aryl, heteroaryl or cyclic hydrocarbon basic ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Deng.Heterocyclic radical can be optionally substituted or unsubstituted.
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the ring of adjacent carbon atoms pair) group, there is multi-ring (namely it is with the ring of the phase adjacency pair carbon atom) group of the pi-electron system gripped altogether, it is preferably 6 to 10 yuan, such as phenyl and naphthyl, it is most preferred that phenyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cyclic hydrocarbon basic ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Aryl can be replace or unsubstituted.
" heteroaryl " refers to comprise 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atomses, and wherein hetero atom includes oxygen, sulfur and nitrogen.It is preferably 5 to 10 yuan.More preferably heteroaryl is 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N-alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, azoles base, isoxazole base, thiazolyl, isothiazolyl etc., described heteroaryl ring can condense on aryl, heterocyclic radical or cyclic hydrocarbon basic ring, the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optionally substituted or unsubstituted.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" cyano group " refers to-CN.
" optionally " or " optionally " mean ground described later event or environment can but need not occur, this explanation includes this event or environment occurs or not spot occasion.Such as, " heterocyclic group optionally replaced by alkyl " mean alkyl can but necessarily exist, this explanation includes situation that heterocyclic group replaced by alkyl and the situation that heterocyclic group is not replaced by alkyl.
" replacement " refers to the one or more hydrogen atoms in group, it is preferred to maximum 5, more preferably 1～3 hydrogen atom is replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible replacement when not paying and too much making great efforts.Such as, have the amino of free hydrogen or hydroxyl with have the carbon atom of unsaturated (such as olefinic) key in conjunction with time be probably instability.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiology upper/mixture of pharmaceutically useful salt or prodrug and other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, is beneficial to the absorption of active component and then plays biological activity.
Embodiment
Compound described in formula of the present invention (I) or the preparation of its pharmaceutically useful salt, the illustrative methods described in following example can be passed through and the relevant open source literature used by those skilled in the art has operated, but these embodiments not limit the scope of the present invention.
The structure of compound is determined by nuclear magnetic resonance, NMR (NMR) or mass spectrum (MS).The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and mensuration solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDC13) or deuterated methanol (CD3OD), being inside designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) provide as unit.
The mensuration of MS AgilentSQD (ESI) mass spectrograph (manufacturer: Agilent, model: 6110) or ShimadzuSQD (ESI) mass spectrograph (manufacturer: Shimadzu, model: 2020).
The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (SunfircC18,150 × 4.6mm, 5 μm, chromatographic column) and Waters2695-2996 high pressure liquid chromatograph (GiminiC18150 × 4.6mm, 5 μm of chromatographic columns).
Tlc silica gel plate uses Qingdao Haiyang GF254 silica gel plate, and the specification that the silica gel plate that thin layer chromatography (TLC) uses adopts is 0.15mm～0.2mm, and the specification that thin layer chromatography separation purified product adopts is 0.4mm～0.5mm silica gel plate.
It is carrier that column chromatography generally uses Qingdao Haiyang 200～300 order silica gel.
The known initiation material of the present invention can adopt or synthesize according to methods known in the art, or it is commercially available from ABCRGmbH&Co.KG, AcrosOrganics, AldrichChemicalCompany, splendid remote chemistry scientific and technological (AccelaChemBioInc), Beijing coupling chemistry Pin Deng company.
In embodiment if no special instructions, reaction all carries out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects argon or the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses pressure hydrogenation instrument in Beijing Jia Wei Kechuang Science and Technology Ltd.'s GCD-500G high-purity hydrogen generator and BLT-2000.
The usual evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.
Microwave reaction uses CEMDiscover-SP type microwave reactor.
In embodiment if no special instructions, the temperature of reaction is room temperature, and temperature range is 20 DEG C-30 DEG C.
The monitoring of the reaction process in embodiment adopts thin layer chromatography (TLC), and the system of the developing solvent that reaction uses has A: dichloromethane and methanol system；B: petroleum ether and ethyl acetate system, the volume ratio of solvent is adjusted according to the polarity difference of compound.
The system of the system of the eluant of the column chromatography that purifying compounds adopts and the developing solvent of thin layer chromatography includes A: dichloromethane and methanol system；B: petroleum ether and ethyl acetate system, the volume ratio of solvent is adjusted according to the polarity difference of compound, it is also possible to add a small amount of triethylamine and acidity or alkaline reagent etc. are adjusted.
Embodiment 1
N-(1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-base) acryloyl group amide
The first step
Tert-butyl group 1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-aminocarbamic acid ester
By compound 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine 1a (154mg, 1.0mmol), tert-butylpiperidin-3-aminocarbamic acid ester 1b (200mg, 1.0mmol), N, N-diisopropylethylamine (387mg, 3.0mmol) mixing with Isosorbide-5-Nitrae-dioxane (5mL), microwave heating to 120 DEG C reacts 0.5 hour.Being cooled to room temperature, reduce pressure precipitation.Residue adds water (20mL), is extracted with ethyl acetate (20mL × 3).Organic facies washes (20mL × 3) with saturated common salt after merging, anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (methylene chloride/methanol=30/1), obtains target product tert-butyl group 1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-aminocarbamic acid ester 1c (210mg, white solid), productivity: 66%.
MSm/z(ESI):318[M+1]
Second step
1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-amine
By compound tert-butyl group 1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-aminocarbamic acid ester 1c (210mg, 0.66mmol), trifluoroacetic acid (3mL) and dichloromethane (10mL) mixing, be stirred at room temperature 1 hour.Decompression precipitation, obtains the trifluoroacetate (500mg, crude product) of target product 1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-amine 1d, productivity: > 100%.Product is not purified yet is directly used in next step reaction.
MSm/z(ESI):218[M+1]
3rd step
N-(1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-base) acryloyl group amide
By mixture 1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-3-amine 1d (500mg, crude product), N, N-diisopropylethylamine (2mL) and dichloromethane (10mL) are cooled to 0 DEG C, add acryloyl chloride (255mg, dichloromethane (0.5mL) solution 0.66mmol), stirs 1 hour at reactant mixture 0 DEG C.Decompression precipitation; residue preparation TLC (methylene chloride/methanol=10/1) purification obtains target product N-(1-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) piperidines-3-base) acryloyl group amide (20mg; white solid), productivity: 11%.
MSm/z(ESI):272[M+1]
1HNMR (400MHz, DMSO-d6) δ 11.66 (s, 1H), 8.17 (d, J=7.3Hz, 1H), 8.12 (s, 1H), 7.18 (s, 1H), 6.71 (s, 1H), 6.27 (dd, J=17.1, 10.0Hz, 1H), 6.13 (dd, J=17.1, 2.3Hz, 1H), 5.60 (dd, J=10.0, 2.3Hz, 1H), 4.56 (d, J=9.8Hz, 1H), 4.43 (d, J=13.1Hz, 1H), 3.82-3.76 (m, 1H), 3.22-3.17 (m, 1H), 3.05 (dd, J=12.8, 9.5Hz, 1H), 1.97-1.94 (m, 1H), 1.85-1.81 (m, 1H), 1.60-1.54 (m, 2H).
Embodiment 2
N-(1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-4-yl) acryloyl group amide
With reference to the operating procedure synthetic example 2 of embodiment 1, but in the first step with tert-butylpiperidin-4-aminocarbamic acid ester substituted tert-butyl piperidines-3-aminocarbamic acid ester.
MSm/z(ESI):272[M+1]
1HNMR (400MHz, DMSO-d6) δ 11.68 (s, 1H), 8.14 (s, 1H), 8.05 (d, J=7.8Hz, 1H), 7.18 (s, 1H), 6.59 (s, 1H), 6.19 (dd, J=17.2,10.0Hz, 1H), 6.09 (d, J=18.9Hz, 1H), 5.58 (d, J=11.9Hz, 1H), 4.58 (d, J=13.2Hz, 2H), 4.05-3.92 (m, 1H), 3.27-3.22 (m, 2H), 1.88 (d, J=10.0Hz, 2H), 1.45-1.37 (m, 2H).
Embodiment 3
1-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-1-yl) the third-2-alkene-1-ketone
The first step
Tert-butyl group 5-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-3,4-dihydropyridine-1 (2H)-carboxylate
By chloro-for mixture 4-7H-pyrrolo-[2,3-d] pyrimidine 1a (1.0g, 6.5mmol), tert-butyl group 5-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-bases)-3,4-dihydropyridine-1 (2H)-carboxylate 3a (1.0g, 6.5mmol), sodium carbonate (1.4g, 13.0mmol), PdCl2(dppf) (475mg, 0.65mmol), Isosorbide-5-Nitrae-dioxane (20mL) and water (10mL) are heated to 95 DEG C, stir overnight under nitrogen protection.After reactant liquor is cooled to room temperature, adds water (50mL), be extracted with ethyl acetate (30mL × 3).Organic facies anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (methylene chloride/methanol=50/1), obtain target product tert-butyl group 5-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-3,4-dihydropyridine-1 (2H)-carboxylate 3b (1.3g, light yellow oil), productivity: 65%.
MSm/z(ESI):301[M+1]
Second step
Tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-1-carboxylate
By mixture tert-butyl group 5-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-3,4-dihydropyridine-1 (2H)-carboxylate (1.3g, 4.3mmol) 3b, 10% palladium carbon (260mg) and methanol (50mL) catalytic hydrogenation 16 hours under 2 atmospheric pressure.Filtering, filter cake methanol washs (20mL × 2).Filtrate decompression precipitation, obtains target product tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-1-carboxylate 3c (1.3g), productivity: 98%.Product is not purified is directly used in next step reaction.
MSm/z(ESI):303[M+1]
3rd step
4-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine
The dioxane solution (4N) of hydrogen chloride is dripped in the mixture of tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidines-1-carboxylate 3c (1.3g, 4.3mmol) and methanol (30mL).Reactant liquor is stirred at room temperature 0.5 hour, and reduce pressure precipitation, obtains the hydrochlorate (0.75g) of target product 4-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine 3d, productivity: 81%.Product is not purified is directly used in next step reaction.
MSm/z(ESI):203[M+1]
4th step
1-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-1-yl) the third-2-alkene-1-ketone
Utilize 4-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine 3d (202mg, 1.0mmol) for raw material, with reference to the synthetic method synthesis of 1 in embodiment 1, obtain title product 1-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-1-yl) the third-2-alkene-1-ketone 3 (20mg), productivity: 10%.
MSm/z(ESI):257[M+1]
1HNMR(400MHz,CD3OD) δ 8.96 (s, 1H), 7.87 (s, 1H), 7.22-7.18 (m, 1H), 6.91-6.76 (m, 1H), 6.32-6.24 (m, 1H), 5.85-5.75 (m, 1H), 4.74 (d, J=12.2Hz, 0.5H), 4.45 (d, J=14.1Hz, 0.5H), 4.29 (d, J=13.1Hz, 1H), 3.73-3.67 (m, 0.5H), 3.53-3.49 (m, 1H), 3.35-3.22 (m, 1H), 2.91 (t, J=12.6Hz, 0.5H), 2.28-2.18 (m, 2H), 2.04-2.01 (m, 1H), 1.80-1.74 (m, 1H).
Embodiment 4
1-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) piperidin-1-yl) the third-2-alkene-1-ketone
With reference to the operating procedure synthetic example 4 of embodiment 3, but in the first step with tert-butyl group 4-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-carboxylate substituted tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-bases)-3,4-dihydropyridine-1 (2H)-carboxylates.
MSm/z(ESI):257[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 8.66 (s, 1H), 7.51 (s, 1H), 6.87 (dd, J=16.7,10.5Hz, 1H), 6.70 (s, 1H), 6.13 (d, J=16.7Hz, 1H), 5.68 (d, J=10.4Hz, 1H), 4.59 (d, J=12.2Hz, 1H), 4.20 (d, J=13.0Hz, 1H), 3.48-3.41 (m, 1H), 3.33-3.24 (m, 1H), 2.84 (t, J=12.3Hz, 1H), 1.91-1.71 (m, 4H).
Embodiment 5
1-(3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino) piperidin-1-yl) the third-2-alkene-1-ketone
The first step
N-methyl-N-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
By compound 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine 1a (130mg, 0.85mmol), tert-butyl group 3-(methylamino) piperidines-1-carboxylate 5a (182mg, 0.85mmol), potassium carbonate (352mg, 2.55mmol), sodium iodide (255mg, 1.7mmol) mixing with water (6mL), microwave heating reacts 1 hour to 100 DEG C.Decompression precipitation, residue over silica gel column chromatography purification (methylene chloride/methanol=10/1), obtains target product N-methyl-N-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 5b (89mg, white solid), productivity: 45%.
MSm/z(ESI):232[M+1]
Second step
1-(3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino) piperidin-1-yl) the third-2-alkene-1-ketone
Utilize N-methyl-N-(piperidines-3-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 5b (89mg, 0.38mmol) for raw material, with reference to the synthetic method synthesis of 1 in embodiment 1, obtain title product 1-(3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino) piperidin-1-yl) the third-2-alkene-1-ketone 5 (29mg, colorless oil), productivity: 26%.
MSm/z(ESI):286[M+1]
1HNMR(400MHz,DMSO-d6)δ11.68(s,1H),8.15-8.14(m,1H),7.18(s,1H),6.92-6.70(m,1H),6.58-6.55(m,1H),6.13-6.10(m,1H),5.70-5.60(m,1H),4.71-4.51(m,2H),4.40-4.36(m,0.5H),3.92-3.88(m,0.5H),3.17-2.89(m,5H),1.97-1.76(m,3H),1.59-1.56(m,1H)。
Embodiment 6
N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) acryloyl group amide
The first step
3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline
By compound 4-chloro-7H-pyrrolo-[2; 3-d] pyrimidine 1a (306mg; 2.0mmol); 3-aminophenyl boronic acid 6a (274mg, 2.0mmol), potassium carbonate (828mg, 6mmol), [1; double; two (diphenylphosphine) ferrocene of 1'-] palladium chloride (280mg; 0.4mmol), Isosorbide-5-Nitrae-dioxane (20mL) and water (4mL) mixing, be heated under nitrogen protection 100 DEG C stir 15 hours.Being cooled to room temperature, filter, filtrate decompression precipitation, residue 20mL water dilutes, and is extracted with ethyl acetate (20mL × 3).With saturated common salt water washing (20mL × 3) after organic facies is merged, anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (methylene chloride/methanol=15/1), obtains target product 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline 6b (205mg, orange), productivity: 48%.
MSm/z(ESI):211[M+1]
Second step
N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) acryloyl group amide
Utilize 3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) aniline 6b (205mg; 0.97mmol) for raw material; with reference to the synthetic method synthesis of 1 in embodiment 1; obtain title product N-(3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) phenyl) acryloyl group amide 6 (130mg, yellow solid), productivity: 50%.
MSm/z(ESI):265[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.29 (s, 1H), 10.41 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.25 (s, 0.5H), 7.93 (d, J=7.7Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.70 (s, 1H), 7.54 (t, J=7.9Hz, 1H), 6.96 (d, J=3.2Hz, 1H), 6.48 (dd, J=16.9,10.0Hz, 1H), 6.32 (d, J=16.8Hz, 1H), 5.81 (d, J=10.1Hz, 1H).
Embodiment 7
(E)-N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide
The first step
N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide
By compound 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline 6b (150mg, 0.71mmol), 2-cyanoacetic acid (73mg, 0.85mmol), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (323mg, 0.85mmol), DIPEA (275mg, 2.13mmol) mix with DMF (10mL).It is stirred at room temperature 1 hour.Reactant liquor add water (30mL) dilution, it is extracted with ethyl acetate (30mL × 3), dry with anhydrous sodium sulfate after organic facies is merged, it is filtered to remove desiccant, decompression precipitation obtains target product N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide 7a (186mg, grass green solid), yield: 94%.Product is not purified is directly used in next step reaction.
MSm/z(ESI):278[M+1]
Second step
(E)-N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide
By compound N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide 7a (24mg, 0.08mmol), ring the third formaldehyde (11mg, 0.16mmol), piperidines (20mg, 0.24mmol), acetic acid (0.1mL) and isopropanol (5mL) mixing, be stirred at room temperature 15 hours.Decompression precipitation; residue preparation HPLC purification obtains target product (E)-N-(3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide hydrochloride (11mg; yellow solid), productivity: 41%.
MSm/z(ESI):330[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.87 (s, 1H), 10.53 (s, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 7.92-7.88 (m, 3H), 7.62 (t, J=7.9Hz, 1H), 7.29 (d, J=11.1Hz, 1H), 7.10 (s, 1H), 2.00-1.98 (m, 1H), 1.41-1.25 (m, 2H), 1.15-0.98 (m, 2H).
Embodiment 8
N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) acryloyl group amide
The first step
4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline
By compound 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine 1a (1.5g, 9.8mmol), 4-(4; 4; 5,5-tetramethyl-1,3; 2-bis-boron penta ring-2-base) aniline 8a (2.57g; 11.7mmol), sodium carbonate (3.11g, 29.3mmol), tetra-triphenylphosphine palladium (0.904g, 0.782mmol), 1; 4-dioxane (40mL) and water (20mL) mixing, return stirring is overnight under nitrogen protection.Being cooled to room temperature, reduce pressure precipitation.Residue 30mL water dilutes, and is extracted with ethyl acetate (80mL × 3).Organic facies washes (20mL × 3) with saturated common salt after merging, anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue petroleum ether and re-crystallizing in ethyl acetate obtain target product 4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline 8b (1.2g, brown solid), productivity: 59%.
MSm/z(ESI):211[M+1]
Second step
N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) acryloyl group amide
Utilize 4-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) aniline 8b (210mg; 1.0mmol) for raw material; with reference to the synthetic method synthesis of 1 in embodiment 1; obtain title product N-(4-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) phenyl) acryloyl group amide 8 (130mg, yellow solid), productivity: 49%.
MSm/z(ESI):265[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.21 (s, 1H), 10.41 (s, 1H), 8.80 (s, 1H), 8.21 (d, J=8.4Hz, 2H), 7.89 (d, J=8.5Hz, 2H), 7.64 (s, 1H), 6.95 (d, J=3.2Hz, 1H), 6.50 (dd, J=17.0,10.2Hz, 1H), 6.31 (d, J=16.8Hz, 1H), 5.81 (d, J=10.4Hz, 1H).
Embodiment 9
(E)-N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-methacryl amide
The first step
N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide
Utilize 4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline 8b (1.2g, 0.71mmol) for raw material, with reference to the synthetic method synthesis of 7a in embodiment 7, obtain title product N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide 9a (1.1g, yellow solid), productivity: 69%.
MSm/z(ESI):278[M+1]
Second step
(E)-N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-methacryl amide
By compound N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide 9a (320mg, 1.15mmol), acetaldehyde (408mg, 9.23mmol), piperidines (330mg, 4.04mmol) mix with acetic acid (5mL), be stirred at room temperature 3 hours.There is yellow mercury oxide to generate, filter, filter cake washing with alcohol, dry to obtain 208mg crude product.Take 100mg crude product petroleum ether, acetone and recrystallizing methanol; obtain target product (E)-N-(4-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-methacryl amide 9 (45mg; gray solid), productivity: 26%.
MSm/z(ESI):304[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.23 (s, 1H), 10.48 (s, 1H), 8.81 (s, 1H), 8.23 (d, J=7.6Hz, 2H), 7.87 (d, J=7.6Hz, 2H), 7.75-7.58 (m, 2H), 6.95 (s, 1H), 2.19 (s, 3H).
Embodiment 10
(E)-N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide
(E)-N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide
By compound N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide 9a (80mg, 0.29mmol), ring the third formaldehyde (80mg, 1.15mmol), piperidines (82mg, 1.0mmol) mix with isopropanol (10mL), be stirred at room temperature 3 hours.Decompression precipitation; residue preparation HPLC purification obtains target product (E)-N-(4-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide 10 (30mg, yellow solid), productivity: 31%.
MSm/z(ESI):330[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.23 (s, 1H), 10.30 (s, 1H), 8.80 (s, 1H), 8.22 (d, J=8.2Hz, 2H), 7.84 (d, J=8.2Hz, 2H), 7.65 (s, 1H), 7.14 (d, J=10.9Hz, 1H), 6.95 (s, 1H), 2.05-1.92 (m, 1H), 1.33-1.29 (m, 2H), 1.06-1.03 (m, 2H).
Embodiment 11
N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide
The first step
The bromo-5-of 2-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine
Bromo-for compound 2-5H-pyrrolo-[2,3-b] pyrazine 11a (300mg, 1.5mmol) and DMF (10mL) are mixed, is cooled to 0 DEG C, be dividedly in some parts sodium hydride (60%, 90mg, 2.25mmol).It is stirred at room temperature 0.5 hour.Reaction system is cooled to 0 DEG C, is slowly added into (2-(chlorine methoxyl group) ethyl) trimethyl silane (500mg, 3.0mmol), is stirred at room temperature 1 hour, and add water cancellation, extraction into ethyl acetate (20mL × 3).Organic facies uses water (20mL × 3) successively after merging, (20mL × 3) are washed with saturated common salt, anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (ethyl acetate/petroleum ether=50/1) obtains the bromo-5-of target product 2-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine 11b (330mg, clear oil thing), productivity: 67%.
MSm/z(ESI):328[M+1]
Second step
Tert-butyl group 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-aminocarbamic acid ester
By bromo-for compound 2-5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine 11b (330mg, 1.0mmol), tert-butylpiperidin-3-aminocarbamic acid ester (200mg, 1.0mmol), double; two (two subunit acetone) palladium (92mg, 0.1mmol), 2-dicyclohexyl phosphorus-2,4,6-tri isopropyl biphenyl (95mg, 0.2mmol), sodium tert-butoxide (288mg, 3.0mmol) He 1,4-dioxane (6mL) mixes, and microwave heating, to 100 DEG C, reacts 0.5 hour.Decompression precipitation, residue over silica gel column chromatography purification (petrol ether/ethyl acetate=6/1), obtain target product tert-butyl 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-aminocarbamic acid ester 11c (270mg, brown oil), productivity: 60%.
MSm/z(ESI):448[M+1]
3rd step
1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-amine
By compound tert-butyl group 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-aminocarbamic acid ester 11c (270mg, 0.6mmol) with the 1 of hydrogen chloride gas, 4-dioxane solution (10mL) mixes, and is stirred at room temperature 1 hour.Decompression precipitation obtains target product 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) hydrochlorate (310mg of piperidines-3-amine 11d, crude product), productivity: > 100%.Product is not purified is directly used in next step reaction.
MSm/z(ESI):348[M+1]
4th step
N-(1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide
Utilize 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2; 3-b] pyrazine-2-base) piperidines-3-amine 11d (310mg; crude product) for raw material; with reference to the synthetic method synthesis of 1 in embodiment 1; obtain title product N-(1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2; 3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide 11e (238mg; yellow solid), two step productivity: 98%.
MSm/z(ESI):402[M+1]
5th step
N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide
By compound N-(1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2; 3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide 11e (238mg; 0.59mmol) add trifluoroacetic acid (5mL) with after dichloromethane (10mL) mixing, be stirred at room temperature 3 hours.Decompression precipitation, residue is dissolved in dichloromethane (5mL) and methanol (5mL), adds ammonia (3mL), is stirred at room temperature 1 hour.Decompression precipitation, residue preparation HPLC purification obtains target product N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) acryloyl group amide 11 (30mg, yellow solid), productivity: 18%.
MSm/z(ESI):272[M+1]
1HNMR (400MHz, DMSO-d6) δ 11.54 (s, 1H), 8.14 (d, J=7.3Hz, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 6.31 (s, 1H), 6.27 (dd, J=17.0Hz, 10.0Hz, 1H), 6.11 (d, J=17.0Hz, 1H), 5.60 (d, J=10.0Hz, 1H), 4.11 (d, J=10.3Hz, 1H), 3.97 (d, J=12.6Hz, 1H), 3.85-3.79 (m, 1H), 3.00-2.95 (m, 1H), 2.85-2.76 (m, 1H), 1.92-1.87 (m, 1H), 1.82-1.77 (m, 1H), 1.62-1.55 (m, 1H), 1.51-1.43 (m, 1H).
Embodiment 12
N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidin-4-yl) acryloyl group amide
With reference to the operating procedure synthetic example 12 of embodiment 11, but with tert-butylpiperidin-4-aminocarbamic acid ester substituted tert-butyl piperidines-3-aminocarbamic acid ester in second step.
MSm/z(ESI):272[M+1]
1HNMR (400MHz, DMSO-d6) δ 11.53 (s, 1H), 8.06-8.03 (m, 2H), 7.57 (s, 1H), 6.32 (s, 1H), 6.20 (dd, J=17.1,9.9Hz, 1H), 6.09 (d, J=16.9Hz, 1H), 5.58 (d, J=9.9Hz, 1H), 4.18-4.15 (m, 2H), 3.89-3.87 (m, 1H), 2.99 (t, J=11.7Hz, 2H), 1.86-1.83 (m, 2H), 1.51-1.43 (m, 2H).
Embodiment 13
1-(4-(5H-pyrrolo-[3,2-b] pyrazine-2-base) piperidin-1-yl) the third-2-alkene-1-ketone
With reference to the operating procedure synthetic example 13 of embodiment 3, but in the first step with bromo-5H-pyrrolo-[2, the 3-b] pyrazine of 2-and tert-butyl group 4-(4,4,5,5-tetramethyls-1,3,2-bis-boron penta ring-2-bases)-5,6-dihydropyridine-1 (2H)-carboxylates replacement chloro-7H-pyrrolo-es [2 of 4-, 3-d] pyrimidine and tert-butyl group 5-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-bases)-3,4-dihydropyridine-1 (2H)-carboxylates.
MSm/z(ESI):257[M+1]
1HNMR(400MHz,CD3OD) δ 8.19 (s, 1H), 7.75 (d, J=3.4Hz, 1H), 6.83 (dd, J=16.8,10.7Hz, 1H), 6.59 (d, J=3.4Hz, 1H), 6.23 (d, J=16.8Hz, 1H), 5.76 (d, J=10.7Hz, 1H), 4.75 (d, J=12.7Hz, 1H), 4.28 (d, J=13.3Hz, 1H), 3.43-3.25 (m, 1H), 3.28-3.07 (m, 1H), 2.98-2.71 (m, 1H), 2.02-1.94 (m, 2H), 1.91-1.82 (m, 2H).
Embodiment 14
N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl) acryloyl group amide
With reference to the operating procedure synthetic example 14 of embodiment 6, but replace 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine with 2-bromo-5H-pyrrolo-[2,3-b] pyrazine in the first step.
MSm/z(ESI):265[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.11 (s, 1H), (10.31 s, 1H), 8.80 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.84-7.81 (m, 2H), 7.46 (t, J=7.9Hz, 1H), 6.69 (s, 1H), 6.48 (dd, J=16.9,10.0Hz, 1H), 6.30 (d, J=16.7Hz, 1H), 5.79 (d, J=10.2Hz, 1H).
Embodiment 15
(E)-N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl)-2-cyano group but-2-enamides
With reference to the operating procedure synthetic example 15 of embodiment 9, but replace 4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline with 3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) aniline in the first step.
MSm/z(ESI):304[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.12 (s, 1H), 10.38 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.87 (d, J=7.6Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.74-7.69 (m, 1H), 7.48 (t, J=7.9Hz, 1H), 6.69 (s, 1H), 2.19 (d, J=6.8Hz, 3H).
Embodiment 16
(E)-N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl)-2-cyano group-3-cyclopropyl acryloyl group amide
Operating procedure synthetic example 16 with reference to embodiment 10, but in the first step with N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl)-2-cyanoacetamide replacement N-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyanoacetamide.
MSm/z(ESI):330[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.12 (s, 1H), 10.20 (s, 1H), 8.81 (s, 1H), 8.36 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=7.8Hz, 1H), 7.79 (d, J=7.9Hz, 1H), 7.47 (t, J=7.9Hz, 1H), 7.15 (d, J=11.0Hz, 1H), 6.68 (d, J=3.2Hz, 1H), 2.02-1.95 (m, 1H), 1.32-1.30 (m, 2H), 1.05-1.03 (m, 2H).
Embodiment 17
N-(4-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl) acryloyl group amide
With reference to the operating procedure synthetic example 17 of embodiment 6, but replace chloro-7H-pyrrolo-[2, the 3-d] pyrimidine of 4-and 3-aminophenyl boronic acid with 2-bromo-5H-pyrrolo-[2,3-b] pyrazine and 4-aminophenyl boronic acid in the first step.
MSm/z(ESI):265[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.31 (s, 1H), 8.82 (s, 1H), 8.11 (d, J=7.9Hz, 2H), 7.88 (s, 1H), 7.82 (d, J=8.0Hz, 2H), 6.66 (s, 1H), 6.56-6.42 (m, 1H), 6.29 (d, J=17.0Hz, 1H), 5.79 (d, J=10.0Hz, 1H).
Embodiment 18
N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) Cyano amides
To 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline 6b (127mg, 0.6mmol), sodium bicarbonate (152mg, 1.8mmol) add Bromine cyanide. (127mg with in the mixture of toluene (10mL), toluene solution (0.5mL) 1.2mmol), is stirred at room temperature 6 hours.Reactant liquor dilute (20mL), is extracted with ethyl acetate (20mL × 3).(20mL × 3) are washed with saturated common salt after organic facies being merged, anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue preparation HPLC separates and obtains target product N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl) Cyano amides 18 (70mg, yellow solid), productivity: 49%.
MSm/z(ESI):236[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 10.45 (s, 1H), 8.89 (s, 1H), 7.86 (d, J=7.6Hz, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.59 (t, J=7.6Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 6.90 (s, 1H).
Embodiment 19
N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenyl) Cyano amides
With reference to the operating procedure synthetic example 19 of embodiment 18, but replace 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline with 3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) aniline.
MSm/z(ESI):236[M+1]
1HNMR (400MHz, CD3OD) δ 8.71 (s, 1H), 7.82 (d, J=3.4Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.51 (t, J=7.9Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.71 (d, J=3.5Hz, 1H).
Embodiment 20
(E)-N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) phenyl)-2-cyano group but-2-enamides
With reference to the operating procedure synthetic example 20 of embodiment 9, but replace 4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline with 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline in the first step.
MSm/z(ESI):304[M+1]
1HNMR (400MHz, CD3OD) δ 8.69 (s, 1H), 8.34 (s, 1H), 7.80 (d, J=7.6Hz, 1H), 7.66 (d, J=8.1Hz, 1H), 7.59 7.54 (m, 1H), 7.51 7.43 (m, 2H), 6.88 (s, 1H), 2.15 (d, J=6.8Hz, 3H).
Embodiment 21 and 22
Cis-N-(-(1R; 3S)-3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide and trans-N-(-(1R; 3S)-3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide
The first step
5-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate and 3-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate
At-78 DEG C, in oxolane (5mL) solution of LDA (10.3mmol), add oxolane (15mL) solution of tert-butyl group 3-carbonyl cyclohexylcarbamate (2g, 9.38mmol).Reactant liquor rises to room temperature, stirs 30 minutes, is down to-78 DEG C, adds oxolane (25mL) solution of three fluoro-N-phenyl-N-(fluoroform sulphonyl) Methanesulfomide (4.63g, 12.2mmol).Reactant liquor is risen to room temperature, stirs 3 hours.Add ethyl acetate (300mL) dilution, wash with water (2 × 200mL) and saline solution (100mL).Organic facies anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (ethyl acetate/petroleum ether=20/1 to 10/1) obtains target product 5-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate 21b-1 and 3-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate 21b-2 (3g, white solid), productivity: 93%.
MSm/z(ESI):368[M+Na+]
Second step
Tert-butyl group 3-(4,4,5,5-tetramethyl-1,3,2-two boron penta ring-2-base) hexamethylene-3-enylcarbamate ester and tert-butyl group 3-(4,4,5,5-tetramethyl-1,3,2-two boron penta ring-2-base) hexamethylene-2-enylcarbamate ester
By compound 5-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate 21b-1 and 3-(tertbutyloxycarbonylamino) hexamethylene-1-thiazolinyl triflate 21b-2 (3g, 8.7mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-Lian (1,3,2-bis-boron penta ring) (2.87g, 11.3mmol), potassium acetate (2.56g, 26mmol), Pd (dppf) Cl2(0.64g, 0.87mmol) and Isosorbide-5-Nitrae-dioxane (50mL) mix, and heating is to return stirring overnight.Reactant liquor is down to room temperature, filters, filtrate decompression precipitation, and add water (100mL) dilution, extracts with dichloromethane (3 × 100mL).Organic facies is washed with water (100mL) and saturated aqueous common salt (100mL) after merging.Organic facies anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (ethyl acetate/petroleum ether=10/1) obtains target product tert-butyl group 3-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-base) hexamethylene-3-enylcarbamate ester 21c-1 and tert-butyl group 3-(4,4,5,5-tetramethyls-1,3,2-bis-boron penta ring-2-base) hexamethylene-2-enylcarbamate ester 21c-2 (2.36g, faint yellow solid), productivity: 84%.
MSm/z(ESI):346[M+Na+]
3rd step
Tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-2-enylcarbamate ester and tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-3-enylcarbamate ester
By mixture tert-butyl group 3-(4,4,5,5-tetramethyl-1,3,2-bis-boron penta ring-2-bases) hexamethylene-3-enylcarbamate ester 21c-1 and tert-butyl group 3-(4,4,5,5-tetramethyls-1,3,2-bis-boron penta ring-2-bases) hexamethylene-2-enylcarbamate ester 21c-2 (988mg, 3.06mmol), 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (391mg, 2.5mmol), sodium carbonate (810mg, 7.64mmol), Pd (PPh3)4(236mg, 0.204mmol), dioxane (25mL) and water (12mL) heating are to backflow, and stirring is overnight.Reactant liquor is down to room temperature, and add water (20mL) dilution, extracts by ethyl acetate (3 × 50mL).Organic facies dries with anhydrous sodium sulfate after merging, it is filtered to remove desiccant, decompression precipitation, residue over silica gel column chromatography purification (ethyl acetate/petroleum ether=3/1) obtains target product tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-2-enylcarbamate ester 21d-1 and tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-3-enylcarbamate ester 21d-2 (530mg, white solid), productivity: 66%.
MSm/z(ESI):315[M+1]
4th step
Tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylcarbamate
Utilize tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-2-enylcarbamate ester 21d-1 and tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) hexamethylene-3-enylcarbamate ester 21d-2 (530mg, 1.7mmol) for raw material, with reference to the synthetic method synthesis of 3c in embodiment 3, obtain title product tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylcarbamate 21e (226mg, white solid), productivity: 42%.
MSm/z(ESI):317[M+1]
5th step
3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylamine
Mixture tert-butyl group 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylcarbamate 21e (226mg, 0.72mmol), stirring 3 hours under the dioxane solution (8mL) of hydrochloric acid and methanol (25mL) room temperature.Decompression precipitation, obtains the hydrochlorate 21f (180mg, white solid) of title product 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylamine, productivity: 99%.
MSm/z(ESI):217[M+1]
6th step
Cis-N-(-(1R; 3S)-3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide and trans-N-(-(1R; 3S)-3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide
Utilize 3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) the hydrochlorate 21f (120mg of cyclohexylamine; 0.48mmol) for raw material; with reference to the synthetic method synthesis of 1 in embodiment 1; obtain title product cis-N-(-(1R; 3S)-3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide 21 (26mg; white solid) and trans-N-(-(1R; 3S)-3-(7H-pyrrolo-[2; 3-d] pyrimidine-4-yl) cyclohexyl) acryloyl group amide 22 (36mg, white solid), productivity: 48%.
MSm/z(ESI):271[M+1]
21:1HNMR(400MHz,CD3OD) δ 8.80 (s, 1H), 7.73 (s, 1H), 7.02 (s, 1H), 6.35 (dd, J=17.0,10.2Hz, 1H), 6.19 (d, J=17.0Hz, 1H), 5.60 (d, J=10.2Hz, 1H), 4.27 (s, 1H), 3.67 3.44 (m, 1H), 2.04 1.85 (m, 4H), 1.75 1.60 (m, 4H).
22:1HNMR (400MHz, DMSO-d6) δ 12.02 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.49 (s, 1H), 6.70 (s, 1H), 6.17 6.13 (m, 2H), 5.56 (s, 1H), 3.86 (s, 1H), 3.27 (s, 1H), 1.94 1.25 (m, 8H).
Embodiment 23
N-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexyl) Cyano amides
With reference to the operating procedure synthetic example 23 of embodiment 18, but replace 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline with 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylamine.
MSm/z(ESI):242[M+1]
1HNMR (400MHz, DMSO-d6) δ 12.04 (s, 1H), 8.66 (s, 1H), 7.50 (s, 1H), 6.93 (s, 1H), 6.69 (d, J=9.3Hz, 1H), 3.72 3.69 (m, 0.5H), 3.48-3.43 (m, 0.5H), 3.28-3.19 (m, 1H), 2.04 1.53 (m, 8H).
Embodiment 24
2-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) Cyclohexylamino) acetyl nitrile
By 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclohexylamine 21f (91mg, 0.36mmol), bromoacetonitrile (87mg, 0.72mmol), potassium carbonate (150mg, 1.08mmol) mix with acetonitrile (20mL), be stirred at room temperature 6 hours.Decompression precipitation, residue preparation HPLC separates and obtains target product 2-(3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) Cyclohexylamino) acetyl nitrile (20mg, Off-white solid), productivity: 21%.
MSm/z(ESI):256[M+1]
1HNMR (400MHz, CD3OD)δ8.65(s,1H),7.45(s,1H),6.77(s,1H),3.73(s,2H),3.65–3.60(m,0.5H),3.30–3.25(m,1H),2.94-2.91(m,0.5H),2.19–1.64(m,8H)。
Embodiment 25
N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) cyclohexyl) acryloyl group amide
With reference to the operating procedure synthetic example 25 of embodiment 21 and 22, but replace 4-chloro-7H-pyrrolo-[23-d] pyrimidine with 2-bromo-5H-pyrrolo-[2,3-b] pyrazine.
MSm/z(ESI):271[M+1]
1HNMR (400MHz, DMSO-d6) δ 11.92 (s, 1H), 8.17 (s, 1H), 8.11 8.04 (m, 1H), 7.82 (s, 1H), 6.55 (s, 1H), 6.42 (dd, J=17.0, 10.2Hz, 0.5H), 6.20 (dd, J=17.1, 10.0Hz, 0.5H), 6.08 (dd, J=17.0, 11.4Hz, 1H), 5.57 (t, J=10.7Hz, 1H) .4.18 (br, 0.5H), 3.85 3.77 (m, 0.5H), 3.24 3.19 (m, 0.5H), 2.99 2.94 (m, 0.5H), 2.01 1.85 (m, 3H), 1.71 1.48 (m, 3.5H), 1.25 1.20 (m, 0.5H).
Embodiment 26
N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) Cyano amides
The first step
1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-amine
By mixture tert-butyl group 1-(5-((2-(trimethyl silyl) ethyoxyl) methyl)-5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-aminocarbamic acid ester 11c (300mg, 0.67mmol), stir overnight under trifluoroacetic acid (2mL) and dichloromethane (10mL) room temperature.Add the sodium hydroxide solution (10mL) of 20% under ice bath, be stirred at room temperature 1 hour.With dichloromethane and methanol (10/1,110mL × 4) extract, organic anhydrous sodium sulfate dries, it is filtered to remove desiccant, decompression precipitation, obtains target product 1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-amine 26a (100mg, crude product), productivity: 69%.
MSm/z(ESI):218[M+1]
Second step
N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) Cyano amides
Utilize 1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-amine 26a (100mg, 0.46mmol) for raw material, synthetic method with reference to embodiment 18 synthesizes, obtain title product N-(1-(5H-pyrrolo-[2,3-b] pyrazine-2-base) piperidines-3-base) Cyano amides 26 (4mg, black solid), productivity: 4%.
MSm/z(ESI):243[M+H]
1HNMR(400MHz,CD3OD) δ 7.86 (s, 1H), 7.43 (s, 1H), 6.29 (s, 1H), 4.53 (s, 1H), 3.97 (d, J=12.8Hz, 1H), 3.68 (d, J=12.7Hz, 1H), 3.13 2.91 (m, 2H), 1.94 1.90 (m, 1H), 1.85 1.80 (m, 1H), 1.68 1.44 (m, 2H).
Embodiment 27
N-(3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) cyclohexyl) Cyano amides
With reference to the operating procedure synthetic example 27 of embodiment 18, but replace 3-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) aniline with 3-(5H-pyrrolo-[2,3-b] pyrazine-2-base) cyclohexylamine.
MSm/z(ESI):242[M+1]
1HNMR(400MHz,CD3OD) δ 8.19 (s, 1H), 7.75 (s, 1H), 6.61 (s, 1H), 3.78 (s, 0.5H), 3.24 (t, J=10.5Hz, 1H), 3.00 (t, J=10.7Hz, 0.5H), 2.22 (d, J=12.6Hz, 0.5H), 2.13 2.04 (m, 1.5H), 1.98-1.91 (m, 2H), 1.82-1.69 (m, 2.5H), 1.65-1.58 (m, 1H), 1.46 1.39 (m, 0.5H).
The activity of JAK3 suppresses test
The experimental technique that affects of JAK3 (JAK3) activity is summarized as follows by the compound using the vitro kinase test experience assessment present invention:
Use homogeneous phase time discrimination fluorescence (HTRF) kinase assay test kit, measure the external activity of JAK3 by detecting the phosphorylation level of substrate in kinase reaction.Reaction buffer comprises following components: 50mMHEPES (pH7.0), 5mMMgCl2And 1mMDTT；People source restructuring JAK3 catalyst structure domain albumen, purchased from Invitrogen (aminoacid sequence 781-1184, article No. PV3855), is diluted to the kinase solution of 0.5ng/ μ L with reaction buffer；Substrate reactions solution includes being diluted to the biotin labeled tyrosine kinase substrate of 140nM (Cisbio, article No. 62TK0PEC) and 3.5 μMs of ATP with reaction buffer；Detection buffer includes being diluted to 0.125ng/ μ LEu with reaction buffer3+The caged antibody (Cisbio, article No. 61T66KLB) of labelling and the XL665 (Cisbio, article No. 610SAXLB) of 8.75nM marked by streptavidin.
By compound, in 100%DMSO, dissolved dilution is to 1mM, and serial dilution to the least concentration then carrying out 3 times with DMSO is 0.05 μM, and each concentration point re-uses reaction buffer and dilutes 40 times.
Detect to 384 holes in plate (Corning, article No. 3674) and add 4 μ L compound solutions and 2 μ LJAK3 kinase solution, incubated at room 15 minutes after mix homogeneously.It is subsequently added 4 μ L substrate reactions solution, by reactant mixture incubated at room 30 minutes.Being subsequently added and react isopyknic 10 μ L detection buffer, mix homogeneously at ambient temperature standing, after 30 minutes, detect reaction process with Envision plate reading machine (PerkinElmer) under 620nm and 665nm wavelength.The being proportionate property of phosphorylation degree of the ratio of 665/620 and substrate, thus detecting the kinase whose activity of JAK3.In this experiment, do not add JAK3 kinase protein group as negative control (100% suppresses), add JAK3 kinase protein but do not add compound group as positive control (0% suppresses).JAK3 activity is suppressed percentage ratio can calculate by below equation by compound:
Suppress percentage ratio=100-100* (under testing compound certain concentration signal value-negative control signal value)/(positive control signal value-negative control signal value)
Compound IC50Value is calculated by below equation by 10 concentration point XLfit (IDBusinessSolutionsLtd., UK) software:
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X)*Hillslope))
Wherein Y is for suppressing percentage ratio, and X is the logarithm value of test compounds substrate concentration, and Bottom is maximum suppression percentage ratio, and Top is minimum suppression percentage ratio.
| Compound number | IC50(nM) | Compound number | IC50(nM) |
| 1. | A | 2. | C |
| 3. | B | 4. | B |
| 5. | A | 6. | A |
| 7. | B | 8. | B |
| 9. | B | 10. | B |
| 11. | C | 12. | C |
| 13. | B | 14. | A |
| 15. | A | 16. | A |
| 17. | C | 18. | B |
| 19. | A | 20. | A |
| 21. | A | 22. | A |
| 23. | B | 24. | C |
| 25. | C | 26. | B |
| 27. | C |
A 100nM；B=100 to 500nM；C 500nM
Conclusion: the activity of JAK3 (JAK3) is had obvious depression effect by the compound of the present invention.
Claims (7)
1. the compound shown in a formula (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein:
A1、A2And A3It is each independently selected from N or CR3, but be asynchronously N；
R1And R2Be each independently selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
R3Selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl, heteroaryl or substituent group (W):
L is independently selected from chemical bond ,-CH2-、-CH(CH3)-、-C(CH3)2-、-CH(OH)-、-C(O)-、-CH2O-、-OCH2-、-SCH2-、-CH2S-、-N(R5)-、-N(R5)C(O)-、-C(O)N(R5)-、-N(R5)CON(R6)-、-O-、-S(O)m-、-N(R5)S(O)2-or-S (O)2N(R5)-；
Ring B independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from hydrogen, halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
Z is independently selected from H, NHR7CN、
Ra、RbAnd RcBe each independently selected from H, halogen, cyano group, alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl optionally by one or more selected from halogen, cyano group, C1-C8 alkyl, C3-C8 cyclic hydrocarbon radical, 3-8 unit heterocyclic radical ,-OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4Or-NR5S(O)mR4Substituent group replaced；
RaAnd RbChemical bond can be formed；
R4、R5And R6It is each independently selected from H, C1-C8 alkyl, the assorted alkyl of C1-C8, C3-C8 cyclic hydrocarbon radical, 3-8 unit monocyclic heterocycles base, bicyclic heteroaryl or monocyclic aryl；
R7Independently be C0-C3 alkyl；And
M is 0,1 or 2.
2. the compound shown in formula according to claim 1 (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the compound described in formula (II) or (III) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein:
R1、R2And R3Definition as described in the appended claim 1.
3. the compound shown in formula (I) according to claim 1-2 any one or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the compound described in formula (IV) or (V) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:
Wherein:
R3Definition as described in the appended claim 1.
4. the compound shown in formula according to claim 1 (I) or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein this compound is:
5. a pharmaceutical composition, described pharmaceutical composition contains the compound shown in formula (I) according to claim 1 any one of therapeutically effective amount or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof and pharmaceutically acceptable carrier, diluent and excipient.
6. the compound shown in formula (I) according to claim 1 any one or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the purposes that pharmaceutical composition according to claim 5 is in preparing JAK3 (JAK3) inhibitor.
7. the compound shown in formula (I) according to claim 1 any one or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the purposes that pharmaceutical composition according to claim 5 is in the medicine of preparation treatment and/or prevention of inflammation relevant disease.
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| CN201410732591.1A CN105712998B (en) | 2014-12-05 | 2014-12-05 | Azaindole derivatives, preparation method and medical application thereof |
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| US12084453B2 (en) | 2021-12-10 | 2024-09-10 | Incyte Corporation | Bicyclic amines as CDK12 inhibitors |
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