CN105753863B - Oxo-dihydro Imidazopyridine compound and its application - Google Patents

Oxo-dihydro Imidazopyridine compound and its application Download PDF

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CN105753863B
CN105753863B CN201610087688.0A CN201610087688A CN105753863B CN 105753863 B CN105753863 B CN 105753863B CN 201610087688 A CN201610087688 A CN 201610087688A CN 105753863 B CN105753863 B CN 105753863B
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amino
dihydro
pyridin
imidazos
dichloromethane
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CN105753863A (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

Abstract

The present invention provides 2 oxos 1 indicated by leading to formula (I), 3 glyoxalidine and pyridine compounds and their and its application in the drug for preparing the various diseases that treatment bruton's tyrosine kinase (Bruton ' s tyrosine kinase, BTK) is participated in.Research has shown that compound disclosed by the invention can effectively inhibit the activity of BTK, and then by inhibiting BTK to prevent existence, proliferation and the diffusion of Hematological malignancies cell.In addition, by inhibiting BTK can be to anti-inflammatory and autoimmune disease.Therefore, the compound of the present invention can be used in the various diseases that treatment BTK is participated in has larger application value especially suitable for the treatment of hematologic malignancies and inflammation and autoimmune disease.

Description

Oxo-dihydro Imidazopyridine compound and its application
Technical field
The present invention relates to chemical medicines, more particularly to oxo-dihydro Imidazopyridine compound and its application.
Background technology
Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) is in B-cell receptor signal complex A kind of key signal molecule, be lymphocyte survival and the key protein kinase of proliferation.BTK malignant B cell existence and It plays an important role in diffusion.
BTK inhibitor plays the role of anticancer by inhibiting tumour cell BTK.Pioneering BTK inhibitor replaces Buddhist nun according to Shandong (Ibrutinib) be a kind of 4 '-amino-pyrazols simultaneously [3,4-d] pyrimidine compound (Proc Natl Acad Sci USA, 107: 13075,2010), by with target protein BTK active site cysteine residues (Cys-481) selectively covalent bond, can not Inhibit BTK to inverse property.To effectively tumour be prevented to move to the lymphoid tissue for being adapted to tumour growth environment from B cell.It is beautiful State FDA ratifies according to Shandong for Buddhist nun in 2013-2015 for refractory lymphoma mantle cell (MCL), the white blood of refractory chronic lymphocytic Sick (CLL), the treatment that del 17p delete the treatment and primary macroglobulinaemia of the CLL being mutated is carried.
BTK inhibitor according to Shandong other than replacing Buddhist nun, AVL-292 (CC292), ONO-4059, BGB-3111 and ACP-196 Into clinical development.For B- cell non-Hodgkin's, chronic lymphocytic leukemia, Huppert's disease, hair The treatments such as chronic myeloid leukemia, adult acute lymphoblastic leukemia.Join for Buddhist nun and chemotherapeutics or other targeting anticarcinogens according to Shandong The effect of closing treatment, these neoplastic hematologic disorders can be increased.The drug being used in combination with BTK inhibitor in clinical test includes Ituximab, lenalidomide, fludarabine；Cyclophosphamide；Adriamycin, vincristine, prednisone.
Compared with normal hematopoetic cells, BTK activity in about 80% acute myeloid leukemia (AML) patient's initial cell Increase, cell is caused to replace sensitive (the Marcel Spaargaren M.Lancet of Buddhist nun according to Shandong to oral BTK inhibitor in vitro Heamat.2：E180,2015).One is applied alone for Buddhist nun according to Shandong or treats acute myeloid leukemia with cytarabine drug combination Clinical research enters II phases clinic.
Normal B cells are developed in activation process, and BTK acts on most important in B-cell receptor (BCR) system of couriers.BCR Abnormal signal is related with autoimmune disease, such as rheumatoid arthritis (RA).In addition, BTK is also in myeloid cell, including Monocyte, macrophage, neutrophil leucocyte and mast cell-expressed.These cellular infiltration synovial membrane chambers and generate inflammatory cell because Son aggravates arthritic symptom.BTK inhibitor can block B-cell receptor dependent cell to be proliferated, and reduce inflammatory factor and generate (Whang J.A.,Chang B.Y.Drug DiscovToday.19:1200,2014).Preclinical study shows BTK inhibitor Also to inflammation and autoimmune disease, as rheumatoid arthritis and animal model are effective.In addition to rheumatoid arthritis with Except lupus erythematosus, this kind of drug is possible to be used in lupus nephritis, multiple sclerosis, gren's syndrome and potential disease Sick asthma etc..The BTK inhibitor such as CC-292 and HM71224 for autoimmune disease treatment (such as rheumatoid arthritis) into Enter clinical experimental stage (ClinicalTrials.gov ID:NCT01975610, NCT01765478).
The studies above all shows that BTK inhibitor has as the drug of anti-curing oncoma, inflammation and autoimmune disease Prodigious potential value.
Invention content
Based on this, one of the objects of the present invention is to provide a kind of novel B TK inhibitor oxo-dihydro imidazopyridines Compound.
Realize that the specific technical solution of foregoing invention purpose is as follows：
2- oxo 1,3- glyoxalidine with formula (I) structure and pyridine compounds and their or its 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 heterocycles；
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 circle heterocyclic rings or carbocyclic ring；
G is selected from following group：
R1And R2It is respectively and independently selected from：H, C1-C6Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxy, cyano, amino, C1- C6Alkyl substituted amido, acyl group, amide groups；
R3And R4It is respectively and independently selected from：H, C1-C6Alkyl, C3-C6Naphthenic base, C3-C6Methyl cycloalkyl, halogen replace C1-C4 Alkyl, hydroxyl replace C1-C4Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, amino replace C1-C4Alkyl, C1-C3Alkyl amine group Replace C1-C4Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxy, C1-C6Alkylthio group, C1-C6Sulfoxide group, C1-C6Sulfuryl, cyano, Amino, C1-C6Alkyl substituted amido, ester group, acyl group, amide groups, carboxyl；
Work as R3And R4It is C1-C6Alkyl, C1-C6Alkoxy, OH or C1-C6Alkyl substituted amido, and it is substituted in the adjacent of Ar When position, R3And R4One carbocyclic ring of connectable composition or heterocycle are 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-C3Alkoxy replaces C1-C4Alkyl, amino replace C1-C4Alkyl, C1-C3Alkylamine Base replaces C1-C4Alkyl, heterocyclic substituted C1-C4Alkyl.
In wherein some embodiments, the compound has structure shown in Formula II：
In formula：X3, X4, X5, X6And X7It is respectively and independently selected from C or N.
In wherein some embodiments, X3, X4, X5, X6And X7It is selected from C；Or X3, X4, X5, X6And X7One of choosing From N, remaining is selected from C.
In wherein some embodiments, G is selected from following group：
In wherein some embodiments, X1And X2It is C.
In wherein some embodiments, L is selected from O, OCH2.
In wherein some embodiments, Y is selected from (CH2)m, wherein m is 0 or 1.
In wherein some embodiments, Z is selected from following group：
In wherein some embodiments, Z is selected from following group：
In wherein some embodiments, R3And R4It is respectively and independently selected from：H, halogen, hydroxyl, C1-C6Alkoxy, hydroxyl substitution C1-C4Alkyl, C1-C6Alkyl substituted amido；Work as R3And R4It is CN1-C6Alkoxy or when OH, and it is substituted in the adjacent position of Ar When, R3And R4One heterocycle of connectable composition is selected from having structure：
Wherein, n is 0 or 1.
In wherein some embodiments, R5And R6It is H；
In wherein some embodiments, R7Selected from H, C1-C6Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, C1-C3Alkyl Amido replaces C1-C4Alkyl, 5-6 members are saturated azacyclo- and replace C1-C4Alkyl.
In wherein 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-C6Alkoxy；Or work as R3And R4For C1-C6Alkoxy or when OH, and it is substituted in the adjacent position of Ar, R3And R4One heterocycle of connectable composition, is selected from Having structure：
Wherein, n is 0 or 1；
R5And R6It is H；R7Selected from H, C1-C6Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, 5-6 members are saturated azacyclo- and replace C1-C4Alkyl.
It is a further object of the present invention to provide the applications of above compound.
Realize that the specific technical solution of above-mentioned purpose is as follows：
Above-mentioned 2- oxos 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt or its alloisomerism The application of body or its prodrugs in preparing bruton's tyrosine kinase inhibitor.
Above-mentioned 2- oxos 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt or its alloisomerism The application of body or its prodrugs in the drug for preparing anti-curing oncoma.
Above-mentioned 2- oxos 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt or its alloisomerism The application of body or its prodrugs in the drug for preparing prevention neoplastic hematologic disorder.
In wherein some embodiments, the neoplastic hematologic disorder is lymthoma, myeloma, lymphocytic leukemia, acute marrow It is leukaemia.
Above-mentioned 2- oxos 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt or its alloisomerism Body or its prodrugs are preparing the drug for preventing inflammation or autoimmune disease as bruton's tyrosine kinase inhibitor In application.
In wherein some embodiments, the inflammation or autoimmune disease are rheumatoid arthritis, lupus erythematosus, wolf Sore ephritis, multiple sclerosis, gren's syndrome and potential disease asthma.
It is a further object of the present invention to provide a kind of pharmaceutical compositions for treating disease.
Realize that the specific technical solution of above-mentioned purpose is as follows：
A kind of pharmaceutical composition for treating disease includes the above-mentioned 2- oxos 1 as active constituent, 3- glyoxalidine and pyrrole Pyridine class compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrugs and pharmaceutically acceptable load Body.
In wherein some embodiments, the disease be neoplastic hematologic disorder or with the relevant inflammation of bruton's tyrosine kinase or Autoimmune disease.
In wherein some embodiments, the neoplastic hematologic disorder is lymthoma, myeloma, lymphocytic leukemia, acute marrow It is leukaemia；The inflammation or autoimmune disease be rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple hard Change disease, gren's syndrome and potential disease asthma.
The present invention provides 2- oxos 1,3- glyoxalidine and pyridine compounds and their, inventor demonstrate,prove by lot of experiments Bright, such compound can effectively inhibit the activity of bruton's tyrosine kinase (Bruton ' s tyrosine kinase, BTK), And then prevent existence, proliferation and the diffusion of Hematological malignancies cell.In addition, by inhibiting BTK can be to anti-inflammatory and itself Immunity disease.Therefore, the compound of the present invention can be used in treating the various diseases that BTK is participated in, especially suitable for blood The treatment of malignant tumour and inflammation and autoimmune disease has larger application value.
Description of the drawings
Fig. 1 is that the compound 11 of embodiment 40 inhibits human lymphoma Jeko-1 and DOHH-2 cell strain BTK phosphorylation assays Result figure；
Fig. 2 is the compound 11 of embodiment 42 in diffusivity large B cell lymphoid tumor cell strain TMD-8SCID mouse models Antitumor activity figure.
Specific implementation mode
In compound of the present invention, as any variable (such as R1, R etc.) occurred more than in any component it is primary, then Its definition occurred every time is independently of other definition occurred every time.Equally, the combination for allowing substituent group and variable, as long as this Combination makes compound stablize.The line that loop system is included in from substituent group indicates that signified key may be connected to any annular atom that can replace On.Be appreciated that those of ordinary skill in the art may be selected the compounds of this invention substituent group and substitution pattern and provide chemically steady Compound that is fixed and being readily synthesized from readily available raw material by art technology and the method for following proposition.Such as Fruit substituent group itself is exceeded the substitution of group, it should be understood that these groups can in identical carbon atoms or on different carbon atoms, As long as making stable structure.
Terms used herein " alkyl " mean include have particular carbon atom number branch and straight chain saturated fat Alkyl.For example, " C1-C6" C in alkyl "1-C6" definition include with linear chain or branched chain arrange have 1,2,3,4,5 or 6 carbon The group of atom.Term " naphthenic base " refers to the monocycle saturated fat alkyl with particular carbon atom number.Such as " naphthenic base " packet Include cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyls, 2- ethyI-cyclopentyls, cyclohexyl etc..
Terms used herein " heterocycle " or " heterocycle " refer to containing the heteroatomic armaticity of 1-4 selected from O, N and S or Non-aromatic heterocyclic rings, and include bicyclic radicals." heterocycle " therefore include heteroaryl, also includes that its dihydro and tetrahydro are similar Object.The connection of heterocyclic substituent can be realized by carbon atom or by hetero atom.
As will be appreciated by a person skilled in the art, " halogen " used herein means to include chlorine, fluorine, bromine and iodine.
The present invention includes the free form of I-III compound of formula, also includes its pharmaceutically acceptable salt and alloisomerism Body.Some specific exemplary compounds herein are the protonated salt of aminated compounds.Term " free form " refer to The aminated compounds of salt-independent shape.The pharmaceutically-acceptable salts being included not only include the example of specific compound described herein Property salt, also includes the typical pharmaceutically acceptable salt of I-III compound free form of all formulas.It can be used known in the art Technology detaches the free form of the compound specific salts.For example, can be by with the dilute water of alkali dilute aqueous solution such as NaOH appropriate Solution, potassium carbonate dilute aqueous solution, weak aqua ammonia and sodium bicarbonate dilute aqueous solution, which handle the salt, makes free form regenerate.Free form exists Certain physical properties for example in polar solvent respectively more or less distinguish with its in solubility by salt form, but is the mesh of invention This hydrochlorate and alkali salt respectively free form is suitable with its in terms of other pharmacy.
It can synthesize the present invention's from the compounds of this invention of alkaline part or acidic moiety is contained by conventional chemical processes Pharmaceutically acceptable salt.In general, by ion-exchange chromatography or passing through free alkali and stoichiometric amount or excessive required salt The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of form prepares the salt of alkali compounds.Similar, The salt of acid compound is formed by being reacted with appropriate inorganic or organic base.
Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkaline the compounds of this invention and inorganic or have Machine acid reacts the conventional non-toxic salts for the compounds of this invention to be formed.For example, conventional nontoxic salts include from inorganic acid such as hydrochloric acid, The salt of the preparations such as hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, also include from organic acid for example acetic acid, propionic acid, succinic acid, Glycolic, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutters acid, maleic acid, hydroxymaleic acid, benzene second at stearic acid Acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2 one acetoxyl group, one benzoic acid, fumaric acid, toluenesulfonic acid, methylsulphur The salt of the preparations such as acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.
If the compounds of this invention is acid, " pharmaceutically acceptable salt " appropriate refers to by pharmaceutically acceptable Nontoxic alkali include salt prepared by inorganic base and organic base.Salt derived from inorganic base includes aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali includes the salt of primary amine, secondary amine and tertiary amine, substituted Amine include naturally occurring substitution amine, cyclic amine and deacidite for example arginine, glycine betaine, caffeine, choline, N, N'- dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, ethylaminoethanol, ethyl alcohol Amine, ethylenediamine, mono- ethyl morpholines of N, mono- ethyl piperidines of N, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine, Lysine, methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, triethylamine, Trimethylamine, tripropyl amine (TPA), tromethamine etc..
Except known in the literature or in experimental arrangement in addition to the standard method of illustration, following synthetic schemes (side can be used Case 1-6) in method prepare the compounds of this invention.It, can be to heretofore described compound in conjunction with following synthetic schemes And synthetic method is better understood.The synthetic schemes, which describes, can be used for preparing heretofore described chemical combination The method of object, the method are only illustrative approach description for the purpose of illustration, are not constituted to possessed by the present invention The limitation of range.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
The present invention will be further described with reference to embodiments, but the embodiment is not intended to limit the guarantor of the present invention Protect range.
Embodiment 1：(R) -4- amidos -1- [1- (2- butine acyl group) pyrrolidin-3-yl] -3- (4- Phenoxyphenyls) -1, 3- dihydro -2H- imidazos [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：Tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- amino of 2-) pyrroles's -1- carboxylates (tert-butyl (R) -3- ((2-chloro-3-nitropyridin-4-yl) amino) pyrrolidine-1-carboxylate) (compound 103) preparation
2,4- dichloro-3-nitropyridines (101) (9.65g, 50.0mmol, 1.0 equivalent), tertiary butyl are added into reaction bulb (R) -3- amino-pyrrolidines -1- t-butyl formates (102) (9.30g, 50.0mmol, 1.0 equivalent), triethylamine (6.56g, 65.0mmol, 1.3 equivalents) and n,N-Dimethylformamide (60ml), room temperature reaction is overnight.Reaction solution adds water (300mL) to dilute, It is extracted with ethyl acetate (100mL × 4), extract liquor is dried with anhydrous sodium sulfate, is concentrated, and is then purified with column chromatography and (is eluted Agent：Petroleum ether：Ethyl acetate=4：1) tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- amino of 2-) pyrroles's -1- carboxylic acids are obtained Ester (13.7g, yield：80%).Pale yellow oil；TLC：Rf0.2 (petroleum ethers：Ethyl acetate=4：1)；LCMS(ESI)：m/ z 343[M+1]+。
Step 1b：Tertiary butyl (R) -3- ((2- dibenzyl amido -3- nitropyridine -4- amino) pyrroles's -1- carboxylates (tert- butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carbox Ylate) the preparation of (compound 104)
Tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- amino of 2-) pyrroles -1- carboxylates (103) are added into reaction bulb (13.7g, 40.06mmol, 1.0 equivalent), dibenzylamine (8.47mL, 44.06mmol, 1.0 equivalent), triethylamine (11.15mL, 80.12mmol, 2.0 equivalents) and acetonitrile (200ml), heated overnight at reflux.Reaction solution is spin-dried for silica gel mixed sample, uses column chromatography Purify (eluant, eluent：Petroleum ether：Ethyl acetate=4：1) tertiary butyl (R) -3- ((2- dibenzyl amido -3- nitropyridine -4- ammonia is obtained Base) pyrroles -1- carboxylate (20.0g, yield：99%).Yellow oil；TLC：Rf0.4 (petroleum ethers：Ethyl acetate=4：1)； LCMS(ESI)：m/z 504[M+1]+。
Step 1c：Tertiary butyl (R) -3- ((3- amino -2- dibenzyls amido) pyridine -4- amino) pyrroles's -1- carboxylates (tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1- Carboxylate) the 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 be added tertiary butyl (R) -3- ((2- dibenzyl amido -3- nitropyridine -4- amino) pyrroles's -1- carboxylic acids Ester (104) (20.0g, 39.71mmol, 1.0 equivalent) is heated to 50 DEG C and reacts 1 hour.Reaction solution is filtered with diatomite, filtrate It is spin-dried for, uses dichloromethane：Methanol=5：The mixed solvent of 1 (50ml) dissolves, and filtering, organic phase is spin-dried for obtaining crude product tertiary butyl (R) -3- ((3- amino -2- dibenzyls amido) pyridine -4- amino) pyrroles -1- carboxylate (18.3g, yield：97%).Pale yellow colored solid Body；TLC：Rf0.1 (petroleum ethers：Ethyl acetate=4：1)；LCMS(ESI)：m/z 474[M+1]+。
Step 1d：Tertiary butyl (R) -3- (4- dibenzyl amido -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) Pyrroles -1- carboxylates (tert-butyl (R) -3- (4- (dibenzylamino) -2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) pyrrolidine-1-carboxylate) (compound 106) preparation
Tertiary butyl (R) -3- ((3- amino -2- dibenzyls amido) pyridine -4- amino) pyrroles's -1- carboxylic acids are added into reaction bulb Ester (105) (18.3g, 38.64mmol, 1.0 equivalent), N, N'- carbonyl dimidazoles (15.7g, 96.6mmol, 2.5 equivalent) and four Reaction solution is heated to being refluxed overnight by hydrogen furans (200ml).Reaction solution is spin-dried for silica gel mixed sample, is purified with column chromatography and (is eluted Agent：Dichloromethane：Methanol=100：1) tertiary butyl (R) -3- (4- dibenzyl amido -2- oxo -2,3- dihydro -1H- imidazos are obtained [4,5-c] pyridine) pyrroles -1- carboxylate (17.5g, yield：91%).Weak yellow liquid；TLC：Rf0.8 (dichloromethane：Methanol =80：1)；LCMS(ESI)：m/z 500[M+1]+。
Step 1e：Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrroles - 1- carboxylates (tert-butyl (R) -3- (4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin- 1-yl) pyrrolidine-1-carboxylate) (compound 107) preparation
Tertiary butyl (R) -3- (4- dibenzyl amido -2- oxo -2,3- dihydro -1H- imidazos [4,5- are added into reaction bulb C] pyridine) pyrroles -1- carboxylates (106) (17.5g, 35.03mmol, 1.0 equivalent), palladium dydroxide (7.0g), ethyl alcohol (240ml) With ethyl acetate (60ml), reaction solution is heated to 70 DEG C, is reacted overnight in atmosphere of hydrogen.Reaction mixture diatomite mistake Filter, filtrate is spin-dried for, and concentrate column chromatography purifies (eluant, eluent：Dichloromethane：Methanol=20：1) tertiary butyl (R) -3- is obtained (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrroles -1- carboxylate (9.0g, yield：80%).Nothing Color solid；TLC：Rf0.1 (dichloromethane：Methanol=20：1)；LCMS(ESI)：m/z 320[M+1]+。
Step 1f：Tertiary butyl (R) -3- (4- amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrroles -1- carboxylates (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 Preparation 109-1)
By tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrroles's -1- carboxylics Acid esters (107) (5.93g, 18.57mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (108-1) (5.17g, 24.14mmol, 1.3 Equivalent) and pyridine (4.5mL, 55.71mmol, 3.0 equivalent) be dissolved in n,N-Dimethylformamide (40mL), add copper acetate (3.72g, 20.43mmol, 1.1 equivalent) and 4A molecular sieves (6.7g), then 50 DEG C of reactions are stayed overnight in air.Reaction solution cools down It is diluted to room temperature and with ethyl acetate (150mL), filtering, filtrate is washed with semi-saturation saline solution (70mL × 4).Organic layer nothing Aqueous sodium persulfate is dried, concentration, obtained crude product column chromatography (eluant, eluent：Dichloromethane：Methanol=50:1) uncle is purified to obtain Butyl (R) -3- (4- amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrroles -1- Carboxylate (2.7g, yield：31%).Brown solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 488[M+1]+。
Step 1g：(R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [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) (compound 110-1) preparation
By (R)-tertiary butyl -3- (4- amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazos [4,5- C] pyridine) pyrroles -1- carboxylates (109-1) (2.7g, 5.54mmol, 1.0 equivalent) are dissolved in dichloromethane (25mL), then to its Middle addition trifluoroacetic acid (5mL) is then reacted 3 hours at room temperature.Reaction mixture is diluted with dichloromethane (150mL), It is washed successively with saturated sodium carbonate solution (50mL × 2) and saturated salt solution (60mL), then by organic layer silica gel silica gel It mixes sample to be spin-dried for, uses column chromatography (eluant, eluent later：Dichloromethane：Methanol：Triethylamine=100：10：1) it purifies：(R) -4- ammonia (2.0g is received base -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones Rate：93%).Gray solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)：m/z 388[M+1]+。
Step 1h：(R) -4- amidos -1- [1- (2- butine acyl group) pyrrolidin-3-yl] -3- (4- Phenoxyphenyls) -1,3- Dihydro -2H- imidazos [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
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (193.5mg, 0.5mmol, 1 equivalent) are dissolved in DMF (2ml), and 2- tetrolic acid (111-1) is added (51.5mg, 0.6mmol, 1.2 equivalent), EDCI (115mg, 0.6mmol, 1.2 equivalent), (7mg, 0.05mmol, 0.1 work as HOBt Amount), it reacts at room temperature 1 hour.Water (5ml) is added to stir, dichloromethane (2ml) extraction, organic phase washed once with water (10ml) again, It is dry, concentration, column chromatography (eluant, eluent：Methanol：EA=1：10) white solid (R) -4- amidos -1- [1- (2- butine acyls are detached to obtain Base) pyrrolidin-3-yl] (163mg is received -3- (4- Phenoxyphenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones Rate 70%).Fusing point：106.5-107.0℃；LCMS(ESI)：m/z 454.40[M+1]+；1HNMR(600MHz,CDCl3):δ 1.97(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=18.1,5.58Hz, 1H).
Embodiment 2：(R) -4- amino -3- (4- phenoxy phenyls) -1- (- 3 base of 1- acryloyl groups pyrrolidines) -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones ((R) -4-amino-3- (4-phenoxyphenyl) -1- (1- Propioloylpyrrolidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 2) preparation
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.1g, 0.26mmol, 1.0 equivalent), (21.7mg, 0.31mmol, 1.2 work as propiolic acid (111-2) Amount), DCC (63.9mg, 0.31mmol, 1.2 equivalent) and DMAP (3.2mg, 0.026mmol, 0.1 equivalent) be dissolved in dichloromethane (5mL) then reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (eluant, eluent：Dichloro Methane：Methanol=50：1) compound (R) -4- amino -3- (4- phenoxy phenyls) -1- (1- acryloyl groups pyrrolidines -3 is purified to obtain Base) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones 50mg, yield：44%).White solid, fusing point：141.5- 143.1℃.TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 440[M+1]+, purity： 98.587%；1HNMR(CDCl3, 500MHz)：δ7.89-7.86(m,1H),7.42-7.37(m,4H),7.20-7.18(m,1H), 7.13-7.09(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, 2H), 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 phenyls) -1,3- Dihydro -2H- imidazos [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) (compound 3) Preparation
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.15g, 0.39mmol, 1.0 equivalent), valerylene sour (46.1mg, 0.47mmol, 1.2 equivalent), DCC (97.0mg, 0.47mmol, 1.2 equivalent) and DMAP (4.8mg, 0.039mmol, 0.1 equivalent) are dissolved in dichloromethane (5mL), Then it reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (eluant, eluent：Dichloromethane： Methanol=50：1) compound (R) -4- amino -1- (1- (valerylene acyl group) pyrrolidin-3-yl) -3- (4- benzene oxygen benzene is purified to obtain Base) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (80mg, yield：44%).White solid, fusing point：180.1- 181.6℃.TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 468[M+1]+, purity： 99.450%；1HNMR(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 groups pyrrolidin-3-yl) -4- amino -3- (4- phenoxy phenyls) -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-3- (4- Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 4) preparation
Acryloyl chloride (202-4) (56.5mg, 0.62mmol, 1.2 equivalent) is dissolved in dichloromethane (5mL), is cooled to 0 DEG C, (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- miaows are then added dropwise dropwise thereto Dichloromethane (5mL) solution of azoles simultaneously [4,5-c] pyridin-2-ones (110-1) (0.2g, 0.52mmol, 1.0 equivalent), then again Dichloromethane (1.0mL) solution of n,N-diisopropylethylamine (101mg, 0.78mmol, 1.5 equivalent) is added dropwise dropwise, this is mixed Liquid is closed to react 10 minutes at 0 DEG C.Reaction solution is quenched with water (50mL), then dichloromethane (50mL × 2) is used to extract.It will obtain Organic layer be spin-dried for silica gel with silica gel mixed sample, later use column chromatography (eluant, eluent：Dichloromethane：Methanol=50：1) it purifies Compound (R) -1- (1- acryloyl groups pyrrolidin-3-yl) -4- amino -3- (4- phenoxy phenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.13g, yield：57%).White solid, fusing point：119.2-120.5℃.TLC：0.4 (dichloros of Rf Methane：Methanol=20：1)；LCMS(ESI)：m/z 442[M+1]+, purity：99.019%；1HNMR(CDCl3, 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- methylacryloyls pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1, 3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R) -4-amino-1- (1-methacryloylpyrrolidin-3- Yl) -3- (4-phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 5) Preparation
Toward in the dichloromethane solution (7ml) of methacrylic chloride (202-5) (0.065g, 0.62mmol, 1.2 equivalent) 0 (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyrrole is added dropwise at DEG C The dichloromethane solution (8ml) of pyridine -2- ketone (110-1) (0.200g, 0.52mmol, 1.0 equivalent), is then added dropwise diisopropyl again The dichloromethane solution (1ml) of ethylamine (0.100g, 0.78mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.By reaction solution It pours into water (100ml), is extracted with dichloromethane (50ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography Purify (eluant, eluent：Dichloromethane：Methanol=40：1) (R) -4- amino -1- (1- methylacryloyls pyrrolidin-3-yl)-is obtained 3- (4- Phenoxyphenyls) -1,3- dihydro -1H- imidazos [4,5-c] pyridin-2-ones (0.140g, yield：59%).It is colourless solid Body, fusing point：114.6-117.5℃.TLC：0.4 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 456[M+1 ]+,1HNMR(CDCl3, 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,3H)。
Embodiment 6：(R, E) -4- amino -1- (1- (but-2-ene acyl group) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) - 1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R, E) -4-amino-1- (1- (but-2-enoyl) pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2- One) the preparation of (compound 6)
Toward the dichloromethane solution (7ml) of (E)-but-2-ene acyl chlorides (202-6) (0.065g, 0.62mmol, 1.2 equivalent) In (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5- is added dropwise at 0 DEG C C] pyridin-2-ones (110-1) (0.200g, 0.52mmol, 1.0 equivalent) dichloromethane solution (8ml), it is different that two are then added dropwise again The dichloromethane solution (1ml) of ethylamine (0.100g, 0.78mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will be anti- It answers liquid to pour into water (100ml), is extracted with dichloromethane (50ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column layer Analysis method purifies (eluant, eluent：Dichloromethane：Methanol=40：1) (R, E) -4- amino -1- (1- (but-2-ene acyl group) pyrroles is obtained Alkane -3- bases) -3- (4- Phenoxyphenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.100g, yield： 42%).Colorless solid, fusing point：102.3-105.8℃.TLC：Rf0.4 (dichloromethane：Methanol=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- pentenoyls) pyrrolidin-3-yl)) -3- (4- phenoxy phenyls) -1, 3- dihydro -2H- imidazos [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) the preparation of (compound 7)
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.2g, 0.52mmol, 1.0 equivalent), (67.7mg, 0.68mmol, 1.3 work as trans- 2- penetenoic acids Amount), HOBT (91.9mg, 0.68mmol, 1.3 equivalent), EDCI (130.4mg, 0.68mmol, 1.3 equivalent) and diisopropyl second Amine (0.26mL, 1.56mmol, 3.0 equivalent) is dissolved in dichloromethane (8mL), then reacts 1 hour at room temperature.After the completion of reaction It is concentrated to give crude product, passes through column chromatography (eluant, eluent：Dichloromethane：Methanol=50：1) compound (R, E) -4- ammonia is purified to obtain Base -1- (1- (2- pentenoyls) pyrrolidin-3-yl)) -3- (4- phenoxy phenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyrrole Pyridine -2- ketone) (83mg, yield：34%).White solid, fusing point：221.3-222.4℃.TLC：0.4 (dichloromethane of Rf：Methanol =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),7.05-7.02(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- (- 3 base of 1- (4- dimethylamino -2- crotonyls) pyrrolidines) -3- (4- benzene Oxygen phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R, E) -4-amino-1- (1- (4- (dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro- 2H-imidazo [4,5-c] pyridin-2-one) (compound 8) preparation
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.5g, 1.29mmol, 1.0 equivalent), 4- bromocrotonic acids (277mg, 1.68mmol, 1.3 equivalent), DCC (347mg, 1.68mmol, 1.3 equivalent) and DMAP (16mg, 0.13mmol, 0.1 equivalent) are dissolved in dichloromethane (15mL), so It is reacted 1.5 hours at 0 DEG C afterwards.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (eluant, eluent：Dichloromethane：First Alcohol=30：1) (R, E) -4- amino -1- (3- (1- (the bromo- 2- crotonyls of 4-) pyrrolidines)) -3- (4- phenoxy phenyls)-is purified 1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.6g, yield：88%).White solid；TLC：0.4 (dichloromethane of Rf：First Alcohol=20：1)；LCMS(ESI)：m/z 535[M+1]+。
By (R, E) -4- amino -1- (3- (1- (the bromo- 2- crotonyls of 4-) pyrrolidines)) -3- (4- benzene oxygen of above-mentioned acquisition Phenyl) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.15g, 0.28mmol, 1.0 equivalent) and dimethylamine (2M tetrahydrochysene furans It mutters solution, 0.63mL, 1.26mmol, 4.5 equivalents) it is dissolved in tetrahydrofuran (3mL), then react 1 hour at room temperature.It has reacted It is concentrated to give crude product after, passes through column chromatography (eluant, eluent：Dichloromethane：Methanol=20：1) compound (R, E)-is purified to obtain 4- amino -1- (- 3 base of 1- (4- dimethylamino -2- crotonyls) pyrrolidines) -3- (4- phenoxy phenyls) -1,3- dihydro -2H- miaows Azoles simultaneously [4,5-c] pyridin-2-ones (60mg, yield：43%).White solid, fusing point：103.6-105.3℃.TLC：Rf 0.3 (dichloromethane：Methanol=10：1)；LCMS(ESI)：m/z 499[M+1]+, purity：95.928%；1HNMR(CDCl3, 500MHz)：δ7.87-7.84(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,1H),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),2.28(s,3H)。
Embodiment 9：(R, E) -4- amino -1- (1- (4- methoxyl group -2- crotonyls) pyrrolidin-3-yl) -3- (4- benzene oxygen Phenyl) -1,3- dihydro -2H- imidazos [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] Pyridin-2-one) the preparation of (compound 9)
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.15g, 0.387mmol, 1.0 equivalent), 4- methoxyl group crotonic acids (58.4mg, 0.503mmol, 1.3 Equivalent), DCC (103.8mg, 0.537mmol, 1.3 equivalent) and DMAP (4.8mg, 0.039mmol, 0.1 equivalent) be dissolved in dichloromethane Alkane (6mL) then reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (eluant, eluent：Two Chloromethanes：Methanol=30：1) compound (R, E) -4- amino -1- (1- (4- methoxyl group -2- crotonyls) pyrrolidines-is purified to obtain 3- yls) -3- (4- phenoxy phenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (60mg, yield：32%).White Solid, fusing point：178.2-179.5℃.TLC：0.4 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)：m/z 486[M+ 1]+, purity：98.464%；1HNMR(CDCl3, 500MHz)：δ7.87-7.83(m,1H),7.40-7.37(m,4H),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 phenyls) -1- (1- (4- (piperidin-1-yl) -2- crotonyls) Pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R, E) -4-amino-3- (4- phenoxyphenyl)-1-(1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin-3-yl)-1,3- Dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 10) preparation
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] Pyridin-2-ones (110-1) (0.16g, 0.413mmol, 1.0 equivalent), 4- piperidyl crotonic acids (90.1mg, 0.537mmol, 1.3 Equivalent), HATU (204.1mg, 0.537mmol, 1.3 equivalent) and triethylamine (125mg, 1.239mmol, 3.0 equivalent) be dissolved in two Chloromethanes (5mL) then reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (elution Agent：Dichloromethane：Methanol=20：1) compound (R, E) -4- amino -3- (4- phenoxy phenyls) -1- (1- (4- (piperidines-is purified to obtain 1- yls) -2- crotonyls) pyrrolidin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (100mg, yield： 45%).White solid, fusing point：107.5-109.1℃.TLC：0.3 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)： m/z 539[M+1]+, purity：97.356%；1HNMR(CDCl3, 500MHz)：δ7.88-7.84(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- bases) -4- amino -3- (4- Phenoxyphenyls) -1,3- two Hydrogen -2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 11) preparation
Step 11a：Tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- bases of 2-) amino) piperidines -1- carboxylates ((R) - tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1- Carboxylate) the preparation of (compound 302)
2,4- dichloro-3-nitropyridines (101) (5.79g, 30.0mmol, 1.0 equivalent), tertiary butyl are added into reaction bulb (R) -3- amino piperidines -1- carboxylates (301) (6.00g, 30.0mmol, 1.0 equivalent), triethylamine (6.06g, 60.0mmol, 2.0 equivalents) and n,N-Dimethylformamide (50ml), room temperature reaction is overnight.Reaction solution is diluted with ethyl acetate (250ml), It is washed with semi-saturation saline solution (200ml × 4), organic phase is spin-dried for silica gel mixed sample, purifies (eluant, eluent with column chromatography：Oil Ether：Ethyl acetate=4：1) tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- bases of 2-) amino) piperidines -1- carboxylates are obtained (8.21g, yield：77%).LCMS(ESI)：m/z 357[M+1]+, pale yellow oil；TLC：0.2 (petroleum ethers of Rf：Acetic acid Ethyl ester=4：1).
Step 11b：Tertiary butyl (R) -3- ((2- (dibenzyl amino) -3- nitropyridine -4- bases) amino) piperidines -1- carboxylic acids Ester ((tert-butyl (R) -3- ((2- (dibenzylamino) -3-nitropyridin-4-yl) amino) piperidine- 1-carboxylate) the preparation of (compound 303)
Tertiary butyl (R) -3- ((the chloro- 3- nitropyridines -4- bases of 2-) amino) piperidines -1- carboxylates are added into reaction bulb (302) (8.27g, 23.2mmol, 1.0 equivalent), dibenzylamine (5.94g, 30.2mmol, 1.3 equivalent), triethylamine (3.52g, 34.8mmol, 1.5 equivalents) and acetonitrile (150ml), heated overnight at reflux.Reaction solution is spin-dried for silica gel mixed sample, pure with column chromatography Change (eluant, eluent：Petroleum ether：Ethyl acetate=4：1) tertiary butyl (R) -3- ((2- (dibenzyl amino) -3- nitropyridines -4- are obtained Base) amino) piperidines -1- carboxylate (10.9g, yield：91%).LCMS(ESI)：m/z 518[M+1]+, yellow oil； TLC：0.4 (petroleum ethers of Rf：Ethyl acetate=4：1).
Step 11c：Tertiary butyl (R) -3- ((3- amino -2- (dibenzyl amino) pyridin-4-yl) amino) piperidines -1- carboxylic acids Ester (tert-butyl (R) -3- ((3-amino-2- (dibenzylamino) pyridin-4-yl) amino) piperidine- 1-carboxylate) the preparation of (compound 304)
Toward zinc powder (13.7g, 210.0mmol, 10.0 equivalent) and ammonium chloride (11.2g, 210.0mmol, 10.0 equivalent) Tertiary butyl (R) -3- ((2- (dibenzyl amino) -3- nitropyridine -4- bases) amino) piperidines-is added in methanol solution (250ml) 1- carboxylates (303) (10.9g, 21.0mmol, 1.0 equivalent) are heated to 50 DEG C of reaction half an hour.Reaction solution diatomite mistake Filter, filtrate are spin-dried for, and use dichloromethane：Methanol=10：1 (100ml) dissolves, and filtering, organic phase is spin-dried for obtaining crude product tertiary butyl (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：0.1 (petroleum ethers of Rf：Ethyl acetate=4：1).
Step 11d：Tertiary butyl (R) -3- (4- (dibenzyl amino) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] Pyridine -1- bases) piperidines -1- carboxylates ((tert-butyl (R) -3- (4- (dibenzylamino) -2-oxo-2,3- Dihydro-1H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) (compound 305) It prepares
Tertiary butyl (R) -3- ((3- amino -2- (dibenzyl amino) pyridin-4-yl) amino) piperidines-is added into reaction bulb 1- carboxylates (304) (11.0g, 22.5mmol, 1.0 equivalent), N, N'- carbonyl dimidazoles (10.9g, 67.5mmol, 3.0 equivalent) With tetrahydrofuran (150ml), reaction solution is heated to being refluxed overnight.Reaction solution is spin-dried for silica gel mixed sample, is purified with column chromatography (eluant, eluent：Dichloromethane：Methanol=100：1) tertiary butyl (R) -3- (4- (dibenzyl amino) -2- oxo -2,3- dihydros-are obtained 1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (9.88g, yield：85%).LCMS(ESI)：m/z 514[M+ 1]+, weak yellow liquid；TLC：0.8 (dichloromethane of Rf：Methanol=80：1).
Step 11e：Tertiary butyl (R) -3- (4- amino -2- oxo -2,3- dihydro -1H- imidazo [4,5-c] pyridines -1- Base) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] Pyridin-1-yl) piperidine-1-carboxylate) (compound 306) preparation
Tertiary butyl (R) -3- (4- (dibenzyl amino) -2- oxo -2,3- dihydro -1H- imidazos are added into reaction bulb [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (305) (9.88g, 19.22mmol, 1.0 equivalent), palladium dydroxide (2.0g), Ethyl alcohol (120ml) and ethyl acetate (30ml), reaction solution are heated to 60 DEG C overnight in hydrogen.Reaction mixture diatomite mistake Filter, filtrate is spin-dried for, and concentrate column chromatography purifies (eluant, eluent：Dichloromethane：Methanol=20：1) tertiary butyl (R) -3- is obtained (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (5.28g, yield： 83%).LCMS(ESI)：m/z 334[M+1]+, colorless solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 11f：Tertiary butyl (R) -3- (4- amino -2- oxos -3- (4- Phenoxyphenyls) -2,3- dihydro -1H- imidazoles And [4,5-c] pyridine -1- bases) piperidines -1- carboxylic acid tert-butyl esters (tert-butyl (R) -3- (4-amino-2-oxo-3- (4- phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) the preparation of (compound 307-11)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (3.0g, 9.0mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (108-1) (2.89g, 13.5mmol, 1.5 equivalents), copper acetate (1.82g, 9.9mmol, 1.1 equivalent), molecular sieve (3.0g), pyridine (2.13g, 27mmol, 3.0 equivalents) and n,N-Dimethylformamide (30ml), reaction solution is heated to 40 DEG C overnight in air.Reaction solution is used Ethyl acetate (200ml) dilutes, and is washed with semi-saturation saline solution (150ml × 3), organic phase is spin-dried for silica gel mixed sample, concentrate Purify (eluant, eluent with column chromatography：Dichloromethane：Methanol=50：1) tertiary butyl (R) -3- (4- amino -2- oxos -3- are obtained (4- Phenoxyphenyls) -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (2.23g, yield： 49%).LCMS(ESI)：m/z 502[M+1]+, yellow oil；TLC：0.7 (dichloromethane of Rf：Methanol=20：1).
Step 11g：(R) -4- amino -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1,3- dihydro -2H- imidazos [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) (compound 308-11) preparation
Tertiary butyl (R) -3- (4- amino -2- oxos -3- (4- Phenoxyphenyls) -2,3- dihydros-are added into reaction bulb 1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (307-11) (2.23g, 4.45mmol, 1.0 equivalent), dichloro Methane (10ml) and trifluoracetic acid (2.0ml), reaction solution is in ambient temperature overnight.Reaction solution is poured into saturated sodium carbonate solution It in (100ml), is extracted with dichloromethane (100ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (elution Agent：Dichloromethane：Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- amino -3- (4- Phenoxyphenyls) -1- (piperazines Pyridine -3- bases) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (1.3g, yield：73%).LCMS(ESI)：m/z 402 [M+1]+, pale solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 11h：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- Phenoxyphenyls) -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 11) preparation
Toward at 0 DEG C in the dichloromethane solution (50ml) of acryloyl chloride (202-4) (0.25g, 3.89mmol, 1.2 equivalent) (R) -4- amino -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1,3- dihydro -2H- imidazos [4,5-c] pyridine-is added dropwise The dichloromethane solution (30ml) of 2- ketone (308-11) (1.3g, 3.24mmol, 1.0 equivalent), is then added dropwise diisopropyl second again The dichloromethane solution (5ml) of base amine (0.63g, 4.86mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.Reaction solution is poured into It in water (100ml), is extracted with dichloromethane (100ml × 2), organic phase is spin-dried for silica gel mixed sample, and concentrate column chromatography is pure Change (dichloromethane：Methanol=40：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- phenoxy group benzene is obtained Base) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.67g, yield：45%).Colorless solid, fusing point：89.5- 91.9℃.TLC：0.5 (dichloromethane of Rf：Methanol=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- bases)-4- amidos-3- (4-(4- chlorophenoxies) phenyl)-1, 3- dihydro -2H- imidazos [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 Object 13) preparation
Step 12a：Tertiary butyl (R) -3- (4- amidos -3- (4- (the chloro- phenoxy groups of 4-) phenyl) -2- oxo -2,3- dihydros - 1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-3- (4- (4- chlorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 307-13)
By 2- (4-(the chloro- phenoxy groups of 4-)-phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxos borines (108-13) (1.78g, 5.39mmol, 1.5 equivalent), which is dissolved in methanol (10ml) and adds after concentrated hydrochloric acid (1ml) is stirred to react 1h, to be washed, dichloro Methane extracts, and filtrated stock is spare after drying, and tertiary butyl (R) -3- (4- amino -2- oxos -2,3- bis- are added into above-mentioned mother liquor Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (306) (1.20g, 3.59mmol, 1 equivalent), Cu (OAc)2(1.30g, 7.18mmol, 2 equivalent), Et3N (0.73g, 7.18mmol, 2 equivalent) and pyridine (0.57g, 7.18mmol, 2 Equivalent), room temperature reaction is overnight.Reaction solution is washed, dichloromethane extraction concentrates after dry, with ethyl acetate/n-hexane (3: 1) column chromatography obtain pale yellow oil tertiary butyl (R)-3- (4- amidos-3- (4- (the chloro- phenoxy groups of 4-) phenyl) oxo-2-2-, 3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (0.77g, yield 40.00%).LCMS(ESI)： m/z 536.50[M+H]+。
Step 12b：(R) -4- amidos -3- (4- (4- chlorophenoxies) phenyl) -1- (pyridin-3-yl) -1,3- dihydros -2H- Imidazo [4,5-c] pyridin-2-ones ((R) -4-amino-3- (4- (4-chlorophenoxy) phenyl) -1- (piperidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 308-13) It prepares
By tertiary butyl (R) -3- (4- amidos -3- (4- (the chloro- phenoxy groups of 4-) phenyl) -2- oxo -2,3- dihydro -1H- imidazoles And [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (307-13) (0.77g, 1.44mmol, 1 equivalent) are dissolved in dichloromethane (5ml) is added TFA (2.5ml), reacts at room temperature 1h.Reaction solution concentrates, and saturated sodium bicarbonate is neutralized to slightly meta-alkalescence, with 5ml bis- Chloromethanes extracts, dry, concentration, ethanol/methylene/triethylamine (1：10：0.3) column chromatography obtains off-white color foaming solid (R) -4- amidos -3- (4- (4- chlorophenoxies) phenyl) -1- (pyridin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyrrole Pyridine -2- ketone (325mg, yield 52.08%).LCMS(ESI)：m/z 436.10[M+H]+。
Step 12c:(R) -1- (1- acryloylpiperidine -3- bases) -4- amidos -3- (4- (4- chlorophenoxies) phenyl) -1, 3- dihydro -2H- imidazos [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 Object 13) preparation
Acryloyl chloride (202-4) (81mg, 0.90mmol, 1.2 equivalent) is dissolved in dichloromethane (10ml), is dripped under ice salt bath Add (R) -4- amidos -3- (4- (4- chlorophenoxies) phenyl) -1- (pyridin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyrrole Dichloromethane (5ml) solution of pyridine -2- ketone (308-13) (325mg, 0.75mmol, 1 equivalent), be eventually adding DIEA (116mg, 0.90mmol, 1.2 equivalents) dichloromethane (5ml) solution, react 10 minutes.Water (40ml) is added to stir, dichloromethane (20ml) Extraction, organic phase washed once with water (20ml) again, dry, concentration, ethanol/methylene (1：And methanol/ethyl acetate 20) (1：20) column chromatography obtains white solid (R) -1- (1- acryloylpiperidine -3- bases) -4- amidos -3- (4- (4- chlorobenzene oxygen twice Base) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (66mg, yield 18%), content 100%, fusing point：90- 92℃；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, 1H), 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- bases) -4- amino -2- oxo -1,2- dihydros -3H- Imidazo [4,5-c] pyridin-3-yl) phenoxy group) cyanophenyl ((R) -4- (4- (1- (1-acryloylpiperidin-3-yl) -4- amino-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrile) The preparation of (compound 15)
Step 13a：Tertiary butyl (R) -3- (- 2 oxo -2,3- dihydro -1H- miaows of 4- amino 3- (4- (4- cyano-benzene oxygens)) Azoles simultaneously [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-3- (4- (4- cyanophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 307-15)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (1.0g, 3.0mmol, 1.0 equivalent), 4- (4- (4,4,5,5- tetramethyls -1,3,2- Dioxaborolane -2- bases) phenoxy group) cyanophenyl (108-15) (1.25g, 3.9mmol, 1.3 equivalent), copper acetate (0.60g, 3.3mmol, 1.1 equivalents), molecular sieve (1.0g), pyridine (0.71g, 9.0mmol, 3.0 equivalent) and n,N-Dimethylformamide (15ml), reaction solution are heated to 40 DEG C overnight in air.Reaction solution is diluted with ethyl acetate (200ml), with semi-saturation salt Water (100ml × 3) washs, and organic phase is spin-dried for silica gel mixed sample, and concentrate column chromatography purifies (eluant, eluent：Dichloromethane：First Alcohol=50：1) tertiary butyl (R) -3- (- 2 oxo -2,3- dihydro -1H- imidazos of 4- amino 3- (4- (4- cyano-benzene oxygens)) are obtained [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (0.36g, yield：23%).LCMS(ESI)：m/z 527[M+1]+, light green Color grease；TLC：0.6 (dichloromethane of Rf：Methanol=20：1).
Step 13b：(R) -4- (4- (4- amino -2- oxos -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridines -3 (2H)-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) (compound 308-15) preparation
Tertiary butyl (R) -3- (4- amino 3- (4- (4- cyano-benzene oxygens)) -2 oxo -2,3- dihydros-are added into reaction bulb 1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (307-15) (0.36g, 0.68mmol, 1.0 equivalent), dichloro Methane (10ml) and trifluoracetic acid (2.0ml), room temperature reaction is overnight.Reaction solution is poured into saturated sodium carbonate solution (100ml), It is extracted with dichloromethane (50ml × 3), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (eluant, eluent：Dichloromethane Alkane：Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- (4- (4- amino -2- oxos -1- (piperidines -3- bases) -1H- miaows Azoles simultaneously [4,5-c] pyridine -3 (2H)-yl) phenoxy group) cyanophenyl (0.122g, yield：42%).LCMS(ESI)：m/z 427[M+1 ]+, colorless solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 13c：(R) -4- (4- (1- (1- acryloylpiperidine -3- bases) -4- amino -2- oxo -1,2- dihydros -3H- Imidazo [4,5-c] pyridin-3-yl) phenoxy group) cyanophenyl ((R) -4- (4- (1- (1-acryloylpiperidin-3-yl) -4- amino-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrile) The preparation of (compound 15)
Toward at 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (202-4) (0.032g, 0.35mmol, 1.2 equivalent) (R) -4- (4- (4- amino -2- oxos -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -3 (2H)-yl) benzene oxygen is added dropwise Base) cyanophenyl (308-15) (0.122g, 0.29mmol, 1.0 equivalent) dichloromethane solution (7ml), diisopropyl is then added dropwise again The dichloromethane solution (1ml) of base ethylamine (0.056g, 0.44mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will reaction Liquid pours into water (100ml), is extracted with dichloromethane (50ml × 2), and organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography Method purifies (eluant, eluent：Dichloromethane：Methanol=40：1) (R) -4- (4- (1- (1- acryloylpiperidine -3- bases) -4- ammonia is obtained Base -2- oxos -1,2- dihydro -3H- imidazos [4,5-c] pyridin-3-yl) phenoxy group) cyanophenyl (0.052g, yield：38%).In vain Color solid, fusing point：116.1-118.7℃.TLC：0.4 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 481[M +1]+,1HNMR(CDCl3, 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- bases) -4- amino -3- (6- phenylpyridine -3- bases) -1,3- Dihydro -2H- imidazos [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) (compound 16) Preparation
Step 13a：Tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- phenoxypyridines -3- bases) -2,3- dihydros -1H- Imidazo [4,5-c] pyridine -1- bases) piperidines -1- carboxylates ((tert-butyl (R) -3- (4-amino-2-oxo-3- (6- phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) the preparation of (compound 307-16)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (0.666g, 2.0mmol, 1.0 equivalent), 2- phenoxy groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolane -2- bases) pyridine (108-16) (0.891g, 3.0mmol, 1.5 equivalent), copper acetate (0.400g, 2.2mmol, 1.1 equivalent), molecular sieve (0.500g), pyridine (0.474g, 6.0mmol, 3.0 equivalent) and N, N- bis- Methylformamide (8ml), reaction solution are heated to 40 DEG C overnight in air.Reaction solution is diluted with ethyl acetate (100ml), with half Saturated salt solution (100ml × 3) washs, and organic phase is spin-dried for silica gel mixed sample, and concentrate column chromatography purifies (eluant, eluent：Two Chloromethanes：Methanol=60：1) tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- phenoxypyridines -3- bases) -2,3- two are obtained Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (0.520g, yield：52%).LCMS(ESI)：m/z 503[M+1]+, yellow oil；TLC：0.7 (dichloromethane of Rf：Methanol=20：1).
Step 13b：(R) -4- amino -3- (6- phenoxypyridines -3- bases) -1- (piperidines -3- bases) -1,3- dihydro -2H- miaows Azoles simultaneously [4,5-c] pyridin-2-ones ((R) -4-amino-3- (6-phenoxypyridin-3-yl) -1- (piperidin-3- Yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 308-16) preparation
Tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- phenoxypyridines -3- bases) -2,3- two are added into reaction bulb Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (0.52g, 1.0mmol, 1.0 equivalent), dichloromethane (10ml) and trifluoracetic acid (2.0ml), reaction solution ambient temperature overnight.Reaction solution is poured into saturated sodium carbonate solution (100ml), is used Dichloromethane (50ml × 2) extracts, and organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (eluant, eluent：Dichloromethane： Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- amino -3- (6- phenoxypyridines -3- bases) -1- (piperidines -3- bases) - 1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.215g, yield：53%).LCMS(ESI)：m/z 403[M+1]+, Pale solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 13c：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (6- phenylpyridine -3- bases) -1,3- two Hydrogen -2H- imidazos [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) (compound 16) It prepares
Toward at 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (202-4) (0.059g, 0.65mmol, 1.2 equivalent) (R) -4- amino -3- (6- phenoxypyridines -3- bases) -1- (piperidines -3- bases) -1,3- dihydro -2H- imidazos [4,5-c] are added dropwise The dichloromethane solution (7ml) of pyridin-2-ones (308-16) (0.215g, 0.54mmol, 1.0 equivalent), it is different to be then added dropwise two again The dichloromethane solution (1ml) of ethylamine (0.104g, 0.81mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will be anti- It answers liquid to pour into water (100ml), is extracted with dichloromethane (50ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column layer Analysis method purifies (eluant, eluent：Dichloromethane：Methanol=30：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- is obtained (6- phenylpyridine -3- bases) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.083g, yield：34%).It is colourless solid Body, fusing point：107.9-109.9℃.TLC：Rf0.7 (dichloromethane：Methanol=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- bases) -4- amino -3- (4- (3,4- methylenedioxybenzenes oxygen Base) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) - 4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5- C] pyridin-2-one) (compound 17) preparation
Step 15a：Tertiary butyl (R) -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4, 5-c] pyridine) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-3- (4-iodophenyl) -2-oxo-2,3- Dihydro-1H-imidazo [4,5-c] pyridin-1-yl) piperidine-1-carboxylate) (compound 402-17) Preparation
By tertiary butyl (R) -3- (4- amino -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines - 1- carboxylates (306) (2.5g, 7.50mmol, 1.0 equivalent), to iodobenzene boric acid (401-17), (2.14g, 8.62mmol, 1.3 work as Amount) and pyridine (1.78g, 22.5mmol, 3.0 equivalent) be dissolved in n,N-Dimethylformamide (20mL), add copper acetate (1.50g, 8.25mmol, 1.1 equivalent) and 4A molecular sieves (3.0g), then 50 DEG C of reactions are stayed overnight in air.Reaction solution cools down It is diluted to room temperature and with ethyl acetate (100mL), filtering, filtrate is washed with semi-saturation saline solution (50mL × 4).Organic layer nothing Aqueous sodium persulfate is dried, concentration, obtained crude product column chromatography (eluant, eluent：Dichloromethane：Methanol=50:1) uncle is purified to obtain Butyl (R) -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines -1- carboxylics Acid esters (1.6g, yield：40%).Brown solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 536[M+1]+。
Step 15b：Tertiary butyl (R) -3- (4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) oxo -2 2-, 3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-3- (4- (benzo[d][1,3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] Pyridin-1-yl) piperidine-1-carboxylate) (compound 307-17) preparation
By tertiary butyl (R) -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyrroles Pyridine) piperidines -1- carboxylates (402-17) (0.8g, 1.49mmol, 1.0 equivalent), sesamol (403-17) (0.31g, 2.24mmol, 1.5 equivalents) and N, N- dimethyl glycine hydrochloride (39mg, 0.28mmol, 0.18 equivalent) be dissolved in dioxane In (8mL), cuprous iodide (14.2mg, 0.075mmol, 0.05 equivalent) and cesium carbonate (0.97g, 2.98mmol, 2.0 are added Equivalent), then in nitrogen protection 100 DEG C react 24 hours.Reaction solution is cooled to room temperature and concentrates, obtained crude product column Chromatography (eluant, eluent：Dichloromethane：Methanol=40:1 to 20:1) tertiary butyl (R) -3- (4- amino -3- (4- (3,4- are purified to obtain Methylene-dioxy phenoxy group) phenyl) 2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines -1- carboxylates (0.35g, yield：44%).Gray solid；TLC：Rf0.4 (dichloromethane：Methanol=20：1)；LCMS(ESI)：m/z 546[M +1]+。
Step 15c：(R) -4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -1- (3- piperidyls) -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) (compound 308-17) Preparation
By tertiary butyl (R) -3- (4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) 2- oxos -2,3- two Hydrogen -1H- imidazos [4,5-c] pyridine) piperidines -1- carboxylates (307-17) (0.35g, 0.64mmol, 1.0 equivalent) are dissolved in dichloro In methane (10mL), then trifluoroacetic acid (2mL) is added thereto, then reacts 2 hours at room temperature.By reaction mixture with two Chloromethanes (50mL) dilutes, and is washed with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (60mL), then will be had successively Machine layer is spin-dried for silica gel mixed sample, uses column chromatography (eluant, eluent later：Dichloromethane：Methanol：Triethylamine=100：10：1) it purifies Obtain (R) -4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -1- (3- piperidyls) -1H- imidazos [4,5-c] pyrrole Pyridine -2 (3H) -one (0.26g, yield：91%).Gray solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1)；LCMS (ESI)：m/z 446[M+1]+。
Step 15d：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (3,4- methylenedioxybenzenes oxygen Base) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) - 4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5- C] pyridin-2-one) (compound 17) preparation
Acryloyl chloride (202-4) (0.057mL, 0.7mmol, 1.2 equivalent) is dissolved in dichloromethane (5mL), is cooled to 0 DEG C, (R) -4- amino -3- (4- (3,4- methylene-dioxy phenoxy group) phenyl) -1- (3- piperidines is then added dropwise dropwise thereto Base) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (308-17) (0.26g, 0.584mmol, 1.0 equivalent) dichloromethane (5mL) solution then adds dropwise the dichloromethane of n,N-diisopropylethylamine (0.156mL, 0.876mmol, 1.5 equivalent) (1.0mL) solution reacts the mixed liquor 10 minutes at 0 DEG C.Reaction solution is quenched with water (50mL), then uses dichloromethane (50mL × 2) extract.Obtained organic layer is spin-dried for silica gel mixed sample, uses column chromatography (eluant, eluent later：Dichloromethane：First Alcohol=50：1) compound (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (3,4- methylene-dioxies are purified to obtain Phenoxy group) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.170g, yield：58%).White solid melts Point：194.5-195.6℃.TLC：0.4 (dichloromethane of Rf：Methanol=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,5H),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- bases) -4- amino -3- (4- (4- hydroxyphenoxies) phenyl) - 1,3- dihydro -2H- imidazos [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 Close object 18) preparation
Step 16a：Tertiary butyl (R) -3- (4- amino -3- (4- (4- benzyloxyphenoxies) phenyl) -2- oxos -2,3- two Hydrogen -1H- imidazos [4,5-c] pyridine) piperidines -1- carboxylates ((R)-tert-butyl 3- (4-amino-3- (4- (4- (benzyloxy)phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 307-18)
By tertiary butyl (R) -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyrroles Pyridine) piperidines -1- carboxylates (402-17) (0.7g, 1.31mmol, 1.0 equivalent), 4- benzyloxy phenols (403-18) (0.39g, 1.96mmol, 1.5 equivalents) and N, N- dimethyl glycine hydrochloride (34mg, 0.24mmol, 0.18 equivalent) be dissolved in dioxane In (10mL), cuprous iodide (12.5mg, 0.066mmol, 0.05 equivalent) and cesium carbonate (0.85g, 2.62mmol, 2.0 are added Equivalent), then in nitrogen protection 100 DEG C react 20 hours.Reaction solution is cooled to room temperature and concentrates, obtained crude product column Chromatography (eluant, eluent：Dichloromethane：Methanol=40:1 to 20:1) tertiary butyl (R) -3- (4- amino -3- (4- (4- benzyls are purified to obtain Oxygroup phenoxy group) phenyl) -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) (0.4g is received piperidines -1- carboxylates Rate：50%).Faint yellow solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 608[M+1]+。
Step 16b：(R) -4- amino -3- (4- (4- benzyloxyphenoxies) phenyl) -1- (3- piperidyls) -1H- imidazos [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) (compound 308-18) preparation
By tertiary butyl (R) -3- (4- amino -3- (4- (4- benzyloxyphenoxies) phenyl) -2- oxo -2,3- dihydros -1H- Imidazo [4,5-c] pyridine) piperidines -1- carboxylates (307-18) (0.40g, 0.658mmol, 1.0 equivalent) are dissolved in dichloromethane In (10mL), then trifluoroacetic acid (2mL) is added thereto, then reacts 2 hours at room temperature.By reaction mixture dichloromethane Alkane (50mL) dilutes, and is washed successively with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (60mL), then by organic layer It is spin-dried for silica gel mixed sample, uses column chromatography (eluant, eluent later：Dichloromethane：Methanol：Triethylamine=100：10：1) it purifies (R) -4- amino -3- (4- (4- benzyloxyphenoxies) phenyl) -1- (3- piperidyls) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.305g, yield：91%).Gray solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)： m/z 508[M+1]+。
Step 16c：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (4- hydroxyphenoxies) phenyl) - 1,3- dihydro -2H- imidazos [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 Close object 18) preparation
By (R) -4- amino -3- (4- (4- benzyloxyphenoxies) phenyl) -1- (3- piperidyls) -1H- imidazos [4,5-c] Pyridine -2 (3H) -one (308-18) (0.305g, 0.6mmol, 1.0 equivalent) is dissolved in ethyl alcohol (10mL), then thereto be added palladium/ Carbon (100mg), then 40 DEG C of reactions are stayed overnight under the atmosphere of hydrogen balloon.Reaction solution filters after being cooled to room temperature, and it is dense to collect filtrate Contracting obtains crude product, with column chromatography (eluant, eluent：Dichloromethane：Methanol=10:1) (R) -4- amino -3- (4- (4- are purified Hydroxyphenoxy) phenyl) -1- (3- piperidyls) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.22g, yield：88%). Gray solid；TLC：0.2 (dichloromethane of Rf：Methanol=8：1)；LCMS(ESI)：m/z 418[M+1]+.By above-mentioned gained (R) -4- amino -3- (4- (4- hydroxyphenoxies) phenyl) -1- (3- piperidyls) -1H- imidazos [4,5-c] pyridine -2 (3H) - Ketone (0.2g, 0.48mmol, 1.0 equivalent), acrylic acid (201-18) (38mg, 0.53mmol, 1.1 equivalent), DCC (119mg, 0.58mmol, 1.2 equivalents) and DMAP (6mg, 0.048mmol, 0.1 equivalent) be dissolved in dichloromethane (10mL), then at 0 DEG C Reaction 1 hour.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (eluant, eluent：Dichloromethane：Methanol=40：1) pure Change to obtain chemical combination (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (4- hydroxyphenoxies) phenyl) -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones (83mg, yield：37%).White solid, fusing point：196.3-198.2℃.TLC：Rf 0.4 (dichloromethane：Methanol=20：1)；LCMS(ESI)：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 =8.5Hz, 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- bases) -4- amino -3- (4- (4-nitrophenoxy) phenyl) - 1,3- dihydro -2H- imidazos [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) (chemical combination Object 19) preparation
Step 17a：Tertiary butyl (R) -3- (- 2 oxo -2,3- dihydro -1H- imidazos of 4- amino 3- (4- hydroxy phenyls) [4, 5-c] pyridine -1- bases) piperidines -1- carboxylates (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) (chemical combination Object 502-19) preparation
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (3.0g, 9.0mmol, 1.0 equivalent), 4- hydroxyls phenyl boric acid (501-19) (1.62g, 11.7mmol, 1.3 equivalents), copper acetate (1.820g, 10mmol, 1.1 equivalent), molecular sieve (3.0g), pyridine (2.13g, 27.0mmol, 3.0 equivalents) and n,N-Dimethylformamide (30ml), reaction solution is heated to 40 DEG C overnight in air.Reaction solution It is diluted with ethyl acetate (200ml), is washed with semi-saturation saline solution (200ml × 3), organic phase is spin-dried for silica gel mixed sample, concentration Object column chromatography purifies (eluant, eluent：Dichloromethane：Methanol=20：1) tertiary butyl (R) -3- (4- amino 3- (4- hydroxyls are obtained Phenyl) -2 oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (0.240g, yield： 6%).LCMS(ESI)：m/z 426[M+1]+, yellow oil；TLC：0.35 (dichloromethane of Rf：Methanol=20：1).
Step 17b：Tertiary butyl (R) -3- (4- amino -3- (4- (4-nitrophenoxy) phenyl) -2- oxo -2,3- dihydros - 1H- imidazos [4,5-c] pyridine -1- bases) piperidines pyridine -1- carboxylates (tert-butyl (R) 3- (4-amino-3- (4- (4- nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 307-19)
It is added into reaction bulb and obtains tertiary butyl (R) -3- (- 2 oxo -2,3- dihydros of 4- amino 3- (4- hydroxy phenyls) - 1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (502-19) (0.240g, 0.56mmol, 1.0 equivalent), to fluorine Nitrobenzene (503-19) (0.088g, 0.62mmol, 1.1 equivalent), potassium carbonate (0.116g, 0.84mmol, 1.5 equivalent) and acetonitrile (15ml), by reaction solution heated overnight at reflux.Reaction solution is spin-dried for silica gel mixed sample, concentrate column chromatography (eluant, eluent：Two Chloromethanes：Methanol=40：1) purifying obtains tertiary butyl (R) -3- (4- amino -3- (4- (4-nitrophenoxy) phenyl) -2- oxygen Generation -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines pyridine -1- carboxylate (0.270g, yield：89%).LCMS (ESI)：m/z 547[M+1]+, yellow oil；TLC：0.5 (dichloromethane of Rf：Methanol=20：1).
Step 17c：(R) -4- amino -3- (4- (4-nitrophenoxy) phenyl) -1- (piperidines -3- bases) -1H- imidazos [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
Into reaction bulb be added tertiary butyl (R)-3- (4- amino-3- (4- (4-nitrophenoxy) phenyl) oxo-2-2-, 3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) (0.27g, 0.5mmol, 1.0 work as piperidines pyridine -1- carboxylates (307-19) Amount), dichloromethane (10ml) and trifluoracetic acid (2.0ml) react at room temperature half an hour.Reaction solution is poured into saturated sodium carbonate solution It in (100ml), is extracted with dichloromethane (50ml × 3), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (elution Agent：Dichloromethane：Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- amino -3- (4- (4-nitrophenoxy) benzene Base) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.220g, yield：99%).LCMS(ESI)： m/z 447[M+1]+, colorless solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 17d：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (4-nitrophenoxy) phenyl) - 1,3- dihydro -2H- imidazos [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) (chemical combination Object 19) preparation
Toward at 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (202-4) (0.054g, 0.60mmol, 1.2 equivalent) (R) -4- amino -3- (4- (4-nitrophenoxy) phenyl) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -2 is added dropwise The dichloromethane solution (7ml) of (3H) -one (308-19) (0.220g, 0.50mmol, 1.0 equivalent), is then added dropwise diisopropyl again The dichloromethane solution (1ml) of base ethylamine (0.097g, 0.75mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will reaction Liquid pours into water (100ml), is extracted with dichloromethane (50ml × 2), and organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography Method purifies (eluant, eluent：Dichloromethane：Methanol=30：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- is obtained (4- (4-nitrophenoxy) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.170g, yield：68%). Yellow solid, fusing point：92.6-98.6℃.TLC：0.5 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 501[M +1]+,1HNMR(CDCl3, 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- bases) -4- amino -3- (4- (benzyl oxygroup) phenyl) -1,3- Dihydro -2H- imidazos [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) system It is standby
Step 18a：Tertiary butyl (R) -3- (4- amino -3- (4- (benzyl oxygroup) phenyl) -2- oxo -2,3- dihydros -1H- Imidazo [4,5-c] pyridine -1- bases) piperidines -1- carboxylates ((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 tertiary butyl (R) -3- (4- amino -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines - 1- carboxylates (306) (500mg, 1.5mmol, 1 equivalent) are dissolved in dichloromethane (5ml), sequentially add 4A molecular sieves (1g), acetic acid Copper (408mg, 2.25mmol, 1.5 equivalent), benzyloxyphenylboronic acid (601-24) (410mg, 1.8mmol, 1.2 equivalent), pyridine (178mg, 2.25mmol, 1.5 equivalent), Et3N (227mg, 2.25mmol, 1.5 equivalent), is stirred at room temperature 24 hours.It has reacted Finish, filtering, mother liquor is washed twice, dry, concentration, ethanol/methylene (1：40) column chromatography obtains brown solid tertiary butyl (R) -3- (4- amino -3- (4- (benzyl oxygroup) phenyl) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) Piperidines -1- carboxylates (350mg, yield 45.3%).LCMS(ESI)：m/z 516.40[M+1]+。
Step 18b：(R) -4- amidos -3- (4- (benzyloxy) phenyl) -1- [piperidines -3- bases] -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) (compound 603-24) preparation
Tertiary butyl (R) -3- (4- amino -3- (4- (benzyl oxygroup) phenyl) -2- oxo -2,3- dihydro -1H- imidazos [4, 5-c] pyridine -1- bases) piperidines -1- carboxylates (602-24) (350mg, 0.68mmol, 1 equivalent) are dissolved in dichloromethane (1ml), add Enter TFA (2ml), reacts at room temperature 1h.Reaction solution concentrates, and saturated sodium bicarbonate is neutralized to slightly meta-alkalescence, is extracted with 5ml dichloromethane It takes, dry, concentration, ethanol/methylene/triethylamine (1：10：0.3) column chromatography obtains off-white color foaming solid (R) -4- amine Base -3- (4- (benzyloxy) phenyl) -1- [piperidines -3- bases] -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (90mg, Yield 32%).LCMS(ESI)：m/z 416.40[M+1]+。
Step 18c：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (benzyl oxygroup) phenyl) -1,3- Dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- (benzyl) oxy) phenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) and (compound 24) system It is standby
Acryloyl chloride (202-4) (24mg, 0.26mmol, 1.2 equivalent) is dissolved in dichloromethane (4ml), is added under ice bath (R) -4- amidos -3- (4- (benzyloxy) phenyl) -1- [piperidines -3- bases] -1,3- dihydro -2H- imidazo [4,5-c] pyridines -2- Dichloromethane (4ml) solution of ketone (603-24) (90mg, 0.217mmol, 1 equivalent), be eventually adding DIEA (34mg, 0.26mmol, 1.2 equivalents) dichloromethane (2ml) solution, react 10 minutes.Water (5ml) is added to stir, dichloromethane (2ml) extraction It takes, organic phase washed once with water (10ml) again, dry, concentration, methanol/ethyl acetate (1：10) column chromatography obtains white solid (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (benzyl oxygroup) phenyl) -1,3- dihydro -2H- imidazos [4, 5-c] pyridin-2-ones (19.4mg, yield 19%).Fusing point：75-76℃；LCMS(ESI)：m/z 470.50[M+1]+；1HNMR (600MHz,CDCl3):δ 1.27 (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 (dd, 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, 3H), 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- bases) -4- amino -3- (4- ((4- chlorobenzyls) oxygroup) benzene Base) -1,3- dihydro -2H- imidazos [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：Tertiary butyl (R) -3- (4- amino -3- (4- ((4- chlorobenzyls) oxygroup) phenyl) -2- oxos -2,3- two Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (tert-butyl (R) -3- (4-amino-3- (4- ((4- chlorobenzyl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 602-26)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (0.423g, 1.27mmol, 1.0 equivalent), (4- ((4- chlorobenzyls) oxygroup) phenyl) 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-Dimethylformamide (10ml), reaction solution is in air It is heated to 40 DEG C overnight.Reaction solution is diluted with ethyl acetate (100ml), is washed with semi-saturation saline solution (100ml × 3), organic It is mutually spin-dried for silica gel mixed sample, concentrate column chromatography purifies (eluant, eluent：Dichloromethane：Methanol=60：1) tertiary butyl is obtained (R) -3- (4- amino -3- (4- ((4- chlorobenzyls) oxygroup) phenyl) -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles Pyridine -1- bases) piperidines -1- carboxylate (0.200g, yield：29%).LCMS(ESI)：m/z 551[M+1]+, yellow oil； TLC：0.7 (dichloromethane of Rf：Methanol=20：1).
Step 19b：(R) -4- amino -3- (4- ((4- chlorobenzyls) oxygroup) phenyl) -1- (piperidines -3- bases) -1H- imidazos [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) (compound 603-26) preparation
Tertiary butyl (R) -3- (4- amino -3- (4- ((4- chlorobenzyls) oxygroup) phenyl) -2- oxos-are added into reaction bulb 2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) (0.20g, 1.0mmol, 1.0 work as piperidines -1- carboxylates (602-26) Amount), dichloromethane (10ml) and trifluoracetic acid (2.0ml) react at room temperature half an hour.Reaction solution is poured into saturated sodium carbonate solution It in (100ml), is extracted with dichloromethane (80ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (elution Agent：Dichloromethane：Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- amino -3- (4- ((4- chlorobenzyls) oxygroup) benzene Base) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.145g, yield：90%).LCMS(ESI)： m/z 451[M+1]+, light yellow solid；TLC：Rf0.1 (dichloromethane：Methanol=20：1).
Step 19c：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- ((4- chlorobenzyls) oxygroup) benzene Base) -1,3- dihydro -2H- imidazos [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)
Toward at 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (202-4) (0.035g, 0.39mmol, 1.2 equivalent) (R) -4- amino -3- (4- ((4- chlorobenzyls) oxygroup) phenyl) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine-is added dropwise The dichloromethane solution (8ml) of 2 (3H) -one (603-26) (0.145g, 0.32mmol, 1.0 equivalent), is then added dropwise diisopropyl again The dichloromethane solution (1ml) of base ethylamine (0.062g, 0.48mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will reaction Liquid pours into water (100ml), is extracted with dichloromethane (50ml × 2), and organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography Method purifies (eluant, eluent：Dichloromethane：Methanol=40：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- is obtained (4- ((4- chlorobenzyls) oxygroup) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.100g, yield： 62%).Colorless solid, fusing point：93.1-95.9℃.TLC：0.4 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 504[M+1]+,1HNMR(CDCl3, 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,2H),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- bases) -4- amino -3- (6- (benzyloxy) pyridin-3-yl) - 1,3- dihydro -2H- imidazos [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) (change Close object 27) preparation
Step 20a：Tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- benzyloxypyridine -3- bases) -2,3- dihydros -1H- Imidazo [4,5-c] pyridine -1- bases) piperidines -1- carboxylates ((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-carboxylate) the preparation of (602-27)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine -1- bases) piperidines -1- carboxylates (306) (0.999g, 3.0mmol, 1.0 equivalent), 2- benzyloxies -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolane -2- bases) pyridine (601-27) (1.400g, 4.5mmol, 1.5 equivalent), copper acetate (0.820g, 4.5mmol, 1.5 equivalent), molecular sieve (0.500g), pyridine (0.710g, 9.0mmol, 3.0 equivalent) and N, N- bis- Methylformamide (10ml), reaction solution are heated to 40 DEG C overnight in air.Reaction solution is diluted with ethyl acetate (100ml), is used Semi-saturation saline solution (100ml × 3) washs, and organic phase is spin-dried for silica gel mixed sample, and concentrate column chromatography purifies (eluant, eluent： Dichloromethane：Methanol=60：1) tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- benzyloxypyridine -3- bases) -2,3- are obtained Dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylate (0.410g, yield：52%).LCMS(ESI)：m/z 517[M+1]+, yellow oil；TLC：0.7 (dichloromethane of Rf：Methanol=20：1).
Step 20b：(R) -4- amino -3- (6- benzyloxypyridine -3- bases) -1- (piperidines -3- bases) -1H- imidazos [4,5- C] pyridine -2 (3H) -one ((R) -4-amino-3- (6- (benzyloxy) pyridin-3-yl) -1- (piperidin-3-yl) - 1H-imidazo [4,5-c] pyridin-2 (3H)-one) (603-27) preparation
Tertiary butyl (R) -3- (4- amino -2- oxos -3- (6- benzyloxypyridine -3- bases) -2,3- two are added into reaction bulb Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- carboxylates (602-27) (0.41g, 1.0mmol, 1.0 equivalent), two Chloromethanes (10ml) and trifluoracetic acid (2.0ml) react at room temperature half an hour.Reaction solution is poured into saturated sodium carbonate solution It in (100ml), is extracted with dichloromethane (50ml × 2), organic phase is spin-dried for silica gel mixed sample, concentrate column chromatography (elution Agent：Dichloromethane：Methanol：Triethylamine=10：1：0.1) purifying obtains (R) -4- amino -3- (6- benzyloxypyridine -3- bases) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.220g, yield：66%).LCMS(ESI)：m/z 417 [M+1]+, light yellow solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 20c：(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (6- (benzyloxy) pyridin-3-yl) -1, 3- dihydro -2H- imidazos [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) (chemical combination Object 27) preparation
Toward at 0 DEG C in the dichloromethane solution (7ml) of acryloyl chloride (202-4) (0.057g, 0.64mmol, 1.2 equivalent) (R) -4- amino -3- (6- benzyloxypyridine -3- bases) -1- (piperidines -3- bases) -1H- imidazos [4,5-c] pyridine -2 is added dropwise The dichloromethane solution (7ml) of (3H) -one (603-27) (0.220g, 0.53mmol, 1.0 equivalent), is then added dropwise diisopropyl again The dichloromethane solution (1ml) of base ethylamine (0.102g, 0.80mmol, 1.5 equivalent) reacts 5 minutes at 0 DEG C.It will reaction Liquid pours into water (100ml), is extracted with dichloromethane (50ml × 2), and organic phase is spin-dried for silica gel mixed sample, residue column chromatography Method purifies (eluant, eluent：Dichloromethane：Methanol=30：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- is obtained (6- (benzyloxy) pyridin-3-yl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.135g, yield：54%).Nothing Color solid, fusing point：107.3-109.2℃.TLC：0.5 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 471[M +1]+,1HNMR(CDCl3, 500MHz)：δ 8.29 (d, J=3Hz, 1H), 7.89 (d, J=5.5Hz, 1H), 7.68 (q, 2H), 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- bases) -4- amino -3- (4- (4- fluorophenoxies) phenyl) - 1H- pyrrolo-es [3,2-c] pyridine -2 (3H) -one (1- ((R) -1-acryloylpiperidin-3-yl) -4-amino-3- (4- (4-fluorophenoxy) phenyl) -1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) (compound 12) preparation
Step 21a：2- (4- (4-fluoro- phenoxy group)-phenyl] penta ring (2- of-4,4,5,5- tetramethyl-1,3,2- dioxies boron (4- (4-fluorophenoxy) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (compound Preparation 108-12)
By the bromo- 4- of 1- (4-fluoro- phenoxy group) benzene (2.00g, 7.54mmol, 1.0 equivalent), join pinacol borate (5.84g, 15.1mmol, 2.0 equivalent), potassium acetate (1.48g, 15.1mmol, 2.0 equivalent) and Pd (dppf) Cl2(0.54g, 0.754mmol, 0.1 equivalent) nitrogen charging gas shielded, dioxane (20ml) is then added, 90 DEG C of reactions are overnight.Reaction solution is cooled down Washing, dichloromethane extraction, concentrates, column chromatography (eluant, eluent after dry：Dichloromethane：N-hexane=1:2) 2- (4- (4-are obtained Fluoro- phenoxy group)-phenyl] -4,4,5,5- tetramethyls -1,3, penta ring of 2- dioxies boron (1.10g, yield 46.5%), off-white color is solid Body, TLC:0.6 (dichloromethane of Rf：N-hexane=1:2)
Step 21b：((3R)-tertiary butyl -3- (4- amino -3- (4- (4- fluorophenoxies) phenyl) -2- oxos -2,3- two Hydrogen -1H- pyrrolo-es [3,2-c] pyridine -1- bases) piperidines -1- carboxylates ((3R)-tert-butyl 3- (4-amino-3- (4- (4-fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 307-12)
Tertiary butyl (R) -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles are added into reaction bulb Pyridine-1- bases) piperidines-1- carboxylates (306) (3.0g, 9.0mmol, 1.0 equivalent), 2- (4- (4-fluoro- phenoxy group)-phenyl]-4, 4,5,5- tetramethyls -1,3, penta ring (108-12) (0.85g, 2.5mmol, 1.00 equivalent) of 2- dioxies boron, copper acetate (0.98g, 5mmol, 2 equivalents), triethylamine (0.5g, 5mmol, 2.00 equivalent), pyridine (0.40g, 5mmol, 2.00 equivalent) and N, N- diformazan Base formamide (10ml), reaction solution are heated to 40 DEG C overnight in air.Reaction solution is diluted with ethyl acetate (200ml), with half Saturated salt solution (150ml × 3) washs, and organic phase is spin-dried for silica gel mixed sample, and residue column chromatography purifies (eluant, eluent：Second Acetoacetic ester：Hexamethylene=2：1) tertiary butyl ((3R)-tertiary butyl -3- (4- amino -3- (4- (4- fluorophenoxies) phenyl) -2- are obtained Oxo -2,3- dihydro -1H- pyrrolo-es [3,2-c] pyridine -1- bases) piperidines -1- carboxylate (0.19g, yield：14%).LCMS (ESI)：m/z 519[M+1]+, yellow oil；TLC：Rf0.57 (ethyl acetate：Hexamethylene=2：1).
Step 21c：4- amino -3- (4- (4- fluorophenoxies) phenyl) -1- ((R)-piperidines -3- bases) -1H- pyrroles [3,2- C] pyridine -2 (3H) -one (4-amino-3- (4- (4-fluorophenoxy) phenyl) -1- ((R)-piperidin-3-yl) - 1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) (compound 308-12) preparation
Tertiary butyl ((3R)-tertiary butyl -3- (4- amino -3- (4- (4- fluorophenoxies) phenyl) -2- are added into reaction bulb Oxo -2,3- dihydro -1H- pyrrolo-es [3,2-c] pyridine -1- bases) piperidines -1- carboxylates (307-12) (0.19g, 0.36mmol, 1.0 equivalents), dichloromethane (5ml) and trifluoracetic acid (1.0ml), reaction solution is in ambient temperature overnight.Reaction solution is poured into unsaturated carbonate It in sodium solution (100ml), is extracted with dichloromethane (10mlX2), organic phase is spin-dried for silica gel mixed sample, residue column chromatography (eluant, eluent：Dichloromethane：Methanol：Triethylamine=10：1：0.1) purifying obtains 4- amino -3- (4- (4- fluorophenoxies) phenyl) - 1- ((R)-piperidines -3- bases) -1H- pyrroles [3,2-c] pyridine -2 (3H) -one (0.1g, yield：66.7%).LCMS(ESI)：m/z 419[M+1]+, yellow oil；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 21d：1- ((R) -1- acryloylpiperidine -3- bases) -4- amino -3- (4- (4- fluorophenoxies) phenyl) -1H- Pyrrolo- [3,2-c] pyridine -2 (3H) -one (1- ((R) -1-acryloylpiperidin-3-yl) -4-amino-3- (4- (4- Fluorophenoxy) phenyl) -1H-pyrrolo [3,2-c] pyridin-2 (3H)-one) (compound 12) preparation
It is added dropwise at 0 DEG C in the dichloromethane solution (5ml) of past acryloyl chloride (0.032g, 0.36mmol, 1.5 equivalent) (4- amino -3- (4- (4- fluorophenoxies) phenyl) -1- ((R)-piperidines -3- bases) -1H- pyrroles [3,2-c] pyridine -2 (3H) -one The dichloromethane solution (3ml) of (308-12) (0.1g, 0.24mmol, 1.0 equivalent), is then added dropwise diisopropyl ethyl amine again The dichloromethane solution (2ml) of (0.062g, 0.48mmol, 2.0 equivalent) reacts 5 minutes at 0 DEG C.Reaction solution is poured into water It in (10ml), is extracted with dichloromethane (10mlX2), organic phase is spin-dried for silica gel mixed sample, and residue column chromatography purifies (two Chloromethanes：Methanol=40：1) (1- ((R) -1- acryloylpiperidine -3- bases) -4- amino -3- (4- (4- fluorophenoxies) benzene is obtained Base) -1H- pyrrolo-es [3,2-c] pyridine -2 (3H) -one (0.028g, yield：24%).Off-white powder, fusing point：86-88℃. TLC：0.5 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 473[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- dimethylaminos phenoxy group) Phenyl) -1,3-2H- imidazos [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) the preparation of (compound 21)
Step 22a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- dimethylamino phenyls) -2,3- two Hydrogen -1H- imidazos [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) the preparation of (compound 307-21)
(R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- hydroxy phenyls) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (502-19) (0.88g, 2.07mmol, 1.0 equivalent), to dimethylamino bromobenzene (1.24g, 6.21mmol, 3.0 equivalents) and N, N- dimethyl glycine hydrochloride (0.35g, 2.48mmol, 1.2 equivalent) be dissolved in dioxane In (20mL), adding cuprous iodide (0.12g, 0.62mmol, 0.3 equivalent) and cesium carbonate, (2.36g, 7.25mmol, 3.5 work as Amount), then in nitrogen protection 100 DEG C react 24 hours.Reaction solution is cooled to room temperature and concentrates, obtained crude product column layer Analysis method (dichloromethane：Methanol=50:1) (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- diformazan ammonia is purified Base phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (0.69g, yield：61%).LCMS(ESI)：m/z 545 [M+1]+, gray solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1).
Step 22b:(R) -4- amino -3- (4- (4- dimethylaminos phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- imidazoles And [4,5-c] pyridine -2 (3H) -one ((R) -4-amino-3- (4- (4- (dimethylamino) phenoxy) phenyl) -1- (piperidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 308-21) It prepares
By ((R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- dimethylamino phenyls) -2,3- dihydros -1H- Imidazo [4,5-c] pyridine) piperidines (307-21) (0.69g, 1.27mmol, 1.0 equivalent) is dissolved in dichloromethane (15mL), then Trifluoroacetic acid (3mL) is added thereto, then reacts 2 hours at room temperature.Reaction mixture is dilute with dichloromethane (100mL) It releases, is washed successively with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (60mL), then by organic layer silica gel mixed sample It is spin-dried for, uses column chromatography (dichloromethane later：Methanol：Triethylamine=100：10：1) (R) -4- amino -3- (4- (4- are purified Dimethylamino phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.52g, yield： 93%).LCMS(ESI)：m/z 445[M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1).
Step 22c:(R) -1- (3- (1- (acryloyl group) piperidines)) -4- amino -3- (4- (4- dimethylaminos phenoxy group) benzene Base) -1,3-2H- imidazos [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) the preparation of (compound 21)
By (R) -4- amino -3- (4- (4- dimethylaminos phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5- C] pyridine -2 (3H) -one (308-21) (0.2g, 0.45mmol, 1.0 equivalent), acrylic acid (39mg, 0.54mmol, 1.2 equivalent), DCC (111mg, 0.54mmol, 1.2 equivalent) and DMAP (5.5mg, 0.045mmol, 0.1 equivalent) are dissolved in dichloromethane (10mL), Then it reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane：Methanol= 50：1) compound (R) -1- (3- (1- (acryloyl group) piperidines)) -4- amino -3- (4- (4- dimethylaminos phenoxy group) are purified to obtain Phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (60mg, yield：27%).White solid, fusing point：92.3-97.6 ℃.TLC：0.5 (dichloromethane of Rf：Methanol=15：1).LCMS(ESI)：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 groups) piperidines -3- bases] -4- amidos -3- [4- (4- trifluoromethylbenzene oxygen Base-phenyl)] -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((3R) -1- (1-Acryloyl-piperidin-3- yl)-4-amino-3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5- C] pyridin-2-one) (compound 22) preparation
Step 23a:(3R) -3- [4- amino -2- oxos -3- [4- (4- 4-trifluoromethylphenopendants-phenyl)] -2,3- dihydros - 1H- imidazos [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (3- { 4-Amino-2-oxo-3- [4- (4- trifluoromethyl-phenoxy)-phenyl]-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl}- Piperidine-1-carboxylic acid tert-butyl ester) (compound 307-22) preparation
By (3R) -3- (4- amino -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines -1- first Tert-butyl acrylate (306) (1.17g, 3.52mmol, 1 equivalent) is dissolved in DMF (15ml), sequentially adds Molecular sieve (2g), acetic acid Copper (0.96g, 5.28mmol, 1.5 equivalent), 4- 4-trifluoromethylphenopendants phenyl boric acid (108-22) (1.19g, 4.22mmol, 1.1 Equivalent), pyridine (0.417g, 5.28mmol, 1.5 equivalent), be stirred overnight at room temperature.Reaction finishes, and filtering, mother liquor is washed twice, It is dry, concentration, methanol/DCM (1：40) column chromatography obtains brown syrup (3R) -3- [4- amino -2- oxos -3- [4- (4- trifluoros Methylphenoxy-phenyl)] -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (0.55g, Yield 27.5%)；TLC：0.7 (dichloromethane of Rf：Methanol=20：1)；LCMS(ESI)：m/z 570[M+1]+1。
Step 23b:(3R) -4- amino -1- [piperidines -3- bases] -3- [4- (4- 4-trifluoromethylphenopendants)-phenyl] 1,3- 2H- imidazos [4,5-c] pyridin-2-ones (4-Amino-1-piperidin-3-yl-3- [4- (4-trifluoromethyl- Phenoxy)-phenyl] -1,3-dihydro-imidazo [4,5-c] pyridin-2-one) (compound 308-22) preparation
By (3R) -3- [4- amido -2- oxos -3- [4- (4- 4-trifluoromethylphenopendants-phenyl)] -2,3- dihydro -1H- miaows Azoles simultaneously [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (307-22) (0.55g, 0.97mmol, 1 equivalent) are dissolved in DCM (2ml) is added TFA (2ml), reacts at room temperature 1h.Reaction solution concentrates, then is neutralized to slightly meta-alkalescence with saturated sodium bicarbonate, uses 5ml DCM is extracted, dry, concentration, methanol/DCM/ triethylamines (1：10：0.1) column chromatography obtains off-white color foaming solid (3R) -4- ammonia Base -1- [piperidines -3- bases] -3- [4- (4- 4-trifluoromethylphenopendants)-phenyl] 1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.408g, yield 90%)；TLC：0.2 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)：m/z 470[M+1]+1。
Step 23c:(3R) -1- [1- (1- acryloyl groups) piperidines -3- bases] -4- amidos -3- [4- (4- trifluoromethylbenzene oxygen Base-phenyl)] -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones ((3R) -1- (1-Acryloyl-piperidin-3- yl)-4-amino-3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5- C] pyridin-2-one) (compound 22) preparation
By 4- amidos -3- [4- (4- 4-trifluoromethylphenopendants-phenyl)] -1- [(3R)-piperidines -3- bases] -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones (308-22) (67mg, 0.143mmol, 1 equivalent), acrylic acid (12mg, 0.171mmol, 1.2 equivalents) it is dissolved in DCM (5ml), HATU (71mg, 0.186mmol, 1.3 equivalent) and Et is added3N (22mg, 0.215mmol, 1.5 equivalents), it reacts 0.5 hour under ice bath.Reaction finishes, and concentration, column chromatography purifies (eluant, eluent：Methanol：Two Chloromethanes=1：20) white solid (3R) -1- [1- (1- acryloyl groups) piperidines -3- bases] -4- amidos -3- [4- (4- fluoroforms are obtained Phenoxyl-phenyl)] -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (20mg, yield 20%)；Purity 95.1%； TLC：0.4 (dichloromethane of Rf：Methanol=20：1)；Fusing point：64~65 DEG C；LCMS(ESI)：m/z 524[M+1]+1；1HNMR (400MHz,CDCl3):δ 1.64 (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,2H),7.18(dd,4H,1J=8.64Hz,2), J=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 groups-piperidines -3- bases) -4- amino -3- [4- (4- hydroxy toluenes oxygroup)-benzene Base] -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 Close object 23) preparation
Step 24a:(3R) -3- [4- amido -2- oxos -3- (4- hydroxy methyl phenyloxies-phenyl) -2,3- dihydro -1H- miaows Azoles simultaneously [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (3- { 4-Amino-2-oxo-3- (4-hydroxy methyl phenoxy-phenoxy)-2,3-dihydro-1-H-imidazo[4,5-c]pyridin-1-yl}-piperidine-1- Carboxylic acid tert-butyl ester) (compound 307-23) preparation
(3R) -3- [4- amido -2- oxos -3- (4- hydroxy phenyls) -2,3- dihydro -1H- imidazos are added in toward flask [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (502-19) (737mg, 1.73mmol, 1 equivalent), Cs2CO3(1.13g, 3.46mmol, 2 equivalents), it is in brown suspension that NMP (10ml), which is added, and stirs, be added 4- fluorobenzaldehydes (258mg, 2.076mmol, 1.2 equivalents), 80 DEG C of reactions are overnight.Reaction system is cooled down, is filtered, mother liquor is added 20ml water and vinegar acid for adjusting pH is added to inclined Acidity, DCM (10ml) are extracted twice, and organic phase is finally washed 2 times with water (20ml) again, concentration, column chromatography (methanol：DCM=1: 40) (3R) -3- [4- amido -2- oxos -3- (4- carboxaldehyde radicals Phenoxy-phenyl) -2,3- dihydro -1H- imidazos [4,5- are obtained C] pyridine -1- bases] piperidines -1- t-butyl formates (500mg, yield 55%), TLC：0.4 (methanol of Rf：Dichloromethane=1： 40), light brown syrup, LCMS (ESI)：m/z 530[M+1]+.By above compound (500mg, 0.945mmol, 1 equivalent), Be dissolved in methanol/tetrahydrofuran (3ml/3ml), be added sodium borohydride (179mg, 4.73mmol, 5 equivalent) and lithium chloride (200mg, 4.73mmol, 5 equivalents).Water (20ml) is added to stir, DCM (10ml x 2) extractions, concentration, column chromatography (methanol：DCM=1: 40) (3R) -3- [4- amido -2- oxos -3- (4- hydroxy methyl phenyloxies-phenyl) -2,3- dihydro -1H- imidazos [4,5- are obtained C] pyridine -1- bases] piperidines -1- t-butyl formates (220mg, yield 44%), TLC：0.3 (methanol of Rf：Dichloromethane=1： 40), light yellow syrup, LCMS (ESI)：m/z 532[M+1]+。
Step 24b:(3R) -4- amidos -3- [4- (4- hydroxy methyl phenyloxies-phenyl)] -1- piperidines -3- base -1,3-2H- miaows Azoles simultaneously [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) (compound 308-23) preparation
(3R) -3- [4- amido -2- oxos -3- [4- (4- hydroxy methyl phenyloxies-phenyl)] -2,3- two are added in toward flask Hydrogen -1H- imidazos [4,5-c] pyridine -1- bases] piperidines -1- t-butyl formates (307-23) (0.22g, 0.41mmol, 1 equivalent), It is dissolved in DCM (2ml), TFA (1ml) is added, reacts at room temperature 1h.Reaction solution concentrates, then is neutralized to slightly meta-alkali with saturated sodium bicarbonate Property, it is extracted with 5ml DCM, dry, concentration, methanol/DCM/ triethylamines (1：10：0.1) column chromatography obtains (3R) -4- amido -3- [4- (4- hydroxy methyl phenyloxies-phenyl)] -1- piperidines -3- bases -1,3-2H- imidazo [4,5-c] pyridin-2-ones (0.092g, yield 52%), off-white color grease, TLC：0.2 (dichloromethane of Rf：Methanol=10：1)；LCMS(ESI)：m/z 432[M+1]+1。
Step 24c:(3R) -1- (1- acryloyl groups-piperidines -3- bases) -4- amino -3- [4- (4- hydroxy toluenes oxygroup)-benzene Base] -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 Close object 23) preparation
(3R) -4- amidos -3- [4- (4- hydroxy methyl phenyloxies-phenyl)] -1- piperidines -3- bases -1,3- is added in toward flask 2H- imidazos [4,5-c] pyridin-2-ones (308-23) (80mg, 0.1854mmol, 1 equivalent), are dissolved in DCM (2ml)/Et3N (56mg), acrylic acid (15mg, 0.2039mmol, 1.1 equivalent) and HATU are added under ice bath, and (92mg, 0.241mmol, 1.3 work as Amount), it reacts 0.5 hour.Reaction finishes, and column chromatography purifies (eluant, eluent：Methanol：Dichloromethane=1：20) white solid 4- amine is obtained Base -1- [(3R) -1- (2- crotonyls) dimethylamine -3- bases] -3- [4- (4- hydroxy methyl phenyloxies-phenyl)] -1,3- dihydros - 2H- imidazos [4,5-c] pyridin-2-ones (20mg, yield 22%)；Purity 95.3%；TLC：0.4 (dichloromethane of Rf：Methanol =20：1)；Fusing point：99~100 DEG C；LCMS(ESI)：m/z 486[M+1]+1；1HNMR(600MHz,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, 4H), 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 groups) piperidyl) -4- amino -3- (4- (4- fluorine benzyloxy) phenyl) - 1,3-2H- imidazos [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) (chemical combination Object 25) preparation
Step 25a:4- (4- fluorine benzyloxy) phenyl boric acid ((4- ((4-fluorobenzyl) oxy) phenyl) boronic Acid) the preparation of (compound 601-25)
Into reaction bulb be added p bromophenol (3.0g, 17.34mmol, 1.0 equivalent), to fluorobenzyl bromide (3.93g, 20.81mmol, 1.2 equivalents), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalent) and n,N-Dimethylformamide (20ml), room Temperature reaction is overnight.Reaction solution adds water (100mL) to dilute, and is extracted with ethyl acetate (50mL × 3), and extract liquor is dry with anhydrous sodium sulfate Dry, then concentration purifies (petroleum ether with column chromatography：Ethyl acetate=20：1) 4- (4- fluorine benzyloxy) bromobenzene is obtained (4.48g, yield：92%).LCMS(ESI)：m/z 281[M+1]+, white solid；TLC：0.5 (petroleum ethers of Rf：Ethyl acetate =10：1).Compound obtained above (3.16g, 11.24mmol, 1.0 equivalent) is dissolved in anhydrous tetrahydro furan (40mL), - 78 DEG C are cooled to dry ice acetone bath, n-BuLi (2.5M, 5.4mL, 13.49mmol, 1.2 equivalent) is then slowly added dropwise, It is stirred 1 hour at -78 DEG C after being added dropwise.Then trimethylborate (2.55mL, 22.48mmol, 2.0 equivalent) is added It is slowly raised to room temperature and is stirred overnight.2N aqueous hydrochloric acid solutions (20mL) are added and stir 2 hours.Aqueous layer with ethyl acetate (50mL × 3) it extracts, is dried with anhydrous sodium sulfate after merging organic layer, concentrated, obtained crude product column chromatography (petroleum ether：Acetic acid Ethyl ester=1:1) 4- (4- fluorine benzyloxy) phenyl boric acid (0.92g, yield is purified to obtain：33%).LCMS(ESI)：m/z 247[M+1 ]+, white solid；TLC：0.2 (petroleum ethers of Rf：Ethyl acetate=2：1).
Step 25b:(R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -2- oxos -2,3- Dihydro -1H- imidazos [4,5-c] pyridine) piperidines (tert-butyl (R) -3- (4-amino-3- (4- ((4- fluorobenzyl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) Piperidine-1-carboxylate) the preparation of (compound 602-25)
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperazine Pyridine (0.85g, 2.55mmol, 1.0 equivalent), 4- (4- fluorine benzyloxy) phenyl boric acid (0.82g, 3.32mmol, 1.3 equivalent) and pyridine (0.62mL, 7.65mmol, 3.0 equivalent) is dissolved in n,N-Dimethylformamide (8mL), add copper acetate (0.51g, 2.81mmol, 1.1 equivalents) andMolecular sieve (1g), then 50 DEG C of reactions are stayed overnight in air.Reaction solution is cooled to room temperature simultaneously It is diluted with ethyl acetate (100mL), filtering, filtrate is washed with semi-saturation saline solution (50mL × 2).Organic layer anhydrous sodium sulfate It is dry, concentration, obtained crude product column chromatography (dichloromethane：Methanol=50:1) (R) -1- tertbutyloxycarbonyls-are purified 3- (4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (0.27g, yield：32%).LCMS(ESI)：m/z 534[M+1]+, brown solid；TLC：0.4 (dichloromethane of Rf：Methanol= 20：1).
Step 25c:(R) -4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -1- (3- piperidyls) -1,3-2H- imidazos [4,5-c] pyridin-2-ones ((R) -4-amino-3- (4- ((4-fluorobenzyl) oxy) phenyl) -1- (piperidin- 3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 603-25) preparation
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -2- oxo -2,3- dihydros - 1H- imidazos [4,5-c] pyridine) piperidines (602-25) (0.27g, 0.51mmol, 1.0 equivalent) is dissolved in dichloromethane (10mL) In, then trifluoroacetic acid (2mL) is added thereto, then react 2 hours at room temperature.By reaction mixture dichloromethane (50mL) dilutes, and is washed with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (30mL), then uses organic layer successively Silica gel mixed sample is spin-dried for, and uses column chromatography (dichloromethane later：Methanol：Triethylamine=100：10：1) (R) -4- amino-is purified 3- (4- (4- fluorine benzyloxy) phenyl) -1- (3- piperidyls) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.20g, yield： 90%).LCMS(ESI)：m/z 434[M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1).
Step 25d:(R) -1- (3- (1- acryloyl groups) piperidyl) -4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -1, 3-2H- imidazos [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) (chemical combination Object 25) preparation
By (R) -4- amino -3- (4- (4- fluorine benzyloxy) phenyl) -1- (3- piperidyls) -1,3-2H- imidazos [4,5-c] Pyridin-2-ones (603-25) (0.20g, 0.46mmol, 1.0 equivalent), acrylic acid (43mg, 0.60mmol, 1.3 equivalent), DCC (124mg, 0.60mmol, 1.3 equivalent) and DMAP (5.6mg, 0.046mmol, 0.1 equivalent) are dissolved in dichloromethane (10mL), so It is reacted 1 hour at 0 DEG C afterwards.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane：Methanol=50：1) Purify to obtain compound 6-7 (110mg, yield：49%).White solid, fusing point：69.7-71.7℃.TLC：0.4 (dichloromethanes of Rf Alkane：Methanol=20：1).LCMS(ESI)：m/z 488[M+1]+,1HNMR(CDCl3, 500MHz)：δ7.86(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,1H),2.02-1.95(m,1H),1.70-1.60(m,1H)。
Embodiment 26:(R) -1- (3- (1- acryloyl groups) piperidyl) -4- amino -3- (4- (2- pyridines oxygroup) phenyl) - 1,3-2H- imidazos [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
Step 26a:4- (2- pyridines oxygroup) phenyl boric acid ((4- (pyridin-2-yloxy) phenyl) boronic acid) The preparation of (compound 108-28)
The addition p bromophenol (3.0g, 17.34mmol, 1.0 equivalent) into reaction bulb, 2- fluorine pyridine (2.02g, 20.81mmol, 1.2 equivalents), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalent) and n,N-Dimethylformamide (20ml), 120 DEG C of reactions are overnight.Reaction solution adds water (100mL) to dilute, and is extracted with ethyl acetate (50mL × 3), extract liquor anhydrous slufuric acid Sodium is dried, then concentration purifies (petroleum ether with column chromatography：Ethyl acetate=10：1) 2- (4- bromobenzenes oxygroup) pyridine is obtained (1.2g, yield：28%).LCMS(ESI)：m/z 250[M+1]+, pale yellow oily liquid；TLC：0.5 (petroleum ethers of Rf：Second Acetoacetic ester=4：1).By above-mentioned gained compound (1.17g, 4.68mmol, 1.0 equivalent) and duplex pinacol borate (1.54g, 6.08mmol, 1.3 equivalent) is dissolved in dioxane (15mL), then be added potassium acetate (1.38g, 14.04mmol, 3.0 equivalents) and [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (0.34g, 0.47mmol, 0.1 equivalent).Use nitrogen Three times are replaced then to react overnight at 100 DEG C.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (petroleum ether：Second Acetoacetic ester=20：1) 4- (2- pyridines oxygroup) phenyl boric acid pinacol ester (1.1g, yield is purified to obtain：79%).LCMS(ESI)：m/z 298[M+1]+, colourless oil liquid；TLC：0.5 (petroleum ethers of Rf：Ethyl acetate=10：1).By the compound of above-mentioned gained (1.0g, 3.37mmol, 1.0 equivalent) is dissolved in tetrahydrofuran (10mL), then be added sodium metaperiodate (1.08g, 5.05mmol, 1.5 equivalents) and 1N hydrochloric acid solutions (10mL), it reacts 3 hours at room temperature.It is molten that sodium bicarbonate solid adjusting is added after the completion of reaction The pH value of liquid is 6-7.Water layer is extracted with dichloromethane (30mL × 3), is washed with saturated salt solution (30mL × 1) after organic layer mixing It washs, is dried with anhydrous sodium sulfate, be concentrated to give 4- (2- pyridines oxygroup) phenyl boric acid (0.62g, yield：86%).LCMS(ESI)： m/z 216[M+1]+, white solid；TLC：0.1 (petroleum ethers of Rf：Ethyl acetate=4：1).
Step 26b:(R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (2- pyridines oxygroup) phenyl) -2,3- Dihydro -1H- imidazos [4,5-c] pyridine) piperidines (tert-butyl (R) -3- (4-amino-2-oxo-3- (4- (pyridin- 2-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) the preparation of (compound 307-28)
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperazine Pyridine (306) (0.74g, 2.22mmol, 1.0 equivalent), 4- (2- pyridines oxygroup) phenyl boric acid (108-28) (0.62g, 2.89mmol, 1.3 equivalents) and pyridine (0.54mL, 6.66mmol, 3.0 equivalent) be dissolved in n,N-Dimethylformamide (10mL), add vinegar Sour copper (0.44g, 2.44mmol, 1.1 equivalent) andMolecular sieve (1g), then 50 DEG C of reactions are stayed overnight in air.React liquid cooling But it arrives room temperature and is diluted with ethyl acetate (100mL), filtering, filtrate is washed with semi-saturation saline solution (50mL × 2).Organic layer is used Anhydrous sodium sulfate is dried, concentration, obtained crude product column chromatography (dichloromethane：Methanol=50:1) (R) -1- uncles are purified Butoxy carbonyl -3- (4- amino -2- oxos -3- (4- (2- pyridines oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyrroles Pyridine) piperidines (0.228g, yield：20%).LCMS(ESI)：m/z503[M+1]+, brown solid；TLC：0.4 (dichloromethanes of Rf Alkane：Methanol=20：1).
Step 26c:(R) -4- amino -1- (3- piperidyls) -3- (4- (2- pyridines oxygroup) phenyl) -1,3-2H- imidazos [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) (compound 308-28) preparation
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (2- pyridines oxygroup) phenyl) -2,3- dihydros - 1H- imidazos [4,5-c] pyridine) piperidines (307-28) (0.228g, 0.454mmol, 1.0 equivalent) is dissolved in dichloromethane (10mL) In, then trifluoroacetic acid (2mL) is added thereto, then react 2 hours at room temperature.By reaction mixture dichloromethane (50mL) dilutes, and is washed with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (30mL), then uses organic layer successively Silica gel mixed sample is spin-dried for, and uses column chromatography (dichloromethane later：Methanol：Triethylamine=100：10：1) (R) -4- amino-is purified 1- (3- piperidyls) -3- (4- (2- pyridines oxygroup) phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.17g, yield： 93%).LCMS(ESI)：m/z 403[M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1).
Step 26d:(R) -1- (3- (1- acryloyl groups) piperidyl) -4- amino -3- (4- (2- pyridines oxygroup) phenyl) -1, 3-2H- imidazos [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- piperidyls) -3- (4- (2- pyridines oxygroup) phenyl) -1,3-2H- imidazos [4,5-c] Pyridin-2-ones (308-28) (0.17g, 0.422mmol, 1.0 equivalent), acrylic acid (40mg, 0.549mmol, 1.3 equivalent), DCC (113mg, 0.549mmol, 1.3 equivalent) and DMAP (5.2mg, 0.042mmol, 0.1 equivalent) are dissolved in dichloromethane (10mL), so It is reacted 1 hour at 0 DEG C afterwards.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane：Methanol=50：1) Purify to obtain compound (R) -1- (3- (1- acryloyl groups) piperidyl) -4- amino -3- (4- (2- pyridines oxygroup) phenyl) -1,3- 2H- imidazos [4,5-c] pyridin-2-ones (115mg, yield：60%).White solid, fusing point：211.2-213.3℃.TLC：Rf 0.4 (dichloromethane：Methanol=20：1).LCMS(ESI)：m/z 457[M+1]+,1HNMR(CDCl3-d1, 500MHz)：δ8.23- 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 groups) piperidines) -4- amino -3- (4- (3- pyridines oxygroup) phenyl) -1, 3-2H- imidazos [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
Step 27a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (3- pyridines oxygroup) phenyl) -2,3- Dihydro -1H- imidazos [4,5-c] pyridine) piperidines (tert-butyl (R) -3- (4-amino-2-oxo-3- (4- (pyridin- 3-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) the preparation of (compound 307-29)
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (402-17) (0.8g, 1.49mmol, 1.0 equivalent), 3- pyridones (403-29) (0.21g, 2.24mmol, 1.5 equivalents) and N, N- dimethyl glycine hydrochloride (39mg, 0.28mmol, 0.18 equivalent) be dissolved in dioxane In (8mL), cuprous iodide (14.2mg, 0.075mmol, 0.05 equivalent) and cesium carbonate (0.97g, 2.98mmol, 2.0 are added Equivalent), then in nitrogen protection 100 DEG C react 60 hours.Reaction solution is cooled to room temperature and concentrates, obtained crude product column Chromatography (dichloromethane：Methanol=40:1 to 20:1) (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- are purified (4- (3- pyridines oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (0.24g, yield：32%).LCMS (ESI)：m/z 503[M+1]+, faint yellow solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1).
Step 27b:(R) -4- amino -1- (3- piperidyls) -3- (4- (3- pyridines oxygroup) phenyl) -1,3-2H- imidazos [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) (compound 308-29) preparation
Synthetic method such as 26 step 26c of embodiment is only by wherein (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxygen Generation -3- (4- (2- pyridines oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (307-28) replaces with (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (3- pyridines oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (307-29) (0.24g, 0.48mmol, 1.0 equivalent), obtain (R) -4- amino -1- (3- piperidyls) - 3- (4- (3- pyridines oxygroup) phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.18g, yield：93%).LCMS (ESI)：m/z 403[M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1).
Step 27c:(R) -1- (3- (1- acryloyl groups) piperidines) -4- amino -3- (4- (3- pyridines oxygroup) phenyl) -1,3- 2H- imidazos [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 26 step 26d of embodiment is only by wherein (R) -4- amino -1- (3- piperidyls) -3- (4- (2- Pyridine oxygroup) phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (308-28) replace with (R) -4- amino -1- (3- piperazines Piperidinyl) -3- (4- (3- pyridines oxygroup) phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (308-29) (0.18g, 0.45mmol, 1.0 equivalents), obtain (R) -1- (3- (1- acryloyl groups) piperidines) -4- amino -3- (4- (3- pyridines oxygroup) benzene Base) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.18g, yield：93%).White solid, fusing point：80.5-83.8℃. TLC：0.4 (dichloromethane of Rf：Methanol=20：1).LCMS(ESI)：m/z 457[M+1]+,1HNMR(CDCl3, 500MHz)：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), 6.65-6.58 (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- bases) -4- amino -3- (4- (pyridin-4-yl oxygroup) benzene Base) -1,3- dihydro -2H- imidazos [4,5c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) -4- amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2- One) the preparation of (compound 30)
Step 28a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (3- pyridines oxygroup) phenyl) -2,3- Dihydro -1H- imidazos [4,5-c] pyridine) piperidines (tert-butyl (R) -3- (4-amino-2-oxo-3- (4- (pyridin- 3-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1- Carboxylate) the preparation of (compound 307-30)
Synthetic method such as 26 step 26b of embodiment is only to replace wherein 4- (2- pyridines oxygroup) phenyl boric acid (108-28) For (4- (pyridin-4-yl oxygroup) phenyl) boric acid (108-30) (0.645g, 3.0mmol, 1.0 equivalent), (R) -3- (4- ammonia is obtained Base -2- oxos -3- (4- (pyridin-4-yl oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine -1- bases) piperidines - 1- carboxylic acid tert-butyl esters (0.21g, yield：14%).LCMS(ESI)：m/z 503[M+1]+, pale solid；TLC：Rf 0.5 (dichloromethane：Methanol=20：1).
Step 28b:(R) -4- amino -1- (piperidines -3- bases) -3- (4- (pyridin-4-yl oxygroup) phenyl) -1,3- dihydros - 2H- imidazos [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) (compound 308-30) preparation
Synthetic method such as 26 step 26c of embodiment is only by wherein (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxygen Generation -3- (4- (2- pyridines oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) piperidines (307-28) replaces with (R) -3- (4- amino -2- oxos -3- (4- (pyridin-4-yl oxygroup) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridines - 1- yls) piperidines -1- carboxylic acid tert-butyl esters (307-30) (0.21g, 0.42mmol, 1.0 equivalent), obtain (R) -4- amino -1- (piperazines Pyridine -3- bases) -3- (4- (pyridin-4-yl oxygroup) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (0.158g, Yield：94%).LCMS(ESI)：m/z403[M+1]+, colorless solid；TLC：0.1 (dichloromethane of Rf：Methanol=20：1).
Step 28c:(R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- (pyridin-4-yl oxygroup) phenyl) - 1,3- dihydro -2H- imidazos [4,5c] pyridin-2-ones ((R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- (pyridin-4-yloxy) phenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Object 30) preparation
It is added dropwise at 0 DEG C in the dichloromethane solution (7ml) of past acryloyl chloride (0.039g, 0.43mmol, 1.1 equivalent) (R) -4- amino -1- (piperidines -3- bases) -3- (4- (pyridin-4-yl oxygroup) phenyl) -1,3- dihydro -2H- imidazos [4,5-c] The dichloromethane solution (10ml) of pyridin-2-ones (308-30) (0.158g, 0.39mmol, 1.0 equivalent), it is different to be then added dropwise two again The dichloromethane solution (1ml) of ethylamine (0.075g, 0.59mmol, 1.5 equivalent) reacts 10 minutes at 0 DEG C.It will be anti- It answers liquid to pour into water (100ml), is extracted with dichloromethane (100ml × 2), organic phase is spin-dried for silica gel mixed sample, residue column Purification by chromatography (dichloromethane：Methanol=20：1) (R) -1- (1- acryloylpiperidine -3- bases) -4- amino -3- (4- are obtained (pyridin-4-yl oxygroup) phenyl) -1,3- dihydro -2H- imidazos [4,5c] pyridin-2-ones (0.050g, yield：28%).It is colourless Solid, fusing point：79.6-81.7℃.TLC：0.5 (dichloromethane of Rf：Methanol=20：1).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=13.5Hz, 1H), 1.69 (m,1H)。
Embodiment 29:(R) -4- amino -3- (4- phenoxy phenyls) -1- (3- (1- propine acylpiperidine)) -1,3-2H- imidazoles And [4,5-c] pyridin-2-ones ((R) -4-amino-3- (4-phenoxyphenyl) -1- (1-propioloylpiperidin- 3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 32) preparation
By (R) -4- amino -3- (4- phenoxy phenyls) -1- (3- piperidyls) -1H- imidazos [4,5-c] pyridine -2 (3H) - Ketone (308-11) (0.20g, 0.50mmol, 1.0 equivalent), propiolic acid (42mg, 0.60mmol, 1.2 equivalent), DCC (123mg, 0.60mmol, 1.2 equivalents) and DMAP (6mg, 0.05mmol, 0.1 equivalent) be dissolved in dichloromethane (10mL), it is then anti-at 0 DEG C It answers 1 hour.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane：Methanol=50：1) chemical combination is purified to obtain Object (R) -4- amino -3- (4- phenoxy phenyls) -1- (3- (1- propine acylpiperidine)) -1,3-2H- imidazos [4,5-c] pyridine - 2- ketone (80mg, yield：35%).White solid, fusing point：89.3-95.6℃.TLC：0.4 (dichloromethane of Rf：Methanol=20： 1).LCMS(ESI)：m/z 454[M+1]+,1HNMR(CDCl3, 500MHz)：δ7.90-7.86(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 phenyls) -1,3- 2H- imidazos [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 is only wherein propiolic acid to be replaced with 2- tetrolic acid (52mg, 0.62mmol, 1.3 work as Amount), obtain (R) -4- amino -1- (3- (1- (2- butine acyl group)) piperidyl) -3- (4- phenoxy phenyls) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (60mg, yield：27%).White solid, fusing point：84.6-89.4℃.TLC：0.4 (dichloromethanes of Rf Alkane：Methanol=20：1).LCMS(ESI)：m/z468[M+1]+,1HNMR(CDCl3, 500MHz)：δ7.89-7.85(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 groups) piperidine methyl) -4- amino -3- (4- phenoxy phenyls) -1,3-2H- imidazoles And [4,5-c] pyridin-2-ones (1- ((1-acryloylpiperidin-3-yl) methyl) -4-amino-3- (4- Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 35) preparation
Step 31a:1- tertbutyloxycarbonyls -3- (4- (the chloro- 3- nitros of 2-) pyridine aminomethyl) piperidines (tert-butyl 3- (((2-chloro-3-nitropyridin-4-yl) amino) methyl) piperidine-1-carboxylate) (compound Preparation 702-35)
2,4- dichloro-3-nitropyridines (101) (1.0g, 5.18mmol, 1.0 equivalent), the tertiary fourths of 1- are added into reaction bulb Oxygen carbonyl -3- aminomethylpiperidines (701-35) (1.11g, 5.18mmol, 1.0 equivalent), triethylamine (1.4mL, 10.36mmol, 2.0 equivalents) and n,N-Dimethylformamide (10ml), room temperature reaction is overnight.Reaction solution adds water (100mL) to dilute, with acetic acid second Ester (30mL × 3) extracts, and extract liquor dried with anhydrous sodium sulfate, concentrates, and then purifies (petroleum ether with column chromatography：Acetic acid second Ester=3：1) 1- tertbutyloxycarbonyls -3- (4- (the chloro- 3- nitros of 2-) pyridine aminomethyl) piperidines (1.66g, yield is obtained：86%). LCMS(ESI)：m/z 371[M+1]+, pale yellow oil；TLC：0.2 (petroleum ethers of Rf：Ethyl acetate=4：1).
Step 31b:1- tertbutyloxycarbonyls -3- (4- (2- dibenzyl amido -3- nitros) pyridine aminomethyl) piperidines (tert- butyl 3-(((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)methyl)piperidine-1- Carboxylate) the preparation of (compound 703-35)
1- tertbutyloxycarbonyls -3- (4- (the chloro- 3- nitros of 2-) pyridine aminomethyl) piperidines (702-35) is added into reaction bulb (1.66g, 4.48mmol, 1.0 equivalent), dibenzylamine (0.95mL, 4.92mmol, 1.1 equivalent), triethylamine (1.24mL, 8.96mmol, 2.0 equivalents) and acetonitrile (25ml), heated overnight at reflux.Reaction solution is spin-dried for silica gel mixed sample, pure with column chromatography Change (petroleum ether：Ethyl acetate=2：1) 1- tertbutyloxycarbonyls -3- (4- (2- dibenzyl amido -3- nitros) pyridine aminomethyl) is obtained Piperidines (2.13g, yield：90%).LCMS(ESI)：m/z 532[M+1]+, yellow oil；TLC：0.4 (petroleum ethers of Rf：Second Acetoacetic ester=3：1).
Step 31c:1- tertbutyloxycarbonyls -3- (4- (3- amino -2- dibenzyls amido) pyridine aminomethyl) piperidines (tert- butyl 3-(((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)methyl)piperidine-1- Carboxylate) the preparation of (compound 704-35)
Toward the first of zinc powder (2.60g, 40.1mmol, 10.0 equivalent) and ammonium chloride (1.50g, 28.07mmol, 7.0 equivalent) 1- tertbutyloxycarbonyls -3- (4- (2- dibenzyl amido -3- nitros) pyridine aminomethyl) piperidines (703- is added in alcoholic solution (40ml) 35) (2.13g, 4.01mmol, 1.0 equivalent) is heated to 50 DEG C and reacts 1 hour.Reaction solution is filtered with diatomite, and filtrate is spin-dried for, Use dichloromethane：Methanol=5：1 (50ml) dissolves, and filtering, organic phase is spin-dried for obtaining crude product 1- tertbutyloxycarbonyls -3- (4- (3- ammonia Base -2- dibenzyls amido) pyridine aminomethyl) piperidines (2.10g, yield：100%).LCMS(ESI)：m/z 502[M+1]+, grey Solid；TLC：0.1 (petroleum ethers of Rf：Ethyl acetate=1：1).
Step 31d:1- tertbutyloxycarbonyls -3- (4- dibenzyl amido -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyrroles Pyridine methyl) piperidines (tert-butyl 3- ((4- (dibenzylamino) -2-oxo-2,3-dihydro-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) piperidine-1-carboxylate) (compound 705-35) preparation
1- tertbutyloxycarbonyls -3- (4- (3- amino -2- dibenzyls amido) pyridine aminomethyl) piperidines is added into reaction bulb (704-35) (2.10g, 4.19mmol, 1.0 equivalent), N, N'- carbonyl dimidazoles (1.70g, 10.46mmol, 2.5 equivalent) and four Reaction solution is heated to being refluxed overnight by hydrogen furans (30ml).Reaction solution is spin-dried for silica gel mixed sample, purifies (dichloro with column chromatography Methane：Methanol=100：1) obtain 1- tertbutyloxycarbonyls -3- (4- dibenzyl amido -2- oxo -2,3- dihydro -1H- imidazos [4, 5-c] picolyl) piperidines (1.87g, yield：85%).LCMS(ESI)：m/z 528[M+1]+, faint yellow solid；TLC：Rf 0.4 (dichloromethane：Methanol=80：1).
Step 31e:1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine first Base) piperidines (tert-butyl 3- ((4-amino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridin-1- Yl) methyl) piperidine-1-carboxylate) (compound 706-35) preparation
Be added into reaction bulb 1- tertbutyloxycarbonyls -3- (4- dibenzyl amido -2- oxo -2,3- dihydro -1H- imidazos [4, 5-c] picolyl) piperidines (705-35) (1.87g, 3.54mmol, 1.0 equivalent), palladium dydroxide (1.6g), ethyl alcohol (40ml) and Ethyl acetate (10ml), reaction solution are heated to 70 DEG C and are stayed overnight in atmosphere of hydrogen.Reaction mixture is filtered with diatomite, filtrate rotation Dry, residue column chromatography purifies (dichloromethane：Methanol=20：1) 1- tertbutyloxycarbonyls -3- (4- amino -2- oxygen is obtained Generation -2,3- dihydro -1H- imidazos [4,5-c] picolyl) piperidines (0.8g, yield：65%).LCMS(ESI)：m/z 348[M +1]+, white solid；TLC：0.2 (dichloromethane of Rf：Methanol=20：1).
Step 31f:1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazoles And [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) (compound Preparation 707-35)
By 1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] picolyl) piperazine Pyridine (706-35) (0.8g, 2.30mmol, 1.0 equivalent), to phenoxy group phenyl boric acid (0.64g, 2.99mmol, 1.3 equivalent) and pyrrole Pyridine (0.55g, 6.90mmol, 3.0 equivalent) is dissolved in n,N-Dimethylformamide (10mL), add copper acetate (0.46g, 2.53mmol, 1.1 equivalents) andMolecular sieve (1g), then 50 DEG C of reactions are stayed overnight in air.Reaction solution is cooled to room temperature simultaneously It is diluted with ethyl acetate (100mL), filtering, filtrate is washed with semi-saturation saline solution (30mL × 3).Organic layer anhydrous sodium sulfate It is dry, concentration, obtained crude product column chromatography (dichloromethane：Methanol=50:1) 1- tertbutyloxycarbonyl -3- (4- are purified to obtain Amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazos [4,5-c] picolyl) piperidines (0.45g, yield： 38%).LCMS(ESI)：m/z 516[M+1]+, faint yellow solid；TLC：Rf0.4 (dichloromethane：Methanol=20：1).
Step 31g:4- amino -3- (4- phenoxy phenyls) -1- (3- piperidine methyls) -1,3-2H- imidazos [4,5-c] pyrrole Pyridine -2- ketone (4-amino-3- (4-phenoxyphenyl) -1- (piperidin-3-ylmethyl) -1,3-dihydro-2H- Imidazo [4,5-c] pyridin-2-one) (compound 708-35) preparation
By 1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- phenoxy phenyls) -2,3- dihydro -1H- imidazos [4, 5-c] picolyl) piperidines (707-35) (0.45g, 0.87mmol, 1.0 equivalent) is dissolved in dichloromethane (15mL), then to its Middle addition trifluoroacetic acid (3mL) is then reacted 2 hours at room temperature.Reaction mixture is diluted with dichloromethane (50mL), according to It is secondary to be washed with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (30mL), then organic layer is spin-dried for silica gel mixed sample, Column chromatography (dichloromethane is used later：Methanol：Triethylamine=100：10：1) 4- amino -3- (4- phenoxy phenyls) -1- is purified to obtain (3- piperidine methyls) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (0.34g, yield：93%).LCMS(ESI)：m/z 416 [M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol=10：1).
Step 31h:1- (3- (1- acryloyl groups) piperidine methyl) -4- amino -3- (4- phenoxy phenyls) -1,3-2H- imidazoles And [4,5-c] pyridin-2-ones (1- ((1-acryloylpiperidin-3-yl) methyl) -4-amino-3- (4- Phenoxyphenyl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 35) preparation
By 4- amino -3- (4- phenoxy phenyls) -1- (3- piperidine methyls) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (708-35) (0.17g, 0.41mmol, 1.0 equivalent), acrylic acid (38mg, 0.53mmol, 1.3 equivalent), DCC (110mg, 0.53mmol, 1.3 equivalents) and DMAP (5.0mg, 0.041mmol, 0.1 equivalent) be dissolved in dichloromethane (10mL), then in room temperature Lower reaction 1 hour.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane：Methanol=50：1) it purifies Compound 1- (3- (1- acryloyl groups) piperidine methyl) -4- amino -3- (4- phenoxy phenyls) -1,3-2H- imidazos [4,5-c] pyrrole Pyridine -2- ketone (55mg, yield：29%).White solid, fusing point：68.5-70.7℃.TLC：0.4 (dichloromethane of Rf：Methanol= 20：1).LCMS(ESI)：m/z 470[M+1]+,1HNMR(CDCl3, 500MHz)：δ 7.86 (d, J=4.0Hz, 1H), 7.41- 7.38(m,4H),7.20-7.17(m,1H),7.13-7.09(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 phenoxies) phenyl) -1- (3- (1- (4- dimethylaminos -2- Crotonyl) pyrrolidines)) -1,3-2H- imidazos [4,5-c] pyridin-2-ones ((R, E) -4-amino-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) (compound 44) preparation
Step 32a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- miaows Azoles simultaneously [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- tertbutyloxycarbonyls -3- (4- amino -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrole Cough up alkane (107) (4.5g, 14.09mmol, 1.0 equivalent), to iodobenzene boric acid (401-17) (4.54g, 18.32mmol, 1.3 equivalent) It is dissolved in n,N-Dimethylformamide (40mL) with pyridine (3.4mL, 42.27mmol, 3.0 equivalent), adds copper acetate (2.82g, 15.50mmol, 1.1 equivalent) andMolecular sieve (5g), then 50 DEG C of reactions are stayed overnight in air.Reaction solution cools down It is diluted to room temperature and with ethyl acetate (200mL), filtering, filtrate is washed with semi-saturation saline solution (50mL × 4).Organic layer nothing Aqueous sodium persulfate is dried, concentration, obtained crude product column chromatography (dichloromethane：Methanol=50:1) the tertiary fourths of (R) -1- are purified Oxygen carbonyl -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrolidines (3.05g, yield：41%).LCMS(ESI)：m/z 522[M+1]+, brown solid；TLC：0.4 (dichloromethane of Rf：Methanol= 20：1).
Step 32b:(R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- (4- methoxy phenoxies) phenyl) oxo -2 2-, 3- dihydro -1H- imidazos [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) Pyrrolidine-1-carboxylate) the preparation of (compound 109-44)
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [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 equivalents) and N, N- dimethyl glycine hydrochloride (1.07g, 7.68mmol, 2.0 equivalent) be dissolved in dioxane In (20mL), adding cuprous iodide (0.37g, 1.92mmol, 0.5 equivalent) and cesium carbonate, (7.51g, 23.04mmol, 6.0 work as Amount), then in nitrogen protection 100 DEG C react 20 hours.Reaction solution is cooled to room temperature and concentrates, obtained crude product column layer Analysis method (dichloromethane：Methanol=40:1 to 20:1) ((R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- (4- methoxies are purified Phenoxyl) phenyl) 2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrolidines (0.61g, yield：31%). LCMS(ESI)：m/z 518[M+1]+, gray solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1).
Step 32c:(R) -4- amino -3- (4- (4- methoxy phenoxies) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4, 5-c] pyridine -2 (3H) -one ((R) -4-amino-3- (4- (4-methoxyphenoxy) phenyl) -1- (pyrrolidin-3- Yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 110-44) preparation
By (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (4- methoxy phenoxies) phenyl) -2,3- two Hydrogen -1H- imidazos [4,5-c] pyridine) pyrrolidines (109-44) (0.61g, 1.18mmol, 1.0 equivalent) is dissolved in dichloromethane In (15mL), then trifluoroacetic acid (3mL) is added thereto, then reacts 2 hours at room temperature.By reaction mixture dichloromethane Alkane (100mL) dilutes, and is washed successively with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (60mL), then will be organic Layer is spin-dried for silica gel mixed sample, uses column chromatography (dichloromethane later：Methanol：Triethylamine=100：10：1) (R) -4- ammonia is purified Base -3- (4- (4- methoxy phenoxies) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.45g, Yield：92%).LCMS(ESI)：m/z 418[M+1]+, faint yellow solid；TLC：Rf0.2 (dichloromethane：Methanol=10：1).
Step 32d:(R, E) -4- amino -3- (4- (4- methoxy phenoxies) phenyl) -1- (3- (1- (4- dimethylaminos -2- Crotonyl) pyrrolidines)) -1,3-2H- imidazos [4,5-c] pyridin-2-ones ((R, E) -4-amino-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) (compound 44) preparation
By (R) -4- amino -3- (4- (4- methoxy phenoxies) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] pyrrole Pyridine -2 (3H) -one (110-44) (0.28g, 0.671mmol, 1.0 equivalent), 4- dimethylamino cronates hydrochlorate (144mg, 0.872mmol, 1.3 equivalents), HATU (332mg, 0.872mmol, 1.3 equivalent) and triethylamine (0.28mL, 2.013mmol, 3.0 Equivalent) it is dissolved in dichloromethane (5mL), then react 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column Chromatography (dichloromethane：Methanol=20：1) compound (R, E) -4- amino -3- (4- (4- methoxy phenoxies) phenyl)-is purified to obtain (70mg is received 1- (3- (1- (4- dimethylamino -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [4,5-c] pyridin-2-ones Rate：20%).White solid, fusing point：50.4-55.9℃.TLC：0.2 (dichloromethane of Rf：Methanol=10：1).LCMS(ESI)： m/z 529[M+1]+,1HNMR(CDCl3, 500MHz)：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,2H),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- bis- Methylamino -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [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-enoyl) Pyrrolidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 45) preparation
Step 33a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) 2- Oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrolidines (tert-butyl (R) -3- (4-amino-3- (4- (benzo[d][1,3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] Pyridin-1-yl) pyrrolidine-1-carboxylate) (compound 109-45) preparation
Synthetic method such as 32 step 32b of embodiment, is only that wherein p methoxy phenol (403-44) is replaced with sesamol (403-45) (1.21g, 8.78mmol, 1.5 equivalent), obtaining (R) -1- tertbutyloxycarbonyls -3-, (((3,4- is sub- by 4- by 4- amino -3- Methylenedioxy group phenoxy group) phenyl) 2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrolidines (1.0g, yield： 39%).LCMS(ESI)：m/z 532[M+1]+, gray solid；TLC：0.4 (dichloromethane of Rf：Methanol=20：1).
Step 33b:(R) -4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- Imidazo [4,5-c] pyridine -2 (3H) -one ((R) -4-amino-3- (4- (benzo [d] [1,3] dioxol-5-yloxy) Phenyl) -1- (pyrrolidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (chemical combination Object 110-45) preparation
Synthetic method such as 32 step 32c of embodiment is only by wherein (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxygen Generation -3- (4- (4- methoxy phenoxies) phenyl) -2,3- dihydro -1H- imidazos [4,5-c] pyridine) pyrrolidines (109-44) replacement For (R) -1- tertbutyloxycarbonyls -3- (4- amino -2- oxos -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -2,3- two Hydrogen -1H- imidazos [4,5-c] pyridine) pyrrolidines (109-45) (1.0g, 1.88mmol, 1.0 equivalent), obtain (R) -4- amino - 3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.76g, yield：94%).LCMS(ESI)：m/z 432[M+1]+, faint yellow solid；TLC：0.2 (dichloromethane of Rf：Methanol =10：1).
Step 33c:(R, E) -4- amino -3- (4- (3,4- methylene-dioxy phenoxy group) phenyl) -1- (3- (1- (4- diformazans Amino -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [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-enoyl) Pyrrolidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 45) preparation
Synthetic method such as 32 step 32d of embodiment is only by wherein (R) -4- amino -3- (4- (4- methoxy phenoxies) benzene Base) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (110-44) replaces with (R) -4- amino -3- (4- (3,4- methylene-dioxies phenoxy group) phenyl) -1- (3- pyrrolidines) -1H- imidazos [4,5-c] (3H) -one of pyridine -2 (110- 45) (0.20g, 0.464mmol, 1.0 equivalent) obtains compound (R, E) -4- amino -3- (4- (3,4- methylenedioxybenzenes oxygen Base) phenyl) -1- (3- (1- (4- dimethylamino -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [4,5-c] pyridine -2- Ketone (38mg, yield：15%).White solid, fusing point：186.3-188.5℃.TLC：0.2 (dichloromethane of Rf：Methanol=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,1H),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 phenoxies) phenyl) -1- (3- (1- (4- piperidyl -2- fourths Enoyl-) pyrrolidines)) -1,3-2H- imidazos [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) (compound 46) preparation
Synthetic method such as 32 step 32d of embodiment, is only that wherein 4- dimethylaminos cronate hydrochlorate is replaced with 4- piperazines Piperidinyl cronate hydrochlorate (109mg, 0.529mmol, 1.3 equivalent) obtains compound (R, E) -4- amino -3- (4- (4- methoxies Phenoxy group) phenyl) -1- (3- (1- (4- piperidyl -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [4,5-c] pyridine - 2- ketone (45mg, yield：19%).White solid, fusing point：79.9-82.4℃.TLC：0.2 (dichloromethane of Rf：Methanol=10： 1).LCMS(ESI)：m/z569[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,1H),3.37-3.29(m,2H), 2.69-2.61(m,5H),2.42-2.36(m,1H),1.70-1.66(m,4H),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- piperazines Piperidinyl -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [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 33 step 33c of embodiment, is only that wherein 4- dimethylaminos cronate hydrochlorate is replaced with 4- piperazines Piperidinyl cronate hydrochlorate (112mg, 0.542mmol, 1.3 equivalent), obtaining compound (R, E) -4- amino -3-, ((3,4- is sub- by 4- Methylenedioxy group phenoxy group) phenyl) -1- (3- (1- (4- piperidyl -2- crotonyls) pyrrolidines)) -1,3-2H- imidazos [4,5- C] pyridin-2-ones (70mg, yield：29%).White solid, fusing point：125.2-128.3℃.TLC：0.2 (dichloromethane of Rf： Methanol=10：1).LCMS(ESI)：m/z 583[M+1]+,1HNMR(CDCl3, 500MHz)：δ7.85-7.83(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- amidos -1- [(3R) -1- (2- crotonyls) piperidines -3- bases] -3- (4- Phenoxyphenyls) -1, 3- dihydro -2H- imidazos [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- amidos -3- (4- Phenoxyphenyls) -1- [(3R)-piperidines -3- bases] -1,3- dihydro -2H- imidazos [4,5- C] pyridin-2-ones (308-11) (80mg, 0.2mmol, 1 equivalent), 4- (piperidinamine) -2- butenoates hydrochlorate (49mg, 0.24mmol, 1.2 equivalents) it is dissolved in DCM (5ml), HATU (99mg, 0.26mmol, 1.3 equivalent) and Et is added3N (61mg, 0.6mmol, 3 equivalents), it reacts 1 hour under ice bath.Reaction finishes, concentration, methanol/ethyl acetate (1：20) column chromatography obtains white Solid 4- amidos -1- [(3R) -1- (2- crotonyls) piperidines -3- bases] -3- (4- Phenoxyphenyls) -1,3- dihydro -2H- imidazoles And [4,5-c] pyridin-2-ones (16mg, yield 15%)；Purity 96.7%；TLC：0.5 (dichloromethane of Rf：Methanol=10：1)； Fusing point：85.2~86.0 DEG C；LC-MS：553[M+1]+；1HNMR(400MHz,CDCl3):δ1.48(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- amidos -1- [(3R) -1- (2- crotonyls) dimethylamine -3- bases] -3- (4- Phenoxyphenyls) - 1,3- dihydro -2H- imidazos [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) the preparation of (compound 49)
Synthetic method such as 36 step of embodiment is only that wherein 4- (piperidinamine) -2- butenoate hydrochlorates are replaced with 4- (two Methylamine) -2- butenoates hydrochlorate (49mg, 0.24mmol, 1.2 equivalent), obtain white solid 4- amidos -1- [(3R) -1- (2- Crotonyl) dimethylamine -3- bases] -3- (4- Phenoxyphenyls) -1,3- dihydro -2H- imidazos [4,5-c] pyridin-2-ones (20mg, yield 20%)；Purity 95.5%；TLC：0.4 (dichloromethane of Rf：Methanol=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= 12.64Hz), 2.21 (t, 0.5H, J=7.52Hz), 2.37 (d, 6H, 17.8Hz), 2.62 (m, 1.5H), 3.21 (m, 2.5H), 3.46 (m, 0.5H), 3.83 (d, 0.5H, J=10.12Hz), 4.15 (s, 4H), 4.80 (m, 1H), 6.60 (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- acryloylpiperidines)) -4- amino -3- (4- (1,4- benzdioxan -6- oxygen Base) phenyl) -1,3-2H- imidazos [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) (compound 52) preparation
Step 38a:(R) -1- tertbutyloxycarbonyls -3- (4- amino -3- (Isosorbide-5-Nitrae-benzdioxan -6- oxygroups) phenyl) -2- Oxo -2,3- dihydro -1H- imidazos [4,5-c] pyridyl group) 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) and (compound 307-52) preparation
By 1- tertbutyloxycarbonyls -3- (4- amino -3- (4- iodophenyls) -2- oxo -2,3- dihydro -1H- imidazos [4,5- C] pyridyl group) 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 (67.8mg, 0.486mmol, 0.4 equivalent) are molten In dioxane (8mL), add cuprous iodide (23mg, 0.121mmol, 0.1 equivalent) and cesium carbonate (1.19g, 3.642mmol, 3.0 equivalents), then in nitrogen protection 100 DEG C react 20 hours.Reaction solution is cooled to room temperature and concentrates, and obtains The crude product arrived column chromatography (dichloromethane：Methanol=40:1 to 20:1) (R) -1- tertbutyloxycarbonyls -3- (4- ammonia is purified Base -3- (Isosorbide-5-Nitrae-benzdioxan -6- oxygroups) phenyl) -2- oxos -2,3- dihydro -1H- imidazos [4,5-c] pyridyl group) piperidines (0.26g, yield：39%).LCMS(ESI)：m/z 560[M+1]+, brown solid；TLC：0.4 (dichloromethane of Rf：Methanol= 20：1).
Step 38b:(R) -4- amino -3- (4- (1,4- benzdioxan -6- oxygroups) phenyl) -1- (3- piperidyls) -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) the preparation of (compound 308-52)
By (R)-1- tertbutyloxycarbonyls-3- (4- amino-3- (Isosorbide-5-Nitrae-benzdioxan-6- oxygroups) phenyl) oxo-2-2-, 3- dihydro -1H- imidazos [4,5-c] pyridyl group) piperidines (307-52) (0.26g, 0.472mmol, 1.0 equivalent) is dissolved in dichloromethane In alkane (10mL), then trifluoroacetic acid (2mL) is added thereto, then reacts 1 hour at room temperature.By reaction mixture dichloro Methane (100mL) dilutes, and is washed with saturated sodium carbonate solution (30mL × 2) and saturated salt solution (60mL), then will be had successively Machine layer is spin-dried for silica gel mixed sample, uses column chromatography (dichloromethane later：Methanol：Triethylamine=100：10：1) (R) -1- is purified (3- piperidyls) -4- amino -3- (4- (1,4- benzdioxan -6- oxygroups) phenyl) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (0.195g, yield：90%).LCMS(ESI)：m/z 460[M+1]+, white solid；TLC：0.2 (dichloromethanes of Rf Alkane：Methanol=10：1).
Step 38c:(R) -1- (3- (1- acryloylpiperidines)) -4- amino -3- (4- (1,4- benzdioxan -6- oxygen Base) phenyl) -1,3-2H- imidazos [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) (compound 52) preparation
By (R) -1- (3- piperidyls) -4- amino -3- (4- (1,4- benzdioxan -6- oxygroups) phenyl) -1H- imidazos [4,5-c] pyridine -2 (3H) -one (308-52) (0.195g, 0.424mmol, 1.0 equivalent), acrylic acid (40mg, 0.552mmol, 1.3 equivalents), DCC (114mg, 0.522mmol, 1.3 equivalent) and DMAP (5.1mg, 0.042mmol, 0.1 equivalent) be dissolved in dichloro Methane (8mL) then reacts 1 hour at room temperature.It is concentrated to give crude product after the completion of reaction, passes through column chromatography (dichloromethane Alkane：Methanol=20：1) compound (R) -1- (3- (1- acryloylpiperidines)) -4- amino -3- (4- (1,4- benzos two are purified to obtain Oxane -6- oxygroups) phenyl) -1,3-2H- imidazos [4,5-c] pyridin-2-ones (62mg, yield：28%).White solid melts Point：235.0-236.7℃.TLC：0.5 (dichloromethane of Rf：Methanol=10：1).LCMS(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 phenyls) -1- (3- (1- ethenesulfonyls) piperidines)) -1,3-2H- Imidazo [4,5-c] pyridin-2-ones ((R) -4-amino-3- (4-phenoxyphenyl) -1- (1- (vinylsulfonyl) Piperidin-3-yl) -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one) (compound 55) preparation
By (R) -4- amino -1- (3- piperidyls) -3- (4- Phenoxyphenyls) -1,3-2H- imidazos [4,5-c] pyridine - 2- ketone (308-11) (0.26g, 0.648mmol, 1.0 equivalent) and triethylamine (0.18mL, 1.296mmol, 2.0 equivalent) are dissolved in two In chloromethanes (20mL), with dry ice-propanone bath be cooled to -60 DEG C, then chloroethyl sulfonic acid chloride (158mg, 0.971mmol, 1.5 equivalents) it is dissolved in dichloromethane (5mL) and adds dropwise.Reaction solution reacts 30 minutes and then is slowly raised at -60 DEG C Room temperature.Solvent is removed with revolving and obtains crude product, passes through column chromatography (dichloromethane：Methanol=50：1) compound 6- is purified to obtain 53 (100mg, yields：31%).White solid, fusing point：86.3-89.4℃.TLC：0.5 (dichloromethane of Rf：Methanol=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)。
40 biological activity test of embodiment
One, BTK inhibition of enzyme activity is tested
1, experimental method
BTK eggs are measured using Caliper mobility shiftings detection technique (Caliper mobility shift assay) White kinase activity is (referring to J Biomol Screen 14:31,2009).With sharp after compound obtained above is dissolved with DMSO Enzyme buffer liquid (50mM HEPES-pH 7.5,0.0015%Brij-35,10mM MgCl2, 2mM DTT) and 10 times of dilution, 384 The compound of 5 times of reaction final concentrations of the 10%DMSO dissolvings of 5 μ l, no compound control hole and non-enzymatic activity pair are added in orifice plate According to the 10%DMSO in hole being 5 μ l.Be added 2.5 times of 10 μ l reaction final concentration BTK enzyme solutions (BTK, Cat.No.08-080, Carna), be incubated at room temperature after compound 10 minutes, wherein without 10 μ l kinase buffer liquids are added in enzyme activity control wells.Again plus Enter 2.5 times of 10 μ l reaction final concentrations substrate FAM-labeled SRCtide peptide (Biochem, Cat.No.112394 it) is reacted with the substrate solution of ATP (90 μM), starting.After be incubated at room temperature 10 minutes.It is incubated 1 at 28 DEG C Hour after plus 25 μ l terminate liquids (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3, 50mM EDTA) terminate reaction.The reading and converting rate number on Caliper EZ Reader II (CaliperLife Sciences) According to.Inhibiting rate is calculated, calculation formula is inhibiting rate %=(max- conversions)/(max-min) × 100%.
2, experimental result
This kind of strong inhibition BTK activity of compound energy, than positive reference compound Ibrutinib's and ONO-4059 Inhibiting effect is quite or more preferable.The possessed work in BTK detections of heretofore described representative compound is listed in table 1 Property.In these detections, following ranks are used：For IC50, I>200nM,200nM>II>100nM,100nM>III> 50nM,50nM>IV>10nM,V<10nM。
The histamine result of 1 BTK enzymatic activitys of table
Note：Compound number in table corresponds to the compound number of embodiment 1-39.
Two, Cytostatic to tumor cell is tested
1, experimental method
Using CellTiter-Glo luminescent cell viability detection kit methods (Promega, #G7572, Madison, WI) The content of atriphos (ATP) is measured to assess cell viability.Diffusivity large B cell lymphoid tumor cell strain TMD-8, big B are thin Born of the same parents' lymphoma cell strain SU-DHL-16 is bought from Shanghai Fudan University IBS cell resource centers and American Type Culture Collecti (ATCC). Cell is digested from Tissue Culture Dish with pancreatin and uses Scepter automated cell calculating instruments with after the resuspension of DPBS culture mediums (Millipore, #PHCC00000), which is counted, measures cell density.By cell be diluted to every milliliter it is molten containing 44,000 cells Liquid.The cell solution after density is adjusted to be added in cell experiment plate with 90 μ l of every hole.Orifice plate is placed in 37 DEG C, 5%CO2Incubator is trained The compound to be tried of various concentration is added after supporting 24 hours.Cell cultivates 72 in the presence of 10% fetal calf serum together with compound Hour.It usesLuminescent Cell ViabilityAssay kit (see shop instruction) are measured The content of ATP assesses cell growth inhibition.Briefly, 30 μ l are added in each holeReagent, rocker 10 minutes, inducing cell lysis, with fluorescence/chemiluminescent analyzer FluoroskanAscent FL (Thermo Scientific FluoroskanAscent FL) detection record fluorescence signal.From dimethyl sulfoxide (DMSO) (DMSO) processing 72 or 120 The cell of hour obtains maximum signal value.Minimum signal value, which is obtained, from individual culture medium (cell number zero) is defined as 0.Suppression Rate %=(maximum signal level-compound signal value)/(maximum signal level-minimum signal value) × 100% processed.Use GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software data processing.It is quasi- by S-shaped dose-response curve It is total to calculate IC50 values.
2, experimental result
This kind of compound on tumor cell such as TMD-8, SU-DHL-16 etc. have the activity of very strong suppressing cell reproduction, than sun Property control compound Ibrutinib and ONO-4059 activity it is quite or more preferable, listed in following tables 2 heretofore described Representative compound possessed suppressing cell reproduction in the detection based on cell activity.In these detections, under use State rank：For IC50, I>1uM,1uM>II>0.1uM,0.1uM>III>0.05uM,0.05uM>IV>0.01uM,V< 0.01uM。
The histamine result of 2 tumor cell proliferation of table
Note：Compound number in table corresponds to the compound number of embodiment 1-39.
Three, protein immunoblot (Western Blot) is tested
1, experimental method
ATCC human body lymphoma mantle cell cells Jeko-1 and DOHH-2 are bought from the Shanghai bio tech ltd Bai Li, Suspend culture growth, is added after examination compound or reference compound culture 1 hour, low-speed centrifugal (1200rpm；4min) collect Then cell is resuspended with serum free medium in cell.GoatF (ab ') 2Anti-Human IgM (10ug/ml), 2min is added Afterwards, it is washed twice with the PBS of precooling, collects cell, be homogenized 3 times with biological sample homogenizer, 12,000rpm in 4 DEG C of centrifugations 10min takes supernatant.Using Branfor methods measure albumen concentration, be added sample-loading buffer (Beyotime, #P0015L) in 100 DEG C are boiled 4min, are separated by electrophoresis after albumen with 10%SDS-PAGE and are transferred to pvdf membrane, then with containing 5% bovine serum albumin(BSA) (BSA) (the green skies；CATNo.ST023 TBST solution) is closed 1 hour, and primary antibody β-actin mAb (CST, #4970), BTK are added (D3H5) mAb (CST, #8547) or phospho-BTK (Try223) mAb (CST, #5802) are incubated overnight at 4 DEG C, then use TBST liquid washes 3 × 10min of film.With fluorescence secondary antibody IRDye@680CW Goat (polyclonal) Anti-Rabbit lgG (H+ L), Highly Cross Adsorbed (LI-COR, #926-68071) wash film, wash conditions again after being protected from light incubation 2h at room temperature Ibid.Finally film is placed in detect on LI-COR Odyssey IR fluorescence scanning imaging systems and be imaged.
2, experimental result
Compound 11 and object of reference Ibrutinib strengths prepared by embodiment 11 inhibits Jeko-1 and DOHH-2 lymthomas thin Born of the same parents' BTK protein phosphorylations make the lower Jeko-1 and DOHH-2 cells p-BTK expression of IgM stimulations be decreased obviously (result such as Fig. 1 institutes Show).Compound 11 provided by the invention acts on Jeko-1 and DOHH-2 human lymphoma cells it can be seen from Fig. 1, can have Effect reduces the phosphorylation of BTK.
41 pharmacokinetics of embodiment (PK) is tested
1, experimental method
Male SD rat, 250-300 grams of weight, overnight fast before testing.Compound to be tried is dissolved in 30% sulphur butyl-β- In cyclodextrin (SBE- β-CD), with 20mg/kg gastric infusions.15 minutes after administration, 30 minutes and 1,2,3,4,6,8 and 24 hour Tail end fracture takes blood, per time point about 0.3ml, is placed in containing K2In the centrifuge tube of-EDTA, and centrifugal treating (2,000g, 10 minutes, 4 DEG C) blood plasma is taken, it is stored in -80 DEG C of ultra low temperature freezer.The plasma sample of 50 μ L is mixed with 5 microlitres of internal standards (IS), uses acetic acid Ethyl ester extracts.Residue is redissolved in acetonitrile after vacuum drying.Sample is filtered, and is injected into LC-MS/MS analyses.
2, experimental result
After implementing the compound 1 that 1 prepares and 11 gastric infusion of compound prepared by embodiment 11, absorb well, blood is sudden and violent It is high to reveal dose-effect.Cmax is respectively 544.3 and 2776.7ng/ml.11 half-life period of compound is shorter (1.2 hours), but AUC higher (4985.5ng/ml*h) (table 3).Tmax refers to peak time in table, and Cmax refers to maximum plasma concentration, and T1/2 is half-life period, AUC0-24Refer to area under 0-24 hours time-concentration curves, AUCinfIt refer to area under 0-Inf time-concentration curves.
3. gastric infusion of table (20mg/kg) pharmacokinetic data
42 pharmacodynamic experiment of embodiment
1, experimental method
Immune function major defect SCAD mouse be purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., raising in SPF animal houses.When people's diffusivity large B cell lymphoid tumor cell strain TMD-8 reaches sufficient amount in culture dish, cell is collected, DPBS is washed 2 times.Last RPMI1640 culture medium and matrigel (1 of the cell without serum:1, v/v) suspend inoculation.It is only big It just can be used for injecting in the single cell suspension of 90% survival rate (trypan-blue exclusion).Using the syringe and 25G syringes of 1ml Syringe needle will be suspended in 0.2 milliliter of culture medium and matrigel (1 for being free of serum:1, v/v) 5,000,000 cells inject every small in Mouse right side flap subcutaneous area simultaneously carefully avoids blood vessel.Tumor size can be measured in implantation within one week or so.Use vernier caliper Measure the size of tumour.It is used in combination following formula to calculate gross tumor volume：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 control group by mouse, 11 gastric infusion group (25mg/ of compound prepared by Ibrutinib gastric infusions group (50mg/kg, 1 times/day) and embodiment 11 Kg, 2 times/day).Every group of 6 animals.Ibrutinib or compound 11 are dissolved in 30% Sulfobutyl ether β _ cyclodextrin (SBE- β- CD) and in 1.0 moles of equivalent hydrochloric acid (pH 3-4), with 10ml/kg gastric infusions, successive administration 14 days.
2, experimental result
Compound 11 and Ibrutinib are high in the antitumor activity of TMD-8 neoplasm transplantations.11 gavage of compound is given Medicine (dosage 25mg/kg, bid) can significantly inhibit the growth of diffusivity large B cell lymphoid tumor cell strain TMD-8, be administered 14 days Afterwards, transplantation tumor TMD-8 is contracted to disappear.Compared with before administration, each administration group is without apparent weight loss (Fig. 2).
Each technical characteristic of embodiment described above can be combined arbitrarily, to keep description succinct, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, it is all considered to be the range of this specification record.
Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention Range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (18)

1. the 2- oxo 1,3- glyoxalidine with formula (I) structure and pyridine compounds and their or its pharmaceutically acceptable salt：
In formula：
X1And X2It is selected from C；
Ar is selected from phenyl ring；
L is selected from O, OCH2；
Y is selected from (CHR5)m, C=O, wherein m are selected from 0,1；
Z is selected from：
G is selected from following group：
R1And R2It is respectively and independently selected from：H, C1-C6Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxy, cyano, amino, C1-C6Alkane Base substituted amido, acyl group, amide groups；
R3And R4It is respectively and independently selected from：H, C1-C6Alkyl, C3-C6Naphthenic base, C3-C6Methyl cycloalkyl, halogen replace C1-C4Alkyl, Hydroxyl replaces C1-C4Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, amino replace C1-C4Alkyl, C1-C3Alkyl amine group replaces C1- C4Alkyl, halogen, nitro, hydroxyl, C1-C6Alkoxy, C1-C6Alkylthio group, C1-C6Sulfoxide group, C1-C6Sulfuryl, cyano, amino, C1-C6Alkyl substituted amido, ester group, acyl group, amide groups, carboxyl；And R3And R4It is asynchronously hydrogen；
Work as R3And R4It is C1-C6Alkyl, C1-C6Alkoxy, OH or C1-C6Alkyl substituted amido, and it is substituted in the adjacent position of Ar When, R3And R4One carbocyclic ring of connectable composition or heterocycle are 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-C3Alkoxy replaces C1-C4Alkyl, amino replace C1-C4Alkyl, C1-C3Alkyl amine group takes For C1-C4Alkyl, heterocyclic substituted C1-C4Alkyl.
2. 2- oxos 1,3- glyoxalidine according to claim 1 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that G is selected from following group：
3. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that Y is selected from (CH2)m, wherein m is 0 or 1.
4. 2- oxos 1,3- glyoxalidine according to claim 1 or 2 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that Z be selected from following group：
5. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R3And R4It is respectively and independently selected from：H, halogen, hydroxyl, C1-C6Alkoxy, hydroxyl replace C1-C4Alkane Base, C1-C6Alkyl substituted amido；And R3And R4It is asynchronously hydrogen；
Work as R3And R4It is C1-C6Alkoxy or when OH, and when being substituted in the adjacent position of Ar, R3And R4Connectable composition one is miscellaneous Ring is selected from having structure：
Wherein, n is 0 or 1.
6. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R5And R6It is H.
7. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R7Selected from H, C1-C6Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, 5-6 members are saturated azacyclo- and replace C1-C4Alkyl.
8. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized 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 fromOr
R1And R2It is hydrogen；
R3And R4In one be hydrogen, another is selected from halogen or hydroxyl or C1-C6Alkoxy；Or work as R3And R4For C1-C6Alcoxyl Base or when OH, and it is substituted in the adjacent position of Ar, R3And R4One heterocycle of connectable composition is selected from having structure：
Wherein, n is 0 or 1；
R5And R6It is H；
R7Selected from H, C1-C6Alkyl, C1-C3Alkoxy replaces C1-C4Alkyl, C1-C3Alkyl amine group replaces C1-C4Alkyl, 5-6 members are full Replace C with azacyclo-1-C4Alkyl.
9. 2- oxos 1,3- glyoxalidine according to claim 1 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that the compound is selected from：
10. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in preparing bruton's tyrosine kinase inhibitor.
11. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in the drug for preparing anti-curing oncoma.
12. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in the drug for preparing prevention neoplastic hematologic disorder.
13. application according to claim 12, which is characterized in that the neoplastic hematologic disorder is that lymthoma, myeloma, lymph are thin Born of the same parents' leukaemia or acute myeloid leukemia.
14. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received as bruton's tyrosine kinase inhibitor in preparing the drug of prevention inflammation or autoimmune disease.
15. application according to claim 14, which is characterized in that the inflammation or autoimmune disease are closed for rheumatoid Save inflammation, lupus erythematosus, lupus nephritis, multiple sclerosis, gren's syndrome and potential disease asthma.
16. a kind of pharmaceutical composition for treating disease, which is characterized in that include as active constituent claim 1-9 it is any 2- oxos 1 described in, 3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier.
17. pharmaceutical composition according to claim 16, which is characterized in that the disease is neoplastic hematologic disorder or and Bu Ludun The relevant inflammation of tyrosine kinase or autoimmune disease.
18. pharmaceutical composition according to claim 17, which is characterized in that the neoplastic hematologic disorder be lymthoma, myeloma, Lymphocytic leukemia, acute myeloid leukemia；The inflammation or autoimmune disease are rheumatoid arthritis, erythema wolf Sore, lupus nephritis, multiple sclerosis, gren's syndrome and potential disease asthma.
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