CN105753863A - 2-oxo-1,3-dihydro imidazopyridine compound and application thereof - Google Patents

2-oxo-1,3-dihydro imidazopyridine compound and application thereof Download PDF

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CN105753863A
CN105753863A CN201610087688.0A CN201610087688A CN105753863A CN 105753863 A CN105753863 A CN 105753863A CN 201610087688 A CN201610087688 A CN 201610087688A CN 105753863 A CN105753863 A CN 105753863A
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amino
imidazo
oxo
dihydro
phenyl
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CN105753863B (en
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蔡雄
钱长庚
何其捷
黄扬兵
马志珂
覃石凤
叶春强
钟宪斌
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Shenzhen Zhenxing Medicine Technology Co.,Ltd.
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Dongguan Zhenxing Beite Medical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention provides a 2-oxo-1,3-dihydro imidazopyridine compound and application thereof in preparation of drugs for treating various diseases with BTK (Bruton tyrosine kinase). The 2-oxo-1,3-dihydro imidazopyridine compound is expressed by a formula (I). After proofing by study, the 2-oxo-1,3-dihydro imidazopyridine compound has the advantages that the activity of the BTK can be effectively inhibited, and furthermore the survival, proliferation and diffusion of malignant blood tumor cells are blocked by inhibiting the BTK; the inflammation and autoimmune diseases can be treated by inhibiting the BTK; the 2-oxo-1,3-dihydro imidazopyridine compound is suitable for treating various diseases with the BTK, and is especially suitable for treating the malignant blood tumor cells, inflammation and autoimmune diseases, and the application value is higher. The formula (I) is shown in the description.

Description

Oxo-dihydro Imidazopyridine compound and application thereof
Technical field
The present invention relates to chemical medicine, particularly relate to oxo-dihydro Imidazopyridine compound and Application.
Background technology
Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) is B-cell receptor signal complex In a kind of key signal molecule, be the key protein kinase of lymphocyte survival and propagation.BTK is pernicious The existence of B cell and diffusion play an important role.
BTK inhibitor plays anticancer effect by suppression tumour cell BTK.Pioneering BTK inhibitor Buddhist nun (Ibrutinib) is replaced to be a kind of 4 '-amino-pyrazol also [3,4-d] pyrimidine compound (Proc Natl Acad Sci according to Shandong USA, 107:13075,2010), by with target protein BTK active site cysteine residue (Cys-481) Optionally covalent bond, irreversibility ground suppression BTK.Thus effectively stop tumour to migrate from B cell To the lymphoid tissue being adapted to tumor growth environment.U.S. FDA is used for Buddhist nun according to Shandong in 2013-2015 approval In refractory lymphoma mantle cell (MCL), refractory chronic lymphocytic leukemia (CLL), carry del 17p deletion The treatment of the CLL of sudden change and the treatment of primary macroglobulinaemia.
BTK inhibitor except according to Shandong in addition to Buddhist nun, AVL-292 (CC292), ONO-4059, BGB-3111 With ACP-196 also into clinical development.For B-cell non-Hodgkin's, chronic lymphocytic Leukaemia, Huppert's disease, hairy cell leukemia, adult acute lymphoblastic leukemia etc. are treated.Depend on Shandong, for Buddhist nun and chemotherapeutics or other targeting anticarcinogen therapeutic alliance, can increase the curative effect of these neoplastic hematologic disorders. The medicine being used in combination with BTK inhibitor in clinical testing includes ituximab, lenalidomide, fludarabine； Endoxan；Adriamycin, vincristine, prednisone.
Compared with normal hematopoetic cells, in acute myeloid leukemia (AML) patient's initial cell of about 80% BTK activity increases, and causes cell oral disposition BTK inhibitor in vitro according to Shandong for the sensitive (Marcel of Buddhist nun Spaargaren M.Lancet Heamat.2:e180,2015).One according to Shandong for Buddhist nun alone or with arabinose born of the same parents It is clinical that the clinical research of glycosides drug combination treatment acute myeloid leukemia enters the II phase.
Normal B cells is grown and in activation process, BTK is in B-cell receptor (BCR) system of couriers effect extremely Close important.BCR abnormal signal is relevant with autoimmune disease, such as rheumatoid arthritis (RA).This Outward, BTK is also at myeloid cell, including monocyte, macrophage, neutrophil leucocyte and mast cell table Reach.These cellular infiltration synovial membrane chambeies also produce inflammatory cytokine, increase the weight of arthritic symptom.BTK inhibitor B-cell receptor dependent cell propagation can be blocked, reduce inflammatory factor and produce (Whang J.A., Chang B.Y. Drug DiscovToday.19:1200,2014).Preclinical study show BTK inhibitor also to inflammation and Autoimmune disease is as effective in rheumatoid arthritis and animal model.Except rheumatoid arthritis and erythema Outside lupus, this kind of medicine is likely used in LN, multiple sclerosis, gren's syndrome And potential disease asthma etc..The BTK inhibitor such as CC-292 and HM71224 are for autoimmune disease Treatment (such as rheumatoid arthritis) entrance clinical experimental stage (ClinicalTrials.gov ID:NCT01975610, NCT01765478)。
The studies above all shows that BTK inhibitor is as anti-curing oncoma, inflammation and autoimmune disease Medicine has the biggest potential value.
Summary of the invention
Based on this, an object of the present invention is to provide a kind of novel B TK inhibitor oxo-dihydro imidazo Pyridine compounds and their.
The concrete technical scheme realizing foregoing invention purpose is as follows:
There is the 2-oxo 1,3-glyoxalidine of formula (I) structure pyridine compounds and their or it is pharmaceutically acceptable Salt or its stereoisomer or its prodrugs:
In formula:
X1And X2It is respectively and independently selected from C or N；
Ar is selected from phenyl ring or 5-6 membered aromatic heterocycle；
L is selected from O, S, NR5, CR5R6, OCH2, CH2O；
Y is selected from (CHR5) m, C=O, wherein m is selected from 0,1,2,3；
Z selects self-saturating 5-7 unit heterocycle or carbocyclic ring；
G is selected from following group:
R1And R2It is respectively and independently selected from: H, C1-C6Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxyl, Cyano group, amino, C1-C6Alkyl substituted amido, acyl group, amide groups；
R3And R4It is respectively and independently selected from: H, C1-C6Alkyl, C3-C6Cycloalkyl, C3-C6Methyl cycloalkyl, Halogen substiuted C1-C4Alkyl, hydroxyl replaces C1-C4Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, amino Replace C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, halogen, nitro, hydroxyl, C1-C6 Alkoxyl, C1-C6Alkylthio group, C1-C6Sulfoxide group, C1-C6Sulfuryl, cyano group, amino, C1-C6Alkyl replaces Amido, ester group, acyl group, amide groups, carboxyl；
Work as R3And R4It is C1-C6Alkyl, C1-C6Alkoxyl, OH or C1-C6Alkyl substituted amido, and When being substituted in the adjacent position of Ar, R3And R4A carbocyclic ring or heterocycle can be connected to form, selected from having structure:
Wherein, n is selected from 0,1,2；Q1And Q2It is respectively and independently selected from O, NR6, CHR6；
R5、R6It is respectively and independently selected from H, C1-C6Alkyl；
R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, amino replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, heterocyclic substituted C1-C4Alkyl.
Wherein in some embodiments, described compound has a structure shown in Formula II:
In formula: X3, X4, X5, X6And X7It is respectively and independently selected from C or N.
Wherein in some embodiments, X3, X4, X5, X6And X7It is selected from C；Or X3, X4, X5, X6And X7One of them selected from N, remaining is selected from C.
Wherein in some embodiments, G is selected from following group:
Wherein in some embodiments, X1And X2It is C.
Wherein in some embodiments, L is selected from O, OCH2.
Wherein in some embodiments, Y is selected from (CH2)m, wherein m is 0 or 1.
Wherein in some embodiments, Z is selected from following group:
Wherein in some embodiments, Z is selected from following group:
Wherein in some embodiments, R3And R4It is respectively and independently selected from: H, halogen, hydroxyl, C1-C6Alcoxyl Base, hydroxyl replaces C1-C4Alkyl, C1-C6Alkyl substituted amido；Work as R3And R4It is CN1-C6Alkoxyl or During OH, and when being substituted in the adjacent position of Ar, R3And R4A heterocycle can be connected to form, selected from following Structure:
Wherein, n is 0 or 1.
Wherein in some embodiments, R5And R6It is H；
Wherein in some embodiments, R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, the saturated azacyclo-of 5-6 unit replaces C1-C4Alkyl.
Wherein in some embodiments, X1And X2It is C；L is selected from O, OCH2；Y is selected from (CH2) M, wherein m is 0 or 1；Z is selected fromR1And R2It is hydrogen；
R3And R4It is hydrogen；Or one of them is hydrogen, another is selected from halogen or hydroxyl or C1-C6Alcoxyl Base；Or work as R3And R4For C1-C6When alkoxyl or OH, and it is substituted in the adjacent position of Ar, R3 And R4A heterocycle can be connected to form, selected from having structure:
Wherein, n is 0 or 1；
R5And R6It is H；R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, C1-C3 Alkyl amine group replaces C1-C4Alkyl, the saturated azacyclo-of 5-6 unit replaces C1-C4Alkyl.
It is a further object of the present invention to provide the application of above-claimed cpd.
The concrete technical scheme realizing above-mentioned purpose is as follows:
Above-mentioned 2-oxo 1,3-glyoxalidine pyridine compounds and their or its pharmaceutically acceptable salt or it is three-dimensional Isomers or the application in preparing bruton's tyrosine kinase inhibitor of its prodrugs.
Above-mentioned 2-oxo 1,3-glyoxalidine pyridine compounds and their or its pharmaceutically acceptable salt or it is three-dimensional Isomers or the application in the medicine preparing anti-curing oncoma of its prodrugs.
Above-mentioned 2-oxo 1,3-glyoxalidine pyridine compounds and their or its pharmaceutically acceptable salt or it is three-dimensional Isomers or the application in the medicine of preparation preventing and treating neoplastic hematologic disorder of its prodrugs.
Wherein in some embodiments, described neoplastic hematologic disorder be lymthoma, myeloma, lymphocytic leukemia, Acute myeloid leukemia.
Above-mentioned 2-oxo 1,3-glyoxalidine pyridine compounds and their or its pharmaceutically acceptable salt or it is three-dimensional Isomers or its prodrugs prevent and treat inflammation or autoimmunity as bruton's tyrosine kinase inhibitor in preparation Application in the medicine of property disease.
Wherein in some embodiments, described inflammation or autoimmune disease are rheumatoid arthritis, erythema Lupus, LN, multiple sclerosis, gren's syndrome and potential disease asthma.
It is a further object of the present invention to provide a kind of pharmaceutical composition treating disease.
The concrete technical scheme realizing above-mentioned purpose is as follows:
A kind of pharmaceutical composition treating disease, including the above-mentioned 2-oxo 1 as active component, 3-glyoxalidine And pyridine compounds and their or its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, and medicine Acceptable carrier on.
Wherein in some embodiments, described disease is neoplastic hematologic disorder or relevant to bruton's tyrosine kinase Inflammation or autoimmune disease.
Wherein in some embodiments, described neoplastic hematologic disorder be lymthoma, myeloma, lymphocytic leukemia, Acute myeloid leukemia；Described inflammation or autoimmune disease are rheumatoid arthritis, lupus erythematosus, wolf Sore ephritis, multiple sclerosis, gren's syndrome and potential disease asthma.
The invention provides 2-oxo 1,3-glyoxalidine pyridine compounds and their, inventor grinds through great many of experiments Study carefully proof, this compounds can effectively suppress bruton's tyrosine kinase (Bruton ' s tyrosine kinase, BTK) activity, and then stop the existence of Hematological malignancies cell, breed and spread.Additionally, pass through Suppression BTK can be to anti-inflammatory and autoimmune disease.Therefore, the compound of the present invention can be used in controlling Treat the various diseases that BTK is participated in, be particularly well-suited to hematologic malignancies and inflammation and LADA disease Sick treatment, has bigger using value.
Accompanying drawing explanation
Fig. 1 is that the compound 11 of embodiment 40 suppresses human lymphoma Jeko-1 and DOHH-2 cell line BTK Phosphorylation assays result figure；
Fig. 2 is that the compound 11 of embodiment 42 is at diffusivity large B cell lymphoid tumor cell line TMD-8SCID The antitumor activity figure of mouse model.
Detailed description of the invention
In compound of the present invention, as any variable (such as R1, R etc.) occur in any component super Cross once, then the definition that its definition every time occurred occurs independent of other every time.Equally, it is allowed to substituent And the combination of variable, as long as this combination makes stability of compounds.The line putting loop systems from substituent under represents institute The key referred to may be connected on the substituted annular atoms of any energy.It is appreciated that those of ordinary skill in the art are optional originally Substituent and the substitution pattern of invention compound and provide the most stable and can by art technology and under The compound that the method that row propose is readily synthesized from readily available raw material.Surpassed if instead of base self Cross a group to replace, it should be understood that these groups can be in identical carbon atoms or on different carbon atom, as long as making Stability Analysis of Structures.
The side chain that terms used herein " alkyl " means to include to have particular carbon atom number and straight chain saturated Aliphatic group.Such as, " C1-C6Alkyl " in " C1-C6" definition include with straight or branched arrangement have 1, 2, the group of 3,4,5 or 6 carbon atoms.Term " cycloalkyl " refers to the monocycle with particular carbon atom number Saturated fat alkyl.Such as " cycloalkyl " include cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyI-cyclopentyl, cyclohexyl etc..
Terms used herein " heterocycle " or " heterocyclic radical " refer to be selected from the miscellaneous former of O, N and S containing 1-4 The armaticity of son or non-aromatic heterocyclic rings, and include bicyclic radicals." heterocyclic radical " therefore includes heteroaryl, also wraps Include its dihydro and tetrahydro analog.The connection of heterocyclic substituent can be by carbon atom or real by hetero atom Existing.
As will be appreciated by a person skilled in the art, used herein to " halogen " mean to include chlorine, fluorine, bromine and iodine.
The present invention includes the free form of formula I-III compound, also includes its pharmaceutically acceptable salt and solid Isomers.Some specific exemplary compounds are the protonated salt of aminated compounds herein.Term " free form " refers to the aminated compounds with salt-independent shape.The pharmaceutically-acceptable salts being included not only includes this The exemplary salt of the described specific compound of literary composition, also includes the typical medicine of all formula I-III compound free forms Acceptable salt on.Techniques known in the art can be used to separate the free form of described compound specific salts. Such as, can be by with suitable alkali dilute aqueous solution such as NaOH dilute aqueous solution, potassium carbonate dilute aqueous solution, dilute Ammoniacal liquor and sodium acid carbonate dilute aqueous solution process this salt makes free form regenerate.Free form is in some physical property Such as in polar solvent, in solubility, salt form respective with it is more or less distinguished, but is the purpose of invention This hydrochlorate and alkali salt free form respective with it in terms of other pharmacy is suitable.
Can be synthesized this from the compounds of this invention containing basic moiety or acidic moiety by conventional chemical processes Bright pharmaceutically acceptable salt.Generally, by ion-exchange chromatography or by free alkali and stoichiometric amount Or the inorganic or organic acid of the required salt form of excess reacts preparation in the combination of appropriate solvent or multi-solvents The salt of alkali compounds.It is similar to, by forming acid compound with suitable inorganic or organic base reaction Salt.
Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkalescence the compounds of this invention and nothing The conventional non-toxic salts of the compounds of this invention that machine or organic acid reaction are formed.Such as, conventional nontoxic salts includes From the salt of preparation such as inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc., also wrap Include from organic acid such as acetic acid, propionic acid, butanedioic acid, glycolic, stearic acid, lactic acid, malic acid, winestone Acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzene first Acid, salicylic acid, p-aminobenzene sulfonic acid, 2 one acetoxyl group one benzoic acid, fumaric acid, toluenesulfonic acid, first The salt of the preparation such as sulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.
If the compounds of this invention is acid, the most suitable " pharmaceutically acceptable salt " refers to by pharmaceutically may be used The nontoxic alkali accepted includes salt prepared by inorganic base and organic base.Derive from the salt of inorganic base include aluminium salt, ammonium salt, Calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt Deng.Particularly preferably ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Derive from pharmaceutically acceptable organic nontoxic The salt of alkali, described alkali include the salt of primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring replacement amine, Cyclic amine and deacidite such as arginine, glycine betaine, caffeine, choline, N, N'-dibenzyl Base ethylenediamine, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, ethylaminoethanol, second Hydramine, ethylenediamine, N mono-ethyl morpholine, N mono-ethyl piperidine, gucosamine, Glucosamine, group ammonia Acid, hydroxycobalamin, isopropylamine, lysine, methyl glucose osamine, morpholine, piperazine are piperidines, croak smack one's lips, many Polyimide resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine etc..
Except known in the literature or in addition to the standard method of illustration, the side of synthesis as follows can be used in experimental arrangement Method in case (scheme 1-6) prepares the compounds of this invention.In conjunction with following synthetic schemes, it is possible to this Compound described in bright and synthetic method are better understood.Described synthetic schemes describes permissible For the method preparing heretofore described compound, described method is only explanation for the purpose of illustration Property scheme describe, be not intended that the restriction of the scope that the present invention is had.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Below in conjunction with embodiment, the present invention will be further described, but this embodiment is not intended to limit this Bright protection domain.
Embodiment 1:(R)-4-amido-1-[1-(2-butine acyl group) pyrrolidin-3-yl]-3-(4-Phenoxyphenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(1-(but-2-ynoyl) pyrrolidin-3-yl)- 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 1) Preparation
Step 1a: the tert-butyl group (R)-3-((2-chloro-3-nitropyridine-4-amino) pyrroles-1-carboxylate (tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl) amino) pyrrolidine-1-carboxylate) (compound 103) Preparation
Addition 2,4-dichloro-3-nitropyridine (101) (9.65g, 50.0mmol, 1.0 equivalent), uncle in reaction bulb Butyl (R)-3-amino-pyrrolidine-1-t-butyl formate (102) (9.30g, 50.0mmol, 1.0 equivalent), triethylamine (6.56g, 65.0mmol, 1.3 equivalent) and DMF (60ml), room temperature reaction is overnight.Reaction Liquid add water (300mL) dilution, with ethyl acetate (100mL × 4) extract, extract anhydrous sodium sulfate is dried, Concentrate, then with column chromatography purify (eluant, eluent: petroleum ether: ethyl acetate=4:1) obtain the tert-butyl group (R)-3-((2-chloro-3-nitropyridine-4-amino) pyrroles's-1-carboxylate (13.7g, yield: 80%).Faint yellow oily Thing；TLC:Rf0.2 (petroleum ether: ethyl acetate=4:1)；LCMS (ESI): m/z 343 [M+1]+。
Step 1b: the tert-butyl group (R)-3-((2-dibenzyl amido-3-nitropyridine-4-amino) pyrroles's-1-carboxylate (tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carbox Ylate) preparation of (compound 104)
The tert-butyl group (R)-3-((2-chloro-3-nitropyridine-4-amino) pyrroles's-1-carboxylate is added in reaction bulb (103) (13.7g, 40.06mmol, 1.0 equivalent), dibenzylamine (8.47mL, 44.06mmol, 1.0 equivalent), Triethylamine (11.15mL, 80.12mmol, 2.0 equivalent) and acetonitrile (200ml), heated overnight at reflux.Reactant liquor Be spin-dried for silica gel mixed sample, with column chromatography purify (eluant, eluent: petroleum ether: ethyl acetate=4:1) obtain tertiary fourth Base (R)-3-((2-dibenzyl amido-3-nitropyridine-4-amino) pyrroles's-1-carboxylate (20.0g, yield: 99%).Yellow Look grease；TLC:Rf0.4 (petroleum ether: ethyl acetate=4:1)；LCMS (ESI): m/z 504 [M+1]+。
Step 1c: the tert-butyl group (R)-3-((3-amino-2-dibenzyl amido) pyridine-4-amino) pyrroles's-1-carboxylate (tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1-carbo Xylate) preparation of (compound 105)
Toward zinc powder (25.82g, 397.1mmol, 10.0 equivalent) and ammonium chloride (17.87g, 277.97mmol, 7.0 Equivalent) methanol solution (500ml) in add the tert-butyl group (R)-3-((2-dibenzyl amido-3-nitropyridine-4-amino) pyrrole Cough up-1-carboxylate (104) (20.0g, 39.71mmol, 1.0 equivalent), be heated to 50 DEG C and react 1 hour.Reaction Liquid diatomite filters, and filtrate is spin-dried for, and dissolves with the mixed solvent of dichloromethane: methyl alcohol=5:1 (50ml), Filtering, organic phase is spin-dried for obtaining the crude product tert-butyl group (R)-3-((3-amino-2-dibenzyl amido) pyridine-4-amino) pyrroles -1-carboxylate (18.3g, yield: 97%).Faint yellow solid；TLC:Rf0.1 (petroleum ether: ethyl acetate= 4:1)；LCMS (ESI): m/z 474 [M+1]+。
Step 1d: the tert-butyl group (R)-3-(4-dibenzyl amido-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Pyrroles's-1-carboxylate (tert-butyl (R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) pyrrolidine-1-carboxylate) preparation of (compound 106)
The tert-butyl group (R)-3-((3-amino-2-dibenzyl amido) pyridine-4-amino) pyrroles's-1-carboxylic acid is added in reaction bulb Ester (105) (18.3g, 38.64mmol, 1.0 equivalent), N, N'-carbonyl dimidazoles (15.7g, 96.6mmol, 2.5 Equivalent) and oxolane (200ml), it is heated to refluxing overnight by reactant liquor.Reactant liquor silica gel mixed sample is spin-dried for, With column chromatography purify (eluant, eluent: dichloromethane: methyl alcohol=100:1) obtain the tert-butyl group (R)-3-(4-dibenzylamine Base-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrroles's-1-carboxylate (17.5g, yield: 91%). Weak yellow liquid；TLC:Rf0.8 (dichloromethane: methyl alcohol=80:1)；LCMS (ESI): m/z 500 [M+1]+。
Step 1e: the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrroles- 1-carboxylate (tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1- Yl) pyrrolidine-1-carboxylate) preparation of (compound 107)
The tert-butyl group (R)-3-(4-dibenzyl amido-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] is added in reaction bulb Pyridine) pyrroles's-1-carboxylate (106) (17.5g, 35.03mmol, 1.0 equivalent), palladium dydroxide (7.0g), ethanol (240ml) with ethyl acetate (60ml), reactant liquor is heated to 70 DEG C, reacts overnight in atmosphere of hydrogen.Reaction Mixture with diatomite filter, filtrate is spin-dried for, concentrate column chromatography purify (eluant, eluent: dichloromethane: Methyl alcohol=20:1) obtain the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrole Cough up-1-carboxylate (9.0g, yield: 80%).Colorless solid；TLC:Rf0.1 (dichloromethane: methyl alcohol=20: 1)；LCMS (ESI): m/z 320 [M+1]+。
Step 1f: the tert-butyl group (R)-3-(4-amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H-imidazo [4, 5-c] pyridine) pyrroles's-1-carboxylate (tert-butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3- Dihydro-1H-imidazo [4,5-c] pyridin-1-yl) pyrrolidine-1-carboxylate) (compound 109-1) Preparation
By the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrroles's-1-carboxylic acid Ester (107) (5.93g, 18.57mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (108-1) (5.17g, 24.14 Mmol, 1.3 equivalents) and pyridine (4.5mL, 55.71mmol, 3.0 equivalent) be dissolved in N,N-dimethylformamide (40mL), in, copper acetate (3.72g, 20.43mmol, 1.1 equivalent) and 4A molecular sieve (6.7g) are added, 50 DEG C of reactions are overnight the most in atmosphere.Reactant liquor is cooled to room temperature and dilutes with ethyl acetate (150mL), Filtering, filtrate is washed with semi-saturation saline solution (70mL × 4).Organic layer anhydrous sodium sulfate is dried, and concentrates, The thick product column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) obtained purifies to obtain the tert-butyl group (R)-3-(4 -amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrroles's-1-carboxylate (2.7 G, yield: 31%).Brown solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 488[M+1]+。
Step 1g:(R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4, 5-c] pyridin-2-ones ((R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H -imidazo [4,5-c] pyridin-2-one) preparation of (compound 110-1)
By (R)-tert-butyl group-3-(4-amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyrrole Pyridine) pyrroles's-1-carboxylate (109-1) (2.7g, 5.54mmol, 1.0 equivalent) is dissolved in dichloromethane (25mL), It is added thereto to trifluoroacetic acid (5mL), the most at room temperature reaction 3 hours again.By reaction mixture with two Chloromethanes (150mL) dilutes, successively with saturated sodium carbonate solution (50mL × 2) and saturated aqueous common salt (60mL) Washing, is then spin-dried for organic layer silica gel silica gel mixed sample, afterwards with column chromatography (eluant, eluent: dichloromethane Alkane: methyl alcohol: triethylamine=100:10:1) purify: (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidines-3 -yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (2.0g, yield: 93%).Gray solid；TLC: Rf 0.2 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 388 [M+1]+。
Step 1h:(R)-4-amido-1-[1-(2-butine acyl group) pyrrolidin-3-yl]-3-(4-Phenoxyphenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(1-(but-2-ynoyl) pyrrolidin-3-yl)-3 -(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 1)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (193.5mg, 0.5mmol, 1 equivalent) is dissolved in DMF (2ml), adds 2-tetrolic acid (111- 1) (51.5mg, 0.6mmol, 1.2 equivalent), EDCI (115mg, 0.6mmol, 1.2 equivalent), HOBt (7 Mg, 0.05mmol, 0.1 equivalent), room temperature reaction 1 hour.Add water (5ml) stirring, dichloromethane (2ml) Extraction, organic phase washed once with water (10ml) again, is dried, and concentrates, column chromatography (eluant, eluent: methyl alcohol: EA =1:10) separate to obtain white solid (R)-4-amido-1-[1-(2-butine acyl group) pyrrolidin-3-yl]-3-(4-benzene oxygen Base phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (163mg, yield 70%).Fusing point: 106.5- 107.0℃；LCMS (ESI): m/z 454.40 [M+1]+；1HNMR(600MHz,CDCl3):δ1. 97(s,1.5H),2.03(s,1.5H),2.37(m,1H),2.64(m,1H),3.57(m,0.5H),3.76(m,0.5H), 3.95 (m, 1.5H), 4.11 (m, 3.5H), 5.11 (m, 1H), 6.52 (d, J=5.64Hz, 0.5H), 6.58 (d, J =5.58Hz, 0.5H), 7.11 (m, 4H), 7.19 (m, 1H), 7.40 (m, 4H), 7.86 (dd, J=18.1,5.58 Hz, 1H).
Embodiment 2:(R)-4-amino-3-(4-phenoxy phenyl)-1-(1-acryloyl group pyrrolidines-3 base)-1,3-dihydro-2 H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpyrr Olidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 2)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.1g, 0.26mmol, 1.0 equivalent), propiolic acid (111-2) (21.7mg, 0.31mm Ol, 1.2 equivalents), DCC (63.9mg, 0.31mmol, 1.2 equivalent) and DMAP (3.2mg, 0.026 Mmol, 0.1 equivalent) it is dissolved in dichloromethane (5mL), the most at room temperature reaction 1 hour.React rear dense Contracting obtains thick product, purifies to obtain compound (R) by column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) -4-amino-3-(4-phenoxy phenyl)-1-(1-acryloyl group pyrrolidines-3 base)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone 50mg, yield: 44%).White solid, fusing point: 141.5-143.1 DEG C.TLC:Rf 0.4 (two Chloromethanes: methyl alcohol=20:1)；LCMS (ESI): m/z 440 [M+1]+, purity: 98.587%；1HNM R(CDCl3, 500MHz): δ 7.89-7.86 (m, 1H), 7.42-7.37 (m, 4H), 7.20-7.18 (m, 1H), 7.1 3-7.09(m,4H),6.58-6.52(m,1H),5.11-5.08(m,1H),4.19-4.14(m,3H),3.99-3.95(m,2 H), 3.80-3.65 (m, 1H), 3.08 (d, J=28Hz, 1H), 2.76-2.65 (m, 1H), 2.45-2.36 (m, 1H).
Embodiment 3:(R)-4-amino-1-(1-(valerylene acyl group) pyrrolidin-3-yl)-3-(4-phenoxy phenyl)-1,3-two Hydrogen-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(1-(pent-2-ynoyl) pyrrolidin-3-yl)-3 -(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) system of (compound 3) Standby
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.15g, 0.39mmol, 1.0 equivalent), valerylene acid (46.1mg, 0.47mmol, 1.2 equivalents), DCC (97.0mg, 0.47mmol, 1.2 equivalent) and DMAP (4.8mg, 0.039mmo L, 0.1 equivalent) it is dissolved in dichloromethane (5mL), the most at room temperature reaction 1 hour.It is concentrated to give after having reacted To thick product, purify to obtain compound (R)-4-by column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) Amino-1-(1-(valerylene acyl group) pyrrolidin-3-yl)-3-(4-phenoxy phenyl)-1,3-dihydro-2H-imidazo [4,5-c] Pyridin-2-ones (80mg, yield: 44%).White solid, fusing point: 180.1-181.6 DEG C.TLC:Rf 0. 4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 468 [M+1]+, purity: 99.450%；1 HNMR(CDCl3, 500MHz): δ 7.87 (dd, J=16.0,6.0Hz, 1H), 7.42-7.38 (m, 4H), 7. 20-7.18(m,1H),7.14-7.09(m,4H),6.60-6.53(m,1H),5.15-5.06(m,1H),4.23(s,2H), 4.13-3.94(m,3H),3.76-3.55(m,1H),2.68-2.60(m,1H),2.40-2.32(m,3H),1.25-1.17 (m,3H)。
Embodiment 4:(R)-1-(1-acryloyl group pyrrolidin-3-yl)-4-amino-3-(4-phenoxy phenyl)-1,3-dihydro-2 H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-pheno Xyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 4)
Acryloyl chloride (202-4) (56.5mg, 0.62mmol, 1.2 equivalent) is dissolved in dichloromethane (5mL), It is cooled to 0 DEG C, the most dropwise dropping (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1, The dichloromethane of 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (110-1) (0.2g, 0.52mmol, 1.0 equivalent) Alkane (5mL) solution, then adds dropwise DIPEA (101mg, 0.78mmol, 1.5 Equivalent) dichloromethane (1.0mL) solution, by this mixed liquor 0 DEG C react 10 minutes.By reactant liquor water (50mL) quencher, then extracts with dichloromethane (50mL × 2).The organic layer silica gel silica gel obtained is mixed Sample is spin-dried for, and purifies to obtain compound (R)-1-(1 with column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) afterwards -acryloyl group pyrrolidin-3-yl)-4-amino-3-(4-phenoxy phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridine-2- Ketone (0.13g, yield: 57%).White solid, fusing point: 119.2-120.5 DEG C.TLC:Rf 0.4 (dichloro Methane: methyl alcohol=20:1)；LCMS (ESI): m/z 442 [M+1]+, purity: 99.019%；1HNMR(C DCl3, 500MHz): δ 7.87-7.84 (m, 1H), 7.42-7.38 (m, 4H), 7.19-7.17 (m, 1H), 7.13-7. 09(m,4H),6.58-6.40(m,3H),5.76-5.71(m,1H),5.16-5.08(m,1H),4.21(s,2H),4.10- 3.96(m,3H),3.73-3.65(m,1H),2.80-2.65(m,1H),2.45-2.36(m,1H)。
Embodiment 5:(R)-4-amino-1-(1-methylacryloyl pyrrolidin-3-yl)-3-(4-Phenoxyphenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(1-methacryloylpyrrolidin-3-y L)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 5) Preparation
Dichloromethane solution (7ml) toward methacrylic chloride (202-5) (0.065g, 0.62mmol, 1.2 equivalent) In drip at 0 DEG C (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4, 5-c] dichloromethane solution (8ml) of pyridin-2-ones (110-1) (0.200g, 0.52mmol, 1.0 equivalent), then Drip the dichloromethane solution (1ml) of diisopropyl ethyl amine (0.100g, 0.78mmol, 1.5 equivalent) again, React 5 minutes at 0 DEG C.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), have Machine silica gel mixed sample is spin-dried for, and concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=40:1) Obtain (R)-4-amino-1-(1-methylacryloyl pyrrolidin-3-yl)-3-(4-Phenoxyphenyl)-1,3-dihydro-1H- Imidazo [4,5-c] pyridin-2-ones (0.140g, yield: 59%).Colorless solid, fusing point: 114.6-117.5 DEG C. TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 456 [M+1]+,1HNMR(C DCl3, 500MHz): δ 7.86 (d, J=5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J=7.5Hz, 1H), 7.12 (m, 4H), 6.57 (d, J=5.5Hz, 1H), 5.30 (s, 1H), 5.21 (s, 1H), 5.08 (m, 1H), 4.21(s,2H),4.03(m,3H),3.68(m,1H),2.64(m,1H),2.36(m,1H),1.99(s,3 H)。
Embodiment 6:(R, E)-4-amino-1-(1-(but-2-ene acyl group) pyrrolidin-3-yl)-3-(4-Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino-1-(1-(but-2-enoyl) pyrrolidi N-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Thing 6) preparation
Dichloromethane solution (7ml) toward (E)-but-2-ene acyl chlorides (202-6) (0.065g, 0.62mmol, 1.2 equivalent) In drip (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo at 0 DEG C The dichloromethane solution (8ml) of [4,5-c] pyridin-2-ones (110-1) (0.200g, 0.52mmol, 1.0 equivalent), so After drip the dichloromethane solution (1ml) of diisopropyl ethyl amine (0.100g, 0.78mmol, 1.5 equivalent) again, React 5 minutes at 0 DEG C.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), have Machine silica gel mixed sample is spin-dried for, and concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=40:1) Obtain (R, E)-4-amino-1-(1-(but-2-ene acyl group) pyrrolidin-3-yl)-3-(4-Phenoxyphenyl)-1,3-dihydro -2H-imidazo [4,5-c] pyridin-2-ones (0.100g, yield: 42%).Colorless solid, fusing point: 102.3-105.8 DEG C. TLC:Rf0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 456 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.86 (dd, 1H), 7.41 (m, 4H), 7.20 (t, J=7.5Hz, 1H), 7.13 (m, 4H), 7.08 (m, 1H),6.58(m,1H),6.20(dd,1H),5.08(m,1H),4.23(s,2H),4.01(m,3H),3.69(m,1H), 2.72(m,1H),2.41(m,1H),1.88(dd,3H)。
Embodiment 7:(R, E)-4-amino-1-(1-(2-pentenoyl) pyrrolidin-3-yl))-3-(4-phenoxy phenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones) ((R, E)-4-amino-1-(1-(pent-2-enoyl) pyrrolidin-3 -yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 7) preparation
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.2g, 0.52mmol, 1.0 equivalent), trans 2-penetenoic acid (67.7mg, 0.68m Mol, 1.3 equivalents), HOBT (91.9mg, 0.68mmol, 1.3 equivalent), EDCI (130.4mg, 0.6 8mmol, 1.3 equivalents) and diisopropylethylamine (0.26mL, 1.56mmol, 3.0 equivalent) be dissolved in dichloromethane Alkane (8mL), the most at room temperature reaction 1 hour.It is concentrated to give thick product after having reacted, passes through column chromatography Method (eluant, eluent: dichloromethane: methyl alcohol=50:1) purifies to obtain compound (R, E)-4-amino-1-(1-(2-pentenoyl) Pyrrolidin-3-yl))-3-(4-phenoxy phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones) (83mg receives Rate: 34%).White solid, fusing point: 221.3-222.4 DEG C.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20: 1)；LCMS (ESI): m/z 470 [M+1]+, purity: 96.527%；1HNMR(CDCl3, 500MHz): δ7.86-7.83(m,1H),7.42-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),7.05-7.0 2(m,1H),6.59-6.55(m,1H),6.16-6.06(m,1H),5.18-5.05(m,1H),4.22(s,2H),4.08-3. 96(m,3H),3.75-3.58(m,1H),2.76-2.65(m,1H),2.45-2.22(m,3H),1.11-1.05(m,3H)。
Embodiment 8:(R, E)-4-amino-1-(1-(4-dimethylamino-2-crotonyl) pyrrolidines-3 base)-3-(4- Phenoxy phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino-1-(1-(4-(dimethyl amino)but-2-enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidaz O [4,5-c] pyridin-2-one) preparation of (compound 8)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.5g, 1.29mmol, 1.0 equivalent), 4-bromocrotonic acid (277mg, 1.68mmol, 1.3 equivalents), DCC (347mg, 1.68mmol, 1.3 equivalent) and DMAP (16mg, 0.13mmol, 0.1 equivalent) it is dissolved in dichloromethane (15mL), then react 1.5 hours at 0 DEG C.It is concentrated to give after having reacted To thick product, purify (R, E)-4-amino by column chromatography (eluant, eluent: dichloromethane: methyl alcohol=30:1) -1-(3-(1-(4-bromo-2-crotonyl) pyrrolidines))-3-(4-phenoxy phenyl)-1H-imidazo [4,5-c] pyridine-2 (3H)- Ketone (0.6g, yield: 88%).White solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；L CMS (ESI): m/z 535 [M+1]+。
By (R, E)-4-amino-1-(3-(1-(4-bromo-2-crotonyl) pyrrolidines))-3-(the 4-benzene oxygen benzene of above-mentioned acquisition Base)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.15g, 0.28mmol, 1.0 equivalent) and dimethylamine (2M Tetrahydrofuran solution, 0.63mL, 1.26mmol, 4.5 equivalents) it is dissolved in oxolane (3mL), then in room The lower reaction of temperature 1 hour.Thick product it is concentrated to give, by column chromatography (eluant, eluent: dichloromethane after having reacted Alkane: methyl alcohol=20:1) purify to obtain compound (R, E)-4-amino-1-(1-(4-dimethylamino-2-crotonyl) pyrroles Alkane-3 base)-3-(4-phenoxy phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (60mg, yield: 43%). White solid, fusing point: 103.6-105.3 DEG C.TLC:Rf 0.3 (dichloromethane: methyl alcohol=10:1)；LCM S (ESI): m/z 499 [M+1]+, purity: 95.928%；1HNMR(CDCl3, 500MHz): δ 7.87- 7.84(m,1H),7.41-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),6.99-6.95(m,1 H),6.58-6.54(m,1H),6.41-6.28(m,1H),5.20-5.02(m,1H),4.17-3.98(m,5H),3.75-3. 56(m,1H),3.17-3.10(m,2H),2.80-2.60(m,1H),2.43-2.38(m,1H),2.32(s,3H),2.2 8(s,3H)。
Embodiment 9:(R, E)-4-amino-1-(1-(4-methoxyl group-2-crotonyl) pyrrolidin-3-yl)-3-(4-benzene oxygen Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino-1-(1-(4-methoxybut-2- enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridi N-2-one) preparation of (compound 9)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.15g, 0.387mmol, 1.0 equivalent), 4-methoxyl group crotonic acid (58.4mg, 0.50 3mmol, 1.3 equivalents), DCC (103.8mg, 0.537mmol, 1.3 equivalent) and DMAP (4.8mg, 0.039mmol, 0.1 equivalent) it is dissolved in dichloromethane (6mL), the most at room temperature reaction 1 hour.React It is concentrated to give thick product after one-tenth, purifies to change by column chromatography (eluant, eluent: dichloromethane: methyl alcohol=30:1) Compound (R, E)-4-amino-1-(1-(4-methoxyl group-2-crotonyl) pyrrolidin-3-yl)-3-(4-phenoxy phenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones (60mg, yield: 32%).White solid, fusing point: 178.2- 179.5℃.TLC:Rf 0.4 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 486 [M+1]+, Purity: 98.464%；1HNMR(CDCl3, 500MHz): δ 7.87-7.83 (m, 1H), 7.40-7.37 (m, 4 H),7.21-7.18(m,1H),7.13-7.09(m,4H),6.98-6.96(m,1H),6.57-6.54(m,1H),6.45-6. 36(m,1H),5.19-5.03(m,1H),4.24(s,2H),4.14-4.03(m,5H),3.75-3.55(m,1H),3.50- 3.42(m,3H),2.75-2.60(m,1H),2.45-2.30(m,1H)。
Embodiment 10:(R, E)-4-amino-3-(4-phenoxy phenyl)-1-(1-(4-(piperidin-1-yl)-2-crotonyl) Pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino-3-(4-phenoxyp henyl)-1-(1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imida Zo [4,5-c] pyridin-2-one) preparation of (compound 10)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (110-1) (0.16g, 0.413mmol, 1.0 equivalent), 4-piperidyl crotonic acid (90.1mg, 0.53 7mmol, 1.3 equivalents), HATU (204.1mg, 0.537mmol, 1.3 equivalent) and triethylamine (125 Mg, 1.239mmol, 3.0 equivalent) it is dissolved in dichloromethane (5mL), the most at room temperature reaction 1 hour.Instead Thick product should be concentrated to give after completing, purified by column chromatography (eluant, eluent: dichloromethane: methyl alcohol=20:1) Obtain compound (R, E)-4-amino-3-(4-phenoxy phenyl)-1-(1-(4-(piperidin-1-yl)-2-crotonyl) pyrrolidines-3 -yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (100mg, yield: 45%).White solid, molten Point: 107.5-109.1 DEG C.TLC:Rf 0.3 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 5 39[M+1]+, purity: 97.356%；1HNMR(CDCl3, 500MHz): δ 7.88-7.84 (m, 1H), 7. 41-7.38(m,4H),7.21-7.18(m,1H),7.13-7.09(m,4H),7.01-6.98(m,1H),6.58-6.54(m, 1H),6.50-6.25(m,1H),5.20-5.05(m,1H),4.13-3.98(m,5H),3.78-3.58(m,1H),2.49(d, J=19.5Hz, 2H), 2.80-2.60 (m, 1H), 2.58-2.30 (m, 5H), 1.78-1.56 (m, 3H), 1.52-1.40 (m,3H)。
Embodiment 11:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-Phenoxyphenyl)-1,3-dihydro- 2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-pheno Xyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 11)
Step 11a: the tert-butyl group (R)-3-((2-chloro-3-nitropyridine-4-base) amino) piperidines-1-carboxylate ((R)-tert- Butyl (R)-3-((2-chloro-3-nitropyridin-4-yl) amino) piperidine-1-carboxylate) (compound 3 02) preparation
Addition 2 in reaction bulb, 4-dichloro-3-nitropyridine (101) (5.79g, 30.0mmol, 1.0 equivalent), The tert-butyl group (R)-3-amino piperidine-1-carboxylate (301) (6.00g, 30.0mmol, 1.0 equivalent), triethylamine (6.0 6g, 60.0mmol, 2.0 equivalent) and DMF (50ml), room temperature reaction is overnight.Will reaction Liquid ethyl acetate (250ml) dilutes, and washs with semi-saturation saline solution (200ml × 4), organic phase silica gel mixed sample Be spin-dried for, with column chromatography purify (eluant, eluent: petroleum ether: ethyl acetate=4:1) obtain the tert-butyl group (R)-3-((2- Chloro-3-nitropyridine-4-base) amino) piperidines-1-carboxylate (8.21g, yield: 77%).LCMS (ESI): m/ z 357[M+1]+, pale yellow oil；TLC:Rf 0.2 (petroleum ether: ethyl acetate=4:1).
Step 11b: the tert-butyl group (R)-3-((2-(dibenzyl amino)-3-nitropyridine-4-base) amino) piperidines-1-carboxylic acid Ester ((tert-butyl (R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl) amino) piperidine-1-car Boxylate) preparation of (compound 303)
The tert-butyl group (R)-3-((2-chloro-3-nitropyridine-4-base) amino) piperidines-1-carboxylate (3 is added in reaction bulb 02) (8.27g, 23.2mmol, 1.0 equivalent), dibenzylamine (5.94g, 30.2mmol, 1.3 equivalent), triethylamine (3.52g, 34.8mmol, 1.5 equivalent) and acetonitrile (150ml), heated overnight at reflux.Reactant liquor silica gel mixed sample Be spin-dried for, with column chromatography purify (eluant, eluent: petroleum ether: ethyl acetate=4:1) obtain the tert-butyl group (R)-3-((2- (dibenzyl amino)-3-nitropyridine-4-base) amino) piperidines-1-carboxylate (10.9g, yield: 91%).LCMS (ESI): m/z 518 [M+1]+, yellow oil；TLC:Rf 0.4 (petroleum ether: ethyl acetate=4:1).
Step 11c: the tert-butyl group (R)-3-((3-amino-2-(dibenzyl amino) pyridin-4-yl) amino) piperidines-1-carboxylic acid Ester (tert-butyl (R)-3-((3-amino-2-(dibenzylamino) pyridin-4-yl) amino) piperidine-1-carb Oxylate) preparation of (compound 304)
Toward zinc powder (13.7g, 210.0mmol, 10.0 equivalent) and ammonium chloride (11.2g, 210.0mmol, 10.0 Equivalent) methanol solution (250ml) in add the tert-butyl group (R)-3-((2-(dibenzyl amino)-3-nitropyridine-4- Base) amino) piperidines-1-carboxylate (303) (10.9g, 21.0mmol, 1.0 equivalent), it is heated to 50 DEG C of reactions half Hour.Reactant liquor diatomite filters, and filtrate is spin-dried for, and dissolves with dichloromethane: methyl alcohol=10:1 (100ml), Filtering, organic phase is spin-dried for obtaining the crude product tert-butyl group (R)-3-((3-amino-2-(dibenzyl amino) pyridin-4-yl) amino) Piperidines-1-carboxylic acid tert-butyl ester (11.0g, yield: 100%).LCMS (ESI): m/z 488 [M+1]+, faint yellow Solid；TLC:Rf 0.1 (petroleum ether: ethyl acetate=4:1).
Step 11d: the tert-butyl group (R)-3-(4-(dibenzyl amino)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] Pyridine-1-base) piperidines-1-carboxylate ((tert-butyl (R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1 H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) preparation of (compound 305)
In reaction bulb add the tert-butyl group (R)-3-((3-amino-2-(dibenzyl amino) pyridin-4-yl) amino) piperidines- 1-carboxylate (304) (11.0g, 22.5mmol, 1.0 equivalent), N, N'-carbonyl dimidazoles (10.9g, 67.5mmol, 3.0 equivalents) and oxolane (150ml), it is heated to refluxing overnight by reactant liquor.Reactant liquor silica gel mixed sample revolves Dry, with column chromatography purify (eluant, eluent: dichloromethane: methyl alcohol=100:1) obtain the tert-butyl group (R)-3-(4-(two Benzylamino)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) (9.88g receives piperidines-1-carboxylate Rate: 85%).LCMS (ESI): m/z 514 [M+1]+, weak yellow liquid；TLC:Rf 0.8 (dichloromethane: Methyl alcohol=80:1).
Step 11e: the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) Piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridi N-1-yl) piperidine-1-carboxylate) preparation of (compound 306)
In reaction bulb add the tert-butyl group (R)-3-(4-(dibenzyl amino)-2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine-1-base) piperidines-1-carboxylate (305) (9.88g, 19.22mmol, 1.0 equivalent), palladium dydroxide (2.0g), Ethanol (120ml) and ethyl acetate (30ml), reactant liquor is heated to 60 DEG C overnight in hydrogen.Reactant mixture Filtering with diatomite, filtrate is spin-dried for, and concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=2 0:1) obtain the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines- 1-carboxylate (5.28g, yield: 83%).LCMS (ESI): m/z 334 [M+1]+, colorless solid；TLC: Rf 0.1 (dichloromethane: methyl alcohol=20:1).
Step 11f: the tert-butyl group (R)-3-(4-amino-2-oxo-3-(4-Phenoxyphenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylic acid tert-butyl ester (tert-butyl (R)-3-(4-amino-2-oxo-3-(4-phenox Yphenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) (chemical combination Thing 307-11) preparation
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (3.0g, 9.0mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (108-1) (2. 89g, 13.5mmol, 1.5 equivalent), copper acetate (1.82g, 9.9mmol, 1.1 equivalent), molecular sieve (3.0g), Pyridine (2.13g, 27mmol, 3.0 equivalent) and DMF (30ml), reactant liquor adds in atmosphere Heat is to 40 DEG C overnight.Reactant liquor ethyl acetate (200ml) dilutes, and washs with semi-saturation saline solution (150ml × 3), Organic phase silica gel mixed sample is spin-dried for, concentrate column chromatography purify (eluant, eluent: dichloromethane: methyl alcohol=50: 1) tert-butyl group (R)-3-(4-amino-2-oxo-3-(4-Phenoxyphenyl)-2,3-dihydro-1H-imidazo [4,5-c] is obtained Pyridine-1-base) piperidines-1-carboxylate (2.23g, yield: 49%).LCMS (ESI): m/z 502 [M+1]+, yellow Look grease；TLC:Rf 0.7 (dichloromethane: methyl alcohol=20:1).
Step 11g:(R)-4-amino-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1,3-dihydro-2H-imidazo [4, 5-c] pyridin-2-ones ((R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H- Imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-11)
The tert-butyl group (R)-3-(4-amino-2-oxo-3-(4-Phenoxyphenyl)-2,3-dihydro-1H-is added in reaction bulb Imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (307-11) (2.23g, 4.45mmol, 1.0 equivalent), two Chloromethanes (10ml) and trifluoracetic acid (2.0ml), reactant liquor is in ambient temperature overnight.Pour reactant liquor into saturated sodium carbonate In solution (100ml), extracting with dichloromethane (100ml × 2), organic phase silica gel mixed sample is spin-dried for, and concentrate is used Column chromatography (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purify obtain (R)-4-amino- 3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (1.3g, yield: 73%).LCMS (ESI): m/z 402 [M+1]+, pale solid；TLC:Rf 0.1 (dichloromethane: first Alcohol=20:1).
Step 11h:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-Phenoxyphenyl)-1,3-dihydro-2 H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyp Henyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 11)
Toward acryloyl chloride (202-4) (0.25g, 3.89mmol, 1.2 equivalent) dichloromethane solution (50ml) in 0 DEG C Lower dropping (R)-4-amino-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole The dichloromethane solution (30ml) of pyridine-2-ketone (308-11) (1.3g, 3.24mmol, 1.0 equivalent), drips the most again The dichloromethane solution (5ml) of diisopropyl ethyl amine (0.63g, 4.86mmol, 1.5 equivalent), at 0 DEG C React 5 minutes.Being poured into by reactant liquor in water (100ml), extract with dichloromethane (100ml × 2), organic phase is used Silica gel mixed sample is spin-dried for, and concentrate column chromatography purifies (dichloromethane: methyl alcohol=40:1) and obtains (R)-1-(1- Acryloylpiperidine-3-base)-4-amino-3-(4-Phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridine-2- Ketone (0.67g, yield: 45%).Colorless solid, fusing point: 89.5-91.9 DEG C.TLC:Rf 0.5 (dichloromethane: Methyl alcohol=20:1).LCMS (ESI): m/z 456 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.84 (d, J=5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J=7.5Hz, 1H), 7.13 (m, 4H), 6.64 (m, 2H), 6.33 (d, J=16.5Hz, 1H), 5.72 (s, 1H), 4.82 (m, 1H), 4.34 (s, 2H), 4.10 (m, 2H), 3.85 (m, 0.5H), 3.48 (m, 0.5H), 3.13 (m, 0.5H), 2.62 (m, 1.5H), 2.11 (d, J= 12.5Hz, 1H), 1.98 (d, J=13.5Hz, 1H), 1.69 (m, 1H).
Embodiment 12:(R)-1-(1-acryloylpiperidine-3-base)-4-amido-3-(4 (4-chlorophenoxy) phenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3- (4-(4-chlorophenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Thing 13) preparation
Step 12a: the tert-butyl group (R)-3-(4-amido-3-(4-(the chloro-phenoxy group of 4-) phenyl)-2-oxo-2,3-dihydro-1 H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-(4-chl orophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) preparation of (compound 307-13)
By 2-(4 (the chloro-phenoxy group of 4-)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxo borine (108-13) (1.78 G, 5.39mmol, 1.5 equivalent) it is dissolved in after methyl alcohol (10ml) adds concentrated hydrochloric acid (1ml) stirring reaction 1h and washing, Dichloromethane extracts, and dried filtrated stock is standby, adds the tert-butyl group (R)-3-(4-amino-2-in above-mentioned mother liquor Oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (306) (1.20g, 3.59mmol, 1 equivalent), Cu (OAc)2(1.30g, 7.18mmol, 2 equivalent), Et3N (0.73g, 7.18mmol, 2 equivalent) With pyridine (0.57g, 7.18mmol, 2 equivalent), room temperature reaction is overnight.Being washed by reactant liquor, dichloromethane extracts Take, concentrate after drying, obtain the pale yellow oil tert-butyl group (R)-3 with ethyl acetate/n-hexane (3:1) column chromatography -(4-amido-3-(4-(the chloro-phenoxy group of 4-) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperazine Pyridine-1-carboxylate (0.77g, yield 40.00%).LCMS (ESI): m/z 536.50 [M+H]+。
Step 12b:(R)-4-amido-3-(4-(4-chlorophenoxy) phenyl)-1-(pyridin-3-yl)-1,3-dihydro- 2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-(4-chlorophenoxy) phenyl)-1-(piperi Din-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-13)
By the tert-butyl group (R)-3-(4-amido-3-(4-(the chloro-phenoxy group of 4-) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (307-13) (0.77g, 1.44mmol, 1 equivalent) is dissolved in dichloromethane Alkane (5ml), adds TFA (2.5ml), room temperature reaction 1h.Reactant liquor concentrates, and saturated sodium bicarbonate is neutralized to slightly Meta-alkalescence, extracts with 5ml dichloromethane, is dried, and concentrates, ethanol/methylene/triethylamine (1:10:0. 3) column chromatography obtains off-white color foaming solid (R)-4-amido-3-(4-(4-chlorophenoxy) phenyl)-1-(pyridin-3-yl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (325mg, yield 52.08%).LCMS (ESI): m/z 436. 10[M+H]+。
Step 12c:(R)-1-(1-acryloylpiperidine-3-base)-4-amido-3-(4-(4-chlorophenoxy) phenyl)-1,3-two Hydrogen-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-c Hlorophenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 13) Preparation
Acryloyl chloride (202-4) (81mg, 0.90mmol, 1.2 equivalent) is dissolved in dichloromethane (10ml), cryosel Lower dropping (R)-4-amido-3-(4-(4-chlorophenoxy) phenyl)-1-(the pyridin-3-yl)-1,3-dihydro-2H-imidazo of bath Dichloromethane (5ml) solution of [4,5-c] pyridin-2-ones (308-13) (325mg, 0.75mmol, 1 equivalent), Dichloromethane (5ml) solution of rear addition DIEA (116mg, 0.90mmol, 1.2 equivalent), reacts 10 minutes. Add water (40ml) stirring, and dichloromethane (20ml) extracts, and organic phase washed once with water (20ml) again, is dried, Concentrate, ethanol/methylene (1:20) and methanol/ethyl acetate (1:20) column chromatography twice obtain white solid (R)- 1-(1-acryloylpiperidine-3-base)-4-amido-3-(4-(4-chlorophenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (66mg, yield 18%), content 100%, fusing point: 90-92 DEG C；LCMS (ESI): m/z 490.05[M+H]+；1HNMR(400MHz,CDCl3): δ 2.03 (d, J=30.0Hz, 1. 5H), 2.10 (d, J=23.7Hz, 1H), 2.60 (m, 1.5H), 3.13 (s, 0.5H), 3.46 (s, 1 H), 3.86 (d, J=37.0Hz, 0.5H), 4.10 (s, 4H), 4.81 (d, J=30.0Hz, 1H), 5.34 (t, J=11.0Hz, 0.5H), 5.73 (d, J=21.6Hz, 1H), 6.32 (d, J=40Hz, 1H), 6.63 (d, J=12.6Hz, 2H), 7.03 (d, J=22.1Hz, 2H), 7.11 (d, J=22. 1Hz, 2H), 7.35 (d, J=22.1Hz, 2H), 7.41 (d, J=21.9Hz, 2H), 7.87 (d, J=14.0Hz, 1H)
Embodiment 13:(R)-4-(4-(1-(1-acryloylpiperidine-3-base)-4-amino-2-oxo-1,2-dihydro-3H -imidazo [4,5-c] pyridin-3-yl) phenoxy group) cyanophenyl ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-a Mino-2-oxo-1,2-dihydro-3H-imidazo [4,5-c] pyridin-3-yl) phenoxy) benzonitrile) (change Compound 15) preparation
Step 13a: the tert-butyl group (R)-3-(4-amino 3-(4-(4-cyano-benzene oxygen))-2 oxo-2,3-dihydro-1H-miaow Azoles also [4,5-c] pyridine-1-base) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-(4-cyanophenox y)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylat E) preparation of (compound 307-15)
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (1.0g, 3.0mmol, 1.0 equivalent), 4-(4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolane-2-base) phenoxy group) cyanophenyl (108-15) (1.25g, 3.9mmol, 1.3 equivalent), copper acetate (0. 60g, 3.3mmol, 1.1 equivalent), molecular sieve (1.0g), pyridine (0.71g, 9.0mmol, 3.0 equivalent) and N, Dinethylformamide (15ml), reactant liquor is heated to 40 DEG C overnight in atmosphere.Reactant liquor ethyl acetate (2 00ml) dilution, washs with semi-saturation saline solution (100ml × 3), and organic phase silica gel mixed sample is spin-dried for, and concentrate is used Column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=50:1) and obtains the tert-butyl group (R)-3-(4-amino 3-(4-(4 -cyano-benzene oxygen))-2 oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (0.36g, Yield: 23%).LCMS (ESI): m/z 527 [M+1]+, light green oil；TLC:Rf 0.6 (dichloro Methane: methyl alcohol=20:1).
Step 13b:(R)-4-(4-(4-amino-2-oxo-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-3 (2 H)-yl) phenoxy group) cyanophenyl ((R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo [4,5-c] Pyridin-3 (2H)-yl) phenoxy) benzonitrile) preparation of (compound 308-15)
The tert-butyl group (R)-3-(4-amino 3-(4-(4-cyano-benzene oxygen))-2 oxo-2,3-dihydros-1 are added in reaction bulb H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (307-15) (0.36g, 0.68mmol, 1.0 equivalent), Dichloromethane (10ml) and trifluoracetic acid (2.0ml), room temperature reaction is overnight.Pour reactant liquor into saturated sodium carbonate molten In liquid (100ml), extracting with dichloromethane (50ml × 3), organic phase silica gel mixed sample is spin-dried for, concentrate post Chromatography (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purifies and obtains (R)-4-(4-(4-ammonia Base-2-oxo-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-3 (2H)-yl) phenoxy group) (0.122g receives cyanophenyl Rate: 42%).LCMS (ESI): m/z 427 [M+1]+, colorless solid；TLC:Rf 0.1 (dichloromethane: Methyl alcohol=20:1).
Step 13c:(R)-4-(4-(1-(1-acryloylpiperidine-3-base)-4-amino-2-oxo-1,2-dihydro-3H- Imidazo [4,5-c] pyridin-3-yl) phenoxy group) cyanophenyl ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-ami No-2-oxo-1,2-dihydro-3H-imidazo [4,5-c] pyridin-3-yl) phenoxy) benzonitrile) (compound 15) preparation
Toward acryloyl chloride (202-4) (0.032g, 0.35mmol, 1.2 equivalent) dichloromethane solution (7ml) in 0 DEG C Lower dropping (R)-4-(4-(4-amino-2-oxo-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-3 (2H)-yl) benzene Epoxide) dichloromethane solution (7ml) of cyanophenyl (308-15) (0.122g, 0.29mmol, 1.0 equivalent), the most again The dichloromethane solution (1ml) of dropping diisopropyl ethyl amine (0.056g, 0.44mmol, 1.5 equivalent), at 0 DEG C Lower reaction 5 minutes.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), organic phase Being spin-dried for silica gel mixed sample, concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=40:1) must To (R)-4-(4-(1-(1-acryloylpiperidine-3-base)-4-amino-2-oxo-1,2-dihydro-3H-imidazo [4,5-c] Pyridin-3-yl) phenoxy group) cyanophenyl (0.052g, yield: 38%).White solid, fusing point: 116.1-118.7 DEG C. TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 481 [M+1]+,1HNMR(C DCl3, 500MHz): δ 7.89 (d, J=5Hz, 1H), 7.67 (d, J=8.5Hz, 2H), 7.49 (d, J= 8.5Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.12 (d, J=8.5Hz, 2H), 6.66 (m, 2H), 6. 34 (d, J=16.5Hz, 1H), 5.72 (s, 1H), 4.82 (m, 1H), 4.16 (m, 4H), 3.85 (m, 0.5H), 3.48(m,0.5H),3.12(m,0.5H),2.60(m,1.5H),2.12(m,1H),1.99(m,1H),1.65 (m,1H)。
Embodiment 14:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-phenylpyridine-3-base)-1,3-two Hydrogen-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-p Henyl pyridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 16) Preparation
Step 13a: the tert-butyl group (R)-3-(4-amino-2-oxo-3-(6-phenoxypyridines-3-base)-2,3-dihydro-1H- Imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate ((tert-butyl (R)-3-(4-amino-2-oxo-3-(6-pheno xypyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) The preparation of (compound 307-16)
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (0.666g, 2.0mmol, 1.0 equivalent), 2-phenoxy group-5-(4,4,5,5-tetramethyls Base-1,3,2-dioxaborolane-2-bases) pyridine (108-16) (0.891g, 3.0mmol, 1.5 equivalent), acetic acid Copper (0.400g, 2.2mmol, 1.1 equivalent), molecular sieve (0.500g), pyridine (0.474g, 6.0mmol, 3.0 Equivalent) and DMF (8ml), reactant liquor is heated to 40 DEG C overnight in atmosphere.Reactant liquor is used Ethyl acetate (100ml) dilutes, and washs with semi-saturation saline solution (100ml × 3), and organic phase silica gel mixed sample is spin-dried for, Concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=60:1) and obtains the tert-butyl group (R)-3-(4- Amino-2-oxo-3-(6-phenoxypyridines-3-base)-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1- Carboxylate (0.520g, yield: 52%).LCMS (ESI): m/z 503 [M+1]+, yellow oil；TLC: Rf 0.7 (dichloromethane: methyl alcohol=20:1).
Step 13b:(R)-4-amino-3-(6-phenoxypyridines-3-base)-1-(piperidines-3-base)-1,3-dihydro-2H-imidazoles And [4,5-c] pyridin-2-ones ((R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-di Hydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-16)
The tert-butyl group (R)-3-(4-amino-2-oxo-3-(6-phenoxypyridines-3-base)-2,3-two is added in reaction bulb Hydrogen-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (0.52g, 1.0mmol, 1.0 equivalent), dichloro Methane (10ml) and trifluoracetic acid (2.0ml), reactant liquor ambient temperature overnight.Pour reactant liquor into saturated sodium carbonate solution (100ml) in, extracting with dichloromethane (50ml × 2), organic phase silica gel mixed sample is spin-dried for, concentrate post layer Analysis method (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purifies and obtains (R)-4-amino-3-(6- Phenoxypyridines-3-base)-1-(piperidines-3-base)-1, (0.215g receives 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones Rate: 53%).LCMS (ESI): m/z 403 [M+1]+, pale solid；TLC:Rf 0.1 (dichloromethane: Methyl alcohol=20:1).
Step 13c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-phenylpyridine-3-base)-1,3-dihydro -2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-phenyl Pyridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 16)
Toward acryloyl chloride (202-4) (0.059g, 0.65mmol, 1.2 equivalent) dichloromethane solution (7ml) in 0 DEG C Lower dropping (R)-4-amino-3-(6-phenoxypyridines-3-base)-1-(piperidines-3-base)-1,3-dihydro-2H-imidazo The dichloromethane solution (7ml) of [4,5-c] pyridin-2-ones (308-16) (0.215g, 0.54mmol, 1.0 equivalent), so After drip the dichloromethane solution (1ml) of diisopropyl ethyl amine (0.104g, 0.81mmol, 1.5 equivalent) again, React 5 minutes at 0 DEG C.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), have Machine silica gel mixed sample is spin-dried for, and concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=30:1) Obtain (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-phenylpyridine-3-base)-1,3-dihydro-2H-imidazoles And [4,5-c] pyridin-2-ones (0.083g, yield: 34%).Colorless solid, fusing point: 107.9-109.9 DEG C.TLC: Rf0.7 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 457 [M+1]+,1HNMR(CDCl3, 500MHz): δ 8.29 (s, 1H), 7.89 (d, 1H), 7.78 (t, J=6Hz, 2H), 7.42 (m, 2H), 7.24 (m, 1H), 7.18 (d, J=7.5Hz, 2H), 7.05 (d, J=9Hz, 1H), 6.65 (m, 1H), 6.57 (m, 1H), 6.30 (m, 1H), 5.71 (m, 1H), 4.82 (m, 1H), 4.02 (m, 4H), 3.85 (m, 0.5H), 3.44 (m, 0.5H), 3.13 (m, 0.5H), 2.57 (m, 1.5H), 2.11 (m, 1H), 1.98 (m, 1H), 1.63 (m, 1H)。
Embodiment 15:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-am ino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyri Din-2-one) preparation of (compound 17)
Step 15a: the tert-butyl group (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihy Dro-1H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) preparation of (compound 402-17)
By the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1- Carboxylate (306) (2.5g, 7.50mmol, 1.0 equivalent), to iodobenzene boric acid (401-17) (2.14g, 8.62mm Ol, 1.3 equivalents) and pyridine (1.78g, 22.5mmol, 3.0 equivalent) be dissolved in N,N-dimethylformamide (20m L), in, add copper acetate (1.50g, 8.25mmol, 1.1 equivalent) and 4A molecular sieve (3.0g), then exist In air, 50 DEG C of reactions are overnight.Reactant liquor is cooled to room temperature and dilutes with ethyl acetate (100mL), filters, Filtrate is washed with semi-saturation saline solution (50mL × 4).Organic layer anhydrous sodium sulfate is dried, and concentrates, obtains Thick product column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) purifies to obtain the tert-butyl group (R)-3-(4-amino-3 -(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate (1.6g, yield: 40%).Brown solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 53 6[M+1]+。
Step 15b: the tert-butyl group (R)-3-(4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl) 2-oxo -2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-im Idazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) preparation of (compound 307-17)
By the tert-butyl group (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Piperidines-1-carboxylate (402-17) (0.8g, 1.49mmol, 1.0 equivalent), sesamol (403-17) (0.31g, 2.24 Mmol, 1.5 equivalents) and N, N-dimethyl glycine hydrochloride (39mg, 0.28mmol, 0.18 equivalent) be dissolved in In dioxane (8mL), add cuprous iodide (14.2mg, 0.075mmol, 0.05 equivalent) and cesium carbonate (0.97g, 2.98mmol, 2.0 equivalent), then nitrogen protect in 100 DEG C react 24 hours.Reactant liquor is cold But arrive room temperature and concentrate, the thick product column chromatography (eluant, eluent: dichloromethane: methyl alcohol=40:1 arrives obtained 20:1) purify to obtain the tert-butyl group (R)-3-(4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl) 2-oxo-2,3- Dihydro-1H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate (0.35g, yield: 44%).Gray solid；TLC: Rf0.4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 546 [M+1]+。
Step 15c:(R)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-piperidyl)-1H- Imidazo [4,5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(benzo [d] [1,3] dioxol-5-yloxy) phenyl) -1-(piperidin-3-yl)-1H-imidazo [4,5-c] pyridin-2 (3H)-one) preparation of (compound 308-17)
By the tert-butyl group (R)-3-(4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl) 2-oxo-2,3-dihydro-1 H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate (307-17) (0.35g, 0.64mmol, 1.0 equivalent) is dissolved in In dichloromethane (10mL), then it is added thereto to trifluoroacetic acid (2mL), the most at room temperature reaction 2 hours. Reaction mixture dichloromethane (50mL) is diluted, uses saturated sodium carbonate solution (30mL × 2) successively and satisfy With saline solution (60mL) wash, then organic layer silica gel mixed sample is spin-dried for, afterwards with column chromatography (eluant, eluent: Dichloromethane: methyl alcohol: triethylamine=100:10:1) purify (R)-4-amino-3-(4-(3,4-methylenedioxybenzenes Epoxide) phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.26g, yield: 91%). Gray solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 446 [M+1]+。
Step 15d:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amin o-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin- 2-one) the preparation of (compound 17)
Acryloyl chloride (202-4) (0.057mL, 0.7mmol, 1.2 equivalent) is dissolved in dichloromethane (5mL), It is cooled to 0 DEG C, the most dropwise dropping (R)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl) -1-(3-piperidyl)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (308-17) (0.26g, 0.584mmol, 1.0 Equivalent) dichloromethane (5mL) solution, then add dropwise DIPEA (0.156mL, 0. 876mmol, 1.5 equivalents) dichloromethane (1.0mL) solution, this mixed liquor is reacted 10 minutes at 0 DEG C. By reactant liquor use water (50mL) quencher, then extract with dichloromethane (50mL × 2).The organic layer obtained is used Silica gel mixed sample is spin-dried for, and purifies to obtain compound with column chromatography (eluant, eluent: dichloromethane: methyl alcohol=50:1) afterwards (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1,3-dihydro -2H-imidazo [4,5-c] pyridin-2-ones (0.170g, yield: 58%).White solid, fusing point: 194.5-195. 6℃.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 500 [M+1]+, pure Degree: 97.054%；1HNMR(CDCl3, 500MHz): δ 7.86 (d, J=5.5Hz, 1H), 7.37 (d, J =8.5Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 6.80 (d, J=8.5Hz, 1H), 6.64-6.55 (m, 4H), 6.34-6.30(m,1H),6.00(s,2H),5.78-5.65(m,1H),4.82-4.78(m,1H),4.25-3.80(m,5 H),3.17-2.45(m,2H),2.15-1.94(m,2H),1.82-1.75(m,1H)。
Embodiment 16:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-hydroxyphenoxy) phenyl)- 1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3- (4-(4-hydroxyphenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (change Compound 18) preparation
Step 16a: the tert-butyl group (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy) phenyl)-2-oxo-2,3-dihydro -1H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate ((R)-tert-butyl 3-(4-amino-3-(4-(4-(benzylox y)phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-c Arboxylate) preparation of (compound 307-18)
By the tert-butyl group (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Piperidines-1-carboxylate (402-17) (0.7g, 1.31mmol, 1.0 equivalent), 4-benzyloxy phenol (403-18) (0.39 G, 1.96mmol, 1.5 equivalent) and N, N-dimethyl glycine hydrochloride (34mg, 0.24mmol, 0.18 Equivalent) it is dissolved in dioxane (10mL), (12.5mg, 0.066mmol, 0.05 work as to add cuprous iodide Amount) and cesium carbonate (0.85g, 2.62mmol, 2.0 equivalent), then 100 DEG C of reactions 20 in nitrogen is protected Hour.Reactant liquor is cooled to room temperature and concentrates, the thick product column chromatography that obtains (eluant, eluent: dichloromethane: Methyl alcohol=40:1 to 20:1) purify to obtain the tert-butyl group (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy) phenyl)-2- Oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines-1-carboxylate (0.4g, yield: 50%).Faint yellow Solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 608 [M+1]+。
Step 16b:(R)-4-amino-3-(4-(4-benzyloxyphenoxy) phenyl)-1-(3-piperidyl)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(4-(benzyloxy) phenoxy) phenyl)-1-(piperidin-3 -yl)-1H-imidazo [4,5-c] pyridin-2 (3H)-one) preparation of (compound 308-18)
By the tert-butyl group (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy) phenyl)-2-oxo-2,3-dihydro-1H-miaow Azoles also [4,5-c] pyridine) piperidines-1-carboxylate (307-18) (0.40g, 0.658mmol, 1.0 equivalent) is dissolved in dichloro In methane (10mL), then it is added thereto to trifluoroacetic acid (2mL), the most at room temperature reaction 2 hours.Will Reaction mixture dichloromethane (50mL) dilutes, successively with saturated sodium carbonate solution (30mL × 2) and saturated Saline solution (60mL) wash, then organic layer silica gel mixed sample is spin-dried for, afterwards with column chromatography (eluant, eluent: Dichloromethane: methyl alcohol: triethylamine=100:10:1) purify (R)-4-amino-3-(4-(4-benzyloxyphenoxy) Phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.305g, yield: 91%).Grey Solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 508 [M+1]+。
Step 16c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-hydroxyphenoxy) phenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4- (4-hydroxyphenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 1 8) preparation
By (R)-4-amino-3-(4-(4-benzyloxyphenoxy) phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] pyrrole Pyridine-2 (3H)-one (308-18) (0.305g, 0.6mmol, 1.0 equivalent) is dissolved in ethanol (10mL), then to it Middle addition palladium/carbon (100mg), then under the atmosphere of hydrogen balloon 40 DEG C reaction overnight.Reactant liquor is cooled to room Filter after temperature, collect filtrate and be concentrated to give thick product, with column chromatography (eluant, eluent: dichloromethane: methyl alcohol=1 0:1) purify (R)-4-amino-3-(4-(4-hydroxyphenoxy) phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] Pyridine-2 (3H)-one (0.22g, yield: 88%).Gray solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol= 8:1)；LCMS (ESI): m/z 418 [M+1]+.By (R)-4-amino-3-(4-(4-hydroxy benzenes of above-mentioned gained Epoxide) phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.2g, 0.48mmol, 1.0 Equivalent), acrylic acid (201-18) (38mg, 0.53mmol, 1.1 equivalent), DCC (119mg, 0.58mm Ol, 1.2 equivalents) and DMAP (6mg, 0.048mmol, 0.1 equivalent) be dissolved in dichloromethane (10mL), so After at 0 DEG C react 1 hour.Be concentrated to give thick product after having reacted, by column chromatography (eluant, eluent: Dichloromethane: methyl alcohol=40:1) purify to obtain chemical combination (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4- Hydroxyphenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (83mg, yield: 37%).In vain Look solid, fusing point: 196.3-198.2 DEG C.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；LCMS(E SI): m/z 471 [M+1]+, purity: 96.893%；1HNMR(CDCl3, 500MHz): δ 7.86 (d, J =5.0Hz, 1H), 7.35 (d, J=8.5Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5Hz, 2H), 6.66-6.59 (m, 2H), 6.34 (d, J=15Hz, 1H), 5.75-5. 73(m,1H),4.83-4.78(m,1H),4.19(s,2H),4.13-4.07(m,2H),3.85-3.47(m,1H),3.14- 2.59(m,2H),2.12-1.96(m,3H)。
Embodiment 17:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4- (4-nitrophenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 19) Preparation
Step 17a: the tert-butyl group (R)-3-(4-amino 3-(4-hydroxy phenyl)-2 oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine-1-base) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-hydroxyphenyl)-2-oxo -2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) (compound 502-1 9) preparation
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (3.0g, 9.0mmol, 1.0 equivalent), 4-hydroxy benzenes boric acid (501-19) (1.6 2g, 11.7mmol, 1.3 equivalent), copper acetate (1.820g, 10mmol, 1.1 equivalent), molecular sieve (3.0g), Pyridine (2.13g, 27.0mmol, 3.0 equivalent) and DMF (30ml), reactant liquor is in atmosphere It is heated to 40 DEG C overnight.Reactant liquor ethyl acetate (200ml) dilutes, with semi-saturation saline solution (200ml × 3) Washing, organic phase silica gel mixed sample is spin-dried for, and concentrate column chromatography purifies (eluant, eluent: dichloromethane: first Alcohol=20:1) obtain the tert-butyl group (R)-3-(4-amino 3-(4-hydroxy phenyl)-2 oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine-1-base) piperidines-1-carboxylate (0.240g, yield: 6%).LCMS (ESI): m/z 426 [M+1]+, Yellow oil；TLC:Rf 0.35 (dichloromethane: methyl alcohol=20:1).
Step 17b: the tert-butyl group (R)-3-(4-amino-3-(4-(4-nitrophenoxy) phenyl)-2-oxo-2,3-dihydro-1 H-imidazo [4,5-c] pyridine-1-base) piperidines pyridine-1-carboxylate (tert-butyl (R) 3-(4-amino-3-(4-(4-nitro phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-car Boxylate) preparation of (compound 307-19)
Add in reaction bulb and obtain the tert-butyl group (R)-3-(4-amino 3-(4-hydroxy phenyl)-2 oxo-2,3-dihydro-1 H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (502-19) (0.240g, 0.56mmol, 1.0 equivalent), P-fluoronitrobenzene (503-19) (0.088g, 0.62mmol, 1.1 equivalent), and potassium carbonate (0.116g, 0.84mmol, 1. 5 equivalents) and acetonitrile (15ml), by reactant liquor heated overnight at reflux.Reactant liquor silica gel mixed sample is spin-dried for, concentrates Thing column chromatography (eluant, eluent: dichloromethane: methyl alcohol=40:1) purify obtain the tert-butyl group (R)-3-(4-amino- 3-(4-(4-nitrophenoxy) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines pyridine-1- Carboxylate (0.270g, yield: 89%).LCMS (ESI): m/z 547 [M+1]+, yellow oil；TLC: Rf 0.5 (dichloromethane: methyl alcohol=20:1).
Step 17c:(R)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1-(piperidines-3-base)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1-(piperidin-3-yl)-1H -imidazo [4,5-c] pyridin-2 (3H)-one) (compound 308-19)) preparation
The tert-butyl group (R)-3-(4-amino-3-(4-(4-nitrophenoxy) phenyl)-2-oxo-2,3-is added in reaction bulb Dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines pyridine-1-carboxylate (307-19) (0.27g, 0.5mmol, 1.0 Equivalent), dichloromethane (10ml) and trifluoracetic acid (2.0ml), room temperature reaction half an hour.Reactant liquor is poured into full With in sodium carbonate liquor (100ml), extracting with dichloromethane (50ml × 3), organic phase silica gel mixed sample is spin-dried for, Concentrate column chromatography (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purifies and obtains (R) -4-amino-3-(4-(4-nitrophenoxy) phenyl)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.220g, yield: 99%).LCMS (ESI): m/z 447 [M+1]+, colorless solid；TLC:Rf 0.1 (two Chloromethanes: methyl alcohol=20:1).
Step 17d:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4- (4-nitrophenoxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 19) Preparation
Toward acryloyl chloride (202-4) (0.054g, 0.60mmol, 1.2 equivalent) dichloromethane solution (7ml) in 0 DEG C Lower dropping (R)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine The dichloromethane solution (7ml) of-2 (3H)-one (308-19) (0.220g, 0.50mmol, 1.0 equivalent), drips the most again Add the dichloromethane solution (1ml) of diisopropyl ethyl amine (0.097g, 0.75mmol, 1.5 equivalent), at 0 DEG C Lower reaction 5 minutes.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), organic phase Being spin-dried for silica gel mixed sample, concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=30:1) must To (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-nitrophenoxy) phenyl)-1,3-dihydro-2H- Imidazo [4,5-c] pyridin-2-ones (0.170g, yield: 68%).Yellow solid, fusing point: 92.6-98.6 DEG C.T LC:Rf 0.5 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 501 [M+1]+,1HNMR(C DCl3, 500MHz): δ 8.27 (d, J=9Hz, 2H), 7.89 (s, 1H), 7.52 (d, J=8.5Hz, 2H), 7.25 (d, J=9Hz, 2H), 7.14 (d, J=9Hz, 2H), 6.67 (m, 2H), 6.34 (d, J=17Hz, 1H), 5.74 (d, J=7.5Hz, 1H), 4.83 (m, 1H), 4.22 (m, 4H), 3.86 (m, 0.5H), 3.48 (m, 0.5H), 3.13 (m, 0.5H), 2.62 (m, 1.5H), 2.12 (d, J=12Hz, 1H), 1.99 (d, J= 13Hz,1H),1.66(m,1H)。
Embodiment 18:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(benzyl epoxide) phenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4 -(benzyloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 24) Preparation
Step 18a: the tert-butyl group (R)-3-(4-amino-3-(4-(benzyl epoxide) phenyl)-2-oxo-2,3-dihydro-1H- Imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate ((tert-butyl (R)-3-(4-amino-3-(4-(benzyloxy) phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) The preparation of (compound 602-24)
By the tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1- Carboxylate (306) (500mg, 1.5mmol, 1 equivalent) is dissolved in dichloromethane (5ml), is sequentially added into 4A molecular sieve (1g), copper acetate (408mg, 2.25mmol, 1.5 equivalent), benzyloxy phenyl boric acid (601-24) (410mg, 1. 8mmol, 1.2 equivalents), pyridine (178mg, 2.25mmol, 1.5 equivalent), Et3N (227mg, 2.25mmo L, 1.5 equivalents), it is stirred at room temperature 24 hours.Reacting complete, filter, mother liquor is washed twice, is dried, and concentrates, Ethanol/methylene (1:40) column chromatography obtains the brown solid tert-butyl group (R)-3-(4-amino-3-(4-(benzyl epoxide) Phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (350mg, yield 4 5.3%).LCMS (ESI): m/z 516.40 [M+1]+。
Step 18b:(R)-4-amido-3-(4-(benzyloxy) phenyl)-1-[piperidines-3-base]-1,3-dihydro-2H-imidazoles And [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-(benzyloxy) phenyl)-1-[(piperidin-3-yl]-1,3- Dihydro-imidazo [4,5-c] pyridin-2-one) preparation of (compound 603-24)
The tert-butyl group (R)-3-(4-amino-3-(4-(benzyl epoxide) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5- C] pyridine-1-base) piperidines-1-carboxylate (602-24) (350mg, 0.68mmol, 1 equivalent) is dissolved in dichloromethane (1 Ml), TFA (2ml), room temperature reaction 1h are added.Reactant liquor concentrates, and saturated sodium bicarbonate is neutralized to slightly meta-alkali Property, extract with 5ml dichloromethane, be dried, concentrate, ethanol/methylene/triethylamine (1:10:0.3) post Chromatograph off-white color foaming solid (R)-4-amido-3-(4-(benzyloxy) phenyl)-1-[piperidines-3-base]-1,3-dihydro- 2H-imidazo [4,5-c] pyridin-2-ones (90mg, yield 32%).LCMS (ESI): m/z 416.40 [M+1]+。
Step 18c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(benzyl epoxide) phenyl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(be Nzyl) oxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 24)
Acryloyl chloride (202-4) (24mg, 0.26mmol, 1.2 equivalent) is dissolved in dichloromethane (4ml), under ice bath Add (R)-4-amido-3-(4-(benzyloxy) phenyl)-1-[piperidines-3-base]-1,3-dihydro-2H-imidazo [4,5-c] pyridine Dichloromethane (4ml) solution of-2-ketone (603-24) (90mg, 0.217mmol, 1 equivalent), is eventually adding DIE Dichloromethane (2ml) solution of A (34mg, 0.26mmol, 1.2 equivalent), reacts 10 minutes.Add water (5ml) Stirring, dichloromethane (2ml) extracts, and organic phase washed once with water (10ml) again, is dried, and concentrates, methyl alcohol/ Ethyl acetate (1:10) column chromatography obtains white solid (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(benzyl Base epoxide) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (19.4mg, yield 19%).Fusing point: 7 5-76℃；LCMS (ESI): m/z 470.50 [M+1]+；1HNMR(600MHz,CDCl3):δ1.27(s, 1.5H), 2.02 (m, 1.5H), 2.12 (s, 1H), 2.51 (d, J=10.74Hz, 0.5H), 2.63 (dd, J=26. 34,11.88Hz, 1H), 3.14 (t, J=11.94Hz, 0.5H), 3.49 (t, J=11.46Hz, 0.5H), 3.86 (t, J=10.86Hz, 0.5H), 4.08 (t, J=28.56Hz, 3.5H), 4.22 (s, 0.5H), 4.84 (d D, J=34.98,10.68Hz, 1H), 5.14 (s, 2H), 5.74 (d, J=9.96Hz, 1H), 6.34 (t, J =15.9Hz, 1H), 6.65 (m, 2H), 7.14 (d, J=8.64Hz, 2H), 7.38 (t, J=8.64Hz, 3 H), 7.43 (q, J=7.32Hz, 2H), 7.46 (d, J=7.32Hz, 2H), 7.87 (s, 1H).
Embodiment 19:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3 -(4-((4-chlorobenzyl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) The preparation of (compound 26)
Step 19a: the tert-butyl group (R)-3-(4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-2-oxo-2,3-dihydro- 1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (tert-butyl (R)-3-(4-amino-3-(4-((4-chlo robenzyl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -carboxylate) preparation of (compound 602-26)
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (0.423g, 1.27mmol, 1.0 equivalent), (4-((4-chlorobenzyl) epoxide) benzene Base) boric acid (601-26) (0.433g, 1.65mmol, 1.3 equivalent), copper acetate (0.254g, 1.40mmol, 1.1 Equivalent), molecular sieve (0.400g), pyridine (0.301g, 3.81mmol, 3.0 equivalent) and N, N-dimethyl formyl Amine (10ml), reactant liquor is heated to 40 DEG C overnight in atmosphere.Reactant liquor ethyl acetate (100ml) dilutes, Washing with semi-saturation saline solution (100ml × 3), organic phase silica gel mixed sample is spin-dried for, and concentrate column chromatography is pure Change (eluant, eluent: dichloromethane: methyl alcohol=60:1) and obtain the tert-butyl group (R)-3-(4-amino-3-(4-((4-chlorobenzyl) Epoxide) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (0.200g, Yield: 29%).LCMS (ESI): m/z 551 [M+1]+, yellow oil；TLC:Rf 0.7 (dichloromethane Alkane: methyl alcohol=20:1).
Step 19b:(R)-4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-1-(piperidines-3-base)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-((4-chlorobenzyl) oxy) phenyl)-1-(piperidin-3-yl) -1H-imidazo [4,5-c] pyridin-2 (3H)-one) preparation of (compound 603-26)
In reaction bulb add the tert-butyl group (R)-3-(4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (602-26) (0.20g, 1.0mmol, 1.0 Equivalent), dichloromethane (10ml) and trifluoracetic acid (2.0ml), room temperature reaction half an hour.Reactant liquor is poured into full With in sodium carbonate liquor (100ml), extracting with dichloromethane (80ml × 2), organic phase silica gel mixed sample is spin-dried for, Concentrate column chromatography (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purifies and obtains (R) -4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-2 (3H)- Ketone (0.145g, yield: 90%).LCMS (ESI): m/z 451 [M+1]+, light yellow solid；TLC:Rf 0.1 (dichloromethane: methyl alcohol=20:1).
Step 19c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3- (4-((4-chlorobenzyl) oxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Thing 26) preparation
Toward acryloyl chloride (202-4) (0.035g, 0.39mmol, 1.2 equivalent) dichloromethane solution (7ml) in 0 DEG C Lower dropping (R)-4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyrrole The dichloromethane solution (8ml) of pyridine-2 (3H)-one (603-26) (0.145g, 0.32mmol, 1.0 equivalent), the most again The dichloromethane solution (1ml) of dropping diisopropyl ethyl amine (0.062g, 0.48mmol, 1.5 equivalent), at 0 DEG C Lower reaction 5 minutes.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), organic phase Being spin-dried for silica gel mixed sample, concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=40:1) must To (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-((4-chlorobenzyl) epoxide) phenyl)-1,3-dihydro-2H- Imidazo [4,5-c] pyridin-2-ones (0.100g, yield: 62%).Colorless solid, fusing point: 93.1-95.9 DEG C.T LC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 504 [M+1]+,1HNMR(C DCl3, 500MHz): δ 7.83 (d, J=5Hz, 1H), 7.37 (m, 6H), 7.09 (d, J=8.5Hz, 1H), 6.62(m,2H),6.32(m,1H),5.71(m,1H),5.08(s,2H),4.80(m,1H),4.22(s,2 H),4.09(m,2H),3.84(m,0.5H),3.45(m,0.5H),3.12(m,0.5),2.60(m,1.5H),2. 19(m,2H),2.09(m,1H),1.97(m,1H)。
Embodiment 20:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-(benzyloxy) pyridin-3-yl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6 -(benzyloxy) pyridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 2 7) preparation
Step 20a: the tert-butyl group (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridine-3-base)-2,3-dihydro-1H- Imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate ((tert-butyl (R)-3-(4-amino-3-(6-(benzyloxy) pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxy Late) preparation of (602-27)
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine is added in reaction bulb -1-base) piperidines-1-carboxylate (306) (0.999g, 3.0mmol, 1.0 equivalent), 2-benzyloxy-5-(4,4,5,5-tetramethyls Base-1,3,2-dioxaborolane-2-bases) pyridine (601-27) (1.400g, 4.5mmol, 1.5 equivalent), acetic acid Copper (0.820g, 4.5mmol, 1.5 equivalent), molecular sieve (0.500g), pyridine (0.710g, 9.0mmol, 3.0 Equivalent) and DMF (10ml), reactant liquor is heated to 40 DEG C overnight in atmosphere.Reactant liquor is used Ethyl acetate (100ml) dilutes, and washs with semi-saturation saline solution (100ml × 3), and organic phase silica gel mixed sample is spin-dried for, Concentrate column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=60:1) and obtains the tert-butyl group (R)-3-(4- Amino-2-oxo-3-(6-benzyloxypyridine-3-base)-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1- Carboxylate (0.410g, yield: 52%).LCMS (ESI): m/z 517 [M+1]+, yellow oil；TLC: Rf 0.7 (dichloromethane: methyl alcohol=20:1).
Step 20b:(R)-4-amino-3-(6-benzyloxypyridine-3-base)-1-(piperidines-3-base)-1H-imidazo [4,5-c] Pyridine-2 (3H)-one ((R)-4-amino-3-(6-(benzyloxy) pyridin-3-yl)-1-(piperidin-3-yl)-1H-i Midazo [4,5-c] pyridin-2 (3H)-one) preparation of (603-27)
The tert-butyl group (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridine-3-base)-2,3-two is added in reaction bulb Hydrogen-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylate (602-27) (0.41g, 1.0mmol, 1.0 equivalent), Dichloromethane (10ml) and trifluoracetic acid (2.0ml), room temperature reaction half an hour.Pour reactant liquor into saturated sodium carbonate In solution (100ml), extracting with dichloromethane (50ml × 2), organic phase silica gel mixed sample is spin-dried for, and concentrate is used Column chromatography (eluant, eluent: dichloromethane: methyl alcohol: triethylamine=10:1:0.1) purify obtain (R)-4-amino- (0.220g receives 3-(6-benzyloxypyridine-3-base)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-2 (3H)-one Rate: 66%).LCMS (ESI): m/z 417 [M+1]+, light yellow solid；TLC:Rf 0.1 (dichloromethane: Methyl alcohol=20:1).
Step 20c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-(benzyloxy) pyridin-3-yl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(be Nzyloxy) pyridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) system of (compound 27) Standby
Toward acryloyl chloride (202-4) (0.057g, 0.64mmol, 1.2 equivalent) dichloromethane solution (7ml) in 0 DEG C Lower dropping (R)-4-amino-3-(6-benzyloxypyridine-3-base)-1-(piperidines-3-base)-1H-imidazo [4,5-c] pyridine-2 (3H) dichloromethane solution (7ml) of-one (603-27) (0.220g, 0.53mmol, 1.0 equivalent), drips the most again Add the dichloromethane solution (1ml) of diisopropyl ethyl amine (0.102g, 0.80mmol, 1.5 equivalent), at 0 DEG C Lower reaction 5 minutes.Reactant liquor is poured in water (100ml), extract with dichloromethane (50ml × 2), organic phase Being spin-dried for silica gel mixed sample, residue column chromatography purifies (eluant, eluent: dichloromethane: methyl alcohol=30:1) must To (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(6-(benzyloxy) pyridin-3-yl)-1,3-dihydro-2H-miaow Azoles also [4,5-c] pyridin-2-ones (0.135g, yield: 54%).Colorless solid, fusing point: 107.3-109.2 DEG C.T LC:Rf 0.5 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 471 [M+1]+,1HNMR(C DCl3, 500MHz): δ 8.29 (d, J=3Hz, 1H), 7.89 (d, J=5.5Hz, 1H), 7.68 (q, 2 H), 7.48 (d, J=7Hz, 2H), 7.40 (t, J=7Hz, 2H), 7.35 (m, 1H), 6.96 (d, J= 8.5Hz, 1H), 6.60 (m, 2H), 6.30 (m, 1H), 5.71 (m, 1H), 5.44 (s, 2H), 4.82 (m, 1H), 4.0-4.19 (m, 4H), 3.84 (m, 0.5H), 3.45 (m, 0.5H), 3.13 (m, 0.5H), 2.58 (m, 1.5H), 2.11 (m, 1H), 1.98 (m, 1H), 1.65 (m, 1H).
Embodiment 21:1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-fluorophenoxy) Phenyl)-1H-pyrrolo-[3,2-c] pyridine-2 (3H)-one (1-((R)-1-acryloylpiperidin-3-yl)-4-a Mino-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) (chemical combination Thing 12) preparation
Step 21a:2-(4-(4 fluoro-phenoxy group)-phenyl]-4,4,5,5-tetramethyl 1,3,2-dioxy boron penta ring (2-(4-(4-fluorophenoxy) phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (compound Preparation 108-12)
By bromo-for 1-4-(4 fluoro-phenoxy group) benzene (2.00g, 7.54mmol, 1.0 equivalent), connection boric acid frequency where Alcohol ester (5.84g, 15.1mmol, 2.0 equivalent), potassium acetate (1.48g, 15.1mmol, 2.0 equivalent) and P d(dppf)Cl2(0.54g, 0.754mmol, 0.1 equivalent) inflated with nitrogen is protected, and is subsequently adding dioxane (2 0ml), 90 DEG C of reactions are overnight.By reactant liquor cooling water washing, dichloromethane extracts, concentrates after drying, column chromatography (eluant, eluent: dichloromethane: n-hexane=1:2) obtain 2-(4-(4 fluoro-phenoxy group)-phenyl]-4, 4,5,5-tetramethyl 1,3,2-dioxy boron penta rings (1.10g, yield 46.5%), off-white color solid, TLC:R F 0.6 (dichloromethane: n-hexane=1:2)
Step 21b:((3R)-the tert-butyl group-3-(4-amino-3-(4-(4-fluorophenoxy) phenyl)-2-oxo-2,3- Dihydro-1H-pyrrolo-[3,2-c] pyridine-1-base) piperidines-1-carboxylate ((3R)-tert-butyl 3-(4-amino-3-(4 -(4-fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidi Ne-1-carboxylate) preparation of (compound 307-12)
The tert-butyl group (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] is added in reaction bulb Pyridine-1-base) piperidines-1-carboxylate (306) (3.0g, 9.0mmol, 1.0 equivalent), 2-(4-(4 Fluoro-phenoxy group)-phenyl]-4,4,5,5-tetramethyls 1,3,2-dioxy boron penta ring (108-12) (0.85g, 2. 5mmol, 1.00 equivalents), copper acetate (0.98g, 5mmol, 2 equivalent), triethylamine (0.5g, 5mmol, 2.00 equivalents), pyridine (0.40g, 5mmol, 2.00 equivalent) and DMF (10ml), Reactant liquor is heated to 40 DEG C overnight in atmosphere.Reactant liquor ethyl acetate (200ml) dilutes, and uses semi-saturation Saline solution (150ml × 3) washs, and organic phase silica gel mixed sample is spin-dried for, and residue column chromatography purifies and (washes De-agent: ethyl acetate: hexamethylene=2:1) obtain the tert-butyl group ((3R)-tert-butyl group-3-(4-amino-3-(4 -(4-fluorophenoxy) phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo-[3,2-c] pyridine-1-base) piperidines-1-carboxylate (0.19g, yield: 14%).LCMS (ESI): m/z 519 [M+1]+, yellow oil；TLC:Rf 0.57 (ethyl acetate: hexamethylene=2:1).
Step 21c:4-amino-3-(4-(4-fluorophenoxy) phenyl)-1-((R)-piperidines-3-base)-1H- Pyrroles [3,2-c] pyridine-2 (3H)-one (4-amino-3-(4-(4-fluorophenoxy) phenyl)-1-((R)-piper Idin-3-yl)-1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) preparation of (compound 308-12)
The tert-butyl group ((3R)-tert-butyl group-3-(4-amino-3-(4-(4-fluorophenoxy) phenyl) is added in reaction bulb -2-oxo-2,3-dihydro-1H-pyrrolo-[3,2-c] pyridine-1-base) piperidines-1-carboxylate (307-12) (0.19g, 0.36mmol, 1.0 equivalents), dichloromethane (5ml) and trifluoracetic acid (1.0ml), reactant liquor is in room temperature mistake Night.Reactant liquor is poured in saturated sodium carbonate solution (100ml), extracts with dichloromethane (10mlX2), Organic phase silica gel mixed sample is spin-dried for, residue column chromatography (eluant, eluent: dichloromethane: methyl alcohol: three second Amine=10:1:0.1) purify obtain 4-amino-3-(4-(4-fluorophenoxy) phenyl)-1-((R)-piperidines- 3-yl)-1H-pyrroles [3,2-c] pyridine-2 (3H)-one (0.1g, yield: 66.7%).LCMS (ESI): m/ z 419[M+1]+, yellow oil；TLC:Rf 0.1 (dichloromethane: methyl alcohol=20:1).
Step 21d:1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-fluorophenoxy) Phenyl)-1H-pyrrolo-[3,2-c] pyridine-2 (3H)-one (1-((R)-1-acryloylpiperidin-3-yl)-4-ami No-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) (compound 12) Preparation
At 0 DEG C in the dichloromethane solution (5ml) of acryloyl chloride (0.032g, 0.36mmol, 1.5 equivalent) Lower dropping (4-amino-3-(4-(4-fluorophenoxy) phenyl)-1-((R)-piperidines-3-base)-1H-pyrroles [3, 2-c] dichloromethane solution (3 of pyridine-2 (3H)-one (308-12) (0.1g, 0.24mmol, 1.0 equivalent) Ml), the dichloromethane dripping diisopropyl ethyl amine (0.062g, 0.48mmol, 2.0 equivalent) the most again is molten Liquid (2ml), reacts 5 minutes at 0 DEG C.Reactant liquor is poured in water (10ml), with dichloromethane (1 0mlX2) extraction, organic phase silica gel mixed sample is spin-dried for, and residue column chromatography purifies (dichloromethane: first Alcohol=40:1) obtain (1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-(4-fluorophenoxy) Phenyl)-1H-pyrrolo-[3,2-c] pyridine-2 (3H)-one (0.028g, yield: 24%).Off-white color solid, Fusing point: 86-88 DEG C.TLC:Rf 0.5 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 4 73[M+1]+,1HNMR(CDCl3, 400MHz): δ 7.87 (d, J=5Hz, 1H), 7.39 (d, J=8. 7Hz, 2H), 7.08 (m, 6H), 6.63 (d, J=5Hz, 2H), 6.30 (d, J=17.6Hz, 1H), 5.72 (s, 1H), 4.82 (d, J=12Hz, 1H), 4.12 (d, J=13.6Hz, 4H), 3.85 (m, 0.5H), 3.48 (d, J=11.2Hz, 0.5H), 3.13 (m, 0.5H), 2.62 (m, 1.5H), 2.11 (d, J=11.2Hz, 1H), 1. 98 (d, J=14Hz, 1H), 1.60 (m, 1H).
Embodiment 22:(R)-1-(3-(1-(acryloyl group) piperidines))-4-amino-3-(4-(4-diformazan ammonia Phenoxyl) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3 -yl)-4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 21)
Step 22a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylamino phenyl)-2, 3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (tert-butyl (R)-3-(4-amino-3-(4-(4-(dimethyl amino)phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine -1-carboxylate) preparation of (compound 307-21)
(R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-hydroxy phenyl)-2,3-dihydro-1H-imidazoles And [4,5-c] pyridine) piperidines (502-19) (0.88g, 2.07mmol, 1.0 equivalent), to dimethylamino bromobenzene (1.24g, 6.21mmol, 3.0 equivalent) and N, N-dimethyl glycine hydrochloride (0.35g, 2.48m Mol, 1.2 equivalents) it is dissolved in dioxane (20mL), add cuprous iodide (0.12g, 0.62m Mol, 0.3 equivalent) and cesium carbonate (2.36g, 7.25mmol, 3.5 equivalent), then in nitrogen is protected 1 00 DEG C is reacted 24 hours.Reactant liquor is cooled to room temperature and concentrates, the thick product column chromatography (two obtained Chloromethanes: methyl alcohol=50:1) purify (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-diformazan Aminophenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (0.69g, yield: 61%).LCM S (ESI): m/z 545 [M+1]+, gray solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 22b:(R)-4-amino-3-(4-(4-dimethylamino phenoxy group) phenyl)-1-(3-pyrrolidines) -1H-imidazo [4,5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(4-(dimethylamino) phenoxy) ph Enyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 308- 21) preparation
Will ((R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylamino phenyl)-2,3-dihydro- 1H-imidazo [4,5-c] pyridine) piperidines (307-21) (0.69g, 1.27mmol, 1.0 equivalent) is dissolved in two In chloromethanes (15mL), then being added thereto to trifluoroacetic acid (3mL), the most at room temperature reaction 2 is little Time.Reaction mixture dichloromethane (100mL) is diluted, successively with saturated sodium carbonate solution (30m L × 2) and saturated aqueous common salt (60mL) washing, then organic layer silica gel mixed sample is spin-dried for, uses post afterwards Chromatography (dichloromethane: methyl alcohol: triethylamine=100:10:1) purifies (R)-4-amino-3-(4-(4 -dimethylamino phenoxy group) phenyl)-1-(3-pyrrolidines)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.5 2g, yield: 93%).LCMS (ESI): m/z 445 [M+1]+, faint yellow solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).
Step 22c:(R)-1-(3-(1-(acryloyl group) piperidines))-4-amino-3-(4-(4-dimethylamino Phenoxy group) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)- 4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]py Ridin-2-one) preparation of (compound 21)
By (R)-4-amino-3-(4-(4-dimethylamino phenoxy group) phenyl)-1-(3-pyrrolidines)-1H-miaow Azoles also [4,5-c] pyridine-2 (3H)-one (308-21) (0.2g, 0.45mmol, 1.0 equivalent), acrylic acid (3 9mg, 0.54mmol, 1.2 equivalent), DCC (111mg, 0.54mmol, 1.2 equivalent) and DM AP (5.5mg, 0.045mmol, 0.1 equivalent) is dissolved in dichloromethane (10mL), the most anti- Answer 1 hour.Be concentrated to give thick product after having reacted, by column chromatography (dichloromethane: methyl alcohol=50: 1) compound (R)-1-(3-(1-(acryloyl group) piperidines))-4-amino-3-(4-(4-diformazan ammonia is purified to obtain Phenoxyl) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (60mg, yield: 27%).White Solid, fusing point: 92.3-97.6 DEG C.TLC:Rf 0.5 (dichloromethane: methyl alcohol=15:1).LCMS(ES I): m/z 499 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.85 (s, 1H), 7.35 (d, J= 9.0Hz, 2H), 7.04 (d, J=9.0Hz, 2H), 7.01 (d, J=2.5Hz, 2H), 6.75 (d, J=6.5Hz, 2H), 6.70-6.51 (m, 2H), 6.33-6.30 (m, 1H), 5.71 (s, 1H), 4.83-4. 81(m,1H),4.25-4.10(m,4H),3.84-3.46(m,1H)。
Embodiment 23:(3R)-1-[1-(1-acryloyl group) piperidines-3-base]-4-amido-3-[4-(4-trifluoro Methylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((3R)-1-(1-Acryloyl- piperidin-3-yl)-4-amino-3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-i Midazo [4,5-c] pyridin-2-one) preparation of (compound 22)
Step 23a:(3R)-3-[4-amino-2-oxo-3-[4-(4-4-trifluoromethylphenopendant-phenyl)]-2,3- Dihydro-1H-imidazo [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (3-{4-Amino-2-oxo-3-[4- (4-trifluoromethyl-phenoxy)-phenyl]-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl}-piperi Dine-1-carboxylic acid tert-butyl ester) preparation of (compound 307-22)
By (3R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1- T-butyl formate (306) (1.17g, 3.52mmol, 1 equivalent) is dissolved in DMF (15ml), is sequentially added into Molecular sieve (2g), copper acetate (0.96g, 5.28mmol, 1.5 equivalent), 4-4-trifluoromethylphenopendant benzene boron (0.417g, 5.28mmol, 1.5 work as acid (108-22) (1.19g, 4.22mmol, 1.1 equivalent), pyridine Amount), stirred overnight at room temperature.Reacting complete, filter, mother liquor is washed twice, is dried, and concentrates, methyl alcohol/DC M (1:40) column chromatography obtains brown syrup (3R)-3-[4-amino-2-oxo-3-[4-(4-trifluoromethylbenzene Epoxide-phenyl)]-2,3-dihydro-1H-imidazo [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (0.55g, Yield 27.5%)；TLC:Rf 0.7 (dichloromethane: methyl alcohol=20:1)；LCMS (ESI): m/z 570 [M +1]+1。
Step 23b:(3R)-4-amino-1-[piperidines-3-base]-3-[4-(4-4-trifluoromethylphenopendant)-phenyl] 1,3-2H-imidazo [4,5-c] pyridin-2-ones (4-Amino-1-piperidin-3-yl-3-[4-(4-trifluoromethy L-phenoxy)-phenyl]-1,3-dihydro-imidazo [4,5-c] pyridin-2-one) system of (compound 308-22) Standby
By (3R)-3-[4-amido-2-oxo-3-[4-(4-4-trifluoromethylphenopendant-phenyl)]-2,3-dihydro-1H -imidazo [4,5-c] pyridine-1-base] (0.55g, 0.97mmol, 1 work as piperidines-1-t-butyl formate (307-22) Amount) it is dissolved in DCM (2ml), add TFA (2ml), room temperature reaction 1h.Reactant liquor concentrates, then with full It is neutralized to slightly meta-alkalescence with sodium acid carbonate, extracts with 5ml DCM, be dried, concentrate, methyl alcohol/DCM/ tri-second Amine (1:10:0.1) column chromatography obtains off-white color foaming solid (3R)-4-amino-1-[piperidines-3-base]-3 -[4-(4-4-trifluoromethylphenopendant)-phenyl] 1,3-2H-imidazo [4,5-c] pyridin-2-ones (0.408g, yield 90%)；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 470 [M+1]+1。
Step 23c:(3R)-1-[1-(1-acryloyl group) piperidines-3-base]-4-amido-3-[4-(4-trifluoro Methylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((3R)-1-(1-Acryloyl- piperidin-3-yl)-4-amino-3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imid Azo [4,5-c] pyridin-2-one) preparation of (compound 22)
By 4-amido-3-[4-(4-4-trifluoromethylphenopendant-phenyl)]-1-[(3R)-piperidines-3-base]-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-ones (308-22) (67mg, 0.143mmol, 1 equivalent), propylene Acid (12mg, 0.171mmol, 1.2 equivalent) is dissolved in DCM (5ml), add HATU (71mg, 0.1 86mmol, 1.3 equivalents) and Et3N (22mg, 0.215mmol, 1.5 equivalent), reacts 0.5 little under ice bath Time.Reacting complete, concentrate, column chromatography purifies (eluant, eluent: methyl alcohol: dichloromethane=1:20) and obtains white Solid (3R)-1-[1-(1-acryloyl group) piperidines-3-base]-4-amido-3-[4-(4-4-trifluoromethylphenopendant -phenyl)]-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (20mg, yield 20%)；Purity 95.1%；T LC:Rf 0.4 (dichloromethane: methyl alcohol=20:1)；Fusing point: 64～65 DEG C；LCMS (ESI): m/z 52 4[M+1]+1；1HNMR(400MHz,CDCl3):δ1.64(m,1H),1.99(m,3H),2.64(m, 1.5H), 3.13 (t, 0.5H, J=12.36Hz), 3.47 (t, 0.5H, J=11.34Hz), 3.86 (s, 0. 5H),4.11(m,1.5H),4.21(s,0.5H),4.31(s,1H),4.83(dd,1H,1J=10.08Hz,2 J=8.34Hz), 5.75 (d, 1H, J=9.66Hz), 6.35 (d, 1H, J=16.2Hz), 6.62 (m, 2 H),7.18(dd,4H,1J=8.64Hz,2J=8.4Hz), 7.46 (d, 2H, J=8.52Hz), 7.65 (d, 2H, J=8.4Hz), 7.86 (s, 1H).
Embodiment 24:(3R)-1-(1-acryloyl group-piperidines-3-base)-4-amino-3-[4-(4-hydroxy toluene epoxide) -phenyl]-1,3-2H-imidazoles [4,5-c] pyridin-2-ones (1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4- (4-hydroxymethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) The preparation of (compound 23)
Step 24a:(3R)-3-[4-amido-2-oxo-3-(4-hydroxy methyl phenyloxy-phenyl)-2,3-dihydro-1 H-imidazo [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (3-{4-Amino-2-oxo-3-(4-hydroxy methyl phenoxy-phenoxy)-2,3-dihydro-1-H-imidazo[4,5-c]pyridin-1-yl}-piperidi Ne-1-carboxylic acid tert-butyl ester) preparation of (compound 307-23)
(3R)-3-[4-amido-2-oxo-3-(4-hydroxy phenyl)-2,3-dihydro-1H-miaow is added in flask Azoles also [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (502-19) (737mg, 1.73mmol, 1 equivalent), Cs2CO3(1.13g, 3.46mmol, 2 equivalent), adds NMP (10ml) and stirs in brown suspension, Adding 4-fluorobenzaldehyde (258mg, 2.076mmol, 1.2 equivalent), 80 DEG C of reactions are overnight.By reaction system Cooling, filters, and mother liquor adds 20ml water and adds vinegar acid for adjusting pH to slant acidity, DCM (10ml) extraction Taking twice, organic phase is washed 2 times with water (20ml) the most again, concentrates, column chromatography (methyl alcohol: DCM=1: 40) (3R)-3-[4-amido-2-oxo-3-(4-carboxaldehyde radicals Phenoxy-phenyl)-2,3-dihydro-1H-miaow is obtained Azoles also [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (500mg, yield 55%), TLC:Rf 0.4 (methyl alcohol: dichloromethane=1:40), light brown syrup, LCMS (ESI): m/z 530 [M+1]+。 By above-claimed cpd (500mg, 0.945mmol, 1 equivalent), it is dissolved in methyl alcohol/oxolane (3ml/3ml), Add sodium borohydride (179mg, 4.73mmol, 5 equivalent) and lithium chloride (200mg, 4.73mmol, 5 Equivalent).Adding water (20ml) stirring, DCM (10ml x 2) extracts, and concentrates, column chromatography (methyl alcohol: DCM=1:40) (3R)-3-[4-amido-2-oxo-3-(4-hydroxy methyl phenyloxy-phenyl)-2,3-two is obtained Hydrogen-1H-imidazo [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (220mg, yield 44%), TLC: Rf 0.3 (methyl alcohol: dichloromethane=1:40), light yellow syrup, LCMS (ESI): m/z 532 [M+ 1]+。
Step 24b:(3R)-4-amido-3-[4-(4-hydroxy methyl phenyloxy-phenyl)]-1-piperidines-3-base-1,3 -2H-imidazo [4,5-c] pyridin-2-ones (4-Amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1 -piperidin-3-yl-1,3-dihydro-imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-23)
(3R)-3-[4-amido-2-oxo-3-[4-(4-hydroxy methyl phenyloxy-phenyl)]-2,3-is added in flask Dihydro-1H-imidazo [4,5-c] pyridine-1-base] piperidines-1-t-butyl formate (307-23) (0.22g, 0.41mm Ol, 1 equivalent), it is dissolved in DCM (2ml), adds TFA (1ml), room temperature reaction 1h.Reactant liquor concentrates, It is neutralized to slightly meta-alkalescence with saturated sodium bicarbonate again, extracts with 5ml DCM, be dried, concentrate, methyl alcohol/DC M/ triethylamine (1:10:0.1) column chromatography obtains (3R)-4-amido-3-[4-(4-hydroxy methyl phenyloxy-phenyl)] -1-piperidines-3-base-1,3-2H-imidazo [4,5-c] pyridin-2-ones (0.092g, yield 52%), off-white color oil Shape thing, TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1)；LCMS (ESI): m/z 432 [M+1]+1。
Step 24c:(3R)-1-(1-acryloyl group-piperidines-3-base)-4-amino-3-[4-(4-hydroxy toluene epoxide) -phenyl]-1,3-2H-imidazoles [4,5-c] pyridin-2-ones (1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4- (4-hydroxymethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo [4,5-c] pyridin-2-one) (change Compound 23) preparation
(3R)-4-amido-3-[4-(4-hydroxy methyl phenyloxy-phenyl)]-1-piperidines-3-base is added in flask -1,3-2H-imidazo [4,5-c] pyridin-2-ones (308-23) (80mg, 0.1854mmol, 1 equivalent), is dissolved in DCM (2ml)/Et3N (56mg), adds acrylic acid (15mg, 0.2039mmol, 1.1 equivalent) under ice bath With HATU (92mg, 0.241mmol, 1.3 equivalent), react 0.5 hour.Reacting complete, column chromatography is pure Change (eluant, eluent: methyl alcohol: dichloromethane=1:20) and obtain white solid 4-amido-1-[(3R)-1-(2- Crotonyl) dimethylamine-3-base]-3-[4-(4-hydroxy methyl phenyloxy-phenyl)]-1,3-dihydro-2H-imidazo [4, 5-c] pyridin-2-ones (20mg, yield 22%)；Purity 95.3%；TLC:Rf 0.4 (dichloromethane: methyl alcohol =20:1)；Fusing point: 99～100 DEG C；LCMS (ESI): m/z 486 [M+1]+1；1HNMR(600M Hz,CDCl3):δ1.64(m,1H),1.89(m,2H),2.10(s,1H),2.64(m,1.5H),3.12(t, 0.5H, J=12.12Hz), 3.46 (t, 0.5H, J=11.04Hz), 3.85 (s, 0.5H), 4.21 (m, 4 H),4.82(dd,1H,1J=8.04Hz,2J=11.22Hz), 5.74 (d, 1H, J=9.84Hz), 6. 34(m,1H),6.62(m,2H),7.11(dd,4H,1J=8.52Hz,2J=8.34Hz), 7.39 (t, 4H, J=6.36Hz), 7.86 (s, 1H).
Embodiment 25:(R)-1-(3-(1-acryloyl group) piperidyl)-4-amino-3-(4-(4-fluorine benzyloxy) Phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino -3-(4-((4-fluorobenzyl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) The preparation of (compound 25)
Step 25a:4-(4-fluorine benzyloxy) phenyl boric acid ((4-((4-fluorobenzyl) oxy) phenyl) boronic aci D) preparation of (compound 601-25)
P bromophenol (3.0g, 17.34mmol, 1.0 equivalent) is added, to fluorobenzyl bromide (3. in reaction bulb 93g, 20.81mmol, 1.2 equivalent), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalent) and N, Dinethylformamide (20ml), room temperature reaction is overnight.Reactant liquor add water (100mL) dilution, use acetic acid Ethyl ester (50mL × 3) extracts, and extract anhydrous sodium sulfate is dried, and concentrates, then pure with column chromatography Change (petroleum ether: ethyl acetate=20:1) and obtain 4-(4-fluorine benzyloxy) bromobenzene (4.48g, yield: 9 2%).LCMS (ESI): m/z 281 [M+1]+, white solid；TLC:Rf 0.5 (petroleum ether: acetic acid second Ester=10:1).Compound obtained above (3.16g, 11.24mmol, 1.0 equivalent) is dissolved in anhydrous four In hydrogen furans (40mL), it is cooled to-78 DEG C by dry ice acetone bath, drips n-BuLi the most lentamente (2. 5M, 5.4mL, 13.49mmol, 1.2 equivalent), stir 1 hour at-78 DEG C after dropping.Boric acid Trimethyl (2.55mL, 22.48mmol, 2.0 equivalent) is added and is then slowly raised to room temperature and is stirred overnight. Add 2N aqueous hydrochloric acid solution (20mL) and stir 2 hours.Aqueous layer with ethyl acetate (50mL × 3) extracts, It is dried with anhydrous sodium sulfate after merging organic layer, concentration, the thick product column chromatography obtained (petroleum ether: Ethyl acetate=1:1) purify to obtain 4-(4-fluorine benzyloxy) phenyl boric acid (0.92g, yield: 33%).LCMS(E SI): m/z 247 [M+1]+, white solid；TLC:Rf 0.2 (petroleum ether: ethyl acetate=2:1).
Step 25b:(R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-(4-fluorine benzyloxy) phenyl)-2- Oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (tert-butyl (R)-3-(4-amino-3-(4-((4-fl uorobenzyl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin E-1-carboxylate) preparation of (compound 602-25)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Piperidines (0.85g, 2.55mmol, 1.0 equivalent), 4-(4-fluorine benzyloxy) phenyl boric acid (0.82g, 3.32mm Ol, 1.3 equivalents) and pyridine (0.62mL, 7.65mmol, 3.0 equivalent) be dissolved in N, N-dimethyl formyl In amine (8mL), add copper acetate (0.51g, 2.81mmol, 1.1 equivalent) andMolecular sieve (1 G), the most in atmosphere 50 DEG C reaction overnight.Reactant liquor is cooled to room temperature and with ethyl acetate (100m L) dilution, filters, and filtrate is washed with semi-saturation saline solution (50mL × 2).Organic layer anhydrous sodium sulfate Be dried, concentrate, the thick product column chromatography (dichloromethane: methyl alcohol=50:1) obtained purify (R)- 1-tertbutyloxycarbonyl-3-(4-amino-3-(4-(4-fluorine benzyloxy) phenyl)-2-oxo-2,3-dihydro-1H-imidazoles And [4,5-c] pyridine) piperidines (0.27g, yield: 32%).LCMS (ESI): m/z 534 [M+1]+, palm fibre Look solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 25c:(R)-4-amino-3-(4-(4-fluorine benzyloxy) phenyl)-1-(3-piperidyl)-1,3- 2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-((4-fluorobenzyl) oxy) phenyl)-1-(pip Eridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 603-25)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-(4-fluorine benzyloxy) phenyl)-2-oxo-2,3 -dihydro-1H-imidazo [4,5-c] pyridine) piperidines (602-25) (0.27g, 0.51mmol, 1.0 equivalent) It is dissolved in dichloromethane (10mL), then is added thereto to trifluoroacetic acid (2mL), the most anti- Answer 2 hours.Reaction mixture dichloromethane (50mL) is diluted, successively with saturated sodium carbonate solution (3 0mL × 2) and saturated aqueous common salt (30mL) washing, then organic layer silica gel mixed sample is spin-dried for, afterwards (R)-4-amino-3-(4 is purified with column chromatography (dichloromethane: methyl alcohol: triethylamine=100:10:1) -(4-fluorine benzyloxy) phenyl)-1-(3-piperidyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (0.20 G, yield: 90%).LCMS (ESI): m/z 434 [M+1]+, faint yellow solid；TLC:Rf 0.2 (two Chloromethanes: methyl alcohol=10:1).
Step 25d:(R)-1-(3-(1-acryloyl group) piperidyl)-4-amino-3-(4-(4-fluorine benzyloxy) Phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino- 3-(4-((4-fluorobenzyl) oxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (change Compound 25) preparation
By (R)-4-amino-3-(4-(4-fluorine benzyloxy) phenyl)-1-(3-piperidyl)-1,3-2H-imidazoles And [4,5-c] pyridin-2-ones (603-25) (0.20g, 0.46mmol, 1.0 equivalent), acrylic acid (43mg, 0.60mmol, 1.3 equivalents), DCC (124mg, 0.60mmol, 1.3 equivalent) and DMAP is (5. 6mg, 0.046mmol, 0.1 equivalent) it is dissolved in dichloromethane (10mL), at 0 DEG C, then react 1 little Time.Thick product it is concentrated to give after having reacted, pure by column chromatography (dichloromethane: methyl alcohol=50:1) Change to obtain compound 6-7 (110mg, yield: 49%).White solid, fusing point: 69.7-71.7 DEG C.TLC: Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 488 [M+1]+,1HNMR(CD Cl3, 500MHz): δ 7.86 (s, 1H), 7.44-7.41 (m, 2H), 7.38-7.35 (m, 2H), 7.11-7.08 (m, 4H),6.64-6.57(m,2H),6.34-6.30(m,1H),5.72(s,1H),5.08(s,2H),4.90-4.82 (m,1H),4.25-4.05(m,4H),3.90-3.46(m,1H),3.16-2.50(m,2H),2.18-2.10(m,1 H),2.02-1.95(m,1H),1.70-1.60(m,1H)。
Embodiment 26:(R)-1-(3-(1-acryloyl group) piperidyl)-4-amino-3-(4-(2-pyridine epoxide) Phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino -3-(4-(pyridin-2-yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (change Compound 28) preparation
Step 26a:4-(2-pyridine epoxide) phenyl boric acid ((4-(pyridin-2-yloxy) phenyl) boronic acid) The preparation of (compound 108-28)
P bromophenol (3.0g, 17.34mmol, 1.0 equivalent), 2-fluorine pyridine (2.0 is added in reaction bulb 2g, 20.81mmol, 1.2 equivalent), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalent) and N, Dinethylformamide (20ml), 120 DEG C of reactions are overnight.Reactant liquor add water (100mL) dilution, use second Acetoacetic ester (50mL × 3) extracts, and extract anhydrous sodium sulfate is dried, and concentrates, then pure with column chromatography Change (petroleum ether: ethyl acetate=10:1) and obtain 2-(4-bromobenzene epoxide) pyridine (1.2g, yield: 28%). LCMS (ESI): m/z 250 [M+1]+, pale yellow oily liquid body；TLC:Rf 0.5 (petroleum ether: acetic acid second Ester=4:1).By above-mentioned gained compound (1.17g, 4.68mmol, 1.0 equivalent) and duplex pinacol boron Acid esters (1.54g, 6.08mmol, 1.3 equivalent) is dissolved in dioxane (15mL), is subsequently adding acetic acid Potassium (1.38g, 14.04mmol, 3.0 equivalent) and [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (0. 34g, 0.47mmol, 0.1 equivalent).Then react overnight at 100 DEG C for three times with nitrogen displacement.React It is concentrated to give thick product after one-tenth, purifies to obtain 4-(2-by column chromatography (petroleum ether: ethyl acetate=20:1) Pyridine epoxide) phenyl boric acid pinacol ester (1.1g, yield: 79%).LCMS (ESI): m/z 298 [M+1]+, Colourless oil liquid；TLC:Rf 0.5 (petroleum ether: ethyl acetate=10:1).Chemical combination by above-mentioned gained Thing (1.0g, 3.37mmol, 1.0 equivalent) is dissolved in oxolane (10mL), is subsequently adding periodic acid Sodium (1.08g, 5.05mmol, 1.5 equivalent) and 1N hydrochloric acid solution (10mL), at room temperature react 3 Hour.The pH value adding sodium bicarbonate solid regulation solution after having reacted is 6-7.Water layer dichloromethane (30mL × 3) extract, and with saturated aqueous common salt (30mL × 1) washing after organic layer mixing, use anhydrous sodium sulfate It is dried, is concentrated to give 4-(2-pyridine epoxide) phenyl boric acid (0.62g, yield: 86%).LCMS (ESI): m/ z 216[M+1]+, white solid；TLC:Rf 0.1 (petroleum ether: ethyl acetate=4:1).
Step 26b:(R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridine epoxide) phenyl) -2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (tert-butyl (R)-3-(4-amino-2-oxo-3-(4-(pyr idin-2-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbox Ylate) preparation of (compound 307-28)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Piperidines (306) (0.74g, 2.22mmol, 1.0 equivalent), 4-(2-pyridine epoxide) phenyl boric acid (108-28) (0. 62g, 2.89mmol, 1.3 equivalent) and pyridine (0.54mL, 6.66mmol, 3.0 equivalent) be dissolved in N, In dinethylformamide (10mL), add copper acetate (0.44g, 2.44mmol, 1.1 equivalent) WithMolecular sieve (1g), 50 DEG C of reactions are overnight the most in atmosphere.Reactant liquor is cooled to room temperature and uses Ethyl acetate (100mL) dilutes, and filters, and filtrate is washed with semi-saturation saline solution (50mL × 2).Organic Layer anhydrous sodium sulfate is dried, and concentrates, the thick product column chromatography (dichloromethane: methyl alcohol=50:1) obtained Purify (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridine epoxide) phenyl)-2,3 -dihydro-1H-imidazo [4,5-c] pyridine) piperidines (0.228g, yield: 20%).LCMS (ESI): m/z 503[M+1]+, brown solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 26c:(R)-4-amino-1-(3-piperidyl)-3-(4-(2-pyridine epoxide) phenyl)-1,3 -2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-2-yloxy) Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-28)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridine epoxide) phenyl)-2,3 -dihydro-1H-imidazo [4,5-c] pyridine) piperidines (307-28) (0.228g, 0.454mmol, 1.0 equivalent) It is dissolved in dichloromethane (10mL), then is added thereto to trifluoroacetic acid (2mL), the most anti- Answer 2 hours.Reaction mixture dichloromethane (50mL) is diluted, successively with saturated sodium carbonate solution (3 0mL × 2) and saturated aqueous common salt (30mL) washing, then organic layer silica gel mixed sample is spin-dried for, afterwards (R)-4-amino-1-(3 is purified with column chromatography (dichloromethane: methyl alcohol: triethylamine=100:10:1) -piperidyl)-3-(4-(2-pyridine epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (0.17 G, yield: 93%).LCMS (ESI): m/z 403 [M+1]+, faint yellow solid；TLC:Rf 0.2 (two Chloromethanes: methyl alcohol=10:1).
Step 26d:(R)-1-(3-(1-acryloyl group) piperidyl)-4-amino-3-(4-(2-pyridine epoxide) Phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino- 3-(4-(pyridin-2-yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 28) preparation
By (R)-4-amino-1-(3-piperidyl)-3-(4-(2-pyridine epoxide) phenyl)-1,3-2H-imidazoles And [4,5-c] pyridin-2-ones (308-28) (0.17g, 0.422mmol, 1.0 equivalent), acrylic acid (40mg, 0.549mmol, 1.3 equivalents), DCC (113mg, 0.549mmol, 1.3 equivalent) and DMAP is (5. 2mg, 0.042mmol, 0.1 equivalent) it is dissolved in dichloromethane (10mL), at 0 DEG C, then react 1 little Time.Thick product it is concentrated to give after having reacted, pure by column chromatography (dichloromethane: methyl alcohol=50:1) Change to obtain compound (R)-1-(3-(1-acryloyl group) piperidyl)-4-amino-3-(4-(2-pyridine epoxide) benzene Base)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (115mg, yield: 60%).White solid, fusing point: 211.2-213.3℃.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 45 7[M+1]+,1HNMR(CDCl3-d1, 500MHz): δ 8.23-8.22 (m, 1H), 7.88 (d, J=5. 0Hz, 1H), 7.76-7.73 (m, 1H), 7.46 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.08-7.06 (m, 1H), 6.99 (d, J=8.5Hz, 1H), 6.64-6.55 (m, 2H), 6.35-6.32 (m, 1H),5.75-5.73(m,1H),4.85-4.76(m,1H),4.18(s,2H),4.15-4.07(m,2H),3.86-3. 49(m,1H),3.13-2.61(m,2H),2.51-2.08(m,1H),2.01-1.95(m,1H),1.86-1.82 (m,1H)。
Embodiment 27:(R)-1-(3-(1-acryloyl group) piperidines)-4-amino-3-(4-(3-pyridine epoxide) Phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino -3-(4-(pyridin-3-yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (change Compound 29) preparation
Step 27a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridine epoxide) phenyl) -2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (tert-butyl (R)-3-(4-amino-2-oxo-3-(4-(pyr idin-3-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbox Ylate) preparation of (compound 307-29)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazoles And [4,5-c] pyridine) piperidines (402-17) (0.8g, 1.49mmol, 1.0 equivalent), 3-pyridone (40 3-29) (0.21g, 2.24mmol, 1.5 equivalent) and N, N-dimethyl glycine hydrochloride (39mg, 0. 28mmol, 0.18 equivalent) be dissolved in dioxane (8mL), add cuprous iodide (14.2mg, 0.075mmol, 0.05 equivalent) and cesium carbonate (0.97g, 2.98mmol, 2.0 equivalent), then at nitrogen In protection, 100 DEG C are reacted 60 hours.Reactant liquor is cooled to room temperature and concentrates, the thick product post layer obtained Analysis method (dichloromethane: methyl alcohol=40:1 to 20:1) purify (R)-1-tertbutyloxycarbonyl-3-(4-amino- 2-oxo-3-(4-(3-pyridine epoxide) phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (0.2 4g, yield: 32%).LCMS (ESI): m/z 503 [M+1]+, faint yellow solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 27b:(R)-4-amino-1-(3-piperidyl)-3-(4-(3-pyridine epoxide) phenyl)-1,3- 2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-3-yloxy) Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 308-29)
Synthetic method such as embodiment 26 step 26c, is only by wherein (R)-1-tertbutyloxycarbonyl-3-(4-ammonia Base-2-oxo-3-(4-(2-pyridine epoxide) phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (3 07-28) replace with (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridine epoxide) benzene Base)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (307-29) (0.24g, 0.48mmol, 1.0 Equivalent), obtain (R)-4-amino-1-(3-piperidyl)-3-(4-(3-pyridine epoxide) phenyl)-1,3-2 H-imidazo [4,5-c] pyridin-2-ones (0.18g, yield: 93%).LCMS (ESI): m/z 403 [M+1]+, Faint yellow solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).
Step 27c:(R)-1-(3-(1-acryloyl group) piperidines)-4-amino-3-(4-(3-pyridine epoxide) benzene Base)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4 -(pyridin-3-yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 29) Preparation
Synthetic method such as embodiment 26 step 26d, be only by wherein (R)-4-amino-1-(3-piperidyl)- 3-(4-(2-pyridine epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (308-28) replaces with (R)-4-amino-1-(3-piperidyl)-3-(4-(3-pyridine epoxide) phenyl)-1,3-2H-imidazo [4,5 -c] pyridin-2-ones (308-29) (0.18g, 0.45mmol, 1.0 equivalent), obtain (R)-1-(3-(1- Acryloyl group) piperidines)-4-amino-3-(4-(3-pyridine epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (0.18g, yield: 93%).White solid, fusing point: 80.5-83.8 DEG C.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 457 [M+1]+,1HNMR(CDCl3, 5 00MHz): δ 8.49 (d, J=2.5Hz, 1H), 8.45 (d, J=4.0Hz, 1H), 7.88 (d, J=5. 5Hz, 1H), 7.45-7.39 (m, 3H), 7.35-7.32 (m, 1H), 7.16 (d, J=8.5Hz, 2H), 6.6 5-6.58(m,2H),6.34-6.31(m,1H),5.72(s,1H),4.83-4.79(m,1H),4.20-4.11 (m,4H),3.92-3.47(m,1H),3.15-2.52(m,2H),2.12-1.96(m,2H),1.70-1.60 (m,1H)。
Embodiment 28:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(pyridin-4-yl epoxide) Phenyl)-1,3-dihydro-2H-imidazo [4,5c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-a mino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-on E) preparation of (compound 30)
Step 28a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridine epoxide) phenyl) -2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (tert-butyl (R)-3-(4-amino-2-oxo-3-(4-(pyr idin-3-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbox Ylate) preparation of (compound 307-30)
Synthetic method such as embodiment 26 step 26b, is only by wherein 4-(2-pyridine epoxide) phenyl boric acid (108-28) (0.645g, 3.0mmol, 1.0 work as to replace with (4-(pyridin-4-yl epoxide) phenyl) boric acid (108-30) Amount), obtain (R)-3-(4-amino-2-oxo-3-(4-(pyridin-4-yl epoxide) phenyl)-2,3-dihydro-1 H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylic acid tert-butyl ester (0.21g, yield: 14%).LCMS(E SI): m/z 503 [M+1]+, pale solid；TLC:Rf 0.5 (dichloromethane: methyl alcohol=20:1).
Step 28b:(R)-4-amino-1-(piperidines-3-base)-3-(4-(pyridin-4-yl epoxide) phenyl)-1, 3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-4 -yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) system of (compound 308-30) Standby
Synthetic method such as embodiment 26 step 26c, is only by wherein (R)-1-tertbutyloxycarbonyl-3-(4-ammonia Base-2-oxo-3-(4-(2-pyridine epoxide) phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) piperidines (3 07-28) replace with (R)-3-(4-amino-2-oxo-3-(4-(pyridin-4-yl epoxide) phenyl)-2,3-two Hydrogen-1H-imidazo [4,5-c] pyridine-1-base) piperidines-1-carboxylic acid tert-butyl ester (307-30) (0.21g, 0.42mmol, 1.0 equivalents), obtain (R)-4-amino-1-(piperidines-3-base)-3-(4-(pyridin-4-yl epoxide) phenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (0.158g, yield: 94%).LCMS (ESI): m/z 403[M+1]+, colorless solid；TLC:Rf 0.1 (dichloromethane: methyl alcohol=20:1).
Step 28c:(R)-1-(1-acryloylpiperidine-3-base)-4-amino-3-(4-(pyridin-4-yl epoxide) Phenyl)-1,3-dihydro-2H-imidazo [4,5c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4-am Ino-3-(4-(pyridin-4-yloxy) phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (change Compound 30) preparation
At 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (0.039g, 0.43mmol, 1.1 equivalent) Lower dropping (R)-4-amino-1-(piperidines-3-base)-3-(4-(pyridin-4-yl epoxide) phenyl)-1,3-dihydro- The dichloromethane of 2H-imidazo [4,5-c] pyridin-2-ones (308-30) (0.158g, 0.39mmol, 1.0 equivalent) Alkane solution (10ml), drips diisopropyl ethyl amine (0.075g, 0.59mmol, 1.5 equivalent) the most again Dichloromethane solution (1ml), reacts 10 minutes at 0 DEG C.Reactant liquor is poured in water (100ml), use Dichloromethane (100ml × 2) extracts, and organic phase silica gel mixed sample is spin-dried for, and residue column chromatography purifies (dichloromethane: methyl alcohol=20:1) obtains (R)-1-(1-acryloylpiperidine-3-base)-4-amino-3- (4-(pyridin-4-yl epoxide) phenyl)-1, (0.050g receives 3-dihydro-2H-imidazo [4,5c] pyridin-2-ones Rate: 28%).Colorless solid, fusing point: 79.6-81.7 DEG C.TLC:Rf 0.5 (dichloromethane: methyl alcohol=2 0:1).LCMS (ESI): m/z 457 [M+1]+,1HNMR(CDCl3, 500MHz): δ 8.51 (d, J=6Hz, 2H), 7.89 (d, J=5Hz, 1H), 7.51 (d, J=8.5Hz, 2H), 7.27 (d, J=8. 5Hz, 2H), 6.94 (d, J=6Hz, 2H), 6.67 (s, 1H), 6.60 (d, J=9.5Hz, 1H), 6.34 (d, J= 16.5Hz,1H),5.72(s,1H),4.84(m,1H),4.31-4.11(m,4H),3.86(m,0.5H),3.48(m, 0.5H), 3.13 (m, 0.5H), 2.63 (m, 1.5H), 2.11 (d, J=12Hz, 1H), 1.98 (d, J=13.5 Hz,1H),1.69(m,1H)。
Embodiment 29:(R)-4-amino-3-(4-phenoxy phenyl)-1-(3-(1-propioloyl phenylpiperidines))-1,3- 2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpi Peridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 32)
By (R)-4-amino-3-(4-phenoxy phenyl)-1-(3-piperidyl)-1H-imidazo [4,5-c] pyridine-2 (3 H)-one (308-11) (0.20g, 0.50mmol, 1.0 equivalent), propiolic acid (42mg, 0.60mmol, 1.2 equivalents), DCC (123mg, 0.60mmol, 1.2 equivalent) and DMAP (6mg, 0.05m Mol, 0.1 equivalent) it is dissolved in dichloromethane (10mL), then react 1 hour at 0 DEG C.Reaction completes After be concentrated to give thick product, purify to obtain compound (R) by column chromatography (dichloromethane: methyl alcohol=50:1) -4-amino-3-(4-phenoxy phenyl)-1-(3-(1-propioloyl phenylpiperidines))-1,3-2H-imidazo [4,5-c] pyridine- 2-ketone (80mg, yield: 35%).White solid, fusing point: 89.3-95.6 DEG C.TLC:Rf 0.4 (two Chloromethanes: methyl alcohol=20:1).LCMS (ESI): m/z 454 [M+1]+,1HNMR(CDCl3, 500M Hz): δ 7.90-7.86 (m, 1H), 7.41-7.38 (m, 4H), 7.20-7.17 (m, 1H), 7.14-7.09 (m, 4H), 6.64-6.60(m,1H),4.79-4.63(m,1H),4.58-4.45(m,1H),4.20-4.05(m,3H),3.95 -3.52(m,1H),3.20-2.70(m,2H),2.68-2.53(m,1H),2.15-1.95(m,2H),1.73-1.65 (m,1H)。
Embodiment 30:(R)-4-amino-1-(3-(1-(2-butine acyl group)) piperidyl)-3-(4-phenoxy phenyl) -1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-1-(1-(but-2-ynoyl) piperidin-3-yl)- 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 33) Preparation
Synthetic method such as embodiment 29, be only wherein propiolic acid is replaced with 2-tetrolic acid (52mg, 0.62 Mmol, 1.3 equivalents), obtain (R)-4-amino-1-(3-(1-(2-butine acyl group)) piperidyl)-3-(4-benzene Oxygen phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (60mg, yield: 27%).White solid, molten Point: 84.6-89.4 DEG C.TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).LCMS (ESI): m/z 468[M+1]+,1HNMR(CDCl3, 500MHz): δ 7.89-7.85 (m, 1H), 7.41-7.37 (m, 4H), 7.21-7.18(m,1H),7.14-7.08(m,4H),6.66-6.60(m,1H),4.77-4.65(m,1H),4.55 -4.45(m,1H),4.28-4.05(m,3H),3.90-3.47(m,1H),3.10-2.62(m,1H),2.60-2.50 (m,1H),2.15-1.95(m,5H),1.75-1.60(m,1H)。
Embodiment 31:1-(3-(1-acryloyl group) piperidine methyl)-4-amino-3-(4-phenoxy phenyl)-1,3-2 H-imidazo [4,5-c] pyridin-2-ones (1-((1-acryloylpiperidin-3-yl) methyl)-4-amino-3-(4-ph Enoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 35)
Step 31a:1-tertbutyloxycarbonyl-3-(4-(2-chloro-3-nitro) pyridine aminomethyl) piperidines (tert-but Yl 3-(((2-chloro-3-nitropyridin-4-yl) amino) methyl) piperidine-1-carboxylate) (compound Preparation 702-35)
Addition 2 in reaction bulb, 4-dichloro-3-nitropyridine (101) (1.0g, 5.18mmol, 1.0 equivalent), 1-tertbutyloxycarbonyl-3-aminomethylpiperidine (701-35) (1.11g, 5.18mmol, 1.0 equivalent), triethylamine (1.4mL, 10.36mmol, 2.0 equivalent) and DMF (10ml), room temperature reaction mistake Night.Reactant liquor add water (100mL) dilution, with ethyl acetate (30mL × 3) extract, extract is with anhydrous Sodium sulphate is dried, concentrate, then with column chromatography purify (petroleum ether: ethyl acetate=3:1) obtain 1- Tertbutyloxycarbonyl-3-(4-(2-chloro-3-nitro) pyridine aminomethyl) piperidines (1.66g, yield: 86%).L CMS (ESI): m/z 371 [M+1]+, pale yellow oil；TLC:Rf 0.2 (petroleum ether: ethyl acetate =4:1).
Step 31b:1-tertbutyloxycarbonyl-3-(4-(2-dibenzyl amido-3-nitro) pyridine aminomethyl) piperidines (t ert-butyl 3-(((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)methyl)piperidine-1-carb Oxylate) preparation of (compound 703-35)
1-tertbutyloxycarbonyl-3-(4-(2-chloro-3-nitro) pyridine aminomethyl) piperidines (7 is added in reaction bulb 02-35) (1.66g, 4.48mmol, 1.0 equivalent), dibenzylamine (0.95mL, 4.92mmol, 1.1 Equivalent), triethylamine (1.24mL, 8.96mmol, 2.0 equivalent) and acetonitrile (25ml), it was heated to reflux Night.Reactant liquor silica gel mixed sample is spin-dried for, and purifying (petroleum ether: ethyl acetate=2:1) with column chromatography must To 1-tertbutyloxycarbonyl-3-(4-(2-dibenzyl amido-3-nitro) pyridine aminomethyl) piperidines (2.13g, yield: 90%).LCMS (ESI): m/z 532 [M+1]+, yellow oil；TLC:Rf 0.4 (petroleum ether: second Acetoacetic ester=3:1).
Step 31c:1-tertbutyloxycarbonyl-3-(4-(3-amino-2-dibenzyl amido) pyridine aminomethyl) piperidines (t ert-butyl 3-(((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)methyl)piperidine-1-ca Rboxylate) preparation of (compound 704-35)
Toward zinc powder (2.60g, 40.1mmol, 10.0 equivalent) and ammonium chloride (1.50g, 28.07mmol, 7.0 equivalents) methanol solution (40ml) in add 1-tertbutyloxycarbonyl-3-(4-(2-dibenzyl amido-3-nitro) Pyridine aminomethyl) piperidines (703-35) (2.13g, 4.01mmol, 1.0 equivalent), it is heated to 50 DEG C of reactions 1 hour.Reactant liquor diatomite filters, and filtrate is spin-dried for, with dichloromethane: methyl alcohol=5:1 (50ml) is molten Solving, filter, organic phase is spin-dried for obtaining crude product 1-tertbutyloxycarbonyl-3-(4-(3-amino-2-dibenzyl amido) pyrrole Pyridine aminomethyl) piperidines (2.10g, yield: 100%).LCMS (ESI): m/z 502 [M+1]+, grey is solid Body；TLC:Rf 0.1 (petroleum ether: ethyl acetate=1:1).
Step 31d:1-tertbutyloxycarbonyl-3-(4-dibenzyl amido-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] Picolyl) piperidines (tert-butyl 3-((4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) piperidine-1-carboxylate) preparation of (compound 705-35)
1-tertbutyloxycarbonyl-3-(4-(3-amino-2-dibenzyl amido) pyridine aminomethyl) is added in reaction bulb Piperidines (704-35) (2.10g, 4.19mmol, 1.0 equivalent), and N, N'-carbonyl dimidazoles (1.70g, 10. 46mmol, 2.5 equivalents) and oxolane (30ml), it is heated to refluxing overnight by reactant liquor.Reactant liquor Be spin-dried for silica gel mixed sample, with column chromatography purify (dichloromethane: methyl alcohol=100:1) obtain 1-tertiary fourth oxygen Carbonyl-3-(4-dibenzyl amido-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] picolyl) piperidines (1.87g, Yield: 85%).LCMS (ESI): m/z 528 [M+1]+, faint yellow solid；TLC:Rf 0.4 (dichloro Methane: methyl alcohol=80:1).
Step 31e:1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine Methyl) piperidines (tert-butyl 3-((4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1- Yl) methyl) piperidine-1-carboxylate) preparation of (compound 706-35)
In reaction bulb add 1-tertbutyloxycarbonyl-3-(4-dibenzyl amido-2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] picolyl) piperidines (705-35) (1.87g, 3.54mmol, 1.0 equivalent), palladium dydroxide (1.6 G), ethanol (40ml) and ethyl acetate (10ml), reactant liquor is heated to 70 DEG C of mistakes in atmosphere of hydrogen Night.Reactant mixture with diatomite filter, filtrate is spin-dried for, residue column chromatography purify (dichloromethane: Methyl alcohol=20:1) obtain 1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] Picolyl) piperidines (0.8g, yield: 65%).LCMS (ESI): m/z 348 [M+1]+, white solid； TLC:Rf 0.2 (dichloromethane: methyl alcohol=20:1).
Step 31f:1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H- Imidazo [4,5-c] picolyl) piperidines (tert-butyl 3-((4-amino-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) methyl) piperidine-1-carboxylate) (chemical combination Thing 707-35) preparation
By 1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] picolyl) piperazine Pyridine (706-35) (0.8g, 2.30mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (0.64g, 2.99m Mol, 1.3 equivalents) and pyridine (0.55g, 6.90mmol, 3.0 equivalent) be dissolved in N,N-dimethylformamide (10mL) in, add copper acetate (0.46g, 2.53mmol, 1.1 equivalent) andMolecular sieve (1 G), the most in atmosphere 50 DEG C reaction overnight.Reactant liquor is cooled to room temperature and with ethyl acetate (100mL) Dilution, filters, and filtrate is washed with semi-saturation saline solution (30mL × 3).Organic layer anhydrous sodium sulfate is dried, Concentrating, the thick product column chromatography (dichloromethane: methyl alcohol=50:1) obtained purifies to obtain 1-tertbutyloxycarbonyl -3-(4-amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H-imidazo [4,5-c] picolyl) piperidines (0.45g, yield: 38%).LCMS (ESI): m/z 516 [M+1]+, faint yellow solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 31g:4-amino-3-(4-phenoxy phenyl)-1-(3-piperidine methyl)-1,3-2H-imidazo [4,5- C] pyridin-2-ones (4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-ylmethyl)-1,3-dihydro-2 H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 708-35)
By 1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxy phenyl)-2,3-dihydro-1H-imidazo [4, 5-c] picolyl) piperidines (707-35) (0.45g, 0.87mmol, 1.0 equivalent) is dissolved in dichloromethane (1 In 5mL), then it is added thereto to trifluoroacetic acid (3mL), the most at room temperature reaction 2 hours.Will be anti- Answer mixed liquor dichloromethane (50mL) to dilute, use saturated sodium carbonate solution (30mL × 2) successively and satisfy Wash with saline solution (30mL), then organic layer silica gel mixed sample is spin-dried for, afterwards with column chromatography (two Chloromethanes: methyl alcohol: triethylamine=100:10:1) purify to obtain 4-amino-3-(4-phenoxy phenyl)-1-(3- Piperidine methyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (0.34g, yield: 93%).LCMS(ES I): m/z 416 [M+1]+, faint yellow solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).
Step 31h:1-(3-(1-acryloyl group) piperidine methyl)-4-amino-3-(4-phenoxy phenyl)-1,3-2H -imidazo [4,5-c] pyridin-2-ones (1-((1-acryloylpiperidin-3-yl) methyl)-4-amino-3-(4-phenox Yphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 35)
By 4-amino-3-(4-phenoxy phenyl)-1-(3-piperidine methyl)-1,3-2H-imidazo [4,5-c] pyridine- 2-ketone (708-35) (0.17g, 0.41mmol, 1.0 equivalent), acrylic acid (38mg, 0.53mmol, 1.3 equivalents), DCC (110mg, 0.53mmol, 1.3 equivalent) and DMAP (5.0mg, 0.041 Mmol, 0.1 equivalent) it is dissolved in dichloromethane (10mL), the most at room temperature reaction 1 hour.Reaction completes After be concentrated to give thick product, purify to obtain compound 1-(3 by column chromatography (dichloromethane: methyl alcohol=50:1) -(1-acryloyl group) piperidine methyl)-4-amino-3-(4-phenoxy phenyl)-1,3-2H-imidazo [4,5-c] pyridine -2-ketone (55mg, yield: 29%).White solid, fusing point: 68.5-70.7 DEG C.TLC:Rf 0.4 (two Chloromethanes: methyl alcohol=20:1).LCMS (ESI): m/z 470 [M+1]+,1HNMR(CDCl3, 500M Hz): δ 7.86 (d, J=4.0Hz, 1H), 7.41-7.38 (m, 4H), 7.20-7.17 (m, 1H), 7.13-7.0 9(m,4H),6.58-6.50(m,2H),6.26-6.23(m,1H),5.68-5.66(m,1H),4.51-4.41(m, 1H),4.19(s,2H),3.83-3.78(m,3H),3.20-3.03(m,1H),2.88-2.75(m,1H),2.20-2. 12(m,1H),1.95-1.75(m,2H),1.59-1.42(m,2H)。
Embodiment 32:(R, E)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-(1-(4- Dimethylamino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-ami no-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-3-(4-(4-methoxyphenoxy) Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 44)
Step 32a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro- 1H-imidazo [4,5-c] pyridine) pyrrolidines (tert-butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo -2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) pyrrolidine-1-carboxylate) (compound 801 -44) preparation
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) Pyrrolidines (107) (4.5g, 14.09mmol, 1.0 equivalent), to iodobenzene boric acid (401-17) (4.54g, 18.32mmol, 1.3 equivalents) and pyridine (3.4mL, 42.27mmol, 3.0 equivalent) be dissolved in N, N-bis- In NMF (40mL), add copper acetate (2.82g, 15.50mmol, 1.1 equivalent) andMolecular sieve (5g), 50 DEG C of reactions are overnight the most in atmosphere.Reactant liquor is cooled to room temperature and uses acetic acid Ethyl ester (200mL) dilutes, and filters, and filtrate is washed with semi-saturation saline solution (50mL × 4).Organic layer is used Anhydrous sodium sulfate is dried, and concentrates, and the thick product column chromatography (dichloromethane: methyl alcohol=50:1) obtained is pure Change (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrolidines (3.05g, yield: 41%).LCMS (ESI): m/z 522 [M+1]+, palm fibre Look solid；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 32b:(R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-(4-methoxy phenoxy) phenyl) 2- Oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrolidines (tert-butyl (R)-3-(4-amino-3-(4-(4- methoxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolid Ine-1-carboxylate) preparation of (compound 109-44)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazoles And [4,5-c] pyridine) pyrrolidines (801-44) (2.0g, 3.84mmol, 1.0 equivalent), p methoxy phenol (403-44) (1.19g, 9.59mmol, 2.5 equivalent) and N, N-dimethyl glycine hydrochloride (1.07 G, 7.68mmol, 2.0 equivalent) it is dissolved in dioxane (20mL), add cuprous iodide (0.37 G, 1.92mmol, 0.5 equivalent) and cesium carbonate (7.51g, 23.04mmol, 6.0 equivalent), then at nitrogen In gas shielded, 100 DEG C are reacted 20 hours.Reactant liquor is cooled to room temperature and concentrates, the thick product post obtained Chromatography (dichloromethane: methyl alcohol=40:1 to 20:1) purifies ((R)-1-tertbutyloxycarbonyl-3-(4-ammonia Base-3-(4-(4-methoxyphenoxy) phenyl) 2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrole Cough up alkane (0.61g, yield: 31%).LCMS (ESI): m/z 518 [M+1]+, gray solid；TLC:R F 0.4 (dichloromethane: methyl alcohol=20:1).
Step 32c:(R)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-pyrrolidines)-1H- Imidazo [4,5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(4-methoxyphenoxy) phenyl)-1-(pyr Rolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 110-44)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(4-methoxy phenoxy) phenyl)- 2,3-dihydro-1H-imidazo [4,5-c] pyridines) (0.61g, 1.18mmol, 1.0 work as pyrrolidines (109-44) Amount) it is dissolved in dichloromethane (15mL), then it is added thereto to trifluoroacetic acid (3mL), then in room temperature Lower reaction 2 hours.Reaction mixture dichloromethane (100mL) is diluted, uses saturated sodium carbonate successively Solution (30mL × 2) and saturated aqueous common salt (60mL) washing, be then spin-dried for organic layer silica gel mixed sample, Afterwards with column chromatography (dichloromethane: methyl alcohol: triethylamine=100:10:1) purify (R)-4-amino- 3-(4-(4-methoxy phenoxy) phenyl)-1-(3-pyrrolidines)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.45g, yield: 92%).LCMS (ESI): m/z 418 [M+1]+, faint yellow solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).
Step 32d:(R, E)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-(1-(4-bis- Methylamino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino- 1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-3-(4-(4-methoxyphenoxy)pheny L)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 44)
By (R)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-pyrrolidines)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (110-44) (0.28g, 0.671mmol, 1.0 equivalent), 4-dimethylamino bar Beans acid hydrochloride (144mg, 0.872mmol, 1.3 equivalent), HATU (332mg, 0.872mmol, 1.3 equivalents) and triethylamine (0.28mL, 2.013mmol, 3.0 equivalent) be dissolved in dichloromethane (5mL), The most at room temperature reaction 1 hour.Thick product it is concentrated to give, by column chromatography (dichloro after having reacted Methane: methyl alcohol=20:1) purify to obtain compound (R, E)-4-amino-3-(4-(4-methoxy phenoxy) benzene Base)-1-(3-(1-(4-dimethylamino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridine- 2-ketone (70mg, yield: 20%).White solid, fusing point: 50.4-55.9 DEG C.TLC:Rf 0.2 (two Chloromethanes: methyl alcohol=10:1).LCMS (ESI): m/z 529 [M+1]+,1HNMR(CDCl3, 500M Hz): δ 7.86-7.83 (m, 1H), 7.35 (d, J=9.0Hz, 2H), 7.07-7.04 (m, 4H), 6.94- 6.91(m,3H),6.57-6.43(m,2H),5.12-5.06(m,1H),4.21(s,2H),4.12-4.02 (m,3H),3.83(s,3H),3.75-3.73(m,1H),3.31-3.23(m,2H),2.75-2.71(m,2 H),2.44(s,3H),2.38(s,3H)。
Embodiment 33:(R, E)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3- (1-(4-dimethylamino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(dimethylamino)b Ut-2-enoyl) pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 45) preparation
Step 33a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) Phenyl) 2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrolidines (tert-butyl (R)-3-(4-amin o-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]p Yridin-1-yl) pyrrolidine-1-carboxylate) preparation of (compound 109-45)
Synthetic method such as embodiment 32 step 32b, is only to be replaced by wherein p methoxy phenol (403-44) For sesamol (403-45) (1.21g, 8.78mmol, 1.5 equivalent), obtain (R)-1-tertbutyloxycarbonyl- 3-(4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl) 2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine) pyrrolidines (1.0g, yield: 39%).LCMS (ESI): m/z 532 [M+1]+, grey is solid Body；TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 33b:(R)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-pyrroles Alkane)-1H-imidazo [4,5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-(benzo [d] [1,3] dioxol-5-yl Oxy) phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Thing 110-45) preparation
Synthetic method such as embodiment 32 step 32c, is only by wherein (R)-1-tertbutyloxycarbonyl-3-(4-ammonia Base-2-oxo-3-(4-(4-methoxy phenoxy) phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrroles Alkane (109-44) replaces with (R)-1-tertbutyloxycarbonyl-3-(4-amino-2-oxo-3-(4-(3,4-methylene two Epoxide phenoxy group) phenyl)-2,3-dihydro-1H-imidazo [4,5-c] pyridine) pyrrolidines (109-45) (1.0g, 1.88mmol, 1.0 equivalents), obtain (R)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) benzene Base)-1-(3-pyrrolidines)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (0.76g, yield: 94%).L CMS (ESI): m/z 432 [M+1]+, faint yellow solid；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10: 1)。
Step 33c:(R, E)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-(1 -(4-dimethylamino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4- amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(dimethylamino)but-2-eno Yl) pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 45)
Synthetic method such as embodiment 32 step 32d, is only by wherein (R)-4-amino-3-(4-(4-methoxy benzene Epoxide) phenyl)-1-(3-pyrrolidines)-1H-imidazo [4,5-c] pyridine-2 (3H)-one (110-44) replaces with (R)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-pyrrolidines)-1H-imidazoles And [4,5-c] pyridine-2 (3H)-one (110-45) (0.20g, 0.464mmol, 1.0 equivalent), obtain chemical combination Thing (R, E)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-(1-(4-diformazan Amino-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones (38mg, yield: 1 5%).White solid, fusing point: 186.3-188.5 DEG C.TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1). LCMS (ESI): m/z 543 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.86-7.83 (m, 1H), 7.36 (d, J=7.0Hz, 2H), 7.09-7.07 (m, 2H), 6.98-6.94 (m, 1H), 6.80 (d, J =8.5Hz, 1H), 6.63 (d, J=2.0Hz, 1H), 6.57-6.54 (m, 2H), 6.45-6.31 (m, 1H), 6.00(s,2H),5.13-5.07(m,1H),4.20(s,2H),4.10-1.00(m,3H),3.73-3.71(m,1 H),3.21-3.14(m,2H),2.79-2.63(m,1H),2.45-2.38(m,1H),2.35(s,3H),2.31(s, 3H)。
Embodiment 34:(R, E)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-(1-(4- Piperidyl-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)-4-amino- 3-(4-(4-methoxyphenoxy)phenyl)-1-(1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin- 3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 46)
Synthetic method such as embodiment 32 step 32d, is only to be replaced by wherein 4-dimethylamino cronate hydrochlorate For 4-piperidyl cronate hydrochlorate (109mg, 0.529mmol, 1.3 equivalent), obtain compound (R, E)-4-amino-3-(4-(4-methoxy phenoxy) phenyl)-1-(3-(1-(4-piperidyl-2-crotonyl) pyrrole Cough up alkane))-1,3-2H-imidazo [4,5-c] pyridin-2-ones (45mg, yield: 19%).White solid, molten Point: 79.9-82.4 DEG C.TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).LCMS (ESI): m/z 569[M+1]+,1HNMR(CDCl3, 500MHz): δ 7.87-7.83 (m, 1H), 7.35 (d, J=9. 0Hz,2H),7.06-7.03(m,4H),6.94-6.91(m,3H),6.61-6.57(m,1H),6.47-6.35 (m,1H),5.15-5.06(m,1H),4.15-4.01(m,5H),3.82(s,3H),3.75-3.62(m,1 H),3.37-3.29(m,2H),2.69-2.61(m,5H),2.42-2.36(m,1H),1.70-1.66(m,4 H),1.50-1.49(m,2H)。
Embodiment 35:(R, E)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3- (1-(4-piperidyl-2-crotonyl) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R, E)- 4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(piperidin-1-yl)but-2- Enoyl) pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 47) Preparation
Synthetic method such as embodiment 33 step 33c, is only to be replaced by wherein 4-dimethylamino cronate hydrochlorate For 4-piperidyl cronate hydrochlorate (112mg, 0.542mmol, 1.3 equivalent), obtain compound (R, E)-4-amino-3-(4-(3,4-methylene-dioxy phenoxy group) phenyl)-1-(3-(1-(4-piperidyl-2-butylene Acyl group) pyrrolidines))-1,3-2H-imidazo [4,5-c] pyridin-2-ones (70mg, yield: 29%).White Solid, fusing point: 125.2-128.3 DEG C.TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).LCMS(E SI): m/z 583 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.85-7.83 (m, 1H), 7.36 (d, J=8.5Hz, 2H), 7.08 (d, J=2.5Hz, 2H), 6.95-6.90 (m, 1H), 6.80 (d, J =8.0Hz, 1H), 6.72-6.54 (m, 4H), 6.00 (s, 2H), 5.10-5.04 (m, 1H), 4.17-4.01 (m,5H),3.78-3.55(m,1H),3.52-3.36(m,2H),2.95-2.60(m,6H),2.42-2.33 (m,2H),1.88-1.83(m,4H)。
Embodiment 36:4-amido-1-[(3R)-1-(2-crotonyl) piperidines-3-base]-3-(4-phenoxy group Phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (4-Amino-3-(4-phenoxy-phenyl)-1-[1- (4-piperidin-1-yl-but-2-enoyl)-piperidin-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin- 2-one) the preparation of (compound 48)
By 4-amido-3-(4-Phenoxyphenyl)-1-[(3R)-piperidines-3-base]-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (308-11) (80mg, 0.2mmol, 1 equivalent), 4-(piperidinamine)-2-butenoic acid Hydrochloride (49mg, 0.24mmol, 1.2 equivalent) is dissolved in DCM (5ml), add HATU (99mg, 0.26mmol, 1.3 equivalents) and Et3N (61mg, 0.6mmol, 3 equivalent), reacts 1 hour under ice bath. Reacting complete, concentrate, methanol/ethyl acetate (1:20) column chromatography obtains white solid 4-amido-1-[(3R) -1-(2-crotonyl) piperidines-3-base]-3-(4-Phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyrrole Pyridine-2-ketone (16mg, yield 15%)；Purity 96.7%；TLC:Rf 0.5 (dichloromethane: methyl alcohol=10: 1)；Fusing point: 85.2～86.0 DEG C；LC-MS:553 [M+1]+；1HNMR(400MHz,CDCl3):δ 1.48 (s, 3.5H), 1.70 (s, 1H), 1.98 (m, 2.5H), 2.10 (d, 1.5H, J=11.56Hz), 2.21 (t, 0.5H, J=7.51Hz), 2.57 (s, 5.5H), 3.12 (t, 1H, J=10.84Hz), 3.27 (s, 2H), 3.48 (t, 1H, J=10.76Hz), 3.84 (s, 0.5H), 4.15 (s, 4H), 4.80 (d, 1H, J=24.72Hz), 6.63 (m, 2H), 6.90 (m, 1H), 7.10 (m, 4H), 7.18 (t, 1H, J=7.4Hz), 7.40 (m, 4H), 7.87 (d, 1H, J=5.44Hz).
Embodiment 37:4-amido-1-[(3R)-1-(2-crotonyl) dimethylamine-3-base]-3-(4-benzene oxygen Base phenyl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-ones (4-Amino-3-(4-phenoxy-phenyl)- 1-[1-(4-piperidin-1-yl-but-2-enoyl)-dimethylamino-3-yl]-1,3-dihydro-imidazo[4,5 -c] pyridin-2-one) preparation of (compound 49)
Synthetic method such as embodiment 36 step, is only to be replaced by wherein 4-(piperidinamine)-2-butenoate hydrochlorate For 4-(dimethylamine)-2-butenoate hydrochlorate (49mg, 0.24mmol, 1.2 equivalent), obtain white solid 4-amido-1-[(3R)-1-(2-crotonyl) dimethylamine-3-base]-3-(4-Phenoxyphenyl)-1,3-two Hydrogen-2H-imidazo [4,5-c] pyridin-2-ones (20mg, yield 20%)；Purity 95.5%；TLC:Rf 0.4 (dichloromethane: methyl alcohol=10:1)；Fusing point: 67～68 DEG C；LC-MS:513 [M+1]+；1HNMR (400MHz,CDCl3): δ 1.65 (m, 0.5H), 1.98 (m, 0.5H), 2.11 (d, 1.5H, J=12.64H Z), 2.21 (t, 0.5H, J=7.52Hz), 2.37 (d, 6H, 17.8Hz), 2.62 (m, 1.5H), 3.21 (m, 2.5 H), 3.46 (m, 0.5H), 3.83 (d, 0.5H, J=10.12Hz), 4.15 (s, 4H), 4.80 (m, 1H), 6.6 0 (m, 2H), 6.87 (m, 1H), 7.10 (m, 4H), 7.18 (t, 1H, J=7.36Hz), 7.40 (m, 4H), 7.86 (d, 1H, J=5.6Hz).
Embodiment 38:(R)-1-(3-(1-acryloylpiperidine))-4-amino-3-((dislike 4-by 1,4-benzo two Alkane-6-epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3 -yl)-4-amino-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)phenyl)-1,3-dihydro -2H-imidazo [4,5-c] pyridin-2-one) preparation of (compound 52)
Step 38a:(R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(Isosorbide-5-Nitrae-benzdioxan-6-epoxide) phenyl) -2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine radicals) piperidines (tert-butyl (R)-3-(4-amino-3-(4- ((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4, 5-c] pyridin-1-yl) piperidine-1-carboxylate) preparation of (compound 307-52)
By 1-tertbutyloxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridine radicals) piperidines (402-17) (0.65g, 1.214mmol, 1.0 equivalent), 1,4-benzdioxan- 6-phenol (403-52) (0.28g, 1.821mmol, 1.5 equivalent) and N, N-dimethyl glycine hydrochloride (6 7.8mg, 0.486mmol, 0.4 equivalent) it is dissolved in dioxane (8mL), add cuprous iodide (2 3mg, 0.121mmol, 0.1 equivalent) and cesium carbonate (1.19g, 3.642mmol, 3.0 equivalent), then In nitrogen is protected, 100 DEG C are reacted 20 hours.Reactant liquor is cooled to room temperature and concentrates, the thick product obtained (R)-1-tertbutyloxycarbonyl-3-(4-is purified with column chromatography (dichloromethane: methyl alcohol=40:1 to 20:1) Amino-3-(Isosorbide-5-Nitrae-benzdioxan-6-epoxide) phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyrrole Piperidinyl) piperidines (0.26g, yield: 39%).LCMS (ESI): m/z 560 [M+1]+, brown solid； TLC:Rf 0.4 (dichloromethane: methyl alcohol=20:1).
Step 38b:(R)-4-amino-3-(4-(1,4-benzdioxan-6-epoxide) phenyl)-1-(3-piperidines Base)-1H-imidazo [4,5-c] pyridine-2 (3H)-one ((R)-4-amino-3-(4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl)oxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2- One) preparation of (compound 308-52)
By (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(Isosorbide-5-Nitrae-benzdioxan-6-epoxide) phenyl)-2-oxygen Generation-2,3-dihydro-1H-imidazo [4,5-c] pyridine radicals) piperidines (307-52) (0.26g, 0.472mmol, 1. 0 equivalent) it is dissolved in dichloromethane (10mL), then it is added thereto to trifluoroacetic acid (2mL), then exist React 1 hour under room temperature.Reaction mixture dichloromethane (100mL) is diluted, uses saturated carbon successively Acid sodium solution (30mL × 2) and saturated aqueous common salt (60mL) washing, then by organic layer silica gel mixed sample Be spin-dried for, afterwards with column chromatography (dichloromethane: methyl alcohol: triethylamine=100:10:1) purify (R)- 1-(3-piperidyl)-4-amino-3-(4-(1,4-benzdioxan-6-epoxide) phenyl)-1H-imidazo [4,5- C] pyridine-2 (3H)-one (0.195g, yield: 90%).LCMS (ESI): m/z 460 [M+1]+, white is solid Body；TLC:Rf 0.2 (dichloromethane: methyl alcohol=10:1).
Step 38c:(R)-1-(3-(1-acryloylpiperidine))-4-amino-3-(4-(1,4-benzdioxan-6- Epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-1-(1-acryloylpiperidin-3-yl)-4- amino-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)phenyl)-1,3-dihydro-2H-imid Azo [4,5-c] pyridin-2-one) preparation of (compound 52)
By (R)-1-(3-piperidyl)-4-amino-3-(4-(1,4-benzdioxan-6-epoxide) phenyl)-1 H-imidazo [4,5-c] pyridine-2 (3H)-one (308-52) (0.195g, 0.424mmol, 1.0 equivalent), third Olefin(e) acid (40mg, 0.552mmol, 1.3 equivalent), DCC (114mg, 0.522mmol, 1.3 equivalent) It is dissolved in dichloromethane (8mL), then in room with DMAP (5.1mg, 0.042mmol, 0.1 equivalent) The lower reaction of temperature 1 hour.Thick product it is concentrated to give, by column chromatography (dichloromethane: first after having reacted Alcohol=20:1) purify to obtain compound (R)-1-(3-(1-acryloylpiperidine))-4-amino-3-(4-(1,4-benzo Dioxanes-6-epoxide) phenyl)-1,3-2H-imidazo [4,5-c] pyridin-2-ones (62mg, yield: 28%). White solid, fusing point: 235.0-236.7 DEG C.TLC:Rf 0.5 (dichloromethane: methyl alcohol=10:1).L CMS (ESI): m/z 514 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7.86 (d, J=5.0Hz, 1H), 7.36 (d, J=9.0Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 6.87 (d, J=9. 0Hz,1H),6.65-6.58(m,4H),6.33-6.30(m,1H),5.71(s,1H),4.83-4.78(m, 1H),4.28(s,4H),4.27-4.01(m,4H),3.84-3.48(m,2H),3.12-2.52(m,2H),2. 11-2.08(m,1H),1.98-1.95(m,1H)。
Embodiment 39:(R)-4-amino-3-(4-phenoxy phenyl)-1-(3-(1-ethenesulfonyl) piperidines)) -1,3-2H-imidazo [4,5-c] pyridin-2-ones ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-(vinylsu Lfonyl) piperidin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 55) Preparation
By (R)-4-amino-1-(3-piperidyl)-3-(4-Phenoxyphenyl)-1,3-2H-imidazo [4,5-c] Pyridin-2-ones (308-11) (0.26g, 0.648mmol, 1.0 equivalent) and triethylamine (0.18mL, 1.29 6mmol, 2.0 equivalents) it is dissolved in dichloromethane (20mL), it is cooled to-60 DEG C, so with dry ice-propanone bath Afterwards chloroethyl sulfonic acid chloride (158mg, 0.971mmol, 1.5 equivalent) is dissolved in dichloromethane (5mL) And dropwise add.Reactant liquor reacts 30 minutes at-60 DEG C and is then slowly raised to room temperature.It is evaporated off molten with rotation Agent obtains crude product, purifies to obtain compound 6-53 (1 by column chromatography (dichloromethane: methyl alcohol=50:1) 00mg, yield: 31%).White solid, fusing point: 86.3-89.4 DEG C.TLC:Rf 0.5 (dichloromethane: Methyl alcohol=15:1).LCMS (ESI): m/z 492 [M+1]+,1HNMR(CDCl3, 500MHz): δ 7. 88 (d, J=5.5Hz, 1H), 7.41-7.37 (m, 4H), 7.20-7.17 (m, 1H), 7.13-7.08 (m, 4H), 6.62 (d, J=5.5Hz, 1H), 6.48-6.42 (m, 1H), 6.27-6.23 (m, 1H), 6.04 (d, J=9.5Hz, 1H), 4.32-4.26 (m, 1H), 4.16 (s, 2H), 3.86-3.83 (m, 2H), 3.48-3. 44(m,1H),2.66-2.65(m,1H),2.46-2.44(m,1H),2.03-1.98(m,2H),1.89-1. 82(m,1H)。
Embodiment 40 biological activity test
One, BTK inhibition of enzyme activity experiment
1, experimental technique
Caliper mobility shifting detection technique (Caliper mobility shift assay) is used to measure BTK Protein kinase activity (see J Biomol Screen 14:31,2009).Compound obtained above is used DMSO uses kinase buffer liquid (50mM HEPES-pH 7.5,0.0015%Brij-35,10mM after dissolving MgCl2, 2mM DTT) dilute 10 times, add in 384 orifice plates 5 μ l 10%DMSO dissolve 5 Times react the compound of final concentration, without compound control hole and non-enzymatic activity control wells being the 10% of 5 μ l DMSO.Add 10 μ l 2.5 times reaction final concentration BTK enzyme solutions (BTK, Cat.No.08-080, Carna), at room temperature hatch 10 minutes after compound, wherein sharp without enzyme control wells alive adds 10 μ l Enzyme buffer liquid.Add the substrate FAM-labeled SRCtide peptide of 2.5 times of reaction final concentrations of 10 μ l The substrate solution of (Biochem, Cat.No.112394) and ATP (90 μMs), initial action.After in room temperature Under hatch 10 minutes.Add after hatching 1 hour at 28 DEG C 25 μ l stop buffers (100mM HEPES, pH 7.5, 0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA) terminate reaction.At Caliper The upper reading and converting rate data of EZ Reader II (CaliperLife Sciences).Calculate inhibiting rate, computing formula For inhibiting rate %=(max-conversion)/(max-min) × 100%.
2, experimental result
This compounds can strong suppression BTK activity, than positive reference compound Ibrutinib with The inhibitory action of ONO-4059 is quite or more preferably.Form 1 is listed heretofore described representative compound The activity being had in BTK detects.In these detect, use following rank: for IC50, I>200nM,200nM>II>100nM,100nM>III>50nM,50nM>IV>10nM,V< 10nM。
The suppression result of table 1 BTK enzymatic activity
Note: the compound number in table is corresponding to the compound number of embodiment 1-39.
Two, Cytostatic to tumor cell experiment
1, experimental technique
Employing CellTiter-Glo luminescent cell viability detection kit method (Promega, #G7572, Madison, WI) content measuring atriphos (ATP) assesses cell viability.Diffusivity large B cell lymphoid tumor Cell line TMD-8, large B cell lymphoid tumor cell line SU-DHL-16 buy from Shanghai Fudan University IBS cell Resource center and American Type Culture Collecti (ATCC).With pancreatin cell digested from Tissue Culture Dish and With Scepter automated cell calculating instrument (Millipore, #PHCC00000) counting after DPBS culture medium is resuspended Measure cell density.Cell is diluted to every milliliter of solution containing 44,000 cells.Adjust after density is thin Cell lysis liquid adds in cell experiment plate with every hole 90 μ l.Orifice plate is placed in 37 DEG C, 5%CO2Incubator cultivates 24 The compound to be tried of variable concentrations is added after hour.Cell in the presence of 10% hyclone together with compound Cultivate 72 hours.UseLuminescent Cell ViabilityAssay kit (says see producer Bright book) measure ATP content assess cell growth inhibition.Briefly, each hole adds 30 μ lReagent, rocker 10 minutes, inducing cell lysis, with fluorescence/chemiluminescent analyzer FluoroskanAscent FL (Thermo Scientific FluoroskanAscent FL) detection record fluorescence letter Number.The cell processing 72 or 120 hours from dimethyl sulfoxide (DMSO) (DMSO) obtains maximum signal value.From Single culture medium (cell number is zero) obtains minimum signal value and is defined as 0.Inhibiting rate %=(peak signal Value-compound signal value)/(maximum signal level-minimum signal value) × 100%.Use GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software data processing.By S-shaped dosage- Response curve the Fitting Calculation IC50 value.
2, experimental result
This kind of compound on tumor cell such as TMD-8, SU-DHL-16 etc. have the work of the strongest suppressing cell reproduction Property, the activity than positive reference compound Ibrutinib and ONO-4059 quite or more preferably, following form 2 In list the suppressing cell reproduction that heretofore described representative compound is had in detection based on cell Activity.In these detect, use following rank: for IC50, I > 1uM, 1uM > II > 0.1 uM,0.1uM>III>0.05uM,0.05uM>IV>0.01uM,V<0.01uM。
The suppression result of table 2 tumor cell proliferation
Note: the compound number in table is corresponding to the compound number of embodiment 1-39.
Three, protein immunoblot (Western Blot) experiment
1, experimental technique
ATCC human body lymphoma mantle cell cell Jeko-1 and DOHH-2 purchase visits power biotechnology from Shanghai to be had Limit company, suspends and cultivates growth, adds after examination compound or reference compound are cultivated 1 hour, low-speed centrifugal (1200rpm；4min) collect cell, then use serum free medium re-suspended cell.Addition GoatF (ab ') 2Anti-Human IgM (10ug/ml), after 2min, washes twice with the PBS of precooling, collects cell, with life Thing sample homogenizer is homogenized 3 times, and 12,000rpm, in 4 DEG C of centrifugal 10min, take supernatant.Use Branfor Method measures protein concentration, adds sample-loading buffer (Beyotime, #P0015L) and boils 4min in 100 DEG C, with It is transferred to pvdf membrane after 10%SDS-PAGE electrophoretic separation albumen, then with containing 5% bovine serum albumin(BSA) (BSA) (the green skies；CATNo.ST023) TBST solution is closed 1 hour, the anti-β-actin mAb that adds (CST, #4970), BTK (D3H5) mAb (CST, #8547) or phospho-BTK (Try223) MAb (CST, #5802) overnight incubation at 4 DEG C, then washes film 3 × 10min with TBST liquid.With glimmering Light two anti-IRDye@680CW Goat (polyclonal) Anti-Rabbit lgG (H+L), Highly Cross Under Adsorbed (LI-COR, #926-68071) room temperature, lucifuge washes film after hatching 2h again, and wash conditions is ibid. Finally film is placed on LI-COR Odyssey IR fluorescence scanning imaging system detection imaging.
2, experimental result
Compound 11 and object of reference Ibrutinib strength suppression Jeko-1 and DOHH-2 of embodiment 11 preparation drench Bar oncocyte BTK protein phosphorylation, makes IgM stimulate lower Jeko-1 and DOHH-2 cell p-BTK to express It is decreased obviously (result is as shown in Figure 1).By in Fig. 1 it can be seen that the present invention provide compound 11 make For Jeko-1 and DOHH-2 human lymphoma cell, can effectively reduce the phosphorylation of BTK.
Embodiment 41 pharmacokinetics (PK) is tested
1, experimental technique
Male SD rat, body weight 250-300 gram, overnight fast before test.Compound to be tried is dissolved in 30% In Sulfobutyl ether β _ cyclodextrin (SBE-β-CD), with 20mg/kg gastric infusion.Be administered latter 15 minutes, 30 Minute and 1,2,3,4,6,8 and 24 hours tail end fractures take blood, every time point about 0.3ml, be placed in Containing K2In the centrifuge tube of-EDTA, centrifugal treating (2,000g, 10 minutes, 4 DEG C) takes blood plasma, stores In the ultra low temperature freezer of-80 DEG C.The plasma sample of 50 μ L and the mixing of 5 microlitre internal standards (IS), use acetic acid second Ester extracts.During after vacuum drying, residue is redissolved in acetonitrile.Sample is filtered, and is injected into LC-MS/MS analyzes.
2, experimental result
After implementing the compound 1 of 1 preparation and compound 11 gastric infusion of embodiment 11 preparation, absorb good, It is high that blood exposes dose-effect.Cmax is respectively 544.3 and 2776.7ng/ml.Compound 11 half-life is shorter (1.2 hours), but AUC higher (4985.5ng/ml*h) (table 3).When in table, Tmax refers to reach peak Between, Cmax refers to maximum plasma concentration, and T1/2 is the half-life, AUC0-24Refer to 0-24 hours-dense Degree TG-AUC, AUCinfRefer to area under 0-Inf time-concentration curve.
Table 3. gastric infusion (20mg/kg) pharmacokinetic data
Embodiment 42 pharmacodynamic experiment
1, experimental technique
Immunologic function major defect SCAD mouse is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., raises Support in SPF Animal House.In culture dish, people's diffusivity large B cell lymphoid tumor cell line TMD-8 reaches enough to count During amount, collecting cell, DPBS washes 2 times.Last cell the RPMI1640 culture medium without serum and base Matter glue (1:1, v/v) suspends and inoculates.Only the survival rate (trypan-blue exclusion) more than 90% is unicellular outstanding Liquid just can be used for injecting.Use syringe and the 25G syringe needle of 1ml, 0.2 milliliter will be suspended in not In culture medium containing serum and matrigel (1:1, v/v), 5,000,000 cells inject every right side of mice wing rim surface zone Blood vessel is also carefully avoided in territory.Within about one week, tumor size can be measured implanting.Use vernier caliper measurement The size of tumour.And calculate gross tumor volume by below equation: gross tumor volume=(long × wide2)/2。
When gross tumor volume reaches 100-300mm3Left and right, is divided into 3 gastric infusion groups, i.e. excipient by mouse Control group, Ibrutinib gastric infusion group (50mg/kg, 1 times/day) and the compound 11 of embodiment 11 preparation Gastric infusion group (25mg/kg, 2 times/day).Often 6 animals of group.By molten to Ibrutinib or compound 11 Solution in 30% Sulfobutyl ether β _ cyclodextrin (SBE-β-CD) and 1.0 moles of equivalent hydrochloric acid (pH 3-4), With 10ml/kg gastric infusion, successive administration 14 days.
2, experimental result
Compound 11 and Ibrutinib is high at the antitumor activity of TMD-8 neoplasm transplantation.Compound 11 Gastric infusion (dosage is 25mg/kg, bid) can significantly inhibit diffusivity large B cell lymphoid tumor cell line The growth of TMD-8, after being administered 14 days, transplantation tumor TMD-8 is contracted to disappear.Compare, respectively before being administered Administration group is without obvious Body weight loss (Fig. 2).
Each technical characteristic of embodiment described above can combine arbitrarily, for making description succinct, the most right The all possible combination of each technical characteristic in above-described embodiment is all described, but, if these skills There is not contradiction in the combination of art feature, is all considered to be the scope that this specification is recorded.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and detailed, But can not therefore be construed as limiting the scope of the patent.It should be pointed out that, for this area For those of ordinary skill, without departing from the inventive concept of the premise, it is also possible to make some deformation and change Entering, these broadly fall into protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended power Profit requires to be as the criterion.

Claims (23)

1. there is the 2-oxo 1,3-glyoxalidine of formula (I) structure pyridine compounds and their or it pharmaceutically can connect The salt being subject to or its stereoisomer or its prodrugs:
In formula:
X1And X2It is respectively and independently selected from C or N；
Ar is selected from phenyl ring or 5-6 membered aromatic heterocycle；
L is selected from O, S, NR5, CR5R6, OCH2, CH2O；
Y is selected from (CHR5)m, C=O, wherein m is selected from 0,1,2,3；
Z selects self-saturating 5-7 unit heterocycle or carbocyclic ring；
G is selected from following group:
R1And R2It is respectively and independently selected from: H, C1-C6Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxyl, Cyano group, amino, C1-C6Alkyl substituted amido, acyl group, amide groups；
R3And R4It is respectively and independently selected from: H, C1-C6Alkyl, C3-C6Cycloalkyl, C3-C6Methyl cycloalkyl, Halogen substiuted C1-C4Alkyl, hydroxyl replaces C1-C4Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, amino Replace C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, halogen, nitro, hydroxyl, C1-C6Alkane Epoxide, C1-C6Alkylthio group, C1-C6Sulfoxide group, C1-C6Sulfuryl, cyano group, amino, C1-C6Alkyl replaces amine Base, ester group, acyl group, amide groups, carboxyl；
Work as R3And R4It is C1-C6Alkyl, C1-C6Alkoxyl, OH or C1-C6Alkyl substituted amido, and When being substituted in the adjacent position of Ar, R3And R4A carbocyclic ring or heterocycle can be connected to form, selected from having structure:
Wherein, n is selected from 0,1,2；Q1And Q2It is respectively and independently selected from O, NR6, CHR6；
R5、R6It is respectively and independently selected from H, C1-C6Alkyl；
R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, amino replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, heterocyclic substituted C1-C4Alkyl.
2-oxo 1,3-glyoxalidine the most according to claim 1 pyridine compounds and their or its pharmaceutically Acceptable salt or its stereoisomer or its prodrugs, it is characterised in that described compound has Formula II Shown structure:
In formula: X3, X4, X5, X6And X7It is respectively and independently selected from C or N.
2-oxo 1,3-glyoxalidine the most according to claim 2 pyridine compounds and their or its pharmaceutically Acceptable salt or its stereoisomer or its prodrugs, it is characterised in that X3, X4, X5, X6And X7 It is selected from C；Or X3, X4, X5, X6And X7One of them selected from N, remaining is selected from C.
2-oxo 1,3-glyoxalidine the most according to claim 1 pyridine compounds and their or its pharmaceutically Acceptable salt or its stereoisomer or its prodrugs, it is characterised in that G is selected from following group:
5. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that X1And X2All For C.
6. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that L is selected from O, OCH2。
7. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that Y is selected from (CH2)m, wherein m is 0 or 1.
8. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that Z is selected from following base Group:
2-oxo 1,3-glyoxalidine the most according to claim 8 pyridine compounds and their or its pharmaceutically Acceptable salt or its stereoisomer or its prodrugs, it is characterised in that Z is selected from following group:
10. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that R3And R4Respectively It is independently selected from: H, halogen, hydroxyl, C1-C6Alkoxyl, hydroxyl replaces C1-C4Alkyl, C1-C6Alkyl takes For amido；
Work as R3And R4It is C1-C6When alkoxyl or OH, and when being substituted in the adjacent position of Ar, R3With R4A heterocycle can be connected to form, selected from having structure:
Wherein, n is 0 or 1.
11. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that R5And R6It is H。
12. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, 5-6 The saturated azacyclo-of unit replaces C1-C4Alkyl.
13. according to the 2-oxo 1,3-glyoxalidine described in any one of claim 1-4 pyridine compounds and their or Its pharmaceutically acceptable salt or its stereoisomer or its prodrugs, it is characterised in that
X1And X2It is C；
L is selected from O, OCH2；
Y is selected from (CH2)m, wherein m is 0 or 1；
Z is selected from
R1And R2It is hydrogen；
R3And R4It is hydrogen；Or one of them is hydrogen, another is selected from halogen or hydroxyl or C1-C6Alcoxyl Base；Or work as R3And R4For C1-C6When alkoxyl or OH, and it is substituted in the adjacent position of Ar, R3 And R4A heterocycle can be connected to form, selected from having structure:
Wherein, n is 0 or 1；
R5And R6It is H；
R7Selected from H, C1-C6Alkyl, C1-C3Alkoxyl replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, the saturated azacyclo-of 5-6 unit replaces C1-C4Alkyl.
14. 2-oxo 1,3-glyoxalidine according to claim 1 pyridine compounds and their or its pharmaceutically Acceptable salt or its stereoisomer or its prodrugs, it is characterised in that described compound is selected from:
2-oxo 1,3-glyoxalidine described in 15. any one of claim 1-14 pyridine compounds and their or its Pharmaceutically acceptable salt or its stereoisomer or its prodrugs are preparing bruton's tyrosine kinase suppression Application in agent.
2-oxo 1,3-glyoxalidine described in 16. any one of claim 1-14 pyridine compounds and their or its Pharmaceutically acceptable salt or its stereoisomer or its prodrugs answering in the medicine preparing anti-curing oncoma With.
2-oxo 1,3-glyoxalidine described in 17. any one of claim 1-14 pyridine compounds and their or its Pharmaceutically acceptable salt or its stereoisomer or its prodrugs are in the medicine of preparation preventing and treating neoplastic hematologic disorder Application.
18. application according to claim 17, it is characterised in that described neoplastic hematologic disorder be lymthoma, Myeloma, lymphocytic leukemia or acute myeloid leukemia.
2-oxo 1,3-glyoxalidine described in 19. any one of claim 1-14 pyridine compounds and their or its Pharmaceutically acceptable salt or its stereoisomer or its prodrugs are as bruton's tyrosine kinase inhibitor Application in preparation prevents and treats the medicine of inflammation or autoimmune disease.
20. application according to claim 19, it is characterised in that described inflammation or LADA Disease is rheumatoid arthritis, lupus erythematosus, LN, multiple sclerosis, gren's syndrome And potential disease asthma.
21. 1 kinds of pharmaceutical compositions treating disease, it is characterised in that include the right as active component Require 2-oxo 1,3-glyoxalidine described in any one of 1-14 pyridine compounds and their or it is pharmaceutically acceptable Salt or its stereoisomer or its prodrugs, and pharmaceutically acceptable carrier.
22. pharmaceutical compositions according to claim 21, it is characterised in that described disease is blood Tumour or the inflammation relevant to bruton's tyrosine kinase or autoimmune disease.
23. pharmaceutical compositions according to claim 22, it is characterised in that described neoplastic hematologic disorder is Lymthoma, myeloma, lymphocytic leukemia, acute myeloid leukemia；Described inflammation or LADA Disease is rheumatoid arthritis, lupus erythematosus, LN, multiple sclerosis, gren's syndrome And potential disease asthma.
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