WO2017041536A1 - Oxo-dihydroimidazo pyridine compound and applications thereof - Google Patents

Oxo-dihydroimidazo pyridine compound and applications thereof Download PDF

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WO2017041536A1
WO2017041536A1 PCT/CN2016/084057 CN2016084057W WO2017041536A1 WO 2017041536 A1 WO2017041536 A1 WO 2017041536A1 CN 2016084057 W CN2016084057 W CN 2016084057W WO 2017041536 A1 WO2017041536 A1 WO 2017041536A1
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amino
imidazo
compound
pyridin
dihydro
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PCT/CN2016/084057
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French (fr)
Chinese (zh)
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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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东莞市真兴贝特医药技术有限公司
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    • 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
    • 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

Definitions

  • the invention relates to the field of chemical medicine, in particular to oxydihydroimidazopyridine compounds and uses thereof.
  • BTK Bruton's tyrosine kinase
  • BTK inhibitors play an anti-cancer role by inhibiting tumor cell BTK.
  • the first BTK inhibitor, Ibrutinib is a 4'-aminopyrazolo[3,4-d]pyrimidine compound (Proc Natl Acad Sci USA, 107:13075, 2010), which is linked to the target protein BTK.
  • the site cysteine residue (Cys-481) selectively binds covalently and irreversibly inhibits BTK. Thereby effectively preventing the migration of tumors from B cells to lymphoid tissues adapted to the environment in which the tumor grows.
  • BTK inhibitors In addition to ibrutinib, AVL-292 (CC292), ONO-4059, BGB-3111 and ACP-196 also entered the clinical development stage. For B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, hairy cell leukemia, adult acute lymphoblastic leukemia and other treatments. Ibrutinib combined with chemotherapy drugs or other targeted anticancer drugs can increase the efficacy of these blood tumors. Drugs used in combination with BTK inhibitors in clinical trials include ituximab, lenalidomide, fludarabine; cyclophosphamide; doxorubicin, vincristine, prednisone.
  • BTK acts in the B cell receptor (BCR) messenger system to It is important. Abnormal BCR signals are associated with autoimmune diseases such as rheumatoid arthritis (RA). In addition, BTK is also expressed in myeloid cells, including monocytes, macrophages, neutrophils and mast cells. These cells immerse the membrane cavity and produce inflammatory cytokines that aggravate the symptoms of arthritis. BTK inhibitors block B cell receptor-dependent cell proliferation and reduce inflammatory factor production (Whang J.A., Chang B.Y. Drug Discov Today. 19:1200, 2014). Preclinical studies have shown that BTK inhibitors are also effective against a variety of inflammatory and autoimmune diseases such as rheumatoid arthritis and animal models.
  • BTK inhibitors such as CC-292 and HM71224 are used in the treatment of autoimmune diseases (such as rheumatoid arthritis) into clinical trials (ClinicalTrials.gov ID: NCT01975610, NCT01765478).
  • BTK inhibitors have great potential as drugs for the prevention and treatment of tumors, various inflammatory and autoimmune diseases.
  • one of the objects of the present invention is to provide a novel BTK inhibitor oxydihydroimidazopyridine compound.
  • X 1 and X 2 are each independently selected from C or N;
  • Ar is selected from a benzene ring or a 5-6 membered aromatic heterocyclic ring
  • L is selected from the group consisting of O, S, NR 5 , CR 5 R 6 , OCH 2 , CH 2 O;
  • Z is selected from a saturated 5-7 membered heterocyclic ring or a carbocyclic ring
  • G is selected from the following groups:
  • R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, cyano, amino, C 1 -C 6 alkyl substituted amine Base, acyl group, amide group;
  • R 3 and R 4 are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, halogen substituted C 1 -C 4 alkyl, Hydroxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 - C 4 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 sulfoxide, C 1 -C 6 sulfonyl, cyano, Amino group, C 1 -C 6 alkyl substituted amine group, ester group, acyl group, amide group, carboxyl group;
  • R 3 and R 4 are C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH or C 1 -C 6 alkyl substituted amine, and substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a carbocyclic or heterocyclic ring selected from the following structures:
  • n is selected from 0, 1 , 2; Q 1 and Q 2 are each independently selected from O, NR 6 , CHR 6 ;
  • R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl
  • R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino Substituting a C 1 -C 4 alkyl group, the heterocyclic ring is substituted with a C 1 -C 4 alkyl group.
  • the compound has the structure of Formula II:
  • X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from C or N.
  • X 3 , X 4 , X 5 , X 6 and X 7 are each selected from C; or one of X 3 , X 4 , X 5 , X 6 and X 7 is selected from N, and the remainder is selected From C.
  • G is selected from the group consisting of:
  • X 1 and X 2 are both C.
  • L is selected from the group consisting of O, OCH 2 .
  • Y is selected from (CH 2 ) m , wherein m is 0 or 1.
  • Z is selected from the group consisting of:
  • Z is selected from the group consisting of:
  • R 3 and R 4 are each independently selected from the group consisting of: H, halo, hydroxy, C 1 -C 6 alkoxy, hydroxy-substituted C 1 -C 4 alkyl, C 1 -C 6 alkyl substituted Amine; when R 3 and R 4 are C 1 -C 6 alkoxy or OH, and when substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
  • n 0 or 1.
  • R 5 and R 6 are both H;
  • R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 -C 4 alkyl, a 5-6 membered saturated nitrogen heterocycle substituted for C 1 -C 4 alkyl.
  • X 1 and X 2 are both C; L is selected from O, OCH 2 ; Y is selected from (CH 2 ) m , wherein m is 0 or 1; Z is selected from R 1 and R 2 are both hydrogen;
  • R 3 and R 4 are both hydrogen; or one of them is hydrogen and the other is selected from halogen or hydroxy or C 1 -C 6 alkoxy; or when R 3 and R 4 are C 1 -C 6 alkoxy or OH And, in place of the adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
  • n 0 or 1
  • R 5 and R 6 are both H;
  • R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy is substituted for C 1 -C 4 alkyl, C 1 -C 3 alkylamino group is substituted C 1 -C 4 alkyl, 5-6 membered saturated nitrogen heterocycle substituted for C 1 -C 4 alkyl.
  • Another object of the invention is to provide the use of the above compounds.
  • the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia.
  • the above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof is prepared as a Bruton's tyrosine kinase inhibitor for controlling inflammation or Application in drugs for autoimmune diseases.
  • the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Xiaogren's syndrome, and underlying disease asthma.
  • Another object of the present invention is to provide a pharmaceutical composition for treating a disease.
  • a pharmaceutical composition for treating a disease comprising the above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, as an active ingredient, And a pharmaceutically acceptable carrier.
  • the disease is a hematological tumor or an inflammatory or autoimmune disease associated with Bruton's tyrosine kinase.
  • the hematological tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia;
  • the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple Sclerosis, Schöngren's syndrome, and underlying disease asthma.
  • the present invention provides 2-oxo1,3-dihydroimidazopyridine compounds, and the inventors have proved through extensive experimental studies that the compounds can effectively inhibit the activity of Bruton's tyrosine kinase (BTK). , thereby preventing the survival, proliferation and spread of malignant blood tumor cells.
  • BTK Bruton's tyrosine kinase
  • inflammation and autoimmune diseases can be combated by inhibiting BTK. Therefore, the compounds of the present invention can be used for the treatment of various diseases in which BTK is involved, and are particularly suitable for hematological malignancies and inflammation as well as autoimmune diseases.
  • the treatment of the disease has great application value.
  • Figure 1 is a graph showing the results of inhibition of BTK phosphorylation of human lymphoma Jeko-1 and DOHH-2 cell lines by the compound 11 of Example 40;
  • Figure 2 is a graph showing the antitumor activity of Compound 11 of Example 42 in a diffuse large B cell lymphoma cell line TMD-8 SCID mouse model.
  • any variable e.g. R 1, R, etc.
  • R 1, R, etc. when any variable (e.g. R 1, R, etc.) appear in any component more than once defined, it is at each occurrence independently each occurrence of other definitions. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 in “C 1 -C 6 alkyl” includes a group having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or a branched chain.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • heterocycle refers to an aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups.
  • Heterocyclyl thus includes heteroaryl, as well as dihydrogenated and tetrahydrogenated analogs thereof.
  • the attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • the present invention includes free forms of the compounds of Formulas I-III, including pharmaceutically acceptable salts thereof, and stereo isomer.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of Formulas I-III.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histamine Acid, hydroxycobalamin, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, Trimethylamine, tripropylamine,
  • the compounds of the invention can be prepared by the methods of the following synthetic schemes (Schemes 1-6). A better understanding of the compounds and synthetic methods described in the present invention can be obtained in conjunction with the synthetic schemes described below.
  • the described synthetic schemes describe the methods that can be used to prepare the compounds described in the present invention, which are merely illustrative of the illustrative examples and are not intended to limit the scope of the invention.
  • Step 1a tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-amino)pyrrole-1-carboxylate (tert-butyl) Preparation of (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate) (Compound 103)
  • Step 1b tert-butyl(R)-3-((2-dibenzylamino-3-nitropyridin-4-amino)pyrrole-1-carboxylate (tert-butyl(R)-3-(( Preparation of 2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carbox ylate)
  • Step 1c tert-butyl(R)-3-((3-amino-2-dibenzylamino)pyridin-4-amino)pyrrole-1-carboxylate (tert-butyl(R)-3-(( Preparation of 3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1-carboxylate) (Compound 105)
  • Step 1d tert-Butyl (R)-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate Tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate Preparation of (Compound 106)
  • Step 1e tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate ( 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
  • LCMS (ESI) m / z 320 [M + 1] +.
  • Step 1f tert-Butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c Pyridine pyrrole-1-carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5 -c]pyridin-1-yl)pyrrolidine-1-carboxylate) (Compound 109-1) Preparation
  • Step 1g (R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c Pyridine-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin Preparation of -2-one) (Compound 110-1)
  • Step 1h (R)-4-amino-1-[1-(2-butynyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4- Preparation of phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 1)
  • Step 11a tert-Butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((R)-tert-butyl(R)- Preparation of 3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 302)
  • Step 11b tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((tert-butyl(R) Preparation of 3-(2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 303)
  • Step 11c tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (tert-butyl(R)- Preparation of 3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 304)
  • Step 11d tert-Butyl (R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl Piperidine-1-carboxylate ((tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1 -yl)piperidine-1-carboxylate) (Compound 305) Preparation
  • Step 11e tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate Preparation of (Compound 306)
  • LCMS (ESI): m / z 334 [M + 1] +, as a colorless solid; TLC: Rf 0.1 (dichloromethane: methanol 20).
  • Step 11f tert-Butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5- c]pyridyl-1-yl)piperidine-1-carboxylic acid tert-butyl ester (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) (Compound 307-11)
  • Step 11g (R)-4-Amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c] Preparation of pyridin-2-one) (Compound 308-11)
  • Step 11h (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ Preparation of 4,5-c]pyridin-2-one) (Compound 11)
  • Step 12a tert-Butyl (R)-3-(4-amino-3-(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-chlorophenoxy)phenyl) Preparation of -2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-13)
  • Step 12b (R)-4-Amino-3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazole [4,5-c]pyridin-2-one ((R)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro- Preparation of 2H-imidazo[4,5-c]pyridin-2-one) (Compound 308-13)
  • Step 12c (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-chlorophenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 13) Preparation
  • Step 13a tert-Butyl (R)-3-(4-amino-3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(4-cyanophenoxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-15)
  • Step 13b (R)-4-(4-(4-Amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-3(2H) -Phenyloxy)benzonitrile ((R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin- Preparation of 3(2H)-yl)phenoxy)benzonitrile) (Compound 308-15)
  • Step 13c (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 ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-ami) Preparation of no-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrile) (Compound 15)
  • Step 13a 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 ((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) (Compound 307-16)
  • Step 13b (R)-4-Amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-16)
  • Step 13c (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H-imidazole And [4,5-c]pyridin-2-one ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-phenyl pyridin-3-yl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 16)
  • Step 15a tert-Butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] Pyridyl) piperidine-1-carboxylate (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)
  • Step 15b tert-Butyl (R)-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridine)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1, 3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-im Preparation of idazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-17)
  • Step 15c (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4 ,5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(piperidin Preparation of -3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one) (Compound 308-17)
  • Step 15d (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1 ,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amin o-3-(4-( Preparation of benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 17)
  • Step 16a tert-Butyl (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridine)piperidine-1-carboxylate ((R)-tert-butyl 3-(4-amino-3-(4-(benzylox y)phenoxy)phenyl) Preparation of -2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-c arboxylate) (Compound 307-18)
  • Step 16b (R)-4-Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c Pyridine-2(3H)-one ((R)-4-amino-3-(4-(4-(benzyloxy)phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4, Preparation of 5-c]pyridin-2(3H)-one) (Compound 308-18)
  • Step 16c (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 18)
  • Step 17a tert-Butyl (R)-3-(4-amino-3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine- 1-yl) piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 502-19) Preparation
  • Step 17b tert-Butyl (R)-3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazole And [4,5-c]pyridin-1-yl)piperidinidine-1-carboxylate (tert-butyl(R)3-(4-amino-3-(4-(4-nitro Preparation of phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-car boxylate) (Compound 307-19)
  • Step 17c (R)-4-Amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c Pyridine-2(3H)-one ((R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c Preparation of pyridin-2(3H)-one) (Compound 308-19))
  • Step 17d (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 19) Preparation
  • Step 18a 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 ((tert-butyl(R)-3-(4-amino-3-(4-(benzyloxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 602-24)
  • Step 18b (R)-4-Amino-3-(4-(benzyloxy)phenyl)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((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
  • Step 18c (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H- Iso[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(be nzyl)oxy)phenyl)-1 , 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 24) Preparation
  • Step 19a 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 (tert-butyl(R)-3-(4-amino-3-(4-((4-chlo robenzyl) Preparation of oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 602-26)
  • Step 19b (R)-4-Amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5 -c]pyridine-2(3H)-one ((R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-y1)-1H-imidazo[ Preparation of 4,5-c]pyridin-2(3H)-one) (Compound 603-26)
  • Step 19c (R)-1-(1-Aroylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl) Preparation of oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 26)
  • Step 20a tert-Butyl (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate ((tert-butyl(R)-3-(4-amino-3-(6-(benzyloxy)pyridin-3-yl)- Preparation of 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (602-27)
  • Step 20b (R)-4-Amino-3-(6-benzyloxypyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine- 2(3H)-keto((R)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c] Preparation of pyridin-2(3H)-one) (603-27)
  • Step 20c (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 ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 27)
  • Step 21a 2-(4-(4-Fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (2-(4) -(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (Compound 108-12) Preparation
  • Step 21b ((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 ((3R)-tert-butyl 3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)) -2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-l-yl)piperidi Preparation of ne-1-carboxylate) (Compound 307-12)
  • Step 21c 4-Amino-3-(4-(4-fluorophenoxy)phenyl)-1-((R)-piperidin-3-yl)-1H-pyrrole[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 Preparation of -2(3H)-one) (Compound 308-12)
  • Step 21d 1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)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[ Preparation of 3,2-c]pyridin-2(3H)-one) (Compound 12)
  • Example 22 (R)-1-(3-(1-(acryloyl)piperidin))-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1, 3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino)) Preparation of phenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 21)
  • Step 22a (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[ 4,5-c]pyridine) piperidine (tert-butyl(R)-3-(4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-21)
  • Step 22b (R)-4-Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[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) Preparation
  • Step 22c (R)-1-(3-(1-(acryloyl)piperidinyl)-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1,3 -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino)phenoxy) Preparation of phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 21)
  • Step 23a (3R)-3-[4-Amino-2-oxo-3-[4-(4-trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazole And 4-(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)
  • Step 23b (3R)-4-Amino-1-[piperidin-3-yl]-3-[4-(4-trifluoromethylphenoxy)-phenyl]1,3-2H-imidazole [4,5-c]pyridin-2-one (4-Amino-1-piperidin-3-yl-3-[4-(4-trifluoromethy1-phenoxy)-phenyl]-1,3-dihydro-imidazo[4 ,5-c]pyridin-2-one) (Compound 308-22) Preparation
  • Step 23c (3R)-1-[1-(1-acryloyl)piperidin-3-yl]-4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl) ]-1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((3R)-1-(1-Acryloyl-piperidin-3-yl)-4-amino-3- Preparation of [4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 22)
  • Step 24a (3R)-3-[4-Amino-2-oxo-3-(4-hydroxymethylphenoxy-phenyl)-2,3-dihydro-1H-imidazo[4, 5- ⁇ ]Amino-2-oxo-3-(4-hydroxymethyl phenoxy-phenoxy)-2,3-dihydro-1 -H-imidazo[4,5-c]pyridin-1-yl ⁇ -piperidine-1-carboxylic acid tert-butyl ester) (Compound 307-23)
  • Step 24b (3R)-4-Amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo[ 4,5-c]pyridin-2-one (4-Amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1-piperidin-3-yl-1,3-dihydro-imidazo[4, Preparation of 5-c]pyridin-2-one) (Compound 308-23)
  • Step 24c (3R)-1-(1-acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethylphenyloxy)-phenyl]-1,3-2H -Imidazo[4-,4-c-yl]-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1 , 3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 23) Preparation
  • Step 25a Preparation of 4-(4-tetrazobenzyloxy)phenyl)boronic acid) (Compound 601-25)
  • Step 25b (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridine) piperidine (tert-butyl(R)-3-(4-amino-3-(4-(4-fluorobenzyl)oxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin e-1-carboxylate) (Compound 602-25)
  • Step 25c (R)-4-Amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidinyl)-1,3- 2H-imidazo[4,5-c]pyridin-2-one ((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
  • Step 25d (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1,3-2H- Iso[4,5-c]pyridin-2-one ((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) (Compound 25) Preparation
  • Step 26a Preparation of 4-(pyridin-2-yloxyphenyl)boronic acid (Compound 108-28)
  • the compound obtained above (1.0 g, 3.37 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), then sodium periodate (1.08 g, 5.05 mmol, 1.5 eq.) and 1N hydrochloric acid (10 mL) at room temperature Reaction for 3 hours. After the completion of the reaction, the sodium hydrogencarbonate solid regulating solution was added to have a pH of 6-7.
  • Step 26b (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-2-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-28)
  • Step 26c (R)-4-Amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-2-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-28)
  • Step 26d (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazole And [4,5-c]pyridin-2-one ((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 27a (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-29)
  • Step 27b (R)-4-Amino-1-(3-piperidinyl)-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-3-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-29)
  • Step 27c (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole [4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(pyridin-3-yloxy)phenyl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 29)
  • Example 28 (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(pyridin-4-yloxy)phenyl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 30)
  • Step 28a (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-30)
  • Step 28b (R)-4-Amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazole And [4,5-c]pyridin-2-one ((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
  • Step 28c (R)-1-(1-Aroylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro -2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-am Preparation of ino-3-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 30)
  • Step 31a 1-tert-Butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridiniumaminomethyl)piperidine (tert-butyl 3-(((chloro)-nitropyridin-4) -yl)amino)methyl)piperidine-1-carboxylate) (Compound 702-35) Preparation
  • 2,4-Dichloro-3-nitropyridine (101) (1.0 g, 5.18 mmol, 1.0 eq.), 1-tert-butoxycarbonyl-3-aminomethylpiperidine (701-35) was added to the reaction flask. (1.11 g, 5.18 mmol, 1.0 eq.), triethylamine (1.4 mL, 10.36 mmol, 2.0 eq.) and N,N-dimethylformamide (10 ml).
  • the reaction mixture was diluted with water (100 mL), EtOAc (EtOAc m.
  • Step 3lb 1-tert-Butoxycarbonyl-3-(4-(2-dibenzylamino-3-nitro)pyridinylamino)piperidine (tert-butyl 3-(((di(dibenzylamino)-) Preparation of 3-nitropyridin-4-yl)amino)methyl)piperidine-1-carboxylate) (Compound 703-35)
  • Step 31c 1-tert-Butoxycarbonyl-3-(4-(3-amino-2-dibenzylamino)pyridinylamino)piperidine (tert-butyl 3-(((3-amino-2-) Preparation of dibenzylamino)pyridin-4-yl)amino)methyl)piperidine-1-carboxylate) (Compound 704-35)
  • Step 31d 1-tert-Butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine ( 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
  • Step 31e 1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (tert-butyl) Preparation of 3-((4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate) (Compound 706-35)
  • Step 31f 1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c Pyridylmethyl) piperidine (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 707-35) Preparation
  • Step 31g 4-Amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one ( 4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 708-35) Preparation
  • Step 31h 1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c] Pyridin-2-one (1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin Preparation of -2-one) (Compound 35)
  • Step 32a (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c Preparation of pyrridin-1-yl)pyrrolidine-1-carboxylate) (Compound 801-44)
  • Step 32b (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridine)pyrrolidine (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) (Compound 109-44)
  • Step 32c (R)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[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
  • Step 32d (R,E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2-butene) Acyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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 33a (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2, 3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1,3]) Preparation of dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate) (Compound 109-45)
  • Step 33b (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4, 5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(pyrrolidin- Preparation of 3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 110-45)
  • Step 33c (R,E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino) -2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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 Preparation of [4,5-c]pyridin-2-one) (Compound 45)
  • step 32d As in Example 32, step 32d, except that 4-dimethylamino crotonate was replaced with 4-piperidinyl croton hydrochloride (109 mg, 0.529 mmol, 1.3 eq.) to afford compound (R, E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butenoyl)pyrrolidine)) -1,3-2H-imidazo[4,5-c]pyridin-2-one (45 mg, yield: 19%).
  • Example 36 4-Amino-1-[(3R)-1-(2-butenoyl)piperidin-3-yl]-3-(4-phenoxy Phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4- Preparation of piperidin-1-yl-but-2-enoyl)-piperidin-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 48)
  • Example 37 4-Amino-1-[(3R)-1-(2-butenoyl)dimethylamino-3-yl]-3-(4-phenoxyphenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4-piperidin-1-yl-but- Preparation of 2-enoyl)-dimethylamino-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 49)
  • Example 38 (R)-1-(3-(1-acryloylpiperidine)-4-amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl )-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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-tert-Butoxycarbonyl-3-(4-amino-3-(1,4-benzodioxan-6-oxy)phenyl)-2-oxo-2, 3-Dihydro-1H-imidazo[4,5-c]pyridyl)piperidine (tert-butyl(R)-3-(4-amino-3-(4-((2,3-dihydrobenzo[b] ][1,4]dioxin-6-yl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate)( Preparation of Compound 307-52)
  • Step 38b (R)-4-Amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl)-1-(3-piperidinyl)-1H-imidazole [4,5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)) Preparation of oxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 308-52)
  • Step 38c (R)-1-(3-(1-acryloylpiperidine)-4-amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl) -1,3-2H-imidazo[4,5-c]pyridin-2-one ((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
  • BTK protein kinase activity was determined using the Caliper mobility shift assay (see J Biomol Screen 14:31, 2009).
  • the compound obtained above was dissolved in DMSO and diluted 10-fold with kinase buffer (50 mM HEPES-pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT), and 5 ⁇ l of 10% DMSO was added to the 384-well plate. Five times the final concentration of the compound, 5 ⁇ l of 10% DMSO in the control-free and non-enzymatically active control wells. 10 ⁇ l of a 2.5-fold final concentration of BTK enzyme solution (BTK, Cat. No.
  • Cell viability was assessed by measuring the amount of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI).
  • Diffuse large B-cell lymphoma cell line TMD-8 and large B-cell lymphoma cell line SU-DHL-16 were purchased from Shanghai Fudan IBS Cell Resource Center and American Type Culture Collection (ATCC). The cells were digested with trypsin from the cell culture dish and resuspended in DPBS medium, and the cell density was determined by counting with a Scepter automatic cell counter (Millipore, #PHCC00000). The cells were diluted to a solution containing 44,000 cells per ml.
  • the cell solution after the density adjustment was added to the cell assay plate at 90 ⁇ l per well.
  • the plates were placed in a 37 ° C, 5% CO 2 incubator for 24 hours and then added with different concentrations of test compound.
  • the cells were incubated with the compound for 72 hours in the presence of 10% fetal bovine serum.
  • the Luminescent Cell Viability Assay kit (see manufacturer's instructions) was assayed for ATP content to assess cell growth inhibition. Briefly, add 30 ⁇ l to each well. The reagents were shaken for 10 minutes, cell lysis was induced, and fluorescence signals were recorded using a fluorescence/chemiluminescence analyzer Fluoroskan Ascent FL (Thermo Scientific Fluoroskan Ascent FL).
  • the cells were treated with dimethyl sulfoxide (DMSO) for 72 or 120 hours to obtain the maximum signal value.
  • DMSO dimethyl sulfoxide
  • the minimum signal value obtained from a separate medium is defined as 0.
  • Inhibition rate % (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) ⁇ 100%.
  • Data was processed using GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software.
  • IC50 values were calculated by sigmoidal dose-response curve fitting.
  • Such compounds have potent anti-cell proliferation activity against tumor cells such as TMD-8, SU-DHL-16, etc., which are comparable or better than the positive control compounds Ibrutinib and ONO-4059, as listed in Table 2 below.
  • Representative compounds described in the present invention have anti-cell proliferation activity in cell-based assays. In these assays, the following levels were used: for IC50, I > 1 uM, 1 uM > II > 0.1 uM, 0.1 uM > III > 0.05 uM, 0.05 uM > IV > 0.01 uM, V ⁇ 0.01 uM.
  • ATCC human mantle cell lymphoma cells Jeko-1 and DOHH-2 were purchased from Shanghai Baili Biotechnology Co., Ltd., grown in suspension culture, and added to the test compound or reference compound for 1 hour, then centrifuged at low speed. The cells were collected (1200 rpm; 4 min) and then resuspended in serum-free medium. Goat F(ab')2 Anti-Human IgM (10 ug/ml) was added. After 2 min, the cells were washed twice with pre-cooled PBS, and the cells were collected, homogenized three times with a biological sample homogenizer, and centrifuged at 12,000 rpm for 10 min at 4 °C. Take the supernatant.
  • the protein concentration was determined by Branfor method, and the sample buffer (Beyotime, #P0015L) was added to cook at 100 ° C for 4 min.
  • the protein was separated by 10% SDS-PAGE and transferred to a PVDF membrane, followed by 5% bovine serum albumin (BSA). ) (Biyuntian; CAT No.ST023) TBST solution blocked for 1 hour, plus primary anti- ⁇ -actin mAb (CST, #4970), BTK (D3H5) mAb (CST, #8547) or phospho-BTK (Try223) mAb (CST, #5802) Incubate overnight at 4 ° C, then wash the membrane with TBST solution for 3 x 10 min.
  • BSA bovine serum albumin
  • the membrane was washed with a fluorescent secondary antibody IRDye@680CW Goat (polyclonal) Anti-Rabbit lgG (H+L), Highly Cross Adsorbed (LI-COR, #926-68071) at room temperature for 2 hours, and the washing conditions were the same as above. Finally, the membrane was placed on a LI-COR Odyssey infrared fluorescence scanning imaging system for imaging.
  • the compound 11 and the reference substance Ibrutinib prepared in Example 11 strongly inhibited the phosphorylation of BTK protein in Jeko-1 and DOHH-2 lymphoma cells, and the expression of p-BTK in Jeko-1 and DOHH-2 cells was significantly decreased under IgM stimulation (results shown in the figure). 1)).
  • the compound 11 provided by the present invention acts on Jeko-1 and DOHH-2 human lymphoma cells, and is effective in reducing phosphorylation of BTK.
  • test compound Male Sprague-Dawley rats weighing 250-300 g were fasted overnight before the test. The test compound was dissolved in 30% sulfobutyl- ⁇ -cyclodextrin (SBE- ⁇ -CD) and administered orally at 20 mg/kg. Blood was taken at the end of 15 minutes, 30 minutes and 1, 2, 3, 4, 6, 8 and 24 hours after administration, about 0.3 ml per time point, placed in a centrifuge tube containing K 2 -EDTA, and centrifuged. Plasma (2,000 g, 10 min, 4 ° C) was taken and stored in an ultra-low temperature freezer at -80 °C.
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • Example 3 After the intragastric administration of Compound 1 prepared in Example 1 and Compound 11 prepared in Example 11, the absorption was good and the blood exposure was high. Cmax was 544.3 and 2776.7 ng/ml, respectively. Compound 11 had a shorter half-life (1.2 hours) but a higher AUC (4985.5 ng/ml*h) (Table 3).
  • Tmax refers to the peak time
  • Cmax refers to the maximum blood concentration
  • T1/2 is the half-life
  • AUC 0-24 refers to the area under the 0-24 hour time-concentration curve
  • AUC inf refers to the 0-Inf time-concentration. The area under the curve.
  • mice were divided into three intragastric administration groups, namely, vehicle control group, Ibrutinib intragastric administration group (50 mg/kg, once per day) and Example 11 Compound 11 was prepared by intragastric administration (25 mg/kg, 2 times/day). 6 animals per group. Ibrutinib or Compound 11 was dissolved in 30% sulfobutyl- ⁇ -cyclodextrin (SBE- ⁇ -CD) and 1.0 molar equivalent of hydrochloric acid (pH 3-4), and administered intragastrically at 10 ml/kg continuously. Dosing for 14 days.
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • hydrochloric acid pH 3-4
  • Compound 11 and Ibrutinib have extremely high antitumor activity in the TMD-8 transplanted tumor model.
  • Administration of Compound 11 by intragastric administration dose of 25 mg/kg, bid
  • the transplanted tumor TMD-8 was reduced to disappear. There was no significant weight loss in each of the drug-administered groups compared to before administration (Fig. 2).

Abstract

Provided in the present invention are a 2-oxo-1,3-dihydroimidazo pyridine compound as represented by formula (I) and applications of the compound in preparing a medicament for treating various diseases involving Bruton's tyrosine kinase (BTK). Research shows that the compound disclosed is capable of effectively inhibiting the activity of BTK, and thus, by inhibiting BTK, preventing the survival, proliferation, and metastasis of malignant hematologic tumor cells. In addition, inflammation and autoimmune diseases can be mitigated by means of inhibiting BTK. Therefore, the compound of the present invention can be used for treating the various diseases involving BTK, specifically applicable in treating malignant hematologic tumors, inflammation, and autoimmune diseases, and has great application value.

Description

氧代二氢咪唑并吡啶类化合物及其应用Oxidized dihydroimidazopyridine compounds and applications thereof 技术领域Technical field
本发明涉及化学医药领域，特别是涉及氧代二氢咪唑并吡啶类化合物及其应用。The invention relates to the field of chemical medicine, in particular to oxydihydroimidazopyridine compounds and uses thereof.
背景技术Background technique
布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase，BTK)是B细胞受体信号复合体中的一种关键信号分子，是淋巴细胞生存和增殖的关键蛋白激酶。BTK在恶性B细胞的生存及扩散中起着重要作用。Bruton's tyrosine kinase (BTK) is a key signaling molecule in the B cell receptor signaling complex and a key protein kinase for lymphocyte survival and proliferation. BTK plays an important role in the survival and spread of malignant B cells.
BTK抑制剂通过抑制肿瘤细胞BTK而起到抗癌的作用。首创BTK抑制剂依鲁替尼(Ibrutinib)是一种4’-氨基吡唑并[3，4-d]嘧啶化合物(Proc Natl Acad Sci USA，107：13075，2010)，通过与靶蛋白BTK活性位点半胱氨酸残基(Cys-481)选择性地共价结合，不可逆性地抑制BTK。从而有效地阻止肿瘤从B细胞迁移到适应于肿瘤生长环境的淋巴组织。美国FDA于2013-2015年批准依鲁替尼用于难治套细胞淋巴瘤(MCL)、难治慢性淋巴细胞白血病(CLL)、携带del 17p删除突变的CLL的治疗和原发性巨球蛋白血症的治疗。BTK inhibitors play an anti-cancer role by inhibiting tumor cell BTK. The first BTK inhibitor, Ibrutinib, is a 4'-aminopyrazolo[3,4-d]pyrimidine compound (Proc Natl Acad Sci USA, 107:13075, 2010), which is linked to the target protein BTK. The site cysteine residue (Cys-481) selectively binds covalently and irreversibly inhibits BTK. Thereby effectively preventing the migration of tumors from B cells to lymphoid tissues adapted to the environment in which the tumor grows. US FDA approved Ibrutinib for the treatment of refractory mantle cell lymphoma (MCL), refractory chronic lymphocytic leukemia (CLL), CLL carrying del 17p deletion mutation, and primary macroglobulin in 2013-2015 Treatment of blood.
BTK抑制剂除了依鲁替尼以外，AVL-292(CC292)、ONO-4059、BGB-3111和ACP-196也进入临床开发阶段。用于B-细胞非霍奇金淋巴瘤、慢性淋巴细胞白血病、多发性骨髓瘤、毛细胞白血病、成人急性淋巴细胞白血病等治疗。依鲁替尼与化疗药物或其它靶向抗癌药联合治疗，可以增加这些血液肿瘤的疗效。临床试验中与BTK抑制剂联合使用的药物包括ituximab，来那度胺，氟达拉滨；环磷酰胺；阿霉素，长春新碱，强的松。BTK inhibitors In addition to ibrutinib, AVL-292 (CC292), ONO-4059, BGB-3111 and ACP-196 also entered the clinical development stage. For B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, hairy cell leukemia, adult acute lymphoblastic leukemia and other treatments. Ibrutinib combined with chemotherapy drugs or other targeted anticancer drugs can increase the efficacy of these blood tumors. Drugs used in combination with BTK inhibitors in clinical trials include ituximab, lenalidomide, fludarabine; cyclophosphamide; doxorubicin, vincristine, prednisone.
与正常造血细胞相比，大约80％的急性髓系白血病(AML)患者原始细胞中BTK活性增高，导致细胞在体外对口服BTK抑制剂依鲁替尼敏感(Marcel Spaargaren M.Lancet Heamat.2：e180，2015)。一项依鲁替尼单用或与阿糖胞苷联合用药治疗急性髓系白血病的临床研究进入II期临床。Compared with normal hematopoietic cells, approximately 80% of patients with acute myeloid leukemia (AML) have increased BTK activity in primordial cells, resulting in cells being sensitive to the oral BTK inhibitor ibrutinib in vitro (Marcel Spaargaren M. Lancet Heamat. 2: E180, 2015). A clinical trial of ibrutinib alone or in combination with cytarabine in the treatment of acute myeloid leukemia entered phase II clinical trials.
正常B细胞发育和活化过程中，BTK在B细胞受体(BCR)信使***作用至 关重要。BCR信号异常是与自身免疫性疾病有关，如类风湿性关节炎(RA)。此外，BTK也在髓系细胞，包括单核细胞，巨噬细胞，中性粒细胞和肥大细胞表达。这些细胞浸润滑膜腔并产生炎性细胞因子，加重关节炎症状。BTK抑制剂可以阻断B细胞受体依赖性细胞增殖，减少炎性因子产生(Whang J.A.，Chang B.Y.Drug Discov Today.19：1200，2014)。临床前研究表明BTK抑制剂还对多种炎症和自身免疫性疾病，如类风湿关节炎和动物模型有效。除了类风湿关节炎与红斑狼疮之外，这类药物有可能会用于狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘等。CC-292和HM71224等BTK抑制剂用于自身免疫性疾病的治疗(如类风湿关节炎)进入临床试验阶段(ClinicalTrials.gov ID：NCT01975610，NCT01765478)。During normal B cell development and activation, BTK acts in the B cell receptor (BCR) messenger system to It is important. Abnormal BCR signals are associated with autoimmune diseases such as rheumatoid arthritis (RA). In addition, BTK is also expressed in myeloid cells, including monocytes, macrophages, neutrophils and mast cells. These cells immerse the membrane cavity and produce inflammatory cytokines that aggravate the symptoms of arthritis. BTK inhibitors block B cell receptor-dependent cell proliferation and reduce inflammatory factor production (Whang J.A., Chang B.Y. Drug Discov Today. 19:1200, 2014). Preclinical studies have shown that BTK inhibitors are also effective against a variety of inflammatory and autoimmune diseases such as rheumatoid arthritis and animal models. In addition to rheumatoid arthritis and lupus erythematosus, these drugs may be used in lupus nephritis, multiple sclerosis, Schöngren's syndrome, and underlying disease asthma. BTK inhibitors such as CC-292 and HM71224 are used in the treatment of autoimmune diseases (such as rheumatoid arthritis) into clinical trials (ClinicalTrials.gov ID: NCT01975610, NCT01765478).
上述研究都表明BTK抑制剂作为防治肿瘤、多种炎症和自身免疫性疾病的药物有很大的潜在价值。All of the above studies have shown that BTK inhibitors have great potential as drugs for the prevention and treatment of tumors, various inflammatory and autoimmune diseases.
发明内容Summary of the invention
基于此，本发明的目的之一在于提供一种新型BTK抑制剂氧代二氢咪唑并吡啶类化合物。Based on this, one of the objects of the present invention is to provide a novel BTK inhibitor oxydihydroimidazopyridine compound.
实现上述发明目的的具体技术方案如下：The specific technical solutions for achieving the above object of the invention are as follows:
具有式(I)结构的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子：A 2-oxo1,3-dihydroimidazopyridine compound having the structure of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:
Figure PCTCN2016084057-appb-000001
Figure PCTCN2016084057-appb-000001
式中： In the formula:
X1和X2分别独立选自C或N；X 1 and X 2 are each independently selected from C or N;
Ar选自苯环或5-6元芳香杂环；Ar is selected from a benzene ring or a 5-6 membered aromatic heterocyclic ring;
L选自O，S，NR5，CR5R6，OCH2，CH2O；L is selected from the group consisting of O, S, NR 5 , CR 5 R 6 , OCH 2 , CH 2 O;
Y选自(CHR5)m，C＝O，其中m选自0、1、2、3；Y is selected from (CHR 5 ) m , C=O, wherein m is selected from 0, 1, 2, 3;
Z选自饱和的5-7元杂环或碳环；Z is selected from a saturated 5-7 membered heterocyclic ring or a carbocyclic ring;
G选自如下基团：G is selected from the following groups:
Figure PCTCN2016084057-appb-000002
Figure PCTCN2016084057-appb-000002
R1和R2分别独立选自：H，C1-C6烷基，卤素，硝基，羟基，C1-C6烷氧基，氰基，氨基，C1-C6烷基取代胺基，酰基，酰胺基；R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, cyano, amino, C 1 -C 6 alkyl substituted amine Base, acyl group, amide group;
R3和R4分别独立选自：H，C1-C6烷基，C3-C6环烷基，C3-C6环烷基甲基，卤素取代C1-C4烷基，羟基取代C1-C4烷基，C1-C3烷氧基取代C1-C4烷基，氨基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，卤素，硝基，羟基，C1-C6烷氧基，C1-C6烷硫基，C1-C6亚砜基，C1-C6砜基，氰基，氨基，C1-C6烷基取代胺基，酯基，酰基，酰胺基，羧基；R 3 and R 4 are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, halogen substituted C 1 -C 4 alkyl, Hydroxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 - C 4 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 sulfoxide, C 1 -C 6 sulfonyl, cyano, Amino group, C 1 -C 6 alkyl substituted amine group, ester group, acyl group, amide group, carboxyl group;
当R3和R4是C1-C6烷基，C1-C6烷氧基，OH或C1-C6烷基取代胺基，并且取代在Ar的相邻位置时，R3和R4可相连组成一个碳环或杂环，选自下列结构：When R 3 and R 4 are C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH or C 1 -C 6 alkyl substituted amine, and substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a carbocyclic or heterocyclic ring selected from the following structures:
Figure PCTCN2016084057-appb-000003
Figure PCTCN2016084057-appb-000003
其中，n选自0、1、2；Q1和Q2分别独立选自O，NR6，CHR6；Wherein n is selected from 0, 1 , 2; Q 1 and Q 2 are each independently selected from O, NR 6 , CHR 6 ;
R5、R6分别独立选自H，C1-C6烷基；R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl;
R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，氨基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，杂环取代C1-C4烷基。R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino Substituting a C 1 -C 4 alkyl group, the heterocyclic ring is substituted with a C 1 -C 4 alkyl group.
在其中一些实施例中，所述化合物具有式II所示结构： In some of these embodiments, the compound has the structure of Formula II:
Figure PCTCN2016084057-appb-000004
Figure PCTCN2016084057-appb-000004
式中：X3，X4，X5，X6和X7分别独立选自C或N。Wherein: X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from C or N.
在其中一些实施例中，X3，X4，X5，X6和X7均选自C；或X3，X4，X5，X6和X7的其中一个选自N，其余选自C。In some of the embodiments, X 3 , X 4 , X 5 , X 6 and X 7 are each selected from C; or one of X 3 , X 4 , X 5 , X 6 and X 7 is selected from N, and the remainder is selected From C.
在其中一些实施例中，G选自如下基团：In some of these embodiments, G is selected from the group consisting of:
Figure PCTCN2016084057-appb-000005
Figure PCTCN2016084057-appb-000005
在其中一些实施例中，X1和X2均为C。In some of these embodiments, X 1 and X 2 are both C.
在其中一些实施例中，L选自O，OCH2。In some of these embodiments, L is selected from the group consisting of O, OCH 2 .
在其中一些实施例中，Y选自(CH2)m，其中m为0或1。In some of these embodiments, Y is selected from (CH 2 ) m , wherein m is 0 or 1.
在其中一些实施例中，Z选自如下基团：In some of these embodiments, Z is selected from the group consisting of:
Figure PCTCN2016084057-appb-000006
Figure PCTCN2016084057-appb-000006
在其中一些实施例中，Z选自如下基团： In some of these embodiments, Z is selected from the group consisting of:
Figure PCTCN2016084057-appb-000007
Figure PCTCN2016084057-appb-000007
在其中一些实施例中，R3和R4分别独立选自：H，卤素，羟基，C1-C6烷氧基，羟基取代C1-C4烷基，C1-C6烷基取代胺基；当R3和R4是C1-C6烷氧基或OH时，并且取代在Ar的相邻位置时，R3和R4可相连组成一个杂环，选自下列结构：In some of these embodiments, R 3 and R 4 are each independently selected from the group consisting of: H, halo, hydroxy, C 1 -C 6 alkoxy, hydroxy-substituted C 1 -C 4 alkyl, C 1 -C 6 alkyl substituted Amine; when R 3 and R 4 are C 1 -C 6 alkoxy or OH, and when substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
Figure PCTCN2016084057-appb-000008
其中，n为0或1。
Figure PCTCN2016084057-appb-000008
Where n is 0 or 1.
在其中一些实施例中，R5和R6均为H；In some of the embodiments, R 5 and R 6 are both H;
在其中一些实施例中，R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，5-6元饱和氮杂环取代C1-C4烷基。In some of these embodiments, R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 -C 4 alkyl, a 5-6 membered saturated nitrogen heterocycle substituted for C 1 -C 4 alkyl.
在其中一些实施例中，X1和X2均为C；L选自O，OCH2；Y选自(CH2)m，其中m为0或1；Z选自
Figure PCTCN2016084057-appb-000009
R1和R2均为氢；In some of these embodiments, X 1 and X 2 are both C; L is selected from O, OCH 2 ; Y is selected from (CH 2 ) m , wherein m is 0 or 1; Z is selected from
Figure PCTCN2016084057-appb-000009
R 1 and R 2 are both hydrogen;
R3和R4均为氢；或者其中一个为氢，另一个选自卤素或羟基或C1-C6烷氧基；或者当R3和R4为C1-C6烷氧基或OH时，并且取代在Ar的相邻位置，R3和R4可相连组成一个杂环，选自下列结构：R 3 and R 4 are both hydrogen; or one of them is hydrogen and the other is selected from halogen or hydroxy or C 1 -C 6 alkoxy; or when R 3 and R 4 are C 1 -C 6 alkoxy or OH And, in place of the adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
Figure PCTCN2016084057-appb-000010
其中，n为0或1；
Figure PCTCN2016084057-appb-000010
Where n is 0 or 1;
R5和R6均为H；R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，5-6元饱和氮杂环取代C1-C4烷基。R 5 and R 6 are both H; R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy is substituted for C 1 -C 4 alkyl, C 1 -C 3 alkylamino group is substituted C 1 -C 4 alkyl, 5-6 membered saturated nitrogen heterocycle substituted for C 1 -C 4 alkyl.
本发明的另一目的是提供上述化合物的应用。Another object of the invention is to provide the use of the above compounds.
实现上述目的的具体技术方案如下：The specific technical solutions to achieve the above objectives are as follows:
上述2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体 异构体或其前药分子在制备布鲁顿酪氨酸激酶抑制剂中的应用。The above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof or a stereo Use of an isomer or a prodrug molecule thereof for the preparation of a Bruton's tyrosine kinase inhibitor.
上述2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备防治肿瘤的药物中的应用。Use of the above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof for the preparation of a medicament for controlling tumors.
上述2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备防治血液肿瘤的药物中的应用。Use of the above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof for the preparation of a medicament for controlling blood tumors.
在其中一些实施例中，所述血液肿瘤为淋巴瘤、骨髓瘤、淋巴细胞白血病、急性髓系白血病。In some of these embodiments, the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia.
上述2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子作为布鲁顿酪氨酸激酶抑制剂在制备防治炎症或自身免疫性疾病的药物中的应用。The above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, is prepared as a Bruton's tyrosine kinase inhibitor for controlling inflammation or Application in drugs for autoimmune diseases.
在其中一些实施例中，所述炎症或自身免疫性疾病为类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘。In some of these embodiments, the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Xiaogren's syndrome, and underlying disease asthma.
本发明的另一目的是提供一种治疗疾病的药物组合物。Another object of the present invention is to provide a pharmaceutical composition for treating a disease.
实现上述目的的具体技术方案如下：The specific technical solutions to achieve the above objectives are as follows:
一种治疗疾病的药物组合物，包括作为活性成分的上述2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，以及药学上可接受的载体。A pharmaceutical composition for treating a disease comprising the above 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, as an active ingredient, And a pharmaceutically acceptable carrier.
在其中一些实施例中，所述疾病是血液肿瘤或与布鲁顿酪氨酸激酶相关的炎症或自身免疫性疾病。In some of these embodiments, the disease is a hematological tumor or an inflammatory or autoimmune disease associated with Bruton's tyrosine kinase.
在其中一些实施例中，所述血液肿瘤为淋巴瘤、骨髓瘤、淋巴细胞白血病、急性髓系白血病；所述炎症或自身免疫性疾病为类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘。In some of the embodiments, the hematological tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia; the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple Sclerosis, Schöngren's syndrome, and underlying disease asthma.
本发明提供了2-氧代1，3-二氢咪唑并吡啶类化合物，发明人经过大量实验研究证明，该类化合物能有效抑制布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase，BTK)的活性，进而阻止恶性血液肿瘤细胞的生存、增殖和扩散。此外，通过抑制BTK可以对抗炎症和自身免疫性疾病。因此，本发明的化合物能够用于治疗BTK所参与的各种疾病，特别适用于血液恶性肿瘤和炎症以及自身免疫性疾 病的治疗，有较大的应用价值。The present invention provides 2-oxo1,3-dihydroimidazopyridine compounds, and the inventors have proved through extensive experimental studies that the compounds can effectively inhibit the activity of Bruton's tyrosine kinase (BTK). , thereby preventing the survival, proliferation and spread of malignant blood tumor cells. In addition, inflammation and autoimmune diseases can be combated by inhibiting BTK. Therefore, the compounds of the present invention can be used for the treatment of various diseases in which BTK is involved, and are particularly suitable for hematological malignancies and inflammation as well as autoimmune diseases. The treatment of the disease has great application value.
附图说明DRAWINGS
图1为实施例40的化合物11抑制人淋巴瘤Jeko-1和DOHH-2细胞株BTK磷酸化实验结果图；Figure 1 is a graph showing the results of inhibition of BTK phosphorylation of human lymphoma Jeko-1 and DOHH-2 cell lines by the compound 11 of Example 40;
图2为实施例42的化合物11在弥漫性大B细胞淋巴瘤细胞株TMD-8 SCID小鼠模型的抗肿瘤活性图。Figure 2 is a graph showing the antitumor activity of Compound 11 of Example 42 in a diffuse large B cell lymphoma cell line TMD-8 SCID mouse model.
具体实施方式Detailed ways
本发明所述化合物中，当任何变量(例如R1、R等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环***的线表示所指的键可连接到任何能取代的环原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。The compounds of the present invention, when any variable (e.g. R 1, R, etc.) appear in any component more than once defined, it is at each occurrence independently each occurrence of other definitions. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. A line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2，2-二甲基-环丁基、2-乙基-环戊基、环己基等。The term "alkyl" as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C 1 -C 6 " in "C 1 -C 6 alkyl" includes a group having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or a branched chain. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
本文所用术语“杂环”或“杂环基”是指含有1-4个选自O、N和S的杂原子的芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括杂芳基，也包括其二氢化及四氢化类似物。杂环取代基的连接可通过碳原子或通过杂原子实现。The term "heterocycle" or "heterocyclyl" as used herein, refers to an aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes heteroaryl, as well as dihydrogenated and tetrahydrogenated analogs thereof. The attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。As understood by those skilled in the art, "halogen" as used herein is meant to include chloro, fluoro, bromo and iodo.
本发明包括式I-III化合物的游离形式，也包括其药学上可接受的盐及立体 异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式I-III化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The present invention includes free forms of the compounds of Formulas I-III, including pharmaceutically acceptable salts thereof, and stereo isomer. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. The pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of Formulas I-III. The free form of the particular salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N，N′-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨 酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪，哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If a compound of the invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. A salt derived from a pharmaceutically acceptable organic non-toxic base, the base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histamine Acid, hydroxycobalamin, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, Trimethylamine, tripropylamine, tromethamine, and the like.
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下合成方案(方案1-6)中的方法制备本发明化合物。结合下述的合成方案，能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法，所述的方法仅仅是为说明目的的说明性方案描述，并不构成对本发明所具有的范围的限制。In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared by the methods of the following synthetic schemes (Schemes 1-6). A better understanding of the compounds and synthetic methods described in the present invention can be obtained in conjunction with the synthetic schemes described below. The described synthetic schemes describe the methods that can be used to prepare the compounds described in the present invention, which are merely illustrative of the illustrative examples and are not intended to limit the scope of the invention.
Figure PCTCN2016084057-appb-000011
Figure PCTCN2016084057-appb-000011
方案1 plan 1
Figure PCTCN2016084057-appb-000012
Figure PCTCN2016084057-appb-000012
方案2 Scenario 2
Figure PCTCN2016084057-appb-000013
Figure PCTCN2016084057-appb-000013
方案3 Option 3
Figure PCTCN2016084057-appb-000014
Figure PCTCN2016084057-appb-000014
方案4 Option 4
Figure PCTCN2016084057-appb-000015
Figure PCTCN2016084057-appb-000015
方案5Option 5
Figure PCTCN2016084057-appb-000016
Figure PCTCN2016084057-appb-000016
方案6 Option 6
Figure PCTCN2016084057-appb-000017
Figure PCTCN2016084057-appb-000017
方案7 Option 7
Figure PCTCN2016084057-appb-000018
Figure PCTCN2016084057-appb-000018
方案8Option 8
以下结合实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。The invention is further described in the following examples, but the examples are not intended to limit the scope of the invention.
实施例1：(R)-4-胺基-1-[1-(2-丁炔酰基)吡咯烷-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物1)的制备Example 1: (R)-4-Amino-1-[1-(2-butynyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one ((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
步骤1a：叔丁基(R)-3-((2-氯-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate)(化合物103)的制备Step 1a: tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-amino)pyrrole-1-carboxylate (tert-butyl) Preparation of (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate) (Compound 103)
往反应瓶中加入2，4-二氯-3-硝基吡啶(101)(9.65g，50.0mmol，1.0当量)，叔丁基(R)-3-氨基吡咯烷-1-甲酸叔丁酯(102)(9.30g，50.0mmol，1.0当量)，三乙胺(6.56g，65.0mmol，1.3当量)和N，N-二甲基甲酰胺(60ml)，室温反应过夜。反应液加水(300mL)稀释，用乙酸乙酯(100mL×4)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用柱层析法纯化(洗脱剂：石油醚∶乙酸乙酯＝4∶1)得到叔丁基(R)-3-((2-氯-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(13.7g，收率：80％)。淡黄色油状物；TLC：Rf0.2(石油醚∶乙酸乙酯＝4∶1)；LCMS(ESI)：m/z 343[M+1]+。To the reaction flask was added 2,4-dichloro-3-nitropyridine (101) (9.65 g, 50.0 mmol, 1.0 eq.), tert-butyl(R)-3-aminopyrrolidin-1-carboxylic acid tert-butyl ester. (102) (9.30 g, 50.0 mmol, 1.0 eq.), triethylamine (6.56 g, 65.0 mmol, 1.3 eq.) and N,N-dimethylformamide (60 ml). The reaction mixture was diluted with water (300 mL), EtOAc (EtOAc m. 1) Obtained tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-amino)pyrrole-1-carboxylate (13.7 g, yield: 80%). thereof; TLC: Rf0.2 (petroleum ether: ethyl acetate = 4:1); LCMS (ESI) : m / z 343 [m + 1] +.
步骤1b：叔丁基(R)-3-((2-二苄胺基-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carbox ylate)(化合物104)的制备Step 1b: tert-butyl(R)-3-((2-dibenzylamino-3-nitropyridin-4-amino)pyrrole-1-carboxylate (tert-butyl(R)-3-(( Preparation of 2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carbox ylate)
往反应瓶中加入叔丁基(R)-3-((2-氯-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(103)(13.7g，40.06mmol，1.0当量)，二苄胺(8.47mL，44.06mmol，1.0当量)，三乙胺(11.15mL，80.12mmol，2.0当量)和乙腈(200ml)，加热回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(洗脱剂：石油醚∶乙酸乙酯＝4∶1)得到叔丁基(R)-3-((2-二苄胺基-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(20.0g，收率：99％)。黄色油状物；TLC：Rf0.4(石油醚∶乙酸乙酯＝4∶1)；LCMS(ESI)：m/z 504[M+1]+。To the reaction flask was added tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-amino)pyrrole-1-carboxylate (103) (13.7 g, 40.06 mmol, 1.0 eq.) Dibenzylamine (8.47 mL, 44.06 mmol, 1.0 eq.), triethylamine (11.15 mL, 80.12 mmol, 2.0 eq.) and acetonitrile (200 mL). Purification by eluent (eluent: petroleum ether: ethyl acetate = 4:1) to give tert-butyl(R)-3-((2-dibenzylamino-3-nitropyridin-4-amino)pyrrole- 1-carboxylic acid ester (20.0 g, yield: 99%). Yellow oil; TLC: Rf 0.4 ( petroleum ether: ethyl acetate = 4:1); LCMS (ESI): m/z 504 [M+ 1] + .
步骤1c：叔丁基(R)-3-((3-氨基-2-二苄胺基)吡啶-4-氨基)吡咯-1-羧酸酯(tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1-carboxylate)(化合物105)的制备Step 1c: tert-butyl(R)-3-((3-amino-2-dibenzylamino)pyridin-4-amino)pyrrole-1-carboxylate (tert-butyl(R)-3-(( Preparation of 3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1-carboxylate) (Compound 105)
往锌粉(25.82g，397.1mmol，10.0当量)和氯化铵(17.87g，277.97mmol，7.0当量)的甲醇溶液(500ml)中加入叔丁基(R)-3-((2-二苄胺基-3-硝基吡啶-4-氨基)吡咯-1-羧酸酯(104)(20.0g，39.71mmol，1.0当量)，加热至50℃反应1小时。反应液用硅藻土过滤，滤液旋干，用二氯甲烷∶甲醇＝5∶1(50ml)的混合溶剂溶解，过滤，有机相旋干得到粗品叔丁基(R)-3-((3-氨基-2-二苄胺基)吡啶-4-氨基)吡咯-1-羧酸酯(18.3g，收率：97％)。淡黄色固体；TLC：Rf0.1(石油醚∶乙酸乙酯＝4∶1)；LCMS(ESI)：m/z 474[M+1]+。 To a solution of zinc powder (25.82 g, 397.1 mmol, 10.0 eq.) and ammonium chloride (17.87 g, 277.97 mmol, 7.0 eq.) in methanol (500 ml) was added tert-butyl(R)-3-((2-dibenzyl) Amino-3-nitropyridin-4-amino)pyrrole-l-carboxylate (104) (20.0 g, 39.71 mmol, 1.0 eq.) was then taken to 50 ° C for 1 hour. The reaction mixture was filtered over Celite. The filtrate was spun dry, dissolved in a mixed solvent of dichloromethane:methanol = 5:1 (50 ml), filtered, and the organic phase was dried to give crude tert-butyl(R)-3-((3-amino-2-dibenzylamine) Pyridyl-4-amino)pyrrole-1-carboxylate (18.3 g, yield: 97%), pale yellow solid; TLC: Rf 0.1 ( petroleum ether: ethyl acetate = 4:1); ESI): m/z 474 [M+1] + .
步骤1d：叔丁基(R)-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)pyrrolidine-1-carboxylate)(化合物106)的制备Step 1d: tert-Butyl (R)-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate Tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate Preparation of (Compound 106)
往反应瓶中加入叔丁基(R)-3-((3-氨基-2-二苄胺基)吡啶-4-氨基)吡咯-1-羧酸酯(105)(18.3g，38.64mmol，1.0当量)，N，N′-羰基二咪唑(15.7g，96.6mmol，2.5当量)和四氢呋喃(200ml)，将反应液加热至回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝100∶1)得到叔丁基(R)-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(17.5g，收率：91％)。淡黄色液体；TLC：Rf0.8(二氯甲烷∶甲醇＝80∶1)；LCMS(ESI)：m/z 500[M+1]+。To the reaction flask was added tert-butyl (R)-3-((3-amino-2-dibenzylamino)pyridin-4-amino)pyrrole-1-carboxylate (105) (18.3 g, 38.64 mmol, 1.0 equivalents, N,N'-carbonyldiimidazole (15.7 g, 96.6 mmol, 2.5 eq.) and tetrahydrofuran (200 mL). The reaction mixture was dried with EtOAc (EtOAc) (EtOAc) Oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (17.5 g, yield: 91%). Light yellow liquid; TLC: Rf0.8 (dichloromethane: methanol = 80:1); LCMS (ESI) : m / z 500 [M + 1] +.
步骤1e：叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(tert-butyl(R)-3-(4-amino-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)pyrrolidine-1-carboxylate)(化合物107)的制备Step 1e: tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate ( 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
往反应瓶中加入叔丁基(R)-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(106)(17.5g，35.03mmol，1.0当量)，氢氧化钯(7.0g)，乙醇(240ml)和乙酸乙酯(60ml)，反应液加热到70℃，在氢气氛围中反应过夜。反应混合物用硅藻土过滤，滤液旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝20∶1)得到叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(9.0g，收率：80％)。无色固体；TLC：Rf0.1(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 320[M+1]+。Add tert-butyl(R)-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1 to the reaction flask. a carboxylic acid ester (106) (17.5 g, 35.03 mmol, 1.0 eq.), palladium hydroxide (7.0 g), ethanol (240 ml) and ethyl acetate (60 ml). The reaction mixture was heated to 70 ° C and reacted in a hydrogen atmosphere. overnight. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness. The purified product was purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to give tert-butyl(R)-3-(4-amino- 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (9.0 g, yield: 80%). As a colorless solid; TLC: Rf0.1 (dichloromethane: methanol = 20:1); LCMS (ESI) : m / z 320 [M + 1] +.
步骤1f：叔丁基(R)-3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(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)(化合物109-1)的制备Step 1f: tert-Butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c Pyridine pyrrole-1-carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5 -c]pyridin-1-yl)pyrrolidine-1-carboxylate) (Compound 109-1) Preparation
将叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(107)(5.93g，18.57mmol，1.0当量)、对苯氧基苯硼酸(108-1)(5.17g，24.14mmol，1.3当量)和吡啶(4.5mL，55.71mmol，3.0当量)溶于N，N-二甲基甲酰胺(40mL)中，再加入醋酸铜(3.72g，20.43mmol，1.1当量)和4A分子筛(6.7g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(150mL)稀释， 过滤，滤液用半饱和食盐水(70mL×4)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得叔丁基(R)-3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(2.7g，收率：31％)。棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 488[M+1]+。tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (107) (5.93 g, 18.57 mmol, 1.0 eq.), p-phenoxyphenylboronic acid (108-1) (5.17 g, 24.14 mmol, 1.3 eq.) and pyridine (4.5 mL, 55.71 mmol, 3.0 eq.) dissolved in N,N- Further, in dimethylformamide (40 mL), copper acetate (3.72 g, 20.43 mmol, 1.1 equivalent) and 4A molecular sieve (6.7 g) were added, and then reacted in air at 50 ° C overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (150 mL), filtered and evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated tolulujjjjjjjjjj 2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (2.7 g, yield : 31%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤1g：(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物110-1)的制备Step 1g: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c Pyridine-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin Preparation of -2-one) (Compound 110-1)
将(R)-叔丁基-3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯-1-羧酸酯(109-1)(2.7g，5.54mmol，1.0当量)溶于二氯甲烷(25mL)中，再向其中加入三氟乙酸(5mL)，然后在室温下反应3小时。将反应混合液用二氯甲烷(150mL)稀释，依次用饱和碳酸钠溶液(50mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶用硅胶拌样旋干，之后用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得：(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(2.0g，收率：93％)。灰色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 388[M+1]+。(R)-tert-Butyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c] Pyridine)-pyrrole-l-carboxylate (109-1) (2.7 g, 5.54 mmol, 1.0 eq.) was dissolved in dichloromethane (25 mL), then trifluoroacetic acid (5 mL) was added and then reacted at room temperature 3 hours. The reaction mixture was diluted with methylene chloride (150 mL), washed successively with saturated sodium carbonate (50 mL×2) and brine (60 mL). Purification by eluent (eluent: dichloromethane:methanol:triethylamine=100:10:1): (R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidine) 3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2.0 g, yield: 93%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;
步骤1h：(R)-4-胺基-1-[1-(2-丁炔酰基)吡咯烷-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物1)的制备Step 1h: (R)-4-amino-1-[1-(2-butynyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4- Preparation of phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 1)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(193.5mg，0.5mmol，1当量)溶于DMF(2ml)，加入2-丁炔酸(111-1)(51.5mg，0.6mmol，1.2当量)，EDCI(115mg，0.6mmol，1.2当量)，HOBt(7mg，0.05mmol，0.1当量)，室温反应1小时。加水(5ml)搅拌，二氯甲烷(2ml)萃取，有机相再用水(10ml)洗涤一次，干燥，浓缩，柱层析(洗脱剂：甲醇∶EA＝1∶10)分离得白色固体(R)-4-胺基-1-[1-(2-丁炔酰基)吡咯烷-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(163mg，收率70％)。熔点：106.5-107.0℃；LCMS(ESI)：m/z 454.40[M+1]+；1HNMR(600MHz，CDCl3)：δ1.97(s，1.5H)，2.03(s，1.5H)，2.37(m，1H)，2.64(m，1H)，3.57(m，0.5H)，3.76(m，0.5H)， 3.95(m，1.5H)，4.11(m，3.5H)，5.11(m，1H)，6.52(d，J＝5.64Hz，0.5H)，6.58(d，J＝5.58Hz，0.5H)，7.11(m，4H)，7.19(m，1H)，7.40(m，4H)，7.86(dd，J＝18.1，5.58Hz，1H)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (193.5 mg, 0.5 mmol, 1 eq.) was dissolved in DMF (2 mL), and 2-butynoic acid (111-1) (51.5 mg, 0.6 mmol, 1.2 eq. 115 mg, 0.6 mmol, 1.2 eq.), HOBt (7 mg, 0.05 mmol, 0.1 eq.). After adding water (5 ml), the mixture was stirred with methylene chloride (2 ml), EtOAc (EtOAc) )-4-amino-1-[1-(2-butynyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazole [4,5-c]pyridin-2-one (163 mg, yield 70%). Melting point: 106.5-107.0 ° C; LCMS (ESI): m/z 454.40 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ): 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 = 5.64 Hz, 0.5H), 6.58 (d, J = 5.58 Hz, 0.5H), 7.11 (m, 4H), 7.19 (m, 1H), 7.40 (m, 4H), 7.86 (dd, J = 18.1, 5.58 Hz, 1H).
实施例2：(R)-4-氨基-3-(4-苯氧苯基)-1-(1-丙烯酰基吡咯烷-3基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpyrrolidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物2)的制备Example 2: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(1-acryloylpyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((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
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.1g，0.26mmol，1.0当量)、丙炔酸(111-2)(21.7mg，0.31mmol，1.2当量)、DCC(63.9mg，0.31mmol，1.2当量)和DMAP(3.2mg，0.026mmol，0.1当量)溶于二氯甲烷(5mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-4-氨基-3-(4-苯氧苯基)-1-(1-丙烯酰基吡咯烷-3基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮50mg，收率：44％)。白色固体，熔点：141.5-143.1℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 440[M+1]+，纯度：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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.1 g, 0.26 mmol, 1.0 eq.), propynoic acid (111-2) (21.7 mg, 0.31 mmol, 1.2 eq.), DCC (63.9 mg, 0.31 mmol, 1.2 eq.) And DMAP (3.2 mg, 0.026 mmol, 0.1 eq.) was dissolved in dichloromethane (5 mL) and then allowed to react at room temperature for 1 hour. After completion of the reaction, the crude product is obtained, which is purified by column chromatography (eluent: methylene chloride:methanol = 50:1) to give compound (R)-4-amino-3-(4-phenoxyphenyl)- 1-(1-acryloylpyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one 50 mg, yield: 44%). White solid, melting point: 141.5-143.1 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 440[M+1] + , purity: 98.587%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.89- 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 = 28 Hz, 1H), 2.76-2.65 (m, 1H), 2.45 -2.36 (m, 1H).
实施例3：(R)-4-氨基-1-(1-(2-戊炔酰基)吡咯烷-3-基)-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物3)的制备Example 3: (R)-4-Amino-1-(1-(2-pentynyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(pent-2-ynoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl) Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 3)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.15g，0.39mmol，1.0当量)、2-戊炔酸(46.1mg，0.47mmol，1.2当量)、DCC(97.0mg，0.47mmol，1.2当量)和DMAP(4.8mg，0.039mmol，0.1当量)溶于二氯甲烷(5mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-4- 氨基-1-(1-(2-戊炔酰基)吡咯烷-3-基)-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(80mg，收率：44％)。白色固体，熔点：180.1-181.6℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 468[M+1]+，纯度：99.450％；1HNMR(CDCl3，500MHz)：δ7.87(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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.15 g, 0.39 mmol, 1.0 eq.), 2-pentynoic acid (46.1 mg, 0.47 mmol, 1.2 eq.), DCC (97.0 mg, 0.47 mmol, 1.2 eq.) and DMAP ( 4.8 mg, 0.039 mmol, 0.1 eq.) was dissolved in dichloromethane (5 mL) and then allowed to react at room temperature for 1 hour. After the reaction is completed, the crude product is concentrated, purified by column chromatography (eluent: dichloromethane:methanol = 50:1) to give compound (R)-4-amino-1-(1-(2-pentynyl) Pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (80 mg, yield: 44 %). White solid, melting point: 180.1-181.6 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 468[M+1] + , purity: 99.450%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.87 ( Dd, J=16.0, 6.0 Hz, 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).
实施例4：(R)-1-(1-丙烯酰基吡咯烷-3-基)-4-氨基-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物4)的制备Example 4: (R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one ((R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ Preparation of 4,5-c]pyridin-2-one) (Compound 4)
将丙烯酰氯(202-4)(56.5mg，0.62mmol，1.2当量)溶于二氯甲烷(5mL)中，冷却到0℃，然后向其中逐滴滴加(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.2g，0.52mmol，1.0当量)的二氯甲烷(5mL)溶液，接着再逐滴滴加N，N-二异丙基乙胺(101mg，0.78mmol，1.5当量)的二氯甲烷(1.0mL)溶液，将该混合液在0℃反应10分钟。将反应液用水(50mL)猝灭，然后用二氯甲烷(50mL×2)萃取。将得到的有机层用硅胶用硅胶拌样旋干，之后用柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-1-(1-丙烯酰基吡咯烷-3-基)-4-氨基-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.13g，收率：57％)。白色固体，熔点：119.2-120.5℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 442[M+1]+，纯度：99.019％；1HNMR(CDCl3，500MHz)：δ7.87-7.84(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)。Acryloyl chloride (202-4) (56.5 mg, 0.62 mmol, 1.2 eq.) was dissolved in dichloromethane (5 mL), cooled to 0 ° C, then (R)-4-amino-3- (4-Phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1) (0.2 a solution of g, 0.52 mmol, 1.0 eq. in dichloromethane (5 mL), then EtOAc (EtOAc, EtOAc. The solution was reacted at 0 ° C for 10 minutes. The reaction solution was quenched with water (50 mL) and then evaporated. The obtained organic layer was spin-dried with silica gel using silica gel, and then purified by column chromatography (eluent: dichloromethane:methanol = 50:1) to give compound (R)-1-(1-acryloylpyrrole). Alkyl-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.13 g, Rate: 57%). White solid, melting point: 119.2-120.5 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 442[M+1] + , purity: 99.019%; 1 H NMR (CDCl 3 , 500 MHz): 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).
实施例5：(R)-4-氨基-1-(1-甲基丙烯酰基吡咯烷-3-基)-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物5) 的制备Example 5: (R)-4-Amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H- Imidazo[4,5-c]pyridin-2-one ((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
往甲基丙烯酰氯(202-5)(0.065g，0.62mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.200g，0.52mmol，1.0当量)的二氯甲烷溶液(8ml)，然后再滴加二异丙基乙基胺(0.100g，0.78mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝40∶1)得到(R)-4-氨基-1-(1-甲基丙烯酰基吡咯烷-3-基)-3-(4-苯氧基苯基)-1，3-二氢-1H-咪唑并[4，5-c]吡啶-2-酮(0.140g，收率：59％)。无色固体，熔点：114.6-117.5℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 456[M+1]+，1HNMR(CDCl3，500MHz)：δ7.86(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)。Add (R)-4-amino-3-(4-phenoxybenzene) to methacryloyl chloride (202-5) (0.065 g, 0.62 mmol, 1.2 eq.) in dichloromethane (7 ml) at 0 ° C -1(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1) (0.200 g, 0.52 mmol, 1.0) Equivalent) of a dichloromethane solution (8 ml) was then added dropwise a solution of diisopropylethylamine (0.100 g, 0.78 mmol, 1.5 eq.) in dichloromethane (1 ml), and reacted at 0 ° C for 5 min. The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 40:1) to give (R)-4-amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-1H - Imidazo[4,5-c]pyridin-2-one (0.140 g, yield: 59%). Colorless solid, melting point: 114.6-117.5 ° C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 456 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.86 (d, J = 5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J = 7.5 Hz, 1H), 7.12 (m, 4H), 6.57 (d, J = 5.5 Hz, 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).
实施例6：(R，E)-4-氨基-1-(1-(丁-2-烯酰基)吡咯烷-3-基)-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物6)的制备Example 6: (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 ((R,E)-4-amino-1-(1-(but-2-enoyl)pyrrolidin-3-yl)- Preparation of 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 6)
往(E)-丁-2-烯酰氯(202-6)(0.065g，0.62mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.200g，0.52mmol，1.0当量)的二氯甲烷溶液(8ml)，然后再滴加二异丙基乙基胺(0.100g，0.78mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝40∶1)得到(R，E)-4-氨基-1-(1-(丁-2-烯酰基)吡咯烷-3-基)-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.100g，收率：42％)。无色固体，熔点：102.3-105.8℃。TLC：Rf0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 456[M+1]+， 1HNMR(CDCl3，500MHz)：δ7.86(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)。Add (R)-4-amino-3- to (E)-but-2-enoyl chloride (202-6) (0.065 g, 0.62 mmol, 1.2 eq.) in dichloromethane (7 ml). (4-Phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1) (0.200 g, 0.52 mmol, 1.0 eq.) in dichloromethane (8 mL), then diisopropylethylamine (0.100 g, 0.78 mmol, 1.5 eq.) in dichloromethane (1 mL) The reaction was carried out for 5 minutes. The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 40:1) gives (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 (0.100 g, yield: 42%). Colorless solid, melting point: 102.3-105.8 ° C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 456 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.86 (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).
实施例7：(R，E)-4-氨基-1-(1-(2-戊烯酰基)吡咯烷-3-基))-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮)((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)(化合物7)的制备Example 7: (R,E)-4-Amino-1-(1-(2-pentenoyl)pyrrolidin-3-yl))-3-(4-phenoxyphenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one)((R,E)-4-amino-1-(1-(pent-2-enoyl)pyrrolidin-3-yl)- Preparation of 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 7)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.2g，0.52mmol，1.0当量)、反式2-戊烯酸(67.7mg，0.68mmol，1.3当量)、HOBT(91.9mg，0.68mmol，1.3当量)、EDCI(130.4mg，0.68mmol，1.3当量)和二异丙基乙胺(0.26mL，1.56mmol，3.0当量)溶于二氯甲烷(8mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得化合物(R，E)-4-氨基-1-(1-(2-戊烯酰基)吡咯烷-3-基))-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮)(83mg，收率：34％)。白色固体，熔点：221.3-222.4℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 470[M+1]+，纯度：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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.2 g, 0.52 mmol, 1.0 equivalent), trans 2-pentenoic acid (67.7 mg, 0.68 mmol, 1.3 eq.), HOBT (91.9 mg, 0.68 mmol, 1.3 eq.), EDCI (130.4 mg, 0.68 mmol, 1.3 eq.) and diisopropylethylamine (0.26 mL, 1.56 mmol, 3.0 eq.) were dissolved in dichloromethane (8 mL) and then allowed to react at room temperature for 1 hour. After the reaction is completed, it is concentrated to give a crude product which is purified by column chromatography (eluent: dichloromethane:methanol = 50:1) to give compound (R,E)-4-amino-1-(1-(2-pent) Alkenyl)pyrrolidin-3-yl))-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (83 mg, Yield: 34%). White solid, melting point: 221.3-222.4 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 470[M+1] + , purity: 96.527%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.86- 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).
实施例8：(R，E)-4-氨基-1-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷-3基)-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物8)的制备Example 8: (R,E)-4-amino-1-(1-(4-dimethylamino-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)- 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-1-(1-(4-(dimethylamino)but-2-enoyl) Preparation of pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 8)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.5g，1.29mmol，1.0当量)、4-溴巴豆酸(277mg，1.68mmol，1.3当量)、DCC(347mg，1.68mmol，1.3当量)和DMAP(16mg，0.13mmol， 0.1当量)溶于二氯甲烷(15mL)，然后在0℃下反应1.5小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝30∶1)纯化得(R，E)-4-氨基-1-(3-(1-(4-溴-2-丁烯酰基)吡咯烷))-3-(4-苯氧苯基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.6g，收率：88％)。白色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 535[M+1]+。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.5 g, 1.29 mmol, 1.0 eq.), 4-bromocrotonic acid (277 mg, 1.68 mmol, 1.3 eq.), DCC (347 mg, 1.68 mmol, 1.3 eq.) and DMAP (16 mg, 0.13 mmol, 0.1 eq.) was dissolved in dichloromethane (15 mL) and then reacted at 0 ° C for 1.5 hours. After the reaction is completed, the crude product is concentrated, purified by column chromatography (eluent: dichloromethane:methanol = 30:1) to afford (R,E)-4-amino-1-(3-(1-(4) -bromo-2-butenoyl)pyrrolidine))-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.6 g, yield :88%). White solid; TLC: Rf 0.4 (dichloromethane: methanol = 20:1); LCMS (ESI) : m / z 535 [M + 1] +.
将上述获得的(R，E)-4-氨基-1-(3-(1-(4-溴-2-丁烯酰基)吡咯烷))-3-(4-苯氧苯基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.15g，0.28mmol，1.0当量)和二甲胺(2M四氢呋喃溶液，0.63mL，1.26mmol，4.5当量)溶于四氢呋喃(3mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝20∶1)纯化得化合物(R，E)-4-氨基-1-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷-3基)-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(60mg，收率：43％)。白色固体，熔点：103.6-105.3℃。TLC：Rf 0.3(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 499[M+1]+，纯度：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)。(R,E)-4-Amino-1-(3-(1-(4-bromo-2-butenoyl)pyrrolidine))-3-(4-phenoxyphenyl)-1H obtained above - Imidazo[4,5-c]pyridine-2(3H)-one (0.15 g, 0.28 mmol, 1.0 eq.) and dimethylamine (2M in tetrahydrofuran, 0.63 mL, 1.26 mmol, 4.5 eq) dissolved in tetrahydrofuran ( 3 mL), and then reacted at room temperature for 1 hour. After completion of the reaction, the crude product was concentrated, purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to give compound (R,E)-4-amino-1-(1-(4-) Methylamino-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (60 mg, yield: 43%). White solid, melting point: 103.6-105.3 ° C. TLC: Rf 0.3 (dichloromethane:methanol = 10:1); LCMS (ESI): m/z 499[M+1] + , purity: 95.928%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.87- 7.84(m,1H), 7.41-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),6.99-6.95(m,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).
实施例9：(R，E)-4-氨基-1-(1-(4-甲氧基-2-丁烯酰基)吡咯烷-3-基)-3-(4-苯氧苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物9)的制备Example 9: (R,E)-4-Amino-1-(1-(4-methoxy-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-1-(1-(4-methoxybut-2-enoyl)pyrrolidin Preparation of -3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 9)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.15g，0.387mmol，1.0当量)、4-甲氧基巴豆酸(58.4mg，0.503mmol，1.3当量)、DCC(103.8mg，0.537mmol，1.3当量)和DMAP(4.8mg，0.039mmol，0.1当量)溶于二氯甲烷(6mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝30∶1)纯化得化合物(R，E)-4-氨基-1-(1-(4-甲氧基-2-丁烯酰基)吡咯烷-3-基)-3-(4-苯氧苯基)-1，3- 二氢-2H-咪唑并[4，5-c]吡啶-2-酮(60mg，收率：32％)。白色固体，熔点：178.2-179.5℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 486[M+1]+，纯度：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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.15 g, 0.387 mmol, 1.0 eq.), 4-methoxy crotonic acid (58.4 mg, 0.503 mmol, 1.3 eq.), DCC (103.8 mg, 0.537 mmol, 1.3 eq.) DMAP (4.8 mg, 0.039 mmol, 0.1 eq.) was dissolved in dichloromethane (6 mL) and then allowed to react at room temperature for 1 hour. After the reaction is completed, the crude product is concentrated, purified by column chromatography (eluent: dichloromethane:methanol = 30:1) to give compound (R,E)-4-amino-1-(1-(4-) Oxy-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2- Ketone (60 mg, yield: 32%). White solid, melting point: 178.2-179.5 °C. TLC: Rf 0.4 (dichloromethane:methanol = 10:1); LCMS (ESI): m/z 486[M+1] + , purity: 98.464%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.87- 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).
实施例10：(R，E)-4-氨基-3-(4-苯氧苯基)-1-(1-(4-(哌啶-1-基)-2-丁烯酰基)吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物10)的制备Example 10: (R,E)-4-Amino-3-(4-phenoxyphenyl)-1-(1-(4-(piperidin-1-yl)-2-butenoyl)pyrrolidine -3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((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) Preparation of 10)
将(R)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(110-1)(0.16g，0.413mmol，1.0当量)、4-哌啶基巴豆酸(90.1mg，0.537mmol，1.3当量)、HATU(204.1mg，0.537mmol，1.3当量)和三乙胺(125mg，1.239mmol，3.0当量)溶于二氯甲烷(5mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂：二氯甲烷∶甲醇＝20∶1)纯化得化合物(R，E)-4-氨基-3-(4-苯氧苯基)-1-(1-(4-(哌啶-1-基)-2-丁烯酰基)吡咯烷-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(100mg，收率：45％)。白色固体，熔点：107.5-109.1℃。TLC：Rf 0.3(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 539[M+1]+，纯度：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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine 2-ketone (110-1) (0.16 g, 0.413 mmol, 1.0 eq.), 4-piperidinyl crotonic acid (90.1 mg, 0.537 mmol, 1.3 eq.), HATU (204.1 mg, 0.537 mmol, 1.3 eq.) Triethylamine (125 mg, 1.239 mmol, 3.0 eq.) was dissolved in dichloromethane (5 mL) and then reacted at room temperature for one hour. After the reaction is completed, the crude product is concentrated, purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to give compound (R,E)-4-amino-3-(4-phenoxyphenyl) )-1-(1-(4-(piperidin-1-yl)-2-butenoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c Pyridin-2-one (100 mg, yield: 45%). White solid, melting point: 107.5-109.1 °C. TLC: Rf 0.3 (dichloromethane:methanol = 10:1); LCMS (ESI): m/z 539[M+1] + , purity: 97.356%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.88- 7.84 (m, 1H), 7.41-7.38 (m, 4H), 7.21-7.18 (m, 1H), 7.13-7.09 (m, 4H), 7.01-6.98 (m, 1H), 6.58-6.54 (m, 1H) ), 6.50-6.25 (m, 1H), 5.20-5.05 (m, 1H), 4.13-3.98 (m, 5H), 3.78-3.58 (m, 1H), 2.49 (d, J = 19.5 Hz, 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).
实施例11：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物11)的制备 Example 11: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazole [4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 11)
步骤11a：叔丁基(R)-3-((2-氯-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯((R)-tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate)(化合物302)的制备Step 11a: tert-Butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((R)-tert-butyl(R)- Preparation of 3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 302)
往反应瓶中加入2，4-二氯-3-硝基吡啶(101)(5.79g，30.0mmol，1.0当量)，叔丁基(R)-3-氨基哌啶-1-羧酸酯(301)(6.00g，30.0mmol，1.0当量)，三乙胺(6.06g，60.0mmol，2.0当量)和N，N-二甲基甲酰胺(50ml)，室温反应过夜。将反应液用乙酸乙酯(250ml)稀释，用半饱和食盐水(200ml×4)洗涤，有机相用硅胶拌样旋干，用柱层析法纯化(洗脱剂：石油醚∶乙酸乙酯＝4∶1)得到叔丁基(R)-3-((2-氯-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(8.21g，收率：77％)。LCMS(ESI)：m/z 357[M+1]+，淡黄色油状物；TLC：Rf 0.2(石油醚∶乙酸乙酯＝4∶1)。To the reaction flask was added 2,4-dichloro-3-nitropyridine (101) (5.79 g, 30.0 mmol, 1.0 eq.), tert-butyl(R)-3-aminopiperidine-1-carboxylate ( 301) (6.00 g, 30.0 mmol, 1.0 eq.), triethylamine (6.06 g, 60.0 mmol, 2.0 eq.) and N,N-dimethylformamide (50 ml). The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) =4:1) tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (8.21 g, yield: 77%) ). </RTI><RTI ID =0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;
步骤11b：叔丁基(R)-3-((2-(二苄基氨基)-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯((tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate)(化合物303)的制备Step 11b: tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((tert-butyl(R) Preparation of 3-(2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 303)
往反应瓶中加入叔丁基(R)-3-((2-氯-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(302)(8.27g，23.2mmol，1.0当量)，二苄胺(5.94g，30.2mmol，1.3当量)，三乙胺(3.52g，34.8mmol，1.5当量)和乙腈(150ml)，加热回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(洗脱剂：石油醚∶乙酸乙酯＝4∶1)得到叔丁基(R)-3-((2-(二苄基氨基)-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(10.9g，收率：91％)。LCMS(ESI)：m/z 518[M+1]+，黄色油状物；TLC：Rf 0.4(石油醚∶乙酸乙酯＝4∶1)。To the reaction flask was added tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (302) (8.27 g, 23.2 mmol, 1.0 equivalent), dibenzylamine (5.94 g, 30.2 mmol, 1.3 eq.), triethylamine (3.52 g, 34.8 mmol, 1.5 eq.) and acetonitrile (150 ml). The reaction mixture was dried with EtOAc (EtOAc) (EtOAc:EtOAc:EtOAc 3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (10.9 g, yield: 91%). LCMS (ESI): m / z 518 [M + 1] +, as a yellow oil; TLC: Rf 0.4 (petroleum ether: ethyl acetate = 4).
步骤11c：叔丁基(R)-3-((3-氨基-2-(二苄基氨基)吡啶-4-基)氨基)哌啶-1-羧酸酯(tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate)(化合物304)的制备Step 11c: tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (tert-butyl(R)- Preparation of 3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate) (Compound 304)
往锌粉(13.7g，210.0mmol，10.0当量)和氯化铵(11.2g，210.0mmol，10.0当量)的甲醇溶液(250ml)中加入叔丁基(R)-3-((2-(二苄基氨基)-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(303)(10.9g，21.0mmol，1.0当量)，加热至50℃反应半小时。反应液用硅藻土过滤，滤液旋干，用二氯甲烷∶甲醇＝10∶1(100ml)溶解，过滤，有机相旋干得到粗品叔丁基(R)-3-((3-氨基-2-(二苄基氨基)吡啶-4-基)氨基)哌啶-1-羧酸叔丁酯(11.0g，收率：100％)。LCMS(ESI)：m/z 488[M+1]+，淡黄色 固体；TLC：Rf 0.1(石油醚∶乙酸乙酯＝4∶1)。To a solution of zinc powder (13.7 g, 210.0 mmol, 10.0 eq.) and ammonium chloride (11.2 g, 210.0 mmol, 10.0 eq.) in methanol (250 ml), tert-butyl(R)-3-((2-(2) Benzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (303) (10.9 g, 21.0 mmol, 1.0 eq.) was heated to 50 ° C for half an hour. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj tert-Butyl 2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (11.0 g, yield: 100%). LCMS (ESI): m / z 488 [M + 1] +, as a pale yellow solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 4).
步骤11d：叔丁基(R)-3-(4-(二苄基氨基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯((tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-carboxylate)(化合物305)的制备Step 11d: tert-Butyl (R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl Piperidine-1-carboxylate ((tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1 -yl)piperidine-1-carboxylate) (Compound 305) Preparation
往反应瓶中加入叔丁基(R)-3-((3-氨基-2-(二苄基氨基)吡啶-4-基)氨基)哌啶-1-羧酸酯(304)(11.0g，22.5mmol，1.0当量)，N，N′-羰基二咪唑(10.9g，67.5mmol，3.0当量)和四氢呋喃(150ml)，将反应液加热至回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝100∶1)得到叔丁基(R)-3-(4-(二苄基氨基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(9.88g，收率：85％)。LCMS(ESI)：m/z 514[M+1]+，淡黄色液体；TLC：Rf 0.8(二氯甲烷∶甲醇＝80∶1)。To the reaction flask was added tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (304) (11.0 g). , 22.5 mmol, 1.0 eq.), N,N'-carbonyldiimidazole (10.9 g, 67.5 mmol, 3.0 eq.) and THF (150 mL). The reaction mixture was dried with EtOAc (EtOAc) (EtOAc) 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (9.88 g, yield: 85%). LCMS (ESI): m / z 514 [M + 1] +, as a pale yellow liquid; TLC: Rf 0.8 (dichloromethane: methanol = 80:1).
步骤11e：叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(tert-butyl(R)-3-(4-amino-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-carboxylate)(化合物306)的制备Step 11e: tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate Preparation of (Compound 306)
往反应瓶中加入叔丁基(R)-3-(4-(二苄基氨基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(305)(9.88g，19.22mmol，1.0当量)，氢氧化钯(2.0g)，乙醇(120ml)和乙酸乙酯(30ml)，反应液在氢气中加热到60℃过夜。反应混合物用硅藻土过滤，滤液旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝20∶1)得到叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(5.28g，收率：83％)。LCMS(ESI)：m/z 334[M+1]+，无色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1 to the reaction flask. -yl) piperidine-1-carboxylate (305) (9.88 g, 19.22 mmol, 1.0 eq.), palladium hydroxide (2.0 g), ethanol (120 ml) and ethyl acetate (30 ml). Heat to 60 ° C overnight. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness. The purified product was purified by column chromatography (eluent: dichloromethane:methanol = 20:1) to give tert-butyl(R)-3-(4-amino- 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (5.28 g, yield: 83%). LCMS (ESI): m / z 334 [M + 1] +, as a colorless solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤11f：叔丁基(R)-3-(4-氨基-2-氧代-3-(4-苯氧基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸叔丁酯(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)(化合物307-11)的制备Step 11f: tert-Butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5- c]pyridyl-1-yl)piperidine-1-carboxylic acid tert-butyl ester (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) (Compound 307-11)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(3.0g，9.0mmol，1.0当量)，对苯氧基苯硼酸(108-1)(2.89g，13.5mmol，1.5当量)，醋酸铜(1.82g，9.9mmol，1.1当量)，分子筛(3.0g)， 吡啶(2.13g，27mmol，3.0当量)和N，N-二甲基甲酰胺(30ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(200ml)稀释，用半饱和食盐水(150ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝50∶1)得到叔丁基(R)-3-(4-氨基-2-氧代-3-(4-苯氧基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(2.23g，收率：49％)。LCMS(ESI)：m/z 502[M+1]+，黄色油状物；TLC：Rf 0.7(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (3.0 g, 9.0 mmol, 1.0 eq.), p-phenoxyphenylboronic acid (108-1) (2.89 g, 13.5 mmol, 1.5 eq.), copper acetate (1.82 g, 9.9 mmol) , 1.1 equivalents), molecular sieves (3.0 g), pyridine (2.13 g, 27 mmol, 3.0 eq.) and N,N-dimethylformamide (30 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) =50:1) to give 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 (2.23 g, yield: 49%). LCMS (ESI): m / z 502 [M + 1] +, as a yellow oil; TLC: Rf 0.7 (dichloromethane: methanol = 20).
步骤11g：(R)-4-氨基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-11)的制备Step 11g: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c] Preparation of pyridin-2-one) (Compound 308-11)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-3-(4-苯氧基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(307-11)(2.23g，4.45mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，反应液在室温过夜。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(100ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-氨基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(1.3g，收率：73％)。LCMS(ESI)：m/z 402[M+1]+，灰白色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。To the reaction flask was added tert-butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazole [4, 5-c]pyridin-1-yl)piperidine-1-carboxylate (307-11) (2.23 g, 4.45 mmol, 1.0 eq.), dichloromethane (10 ml) and trifluoroacetic acid (2.0 ml) The solution was allowed to stand overnight at room temperature. The reaction solution was poured into a saturated aqueous solution of sodium carbonate (100 ml), and extracted with dichloromethane (100 ml × 2). Purification of methanol (triethylamine = 10:1:0.1) to give (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one (1.3 g, yield: 73%). LCMS (ESI): m / z 402 [M + 1] +, an off-white solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤11h：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物11)的制备Step 11h: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ Preparation of 4,5-c]pyridin-2-one) (Compound 11)
往丙烯酰氯(202-4)(0.25g，3.89mmol，1.2当量)的二氯甲烷溶液(50ml)中0℃下滴加(R)-4-氨基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-11)(1.3g，3.24mmol，1.0当量)的二氯甲烷溶液(30ml)，然后再滴加二异丙基乙基胺(0.63g，4.86mmol，1.5当量)的二氯甲烷溶液(5ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(100ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(二氯甲烷∶甲醇＝40∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.67g，收率：45％)。无色固体，熔点：89.5-91.9℃。TLC：Rf 0.5(二氯甲烷∶ 甲醇＝20∶1)。LCMS(ESI)：m/z 456[M+1]+，1HNMR(CDCl3，500MHz)：δ7.84(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)。Add (R)-4-amino-3-(4-phenoxyphenyl) dropwise to acryloyl chloride (202-4) (0.25 g, 3.89 mmol, 1.2 eq.) in dichloromethane (50 ml). --1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-11) (1.3 g, 3.24 mmol, 1.0 eq. A dichloromethane solution (30 ml) was added dropwise to a solution of diisopropylethylamine (0.63 g, 4.86 mmol, 1.5 eq.) in dichloromethane (5 ml), and reacted at 0 ° C for 5 min. The reaction mixture was poured into water (100 ml), EtOAc (EtOAc) (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4, 5-c]pyridin-2-one (0.67 g, yield: 45%). Colorless solid, melting point: 89.5-91.9 ° C. TLC: Rf 0.5 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 456 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.84 (d, J = 5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (m, 4H), 6.64 (m, 2H), 6.33 (d, J = 16.5 Hz, 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 = 12.5) Hz, 1H), 1.98 (d, J = 13.5 Hz, 1H), 1.69 (m, 1H).
实施例12：(R)-1-(1-丙烯酰基哌啶-3-基)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物13)的制备Example 12: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 13)
步骤12a：叔丁基(R)-3-(4-胺基-3-(4-(4-氯-苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(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)(化合物307-13)的制备Step 12a: tert-Butyl (R)-3-(4-amino-3-(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-chlorophenoxy)phenyl) Preparation of -2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-13)
将2-(4-(4-氯-苯氧基)-苯基)-4，4，5，5-四甲基-1，3，2-二氧代硼烷(108-13)(1.78g，5.39mmol，1.5当量)溶于甲醇(10ml)再加入浓盐酸(1ml)搅拌反应1h后水洗，二氯甲烷萃取，干燥后过滤母液备用，往上述母液中加叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(1.20g，3.59mmol，1当量)，Cu(OAc)2(1.30g，7.18mmol，2当量)，Et3N(0.73g，7.18mmol，2当量)和吡啶(0.57g，7.18mmol，2当量)，室温反应过夜。将反应液水洗，二氯甲烷萃取，干燥后浓缩，用乙酸乙酯/正己烷(3∶1)柱层析得到淡黄色油状物叔丁基(R)-3-(4-胺基-3-(4-(4-氯-苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.77g，收率40.00％)。LCMS(ESI)：m/z 536.50[M+H]+。2-(4-(4-Chloro-phenoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (108-13) (1.78 g, 5.39mmol, 1.5 eq.) dissolved in methanol (10ml) and then added concentrated hydrochloric acid (1ml), stirred for 1h, washed with water, extracted with dichloromethane, dried, filtered, and filtered, and then added to the above mother liquid to add tert-butyl (R)- 3-(4-Amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (306) (1.20 g , 3.59 mmol, 1 eq.), Cu (OAc) 2 (1.30 g, 7.18 mmol, 2 eq.), Et 3 N (0.73 g, 7.18 mmol, 2 eq.) and pyridine (0.57 g, 7.18 mmol, 2 eq.). The reaction was carried out at room temperature overnight. The reaction mixture was washed with water and dried with CH~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 - Carboxylic ester (0.77 g, yield 40.00%). LCMS (ESI): m / z 536.50 [M + H] +.
步骤12b：(R)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1-(吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-13)的制备Step 12b: (R)-4-Amino-3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazole [4,5-c]pyridin-2-one ((R)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro- Preparation of 2H-imidazo[4,5-c]pyridin-2-one) (Compound 308-13)
将叔丁基(R)-3-(4-胺基-3-(4-(4-氯-苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(307-13)(0.77g，1.44mmol，1当量)溶于二氯甲 烷(5ml)，加入TFA(2.5ml)，室温反应1h。反应液浓缩，饱和碳酸氢钠中和至稍偏碱性，用5ml二氯甲烷萃取，干燥，浓缩，甲醇/二氯甲烷/三乙胺(1∶10∶0.3)柱层析得类白色泡沫状固体(R)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1-(吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(325mg，收率52.08％)。LCMS(ESI)：m/z 436.10[M+H]+。tert-Butyl (R)-3-(4-amino-3-(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (307-13) (0.77 g, 1.44 mmol, 1 eq.) was dissolved in dichloromethane (5 ml). ), reacted at room temperature for 1 h. The reaction mixture was concentrated, neutralized with saturated sodium bicarbonate to a little basic, extracted with 5 ml of dichloromethane, dried, concentrated, and purified by column chromatography with methanol / methylene chloride / triethylamine (1:10:0.3). (R)-4-Amino-3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one (325 mg, yield 52.08%). LCMS (ESI): m / z 436.10 [M + H] +.
步骤12c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物13)的制备Step 12c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-chlorophenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 13) Preparation
将丙烯酰氯(202-4)(81mg，0.90mmol，1.2当量)溶于二氯甲烷(10ml)，冰盐浴下滴加(R)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1-(吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-13)(325mg，0.75mmol，1当量)的二氯甲烷(5ml)溶液，最后加入DIEA(116mg，0.90mmol，1.2当量)的二氯甲烷(5ml)溶液，反应10分钟。加水(40ml)搅拌，二氯甲烷(20ml)萃取，有机相再用水(20ml)洗涤一次，干燥，浓缩，甲醇/二氯甲烷(1∶20)和甲醇/乙酸乙酯(1∶20)柱层析两次得白色固体(R)-1-(1-丙烯酰基哌啶-3-基)-4-胺基-3-(4-(4-氯苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(66mg，收率18％)，含量100％，熔点：90-92℃；LCMS(ESI)：m/z 490.05[M+H]+；1HNMR(400MHz，CDCl3)：δ2.03(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)Acryloyl chloride (202-4) (81 mg, 0.90 mmol, 1.2 eq.) was dissolved in dichloromethane (10 ml), and (R)-4-amino-3-(4-(4-chloro) Phenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-13) (325 mg, 0.75 A solution of mmol (1 eq.) in dichloromethane (5 mL), EtOAc (EtOAc) Add water (40 ml), stir with dichloromethane (20 ml), then dry with EtOAc (EtOAc) (EtOAc) Chromatography twice to give (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1 as a white solid. 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (66 mg, yield 18%), 100%, m.p.: 90-92 C; LCMS (ESI): m/z [M+H] + ; 1 H NMR (400MHz, CDCl 3 ): δ 2.03 (d, J = 30.0 Hz, 1.5H), 2.10 (d, J = 23.7 Hz, 1H), 2.60 (m, 1.5H) , 3.13 (s, 0.5H), 3.46 (s, 1H), 3.86 (d, J = 37.0 Hz, 0.5H), 4.10 (s, 4H), 4.81 (d, J = 30.0 Hz, 1H), 5.34 ( t, J = 11.0 Hz, 0.5H), 5.73 (d, J = 21.6 Hz, 1H), 6.32 (d, J = 40 Hz, 1H), 6.63 (d, J = 12.6 Hz, 2H), 7.03 (d, J = 22.1 Hz, 2H), 7.11 (d, J = 22.1 Hz, 2H), 7.35 (d, J = 22.1 Hz, 2H), 7.41 (d, J = 21.9 Hz, 2H), 7.87 (d, J = 14.0 Hz, 1H)
实施例13：(R)-4-(4-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-2-氧代-1，2-二氢-3H-咪唑并[4，5-c]吡啶-3-基)苯氧基)苯腈((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)(化 合物15)的制备Example 13: (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 ((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) Preparation of compound 15)
步骤13a：叔丁基(R)-3-(4-氨基3-(4-(4-氰基苯氧基))-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(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)(化合物307-15)的制备Step 13a: tert-Butyl (R)-3-(4-amino-3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(4-cyanophenoxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-15)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(1.0g，3.0mmol，1.0当量)，4-(4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苯氧基)苯腈(108-15)(1.25g，3.9mmol，1.3当量)，醋酸铜(0.60g，3.3mmol，1.1当量)，分子筛(1.0g)，吡啶(0.71g，9.0mmol，3.0当量)和N，N-二甲基甲酰胺(15ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(200ml)稀释，用半饱和食盐水(100ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝50∶1)得到叔丁基(R)-3-(4-氨基3-(4-(4-氰基苯氧基))-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.36g，收率：23％)。LCMS(ESI)：m/z 527[M+1]+，浅绿色油状物；TLC：Rf 0.6(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (1.0 g, 3.0 mmol, 1.0 equivalent), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Alkan-2-yl)phenoxy)benzonitrile (108-15) (1.25 g, 3.9 mmol, 1.3 eq.), copper acetate (0.60 g, 3.3 mmol, 1.1 eq.), molecular sieve (1.0 g), pyridine (0.71) g, 9.0 mmol, 3.0 eq.) and N,N-dimethylformamide (15 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) =50:1) to give tert-butyl(R)-3-(4-amino3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.36 g, yield: 23%). LCMS (ESI): m / z 527 [M + 1] +, pale green oil; TLC: Rf 0.6 (dichloromethane: methanol = 20).
步骤13b：(R)-4-(4-(4-氨基-2-氧代-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-3(2H)-基)苯氧基)苯腈((R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4，5-c]pyridin-3(2H)-yl)phenoxy)benzonitrile)(化合物308-15)的制备Step 13b: (R)-4-(4-(4-Amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-3(2H) -Phenyloxy)benzonitrile ((R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin- Preparation of 3(2H)-yl)phenoxy)benzonitrile) (Compound 308-15)
往反应瓶中加入叔丁基(R)-3-(4-氨基3-(4-(4-氰基苯氧基))-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(307-15)(0.36g，0.68mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，室温反应过夜。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(50ml×3)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-(4-(4-氨基-2-氧代-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-3(2H)-基)苯氧基)苯腈(0.122g，收率：42％)。LCMS(ESI)：m/z 427[M+1]+，无色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。To the reaction flask was added tert-butyl(R)-3-(4-amino3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazole [ 4,5-c]pyridin-1-yl)piperidine-1-carboxylate (307-15) (0.36 g, 0.68 mmol, 1.0 eq.), dichloromethane (10 ml) and trifluoroacetic acid (2.0 ml) Reactive overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of sodium carbonate (100 ml), and extracted with dichloromethane (50 ml × 3). Purification of methanol (triethylamine = 10:1:0.1) gave (R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4 , 5-c]pyridine-3(2H)-yl)phenoxy)benzonitrile (0.122 g, yield: 42%). LCMS (ESI): m / z 427 [M + 1] +, as a colorless solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤13c：(R)-4-(4-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-2-氧代-1，2-二氢-3H-咪唑并[4，5-c]吡啶-3-基)苯氧基)苯腈((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-ami no-2-oxo-1，2-dihydro-3H-imidazo[4，5-c]pyridin-3-yl)phenoxy)benzonitrile)(化合物15)的制备Step 13c: (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 ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-ami) Preparation of no-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrile) (Compound 15)
往丙烯酰氯(202-4)(0.032g，0.35mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-(4-(4-氨基-2-氧代-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-3(2H)-基)苯氧基)苯腈(308-15)(0.122g，0.29mmol，1.0当量)的二氯甲烷溶液(7ml)，然后再滴加二异丙基乙基胺(0.056g，0.44mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝40∶1)得到(R)-4-(4-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-2-氧代-1，2-二氢-3H-咪唑并[4，5-c]吡啶-3-基)苯氧基)苯腈(0.052g，收率：38％)。白色固体，熔点：116.1-118.7℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 481[M+1]+，1HNMR(CDCl3，500MHz)：δ7.89(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)。Add (R)-4-(4-(4-amino-2-oxo) to acryloyl chloride (202-4) (0.032 g, 0.35 mmol, 1.2 eq.) in dichloromethane (7 ml). 1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-3(2H)-yl)phenoxy)benzonitrile (308-15) (0.122 g, 0.29 mmol, A solution of 1.0% by weight of dichloromethane (7 ml) was then added dropwise to dichloromethane (1 ml) of diisopropylethylamine (0.056 g, 0.44 mmol, 1.5 eq.), and reacted at 0 ° C for 5 min. The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 40:1) to give (R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1,2-dihydro-3H-imidazole [4,5-c]pyridin-3-yl)phenoxy)benzonitrile (0.052 g, yield: 38%). White solid, melting point: 116.1-118.7 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 481 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.89 (d, J = 5Hz, 1H), 7.67 (d, J = 8.5Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.66 (m, 2H), 6.34 (d, J = 16.5) Hz, 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).
实施例14：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-苯基吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物16)的制备Example 14: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H- Imidazo[4,5-c]pyridin-2-one ((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
步骤13a：叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苯氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯((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)(化合物307-16)的制备Step 13a: 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 ((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) (Compound 307-16)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(0.666g，2.0mmol，1.0当量)，2-苯氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)吡啶(108-16)(0.891g，3.0mmol，1.5当量)，醋酸 铜(0.400g，2.2mmol，1.1当量)，分子筛(0.500g)，吡啶(0.474g，6.0mmol，3.0当量)和N，N-二甲基甲酰胺(8ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝60∶1)得到叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苯氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.520g，收率：52％)。LCMS(ESI)：m/z 503[M+1]+，黄色油状物；TLC：Rf 0.7(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (0.666 g, 2.0 mmol, 1.0 equivalent), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclic pentan-2-yl)pyridine (108-16) (0.891 g, 3.0 mmol, 1.5 eq.), copper acetate (0.400 g, 2.2 mmol, 1.1 eq.), molecular sieve (0.500 g), pyridine (0.474 g, 6.0 mmol, 3.0 eq.) and N,N-dimethylformamide (8 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with ethyl acetate (100 ml), washed with EtOAc EtOAc (EtOAc) =60:1) to give tert-butyl(R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazole And [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.520 g, yield: 52%). LCMS (ESI): m / z 503 [M + 1] +, as a yellow oil; TLC: Rf 0.7 (dichloromethane: methanol = 20).
步骤13b：(R)-4-氨基-3-(6-苯氧基吡啶-3-基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-16)的制备Step 13b: (R)-4-Amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-16)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苯氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.52g，1.0mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，反应液室温过夜。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-氨基-3-(6-苯氧基吡啶-3-基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.215g，收率：53％)。LCMS(ESI)：m/z 403[M+1]+，灰白色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazole to the reaction flask. [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.52 g, 1.0 mmol, 1.0 eq.), dichloromethane (10 ml) and trifluoroacetic acid (2.0 ml) overnight. The reaction solution was poured into a saturated sodium carbonate solution (100 ml), and extracted with dichloromethane (50 ml × 2). Purification of methanol (triethylamine = 10:1:0.1) gave (R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1, 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.215 g, yield: 53%). LCMS (ESI): m / z 403 [M + 1] +, an off-white solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤13c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-苯基吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物16)的制备Step 13c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H-imidazole And [4,5-c]pyridin-2-one ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-phenyl pyridin-3-yl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 16)
往丙烯酰氯(202-4)(0.059g，0.65mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(6-苯氧基吡啶-3-基)-1-(哌啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-16)(0.215g，0.54mmol，1.0当量)的二氯甲烷溶液(7ml)，然后再滴加二异丙基乙基胺(0.104g，0.81mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝30∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-苯基吡啶-3-基)-1，3-二氢-2H-咪 唑并[4，5-c]吡啶-2-酮(0.083g，收率：34％)。无色固体，熔点：107.9-109.9℃。TLC：Rf0.7(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 457[M+1]+，1HNMR(CDCl3，500MHz)：δ8.29(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)。To a solution of acryloyl chloride (202-4) (0.059 g, 0.65 mmol, 1.2 eq.) in dichloromethane (7 ml), (R)-4-amino-3-(6-phenoxypyridine- 3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-16) (0.215 g, 0.54 mmol , 1.0 eq.) of dichloromethane (7 ml), then a solution of diisopropylethylamine (0.104 g, 0.81 mmol, 1.5 eq.) in dichloromethane (1 ml). . The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 30:1) to give (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H - Imidazo[4,5-c]pyridin-2-one (0.083 g, yield: 34%). Colorless solid, melting point: 107.9-109.9 ° C. TLC: Rf 0.7 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 457 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ8.29 (s, 1H), 7.89 (d, 1H), 7.78 (t, J = 6Hz, 2H ), 7.42 (m, 2H), 7.24 (m, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.05 (d, J = 9 Hz, 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).
实施例15：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物17)的制备Example 15: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)- 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-( Preparation of benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 17)
步骤15a：叔丁基(R)-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(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)(化合物402-17)的制备Step 15a: tert-Butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] Pyridyl) piperidine-1-carboxylate (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)
将叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(2.5g，7.50mmol，1.0当量)、对碘苯硼酸(401-17)(2.14g，8.62mmol，1.3当量)和吡啶(1.78g，22.5mmol，3.0当量)溶于N，N-二甲基甲酰胺(20mL)中，再加入醋酸铜(1.50g，8.25mmol，1.1当量)和4A分子筛(3.0g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(100mL)稀释，过滤，滤液用半饱和食盐水(50mL×4)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得叔丁基(R)-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(1.6g，收率：40％)。棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 536[M+1]+。tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate Acid ester (306) (2.5 g, 7.50 mmol, 1.0 eq.), p-iodobenzeneboronic acid (401-17) (2.14 g, 8.62 mmol, 1.3 eq.) and pyridine (1.78 g, 22.5 mmol, 3.0 eq.) dissolved in N Further, N-dimethylformamide (20 mL) was further added with copper acetate (1.50 g, 8.25 mmol, 1.1 eq.) and 4A molecular sieve (3.0 g), and then reacted in air at 50 ° C overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL) and filtered. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated tolulujjjjjjjjjj -3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine-1-carboxylate (1.6 g, yield :40%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤15b：叔丁基(R)-3-(4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1，3]dioxol-5-yloxy)phenyl)-2-oxo-2，3-dihydro-1H-im idazo[4，5-c]pyridin-1-yl)piperidine-1-carboxylate)(化合物307-17)的制备Step 15b: tert-Butyl (R)-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridine)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1, 3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-im Preparation of idazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-17)
将叔丁基(R)-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(402-17)(0.8g，1.49mmol，1.0当量)、芝麻酚(403-17)(0.31g，2.24mmol，1.5当量)和N，N-二甲基甘氨酸盐酸盐(39mg，0.28mmol，0.18当量)溶于二氧六环(8mL)中，再加入碘化亚铜(14.2mg，0.075mmol，0.05当量)和碳酸铯(0.97g，2.98mmol，2.0当量)，然后在氮气保护中100℃反应24小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(洗脱剂：二氯甲烷∶甲醇＝40∶1到20∶1)纯化得叔丁基(R)-3-(4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(0.35g，收率：44％)。灰色固体；TLC：Rf0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 546[M+1]+。tert-Butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) Piperidine-1-carboxylate (402-17) (0.8 g, 1.49 mmol, 1.0 eq.), sesame phenol (403-17) (0.31 g, 2.24 mmol, 1.5 eq.) and N,N-dimethylglycine Hydrochloride (39 mg, 0.28 mmol, 0.18 eq.) was dissolved in dioxane (8 mL), then cuprous iodide (14.2 mg, 0.075 mmol, 0.05 eq.) and cesium carbonate (0.97 g, 2.98 mmol, 2.0) Equivalent), then reacted at 100 ° C for 24 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature and concentrated, and the obtained crude product is purified by column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give tert-butyl(R)-3-(4- Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) Pyridine-1-carboxylate (0.35 g, yield: 44%). </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤15c：(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((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)(化合物308-17)的制备Step 15c: (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4 ,5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(piperidin Preparation of -3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one) (Compound 308-17)
将叔丁基(R)-3-(4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(307-17)(0.35g，0.64mmol，1.0当量)溶于二氯甲烷(10mL)中，再向其中加入三氟乙酸(2mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(50mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.26g，收率：91％)。灰色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 446[M+1]+。tert-Butyl (R)-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H -Imidazo[4,5-c]pyridine)piperidine-1-carboxylate (307-17) (0.35 g, 0.64 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). Fluorineacetic acid (2 mL) was then reacted at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (50 mL), washed successively with saturated sodium carbonate (30 mL×2) and brine (60 mL). (eluent: dichloromethane:methanol:triethylamine=100:10:1) was purified to give (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy) Phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.26 g, yield: 91%). </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤15d：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amin o-3-(4-(benzo[d][1，3]dioxol-5-yloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物17)的制备Step 15d: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1 ,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amin o-3-(4-( Preparation of benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 17)
将丙烯酰氯(202-4)(0.057mL，0.7mmol，1.2当量)溶于二氯甲烷(5mL)中，冷却到0℃，然后向其中逐滴滴加(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基) -1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-17)(0.26g，0.584mmol，1.0当量)的二氯甲烷(5mL)溶液，接着再逐滴滴加N，N-二异丙基乙胺(0.156mL，0.876mmol，1.5当量)的二氯甲烷(1.0mL)溶液，将该混合液在0℃反应10分钟。将反应液用水(50mL)猝灭，然后用二氯甲烷(50mL×2)萃取。将得到的有机层用硅胶拌样旋干，之后用柱层析法(洗脱剂：二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.170g，收率：58％)。白色固体，熔点：194.5-195.6℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 500[M+1]+，纯度：97.054％；1HNMR(CDCl3，500MHz)：δ7.86(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)。Acryloyl chloride (202-4) (0.057 mL, 0.7 mmol, 1.2 eq.) was dissolved in dichloromethane (5 mL), cooled to 0 ° C, then (R)-4-amino-3- (4-(3,4-Methylenedioxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (308-17) (0.26 g, 0.584 mmol, 1.0 eq.) in dichloromethane (5 mL) EtOAc EtOAc (EtOAc) A solution of dichloromethane (1.0 mL) was taken and the mixture was reacted at 0 ° C for 10 min. The reaction solution was quenched with water (50 mL) and then evaporated. The obtained organic layer was spin-dried with silica gel, and then purified by column chromatography (eluent: dichloromethane:methanol = 50:1) to give compound (R)-1-(1-acryloylpiperidine- 3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c] Pyridin-2-one (0.170 g, yield: 58%). White solid, melting point: 194.5-195.6 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 500[M+1] + , purity: 97.054%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.86 ( d, J = 5.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 8.5 Hz, 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).
实施例16：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-羟基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物18)的制备Example 16: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydrogen -2H-Imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 18) Preparation
步骤16a：叔丁基(R)-3-(4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯((R)-tert-butyl 3-(4-amino-3-(4-(4-(benzylox y)phenoxy)phenyl)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-c arboxylate)(化合物307-18)的制备Step 16a: tert-Butyl (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridine)piperidine-1-carboxylate ((R)-tert-butyl 3-(4-amino-3-(4-(benzylox y)phenoxy)phenyl) Preparation of -2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-c arboxylate) (Compound 307-18)
将叔丁基(R)-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(402-17)(0.7g，1.31mmol，1.0当量)、4-苄氧基苯酚(403-18)(0.39g，1.96mmol，1.5当量)和N，N-二甲基甘氨酸盐酸盐(34mg，0.24mmol，0.18当量)溶于二氧六环(10mL)中，再加入碘化亚铜(12.5mg，0.066mmol，0.05当量)和碳酸铯(0.85g，2.62mmol，2.0当量)，然后在氮气保护中100℃反应20小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(洗脱剂：二氯甲烷∶甲醇＝40∶1到20∶1)纯化得叔丁基(R)-3-(4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-2- 氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(0.4g，收率：50％)。淡黄色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 608[M+1]+。tert-Butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) Piperidine-1-carboxylate (402-17) (0.7 g, 1.31 mmol, 1.0 eq.), 4-benzyloxyphenol (403-18) (0.39 g, 1.96 mmol, 1.5 eq.) and N,N- Dimethylglycine hydrochloride (34 mg, 0.24 mmol, 0.18 eq.) was dissolved in dioxane (10 mL), and then cuprous iodide (12.5 mg, 0.066 mmol, 0.05 eq.) and cesium carbonate (0.85 g, 2.62 mmol, 2.0 eq.), then reacted at 100 ° C for 20 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature and concentrated, and the obtained crude product is purified by column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give tert-butyl(R)-3-(4- Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine-1 - Carboxylic ester (0.4 g, yield: 50%). </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤16b：(R)-4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(4-(4-(benzyloxy)phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4，5-c]pyridin-2(3H)-one)(化合物308-18)的制备Step 16b: (R)-4-Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c Pyridine-2(3H)-one ((R)-4-amino-3-(4-(4-(benzyloxy)phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4, Preparation of 5-c]pyridin-2(3H)-one) (Compound 308-18)
将叔丁基(R)-3-(4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶-1-羧酸酯(307-18)(0.40g，0.658mmol，1.0当量)溶于二氯甲烷(10mL)中，再向其中加入三氟乙酸(2mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(50mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.305g，收率：91％)。灰色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 508[M+1]+。tert-Butyl (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazole [4,5-c]pyridine)piperidine-1-carboxylate (307-18) (0.40 g, 0.658 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). 2 mL), then reacted at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (50 mL), washed successively with saturated sodium carbonate (30 mL×2) and brine (60 mL). (eluent: dichloromethane:methanol:triethylamine=100:10:1) was purified to give (R)-4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)- 1-(3-Piperidinyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.305 g, yield: 91%). </RTI><RTIID=0.0></RTI></RTI><RTIgt;
步骤16c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-羟基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物18)的制备Step 16c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 18)
将(R)-4-氨基-3-(4-(4-苄氧基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-18)(0.305g，0.6mmol，1.0当量)溶于乙醇(10mL)中，再向其中加入钯/碳(100mg)，然后在氢气球的气氛下40℃反应过夜。反应液冷却到室温后过滤，收集滤液浓缩得到粗产品，用柱层析法(洗脱剂：二氯甲烷∶甲醇＝10∶1)纯化得(R)-4-氨基-3-(4-(4-羟基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.22g，收率：88％)。灰色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝8∶1)；LCMS(ESI)：m/z 418[M+1]+。将上述所得的(R)-4-氨基-3-(4-(4-羟基苯氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.2g，0.48mmol，1.0当量)、丙烯酸(201-18)(38mg，0.53mmol，1.1当量)、DCC(119mg，0.58mm ol，1.2当量)和DMAP(6mg，0.048mmol，0.1当量)溶于二氯甲烷(10mL)，然后在0℃下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(洗脱剂： 二氯甲烷∶甲醇＝40∶1)纯化得化合(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-羟基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(83mg，收率：37％)。白色固体，熔点：196.3-198.2℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；LCMS(E SI)：m/z 471[M+1]+，纯度：96.893％；1HNMR(CDCl3，500MHz)：δ7.86(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)。(R)-4-Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine -2(3H)-one (308-18) (0.305 g, 0.6 mmol, 1.0 eq.) was dissolved in ethanol (10 mL), and then palladium/carbon (100 mg) was added thereto, then 40 ° C under a hydrogen balloon atmosphere. The reaction was overnight. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to afford (R)-4-amino-3-(4- (4-Hydroxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.22 g, yield: 88% ). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; (R)-4-Amino-3-(4-(4-hydroxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c] obtained above Pyridine-2(3H)-one (0.2g, 0.48mmol, 1.0 eq.), acrylic acid (201-18) (38mg, 0.53mmol, 1.1 eq.), DCC (119mg, 0.58mm ol, 1.2 eq.) and DMAP (6mg) , 0.048 mmol, 0.1 eq.) was dissolved in dichloromethane (10 mL) and then reacted at 0 ° C for 1 hour. After the reaction is completed, it is concentrated to give a crude product which is purified by column chromatography (eluent: methylene chloride:methanol = 40:1) to yield (R)-1-(1-propionylpiperidin-3-yl)- 4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (83 mg, yield: 37%). White solid, melting point: 196.3-198.2 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1); LCMS (ESI): m/z 471[M+1] + , purity: 96.893%; 1 H NMR (CDCl 3 , 500 MHz): δ 7.86 (d, J = 5.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.81 (d , J=8.5Hz, 2H), 6.66-6.59(m, 2H), 6.34(d, J=15Hz, 1H), 5.75-5.73(m,1H), 4.83-4.78(m,1H), 4.19(s , 2H), 4.13-4.07 (m, 2H), 3.85-3.47 (m, 1H), 3.14 - 2.59 (m, 2H), 2.12-1.96 (m, 3H).
实施例17：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物19)的制备Example 17: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 19)
步骤17a：叔丁基(R)-3-(4-氨基3-(4-羟基苯基)-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(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)(化合物502-19)的制备Step 17a: tert-Butyl (R)-3-(4-amino-3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine- 1-yl) piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 502-19) Preparation
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(3.0g，9.0mmol，1.0当量)，4-羟基苯硼酸(501-19)(1.62g，11.7mmol，1.3当量)，醋酸铜(1.820g，10mmol，1.1当量)，分子筛(3.0g)，吡啶(2.13g，27.0mmol，3.0当量)和N，N-二甲基甲酰胺(30ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(200ml)稀释，用半饱和食盐水(200ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝20∶1)得到叔丁基(R)-3-(4-氨基3-(4-羟基苯基)-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.240g，收率：6％)。LCMS(ESI)：m/z 426[M+1]+，黄色油状物；TLC：Rf 0.35(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (3.0 g, 9.0 mmol, 1.0 eq.), 4-hydroxyphenylboronic acid (501-19) (1.62 g, 11.7 mmol, 1.3 eq.), copper acetate (1.820 g, 10 mmol, 1.1 Equivalent), molecular sieve (3.0 g), pyridine (2.13 g, 27.0 mmol, 3.0 eq.) and N,N-dimethylformamide (30 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) =20:1) to give tert-butyl(R)-3-(4-amino-3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c Pyridin-1-yl)piperidine-1-carboxylate (0.240 g, yield: 6%). LCMS (ESI): m / z 426 [M + 1] +, as a yellow oil; TLC: Rf 0.35 (dichloromethane: methanol = 20).
步骤17b：叔丁基(R)-3-(4-氨基-3-(4-(4-硝基苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶啶-1-羧酸酯(tert-butyl(R)3-(4-amino-3-(4-(4-nitro  phenoxy)phenyl)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-car boxylate)(化合物307-19)的制备Step 17b: tert-Butyl (R)-3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazole And [4,5-c]pyridin-1-yl)piperidinidine-1-carboxylate (tert-butyl(R)3-(4-amino-3-(4-(4-nitro Preparation of phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-car boxylate) (Compound 307-19)
往反应瓶中加入得到叔丁基(R)-3-(4-氨基3-(4-羟基苯基)-2氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(502-19)(0.240g，0.56mmol，1.0当量)，对氟硝基苯(503-19)(0.088g，0.62mmol，1.1当量)，碳酸钾(0.116g，0.84mmol，1.5当量)和乙腈(15ml)，将反应液加热回流过夜。将反应液用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇＝40∶1)纯化得到叔丁基(R)-3-(4-氨基-3-(4-(4-硝基苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶啶-1-羧酸酯(0.270g，收率：89％)。LCMS(ESI)：m/z 547[M+1]+，黄色油状物；TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。Adding to the reaction flask gives tert-butyl(R)-3-(4-amino-3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c Pyridin-1-yl)piperidine-1-carboxylate (502-19) (0.240 g, 0.56 mmol, 1.0 eq.), p-fluoronitrobenzene (503-19) (0.088 g, 0.62 mmol, 1.1 eq. Potassium carbonate (0.116 g, 0.84 mmol, 1.5 eq.) and acetonitrile (15 mL). The reaction mixture was dried with EtOAc (EtOAc) (EtOAc) (4-(4-Nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 - Carboxylic ester (0.270 g, yield: 89%). LCMS (ESI): m / z 547 [M + 1] +, as a yellow oil; TLC: Rf 0.5 (methylene chloride: methanol = 20).
步骤17c：(R)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4，5-c]pyridin-2(3H)-one)(化合物308-19))的制备Step 17c: (R)-4-Amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c Pyridine-2(3H)-one ((R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c Preparation of pyridin-2(3H)-one) (Compound 308-19))
往反应瓶中加入叔丁基(R)-3-(4-氨基-3-(4-(4-硝基苯氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶啶-1-羧酸酯(307-19)(0.27g，0.5mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，室温反应半小时。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(50mi×3)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.220g，收率：99％)。LCMS(ESI)：m/z 447[M+1]+，无色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H to the reaction flask. -Imidazo[4,5-c]pyridin-1-yl)piperidinidine-1-carboxylate (307-19) (0.27 g, 0.5 mmol, 1.0 eq.), dichloromethane (10 ml) Acetic acid (2.0 ml) was reacted at room temperature for half an hour. The reaction solution was poured into a saturated aqueous solution of sodium carbonate (100 ml), and extracted with dichloromethane (50 mi×3). Purification of methanol (triethylamine = 10:1:0.1) to give (R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl) -1H-imidazo[4,5-c]pyridine-2(3H)-one (0.220 g, yield: 99%). LCMS (ESI): m / z 447 [M + 1] +, as a colorless solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤17d：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物19)的制备Step 17d: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 19) Preparation
往丙烯酰氯(202-4)(0.054g，0.60mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-19)(0.220g，0.50mmol，1.0当量)的二氯甲烷溶液(7ml)，然后再滴 加二异丙基乙基胺(0.097g，0.75mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝30∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-硝基苯氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.170g，收率：68％)。黄色固体，熔点：92.6-98.6℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 501[M+1]+，1HNMR(CDCl3，500MHz)：δ8.27(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)。Add (R)-4-amino-3-(4-(4-nitro) to acryloyl chloride (202-4) (0.054 g, 0.60 mmol, 1.2 eq.) in dichloromethane (7 ml). Phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (308-19) (0.220 g, 0.50 mmol, A solution of 1.0% by weight of dichloromethane (7 ml) was added dropwise to dichloromethane (1.sub.1 g, EtOAc, EtOAc (EtOAc) The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 30:1) to give (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.170 g, yield: 68%). Yellow solid, melting point: 92.6-98.6 °C. TLC: Rf 0.5 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 501 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ8.27 (d, J = 9Hz, 2H), 7.89 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 7.14 (d, J = 9 Hz, 2H), 6.67 (m, 2H), 6.34 (d, J = 17 Hz, 1H), 5.74 (d , J=7.5 Hz, 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 = 12 Hz, 1H), 1.99 (d, J = 13 Hz, 1H), 1.66 (m, 1H).
实施例18：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(苄基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物24)的制备Example 18: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H -(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3 -dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 24) Preparation
步骤18a：叔丁基(R)-3-(4-氨基-3-(4-(苄基氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯((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)(化合物602-24)的制备Step 18a: 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 ((tert-butyl(R)-3-(4-amino-3-(4-(benzyloxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 602-24)
将叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(500mg，1.5mmol，1当量)溶于二氯甲烷(5ml)，依次加入4A分子筛(1g)、醋酸铜(408mg，2.25mmol，1.5当量)、苄氧基苯硼酸(601-24)(410mg，1.8mmol，1.2当量)、吡啶(178mg，2.25mmol，1.5当量)、Et3N(227mg，2.25mmo l，1.5当量)，室温搅拌24小时。反应完毕，过滤，母液水洗两遍，干燥，浓缩，甲醇/二氯甲烷(1∶40)柱层析得黄棕色固体叔丁基(R)-3-(4-氨基-3-(4-(苄基氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(350mg，收率45.3％)。LCMS(ESI)：m/z 516.40[M+1]+。 tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate The acid ester (306) (500 mg, 1.5 mmol, 1 eq.) was dissolved in dichloromethane (5 ml), then 4A molecular sieves (1 g), copper acetate (408 mg, 2.25 mmol, 1.5 equivalents), benzyloxybenzeneboronic acid (601) -24) (410 mg, 1.8 mmol, 1.2 eq.), pyridine (178 mg, 2.25 mmol, 1.5 eq.), Et3N (227 mg, 2.25 mmol, 1.5 eq.). After completion of the reaction, the mixture was filtered, and the mother liquid was washed twice with water, dried, concentrated, and then purified by methanol/dichloromethane (1:40) to give a yellow brown solid t-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 (350 mg, The yield was 45.3%). LCMS (ESI): m / z 516.40 [M + 1] +.
步骤18b：(R)-4-胺基-3-(4-(苄氧基)苯基)-1-[哌啶-3-基]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-(benzyloxy)phenyl)-1-[(piperidin-3-yl]-1，3-dihydro-imidazo[4，5-c]pyridin-2-one)(化合物603-24)的制备Step 18b: (R)-4-Amino-3-(4-(benzyloxy)phenyl)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((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
叔丁基(R)-3-(4-氨基-3-(4-(苄基氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(602-24)(350mg，0.68mmol，1当量)溶于二氯甲烷(1ml)，加入TFA(2ml)，室温反应1h。反应液浓缩，饱和碳酸氢钠中和至稍偏碱性，用5ml二氯甲烷萃取，干燥，浓缩，甲醇/二氯甲烷/三乙胺(1∶10∶0.3)柱层析得类白色泡沫状固体(R)-4-胺基-3-(4-(苄氧基)苯基)-1-[哌啶-3-基]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(90mg，收率32％)。LCMS(ESI)：m/z 416.40[M+1]+。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 (602-24) (350 mg, 0.68 mmol, 1 eq.) was dissolved in dichloromethane (1 mL). The reaction mixture was concentrated, neutralized with saturated sodium bicarbonate to a little basic, extracted with 5 ml of dichloromethane, dried, concentrated, and purified by column chromatography with methanol / methylene chloride / triethylamine (1:10:0.3). (R)-4-Amino-3-(4-(benzyloxy)phenyl)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4, 5-c]pyridin-2-one (90 mg, yield 32%). LCMS (ESI): m / z 416.40 [M + 1] +.
步骤18c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(苄基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(be nzyl)oxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物24)的制备Step 18c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H- Iso[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(be nzyl)oxy)phenyl)-1 , 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 24) Preparation
将丙烯酰氯(202-4)(24mg，0.26mmol，1.2当量)溶于二氯甲烷(4ml)，冰浴下加入(R)-4-胺基-3-(4-(苄氧基)苯基)-1-[哌啶-3-基]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(603-24)(90mg，0.217mmol，1当量)的二氯甲烷(4ml)溶液，最后加入DIE A(34mg，0.26mmol，1.2当量)的二氯甲烷(2ml)溶液，反应10分钟。加水(5ml)搅拌，二氯甲烷(2ml)萃取，有机相再用水(10ml)洗涤一次，干燥，浓缩，甲醇/乙酸乙酯(1∶10)柱层析得白色固体(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(苄基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(19.4mg，收率19％)。熔点：75-76℃；LCMS(ESI)：m/z 470.50[M+1]+；1HNMR(600MHz，CDCl3)：δ1.27(s，1.5H)，2.02(m，1.5H)，2.12(s，1H)，2.51(d，J＝10.74Hz，0.5H)，2.63(dd，J＝26.34，11.88Hz，1H)，3.14(t，J＝11.94Hz，0.5H)，3.49(t，J＝11.46Hz，0.5H)，3.86(t，J＝10.86Hz，0.5H)，4.08(t，J＝28.56Hz，3.5H)，4.22(s，0.5H)，4.84(d d，J＝34.98，10.68Hz，1H)，5.14(s，2H)，5.74(d，J＝9.96Hz，1H)，6.34(t，J＝15.9Hz，1H，)，6.65(m，2H)，7.14(d，J＝8.64Hz，2H，)，7.38(t，J＝8.64Hz，3H)，7.43(q，J＝7.32Hz，2H)，7.46(d，J＝7.32Hz，2H)，7.87(s，1H)。 Acryloyl chloride (202-4) (24 mg, 0.26 mmol, 1.2 eq.) was dissolved in dichloromethane (4 ml) and (R)-4-amino-3-(4-(benzyloxy)benzene -1 [piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (603-24) (90 mg, 0.217 mmol, 1 eq. A solution of dichloromethane (4 ml) was added and a solution of DIE A (34 mg, 0.26 mmol, 1.2 eq. The mixture was stirred with EtOAc (EtOAc) (EtOAc) (1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c] Pyridin-2-one (19.4 mg, yield 19%). Melting point: 75-76 ℃; LCMS (ESI) : m / z 470.50 [M + 1] +; 1 HNMR (600MHz, CDCl 3): δ1.27 (s, 1.5H), 2.02 (m, 1.5H), 2.12(s, 1H), 2.51 (d, J = 10.74 Hz, 0.5H), 2.63 (dd, J = 26.34, 11.88 Hz, 1H), 3.14 (t, J = 1.94 Hz, 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, 10.68 Hz, 1H), 5.14 (s, 2H), 5.74 (d, J = 9.96 Hz, 1H), 6.34 (t, J = 15.9 Hz, 1H,), 6.65 (m, 2H), 7.14 (d) , J = 8.64 Hz, 2H,), 7.38 (t, J = 8.64 Hz, 3H), 7.43 (q, J = 7.32 Hz, 2H), 7.46 (d, J = 7.32 Hz, 2H), 7.87 (s, 1H).
实施例19：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物26)的制备Example 19: (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 ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4- Preparation of chlorobenzyl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 26)
步骤19a：叔丁基(R)-3-(4-氨基-3-(4-((4-氯苄基)氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(tert-butyl(R)-3-(4-amino-3-(4-((4-chlo robenzyl)oxy)phenyl)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-carboxylate)(化合物602-26)的制备Step 19a: 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 (tert-butyl(R)-3-(4-amino-3-(4-((4-chlo robenzyl) Preparation of oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 602-26)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(0.423g，1.27mmol，1.0当量)，(4-((4-氯苄基)氧基)苯基)硼酸(601-26)(0.433g，1.65mmol，1.3当量)，醋酸铜(0.254g，1.40mmol，1.1当量)，分子筛(0.400g)，吡啶(0.301g，3.81mmol，3.0当量)和N，N-二甲基甲酰胺(10ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝60∶1)得到叔丁基(R)-3-(4-氨基-3-(4-((4-氯苄基)氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.200g，收率：29％)。LCMS(ESI)：m/z 551[M+1]+，黄色油状物；TLC：Rf 0.7(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (0.423 g, 1.27 mmol, 1.0 eq.), (4-((4-chlorobenzyl)oxy)phenyl)boronic acid (601-26) (0.433 g, 1. 1.3 equivalents), copper acetate (0.254 g, 1.40 mmol, 1.1 equivalents), molecular sieve (0.400 g), pyridine (0.301 g, 3.81 mmol, 3.0 eq.) and N,N-dimethylformamide (10 ml), reaction solution Heat to 40 ° C overnight in air. The reaction mixture was diluted with ethyl acetate (100 ml), washed with EtOAc EtOAc (EtOAc) =60:1) to give tert-butyl(R)-3-(4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-2-oxo-2,3-di Hydrogen-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.200 g, yield: 29%). LCMS (ESI): m / z 551 [M + 1] +, as a yellow oil; TLC: Rf 0.7 (dichloromethane: methanol = 20).
步骤19b：(R)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-y1)-1H-imidazo[4，5-c]pyridin-2(3H)-one)(化合物603-26)的制备Step 19b: (R)-4-Amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5 -c]pyridine-2(3H)-one ((R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-y1)-1H-imidazo[ Preparation of 4,5-c]pyridin-2(3H)-one) (Compound 603-26)
往反应瓶中加入叔丁基(R)-3-(4-氨基-3-(4-((4-氯苄基)氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(602-26)(0.20g，1.0mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，室温反应半小时。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(80ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.145g，收率：90％)。LCMS(ESI)：m/z 451[M+1]+，浅黄色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。Add to the reaction flask t-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 (602-26) (0.20 g, 1.0 mmol, 1.0 eq.), dichloromethane (10 ml) Fluorineacetic acid (2.0 ml) was reacted at room temperature for half an hour. The reaction solution was poured into a saturated aqueous solution of sodium carbonate (100 ml), and extracted with dichloromethane (80 ml × 2). Purification of methanol (triethylamine = 10:1:0.1) gave (R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3- -1H-imidazo[4,5-c]pyridine-2(3H)-one (0.145 g, yield: 90%). LCMS (ESI): m / z 451 [M + 1] +, as a pale yellow solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤19c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物26)的制备Step 19c: (R)-1-(1-Aroylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl) Preparation of oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 26)
往丙烯酰氯(202-4)(0.035g，0.39mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(603-26)(0.145g，0.32mmol，1.0当量)的二氯甲烷溶液(8ml)，然后再滴加二异丙基乙基胺(0.062g，0.48mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝40∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-((4-氯苄基)氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.100g，收率：62％)。无色固体，熔点：93.1-95.9℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 504[M+1]+，1HNMR(CDCl3，500MHz)：δ7.83(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)。To a solution of acryloyl chloride (202-4) (0.035 g, 0.39 mmol, 1.2 eq.) in dichloromethane (7 ml), (R)-4-amino-3-(4-((4-chloro) Benzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (603-26) (0.145 g, 0.32 Methylene chloride solution (8 ml) of mmol, 1.0 eq.), then diisopropylethylamine (0.062 g, 0.48 mmol, 1.5 eq.) in dichloromethane (1 ml). minute. The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol = 40:1) gives (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 (0.100 g, yield: 62%). Colorless solid, melting point: 93.1-95.9 ° C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 504 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.83 (d, J = 5Hz, 1H), 7.37 (m, 6H), 7.09 (d, J = 8.5 Hz, 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).
实施例20：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-(苄氧基)吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物27)的制备Example 20: (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 ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3- Preparation of yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 27)
步骤20a：叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苄氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯((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)(602-27)的制备Step 20a: tert-Butyl (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate ((tert-butyl(R)-3-(4-amino-3-(6-(benzyloxy)pyridin-3-yl)- Preparation of 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (602-27)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶 -1-基)哌啶-1-羧酸酯(306)(0.999g，3.0mmol，1.0当量)，2-苄氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)吡啶(601-27)(1.400g，4.5mmol，1.5当量)，醋酸铜(0.820g，4.5mmol，1.5当量)，分子筛(0.500g)，吡啶(0.710g，9.0mmol，3.0当量)和N，N-二甲基甲酰胺(10ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×3)洗涤，有机相用硅胶拌样旋干，浓缩物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝60∶1)得到叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苄氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(0.410g，收率：52％)。LCMS(ESI)：m/z 517[M+1]+，黄色油状物；TLC：Rf 0.7(二氯甲烷∶甲醇＝20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (0.999 g, 3.0 mmol, 1.0 equivalent), 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclic pentan-2-yl)pyridine (601-27) (1.400 g, 4.5 mmol, 1.5 eq.), copper acetate (0.820 g, 4.5 mmol, 1.5 eq.), molecular sieve (0.500 g), pyridine (0.710 g, 9.0 mmol, 3.0 eq.) and N,N-dimethylformamide (10 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with ethyl acetate (100 ml), washed with EtOAc EtOAc (EtOAc) =60:1) to give tert-butyl(R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazole And [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.410 g, yield: 52%). LCMS (ESI): m / z 517 [M + 1] +, as a yellow oil; TLC: Rf 0.7 (dichloromethane: methanol = 20).
步骤20b：(R)-4-氨基-3-(6-苄氧基吡啶-3-基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4，5-c]pyridin-2(3H)-one)(603-27)的制备Step 20b: (R)-4-Amino-3-(6-benzyloxypyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine- 2(3H)-keto((R)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c] Preparation of pyridin-2(3H)-one) (603-27)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-3-(6-苄氧基吡啶-3-基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(602-27)(0.41g，1.0mmol，1.0当量)，二氯甲烷(10ml)和三氟醋酸(2.0ml)，室温反应半小时。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，浓缩物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到(R)-4-氨基-3-(6-苄氧基吡啶-3-基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.220g，收率：66％)。LCMS(ESI)：m/z 417[M+1]+，浅黄色固体；TLC：Rf 0.1(二氯甲烷∶甲醇-20∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazole to the reaction flask. [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (602-27) (0.41 g, 1.0 mmol, 1.0 eq.), dichloromethane (10 ml) and trifluoroacetic acid (2.0 ml) ), react at room temperature for half an hour. The reaction solution was poured into a saturated sodium carbonate solution (100 ml), and extracted with dichloromethane (50 ml × 2). Purification of methanol (triethylamine = 10:1:0.1) gave (R)-4-amino-3-(6-benzyloxypyridin-3-yl)-1-(piperidin-3-yl)-1H- Imidazo[4,5-c]pyridine-2(3H)-one (0.220 g, yield: 66%). LCMS (ESI): m / z 417 [M + 1] +, as a pale yellow solid; TLC: Rf 0.1 (methylene chloride: methanol -20:1).
步骤20c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-(苄氧基)吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物27)的制备Step 20c: (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 ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 27)
往丙烯酰氯(202-4)(0.057g，0.64mmol，1.2当量)的二氯甲烷溶液(7ml)中0℃下滴加(R)-4-氨基-3-(6-苄氧基吡啶-3-基)-1-(哌啶-3-基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(603-27)(0.220g，0.53mmol，1.0当量)的二氯甲烷溶液(7ml)，然后再滴加二异丙基乙基胺(0.102g，0.80mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃ 下反应5分钟。将反应液倒入水(100ml)中，用二氯甲烷(50ml×2)萃取，有机相用硅胶拌样旋干，剩余物用柱层析法纯化(洗脱剂：二氯甲烷∶甲醇＝30∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(6-(苄氧基)吡啶-3-基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.135g，收率：54％)。无色固体，熔点：107.3-109.2℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 471[M+1]+，1HNMR(CDCl3，500MHz)：δ8.29(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)。To a solution of acryloyl chloride (202-4) (0.057 g, 0.64 mmol, 1.2 eq.) in dichloromethane (7 ml), (R)-4-amino-3-(6-benzyloxypyridine- 3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (603-27) (0.220 g, 0.53 mmol, 1.0 eq.) A solution of dichloromethane (7 ml) was added dropwise a solution of diisopropylethylamine (0.102 g, 0.80 mmol, 1.5 eq.) in dichloromethane (1 ml). The reaction solution was poured into water (100 ml), extracted with dichloromethane (50 ml × 2), and the organic phase was dried with silica gel, and the residue was purified by column chromatography (eluent: dichloromethane: methanol = 30:1) to give (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one (0.135 g, yield: 54%). Colorless solid, melting point: 107.3-109.2 ° C. TLC: Rf 0.5 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 471 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ8.29 (d, J = 3Hz, 1H), 7.89 (d, J = 5.5Hz, 1H), 7.68 (q, 2H), 7.48 (d, J = 7 Hz, 2H), 7.40 (t, J = 7 Hz, 2H), 7.35 (m, 1H), 6.96 (d, J = 8.5 Hz, 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).
实施例21：1-((R)-1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡咯并[3，2-c]吡啶-2(3H)-酮(1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3，2-c]pyridin-2(3H)-one)(化合物12)的制备Example 21:1-((R)-1-Anoylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)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 Preparation of [3,2-c]pyridin-2(3H)-one) (Compound 12)
步骤21a：2-(4-(4-氟-苯氧基)-苯基]-4，4，5，5-四甲基-1，3，2-二氧硼戊环(2-(4-(4-fluorophenoxy)phenyl)-4，4，5，5-tetramethyl-1，3，2-dioxaborolane)(化合物108-12)的制备Step 21a: 2-(4-(4-Fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (2-(4) -(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (Compound 108-12) Preparation
将1-溴-4-(4-氟-苯氧基)苯(2.00g，7.54mmol，1.0当量)，联硼酸频哪醇酯(5.84g，15.1mmol，2.0当量)，醋酸钾(1.48g，15.1mmol，2.0当量)和Pd(dppf)Cl2(0.54g，0.754mmol，0.1当量)充氮气保护，然后加入二氧六环(20ml)，90℃反应过夜。将反应液冷却水洗，二氯甲烷萃取，干燥后浓缩，柱层析(洗脱剂：二氯甲烷∶正己烷＝1∶2)得到2-(4-(4-氟-苯氧基)-苯基]-4，4，5，5-四甲基-1，3，2-二氧硼戊环(1.10g，收率46.5％)，类白色固体，TLC：Rf 0.6(二氯甲烷∶正己烷＝1∶2)1-Bromo-4-(4-fluoro-phenoxy)benzene (2.00 g, 7.54 mmol, 1.0 eq.), boronic acid pinacol ester (5.84 g, 15.1 mmol, 2.0 eq.), potassium acetate (1.48 g) , 15.1 mmol, 2.0 eq.) and Pd(dppf)Cl 2 (0.54 g, 0.754 mmol, 0.1 eq.) were then taken up with nitrogen and then dioxane (20 ml). The reaction solution was cooled and washed with water, extracted with dichloromethane, dried, and then evaporated. Phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 g, yield 46.5%), off-white solid, TLC: Rf 0.6 (dichloromethane: N-hexane = 1:2)
步骤21b：((3R)-叔丁基-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-2-氧代-2，3-二氢-1H-吡咯并[3，2-c]吡啶-1-基)哌啶-1-羧酸酯((3R)-tert-butyl 3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-2-oxo-2，3-dihydro-1H-pyrrolo[3，2-c]pyridin-l-yl)piperidi ne-1-carboxylate)(化合物307-12)的制备Step 21b: ((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 ((3R)-tert-butyl 3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)) -2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-l-yl)piperidi Preparation of ne-1-carboxylate) (Compound 307-12)
往反应瓶中加入叔丁基(R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸酯(306)(3.0g，9.0mmol，1.0当量)，2-(4-(4-氟-苯氧基)-苯基]-4，4，5，5-四甲基-1，3，2-二氧硼戊环(108-12)(0.85g，2.5mmol，1.00当量)，醋酸铜(0.98g，5mmol，2当量)，三乙胺(0.5g，5mmol，2.00当量)，吡啶(0.40g，5mmol，2.00当量)和N，N-二甲基甲酰胺(10ml)，反应液在空气中加热到40℃过夜。反应液用乙酸乙酯(200ml)稀释，用半饱和食盐水(150ml×3)洗涤，有机相用硅胶拌样旋干，剩余物用柱层析法纯化(洗脱剂：乙酸乙酯∶环己烷＝2∶1)得到叔丁基((3R)-叔丁基-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-2-氧代-2，3-二氢-1H-吡咯并[3，2-c]吡啶-1-基)哌啶-1-羧酸酯(0.19g，收率：14％)。LCMS(ESI)：m/z 519[M+1]+，黄色油状物；TLC：Rf0.57(乙酸乙酯∶环己烷＝2∶1)。Add tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask. 1-carboxylic acid ester (306) (3.0 g, 9.0 mmol, 1.0 eq.), 2-(4-(4-fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl -1,3,2-dioxaborolan (108-12) (0.85 g, 2.5 mmol, 1.00 equiv), copper acetate (0.98 g, 5 mmol, 2 eq.), triethylamine (0.5 g, 5 mmol, 2.00) Equivalent), pyridine (0.40 g, 5 mmol, 2.00 eq.) and N,N-dimethylformamide (10 ml). The reaction mixture was heated to 40 ° C overnight in air. The reaction mixture was diluted with ethyl acetate (200 ml) The organic phase was washed with a silica gel and the residue was purified by column chromatography (eluent: ethyl acetate:hexanehexane = 2:1) (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 (0.19g, yield: 14%) LCMS (ESI) : m / z 519 [m + 1] +, as a yellow oil; TLC: Rf 0.57 (ethyl acetate:hexanehexane = 2:1).
步骤21c：4-氨基-3-(4-(4-氟苯氧基)苯基)-1-((R)-哌啶-3-基)-1H-吡咯[3，2-c]吡啶-2(3H)-酮(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1-((R)-piperidin-3-yl)-1H-pyrrolo[3，2-c]pyridin-2(3H)-one)(化合物308-12)的制备Step 21c: 4-Amino-3-(4-(4-fluorophenoxy)phenyl)-1-((R)-piperidin-3-yl)-1H-pyrrole[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 Preparation of -2(3H)-one) (Compound 308-12)
往反应瓶中加入叔丁基((3R)-叔丁基-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-2-氧代-2，3-二氢-1H-吡咯并[3，2-c]吡啶-1-基)哌啶-1-羧酸酯(307-12)(0.19g，0.36mmol，1.0当量)，二氯甲烷(5ml)和三氟醋酸(1.0ml)，反应液在室温过夜。将反应液倒入饱和碳酸钠溶液(100ml)中，用二氯甲烷(10mlX2)萃取，有机相用硅胶拌样旋干，剩余物用柱层析法(洗脱剂：二氯甲烷∶甲醇∶三乙胺＝10∶1∶0.1)纯化得到4-氨基-3-(4-(4-氟苯氧基)苯基)-1-((R)-哌啶-3-基)-1H-吡咯[3，2-c]吡啶-2(3H)-酮(0.1g，收率：66.7％)。LCMS(ESI)：m/z 419[M+1]+，黄色油状物；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。To the reaction flask was added tert-butyl ((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 (307-12) (0.19 g, 0.36 mmol, 1.0 eq.), dichloromethane (5 ml) The mixture was poured into a saturated sodium carbonate solution (100 ml Column chromatography (eluent: dichloromethane:methanol:triethylamine = 10:1:0.1) afforded 4-amino-3-(4-(4-fluorophenoxy)phenyl)-1- ((R)-piperidin-3-yl)-1H-pyrrole[3,2-c]pyridine-2(3H)-one (0.1 g, yield: 66.7%). LCMS (ESI): m/z 419 [M + 1] +, as a yellow oil; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤21d：1-((R)-1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡咯并[3，2-c]吡啶-2(3H)-酮(1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3，2-c]pyridin-2(3H)-one)(化合物12)的制备Step 21d: 1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)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[ Preparation of 3,2-c]pyridin-2(3H)-one) (Compound 12)
往丙烯酰氯(0.032g，0.36mmol，1.5当量)的二氯甲烷溶液(5ml)中在0℃ 下滴加(4-氨基-3-(4-(4-氟苯氧基)苯基)-1-((R)-哌啶-3-基)-1H-吡咯[3，2-c]吡啶-2(3H)-酮(308-12)(0.1g，0.24mmol，1.0当量)的二氯甲烷溶液(3ml)，然后再滴加二异丙基乙基胺(0.062g，0.48mmol，2.0当量)的二氯甲烷溶液(2ml)，在0℃下反应5分钟。将反应液倒入水(10ml)中，用二氯甲烷(10mlX2)萃取，有机相用硅胶拌样旋干，剩余物用柱层析法纯化(二氯甲烷∶甲醇-40∶1)得到(1-((R)-1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡咯并[3，2-c]吡啶-2(3H)-酮(0.028g，收率：24％)。类白色固体，熔点：86-88℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 473[M+1]+，1HNMR(CDCl3，400MHz)：δ7.87(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)。To a solution of acryloyl chloride (0.032 g, 0.36 mmol, 1.5 eq.) in dichloromethane (5 ml) (4-amino-3-(4-(4-fluorophenoxy)phenyl)- 1-((R)-piperidin-3-yl)-1H-pyrrole[3,2-c]pyridine-2(3H)-one (308-12) (0.1 g, 0.24 mmol, 1.0 eq.) A solution of dichloromethane (3 ml), followed by dropwise addition of diisopropylethylamine (0.062 g, 0.48 mmol, 2.0 eq.) in dichloromethane (2 ml), and reacted for 5 min at 0 ° C. In water (10 ml), it was extracted with dichloromethane (10 ml×2), and the organic phase was dried with silica gel, and the residue was purified by column chromatography (dichloromethane:methanol -40:1) )-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3,2-c]pyridine-2 ( 3H)-ketone (0.028 g, yield: 24%) mp. mp.: EtOAc: EtOAc: EtOAc: 473[M+1] + , 1 H NMR (CDCl 3 , 400MHz): δ 7.87 (d, J = 5 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.08 (m, 6H), 6.63 (d, J = 5 Hz, 2H), 6.30 (d, J = 17.6 Hz, 1H), 5.72 (s, 1H), 4.82 (d, J = 12 Hz, 1H), 4.12 (d, J = 13.6) Hz, 4H), 3.85 (m, 0.5H), 3.48 (d, J = 11.2 Hz, 0.5H), 3.13 (m, 0.5H), 2.62 (m, 1.5H), 2.11 (d, J = 11.2 Hz) , 1H), 1.98 (d, J = 14 Hz, 1H), 1.60 (m, 1H).
实施例22：(R)-1-(3-(1-(丙烯酰基)哌啶))-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物21)的制备Example 22: (R)-1-(3-(1-(acryloyl)piperidin))-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1, 3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino)) Preparation of phenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 21)
步骤22a：(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-二甲氨基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(tert-butyl(R)-3-(4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)piperidine-1-carboxylate)(化合物307-21)的制备Step 22a: (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[ 4,5-c]pyridine) piperidine (tert-butyl(R)-3-(4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-21)
(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-羟基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(502-19)(0.88g，2.07mmol，1.0当量)、对二甲氨基溴苯(1.24g，6.21mmol，3.0当量)和N，N-二甲基甘氨酸盐酸盐(0.35g，2.48mmol，1.2当量)溶于二氧六环(20mL)中，再加入碘化亚铜(0.12g，0.62mmol，0.3当量)和碳酸铯(2.36g，7.25mmol，3.5当量)，然后在氮气保护中100℃反应24小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(二 氯甲烷∶甲醇＝50∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-二甲氨基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(0.69g，收率：61％)。LCMS(ESI)：m/z 545[M+1]+，灰色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-hydroxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c Pyridine) piperidine (502-19) (0.88 g, 2.07 mmol, 1.0 eq.), p-dimethylaminobromobenzene (1.24 g, 6.21 mmol, 3.0 eq.) and N,N-dimethylglycine hydrochloride ( 0.35 g, 2.48 mmol, 1.2 eq.) was dissolved in dioxane (20 mL), then cuprous iodide (0.12 g, 0.62 mmol, 0.3 eq.) and cesium carbonate (2.36 g, 7.25 mmol, 3.5 eq.). It was then reacted at 100 ° C for 24 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol = 50:1) to afford (R)-1-tert-butoxycarbonyl-3-(4-amino-2- Oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.69 g, yield: 61%). LCMS (ESI): m / z 545 [M + 1] +, gray solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤22b：(R)-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-1-(piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-21)的制备Step 22b: (R)-4-Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[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) Preparation
将((R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-二甲氨基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(307-21)(0.69g，1.27mmol，1.0当量)溶于二氯甲烷(15mL)中，再向其中加入三氟乙酸(3mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(100mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.52g，收率：93％)。LCMS(ESI)：m/z 445[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。((R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[4] ,5-c]pyridine)piperidine (307-21) (0.69 g, 1.27 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL), then trifluoroacetic acid (3 mL) was added and then reacted at room temperature After 2 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed successively with saturated sodium carbonate (30 mL×2) and brine (60 mL), and then the Purification by chromatography (dichloromethane:methanol:triethylamine =100:10:1) gave (R)-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1 -(3-Pyrrolidine)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.52 g, yield: 93%). LCMS (ESI): m/z 445 [M+ 1] + , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol = 10:1).
步骤22c：(R)-1-(3-(1-(丙烯酰基)哌啶))-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物21)的制备Step 22c: (R)-1-(3-(1-(acryloyl)piperidinyl)-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1,3 -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino)phenoxy) Preparation of phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 21)
将(R)-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-21)(0.2g，0.45mmol，1.0当量)、丙烯酸(39mg，0.54mmol，1.2当量)、DCC(111mg，0.54mmol，1.2当量)和DMAP(5.5mg，0.045mmol，0.1当量)溶于二氯甲烷(10mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-1-(3-(1-(丙烯酰基)哌啶))-4-氨基-3-(4-(4-二甲氨基苯氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(60mg，收率：27％)。白色固体，熔点：92.3-97.6℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝15∶1)。LCMS(ES I)：m/z 499[M+1]+，1HNMR(CDCl3，500MHz)：δ7.85(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)。(R)-4-Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[4,5-c]pyridine- 2(3H)-one (308-21) (0.2g, 0.45mmol, 1.0 eq.), acryl (39mg, 0.54mmol, 1.2 eq.), DCC (111mg, 0.54mmol, 1.2 eq.) and DMAP (5.5mg, 0.045) Methyl, 0.1 eq.) was dissolved in dichloromethane (10 mL) and then allowed to react at room temperature for 1 hour. After the reaction is completed, the crude product is concentrated, purified by column chromatography (dichloromethane:methanol = 50:1) to give compound (R)-1-(3-(1-(acryloyl)piperidine))-4- Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (60 mg, yield: 27%) . White solid, melting point: 92.3-97.6 °C. TLC: Rf 0.5 (dichloromethane:methanol = 15:1). LCMS (ES I): m/z 499 [M+1] + , 1 H NMR (CDCl 3 , 500 MHz): δ 7.85 (s, 1H), 7.35 (d, J = 9.0 Hz, 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).
实施例23：(3R)-1-[1-(1-丙烯酰基)哌啶-3-基]-4-胺基-3-[4-(4-三氟甲基苯氧基-苯基)]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物22)的制备Example 23: (3R)-1-[1-(1-acryloyl)piperidin-3-yl]-4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl) ]]-1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((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
步骤23a：(3R)-3-[4-氨基-2-氧代-3-[4-(4-三氟甲基苯氧基-苯基)]-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(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)(化合物307-22)的制备Step 23a: (3R)-3-[4-Amino-2-oxo-3-[4-(4-trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazole And 4-(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)
将(3R)-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-甲酸叔丁酯(306)(1.17g，3.52mmol，1当量)溶于DMF(15ml)，依次加入
Figure PCTCN2016084057-appb-000019
Figure PCTCN2016084057-appb-000020
分子筛(2g)、醋酸铜(0.96g，5.28mmol，1.5当量)、4-三氟甲基苯氧基苯硼酸(108-22)(1.19g，4.22mmol，1.1当量)、吡啶(0.417g，5.28mmol，1.5当量)，室温搅拌过夜。反应完毕，过滤，母液水洗两遍，干燥，浓缩，甲醇/DCM(1∶40)柱层析得棕色浆状物(3R)-3-[4-氨基-2-氧代-3-[4-(4-三氟甲基苯氧基-苯基)]-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(0.55g，收率27.5％)；TLC：Rf 0.7(二氯甲烷∶甲醇＝20∶1)；LCMS(ESI)：m/z 570[M+1]+1。(3R)-3-(4-Amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (306) (1.17 g, 3.52 mmol, 1 eq.) was dissolved in DMF (15 mL).
Figure PCTCN2016084057-appb-000019
Figure PCTCN2016084057-appb-000020
Molecular sieves (2g), copper acetate (0.96g, 5.28mmol, 1.5 equivalents), 4-trifluoromethylphenoxybenzeneboronic acid (108-22) (1.19g, 4.22mmol, 1.1 equivalents), pyridine (0.417g, 5.28 mmol, 1.5 eq.), stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, and the mother liquid was washed twice, dried, concentrated, and then purified by methanol/DCM (1:40) column chromatography to obtain a brown syrup (3R)-3-[4-amino-2-oxo-3-[4 -(4-Trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (0.55 g, yield 27.5%); TLC: Rf 0.7 (dichloromethanol:methanol = 20:1); LCMS (ESI): m/z 570[M+1] +1 .
步骤23b：(3R)-4-氨基-1-[哌啶-3-基]-3-[4-(4-三氟甲基苯氧基)-苯基]1，3-2H-咪唑并[4，5-c]吡啶-2-酮(4-Amino-1-piperidin-3-yl-3-[4-(4-trifluoromethy1-phenoxy)-phenyl]-1，3-dihydro-imidazo[4，5-c]pyridin-2-one)(化合物308-22)的制备Step 23b: (3R)-4-Amino-1-[piperidin-3-yl]-3-[4-(4-trifluoromethylphenoxy)-phenyl]1,3-2H-imidazole [4,5-c]pyridin-2-one (4-Amino-1-piperidin-3-yl-3-[4-(4-trifluoromethy1-phenoxy)-phenyl]-1,3-dihydro-imidazo[4 ,5-c]pyridin-2-one) (Compound 308-22) Preparation
将(3R)-3-[4-胺基-2-氧代-3-[4-(4-三氟甲基苯氧基-苯基)]-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(307-22)(0.55g，0.97mmol，1当 量)溶于DCM(2ml)，加入TFA(2ml)，室温反应1h。反应液浓缩，再用饱和碳酸氢钠中和至稍偏碱性，用5ml DCM萃取，干燥，浓缩，甲醇/DCM/三乙胺(1∶10∶0.1)柱层析得类白色泡沫状固体(3R)-4-氨基-1-[哌啶-3-基]-3-[4-(4-三氟甲基苯氧基)-苯基]1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.408g，收率90％)；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 470[M+1]+1。(3R)-3-[4-Amino-2-oxo-3-[4-(4-trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (307-22) (0.55 g, 0.97 mmol, 1 eq. The reaction was carried out for 1 h at room temperature. The reaction mixture was concentrated, then neutralized with saturated sodium bicarbonate to a little basic, extracted with 5 ml of DCM, dried, concentrated, and purified by methanol/DCM/triethylamine (1:10:0.1) column to obtain white foamy solid. (3R)-4-amino-1-[piperidin-3-yl]-3-[4-(4-trifluoromethylphenoxy)-phenyl]1,3-2H-imidazo[4, 5-c] pyridin-2-one (0.408g, yield 90%); TLC: Rf 0.2 ( methylene chloride: methanol = 10:1); LCMS (ESI) : m / z 470 [m + 1] + 1 .
步骤23c：(3R)-1-[1-(1-丙烯酰基)哌啶-3-基]-4-胺基-3-[4-(4-三氟甲基苯氧基-苯基)]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物22)的制备Step 23c: (3R)-1-[1-(1-acryloyl)piperidin-3-yl]-4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl) ]-1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((3R)-1-(1-Acryloyl-piperidin-3-yl)-4-amino-3- Preparation of [4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 22)
将4-胺基-3-[4-(4-三氟甲基苯氧基-苯基)]-1-[(3R)-哌啶-3-基]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-22)(67mg，0.143mmol，1当量)、丙烯酸(12mg，0.171mmol，1.2当量)溶于DCM(5ml)，加入HATU(71mg，0.186mmol，1.3当量)和Et3N(22mg，0.215mmol，1.5当量)，冰浴下反应0.5小时。反应完毕，浓缩，柱层析纯化(洗脱剂：甲醇∶二氯甲烷＝1∶20)得白色固体(3R)-1-[1-(1-丙烯酰基)哌啶-3-基]-4-胺基-3-[4-(4-三氟甲基苯氧基-苯基)]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(20mg，收率20％)；纯度95.1％；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；熔点：64～65℃；LCMS(ESI)：m/z 524[M+1]+1；1HNMR(400MHz，CDCl3)：δ1.64(m，1H)，1.99(m，3H)，2.64(m，1.5H)，3.13(t，0.5H，J＝12.36Hz)，3.47(t，0.5H，J＝11.34Hz)，3.86(s，0.5H)，4.11(m，1.5H)，4.21(s，0.5H)，4.31(s，1H)，4.83(dd，1H，1J＝10.08Hz，2J＝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，2J＝8.4Hz)，7.46(d，2H，J＝8.52Hz)，7.65(d，2H，J＝8.4Hz)，7.86(s，1H)。4-Amino-3-[4-(4-trifluoromethylphenoxy-phenyl)]-1-[(3R)-piperidin-3-yl]-1,3-dihydro-2H -Imidazo[4,5-c]pyridin-2-one (308-22) (67 mg, 0.143 mmol, 1 eq.), EtOAc (12 mg, 0.171 mmol, 1.2 eq.). 71mg, 0.186mmol, 1.3 eq.) and Et 3 N (22mg, 0.215mmol, 1.5 equiv) and the reaction under ice-cooling for 0.5 hours. After completion of the reaction, the residue was purified by purified mjjjjjlililililili 4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ( 20mg, yield 20%); purity 95.1%; TLC: Rf 0.4 (dichloromethane: methanol = 20); Melting point: 64 ~ 65 ℃; LCMS ( ESI): m / z 524 [m + 1] + 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.64 (m, 1H), 1.99 (m, 3H), 2.64 (m, 1.5H), 3.13 (t, 0.5H, J = 12.36 Hz), 3.47 ( t, 0.5H, J = 11.34 Hz), 3.86 (s, 0.5H), 4.11 (m, 1.5H), 4.21 (s, 0.5H), 4.31 (s, 1H), 4.83 (dd, 1H, 1 J) =10.08 Hz, 2 J=8.34 Hz), 5.75 (d, 1H, J = 9.66 Hz), 6.35 (d, 1H, J = 16.2 Hz), 6.62 (m, 2H), 7.18 (dd, 4H, 1 J) = 8.64 Hz, 2 J = 8.4 Hz), 7.46 (d, 2H, J = 8.52 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.86 (s, 1H).
实施例24：(3R)-1-(1-丙烯酰基-哌啶-3-基)-4-氨基-3-[4-(4-羟甲苯氧基)-苯基]-1，3-2H-咪唑[4，5-c]吡啶-2-酮(1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1，3-dihydro-imidazo[4，5-c]pyridin-2-one)(化合物23)的制备 Example 24: (3R)-1-(1-acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethylphenyloxy)-phenyl]-1,3- 2H-imidazoyl [4,5-c]pyridin-2-one (1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]- Preparation of 1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 23)
步骤24a：(3R)-3-[4-胺基-2-氧代-3-(4-羟甲基苯氧基-苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(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)(化合物307-23)的制备Step 24a: (3R)-3-[4-Amino-2-oxo-3-(4-hydroxymethylphenoxy-phenyl)-2,3-dihydro-1H-imidazo[4, 5-{]Amino-2-oxo-3-(4-hydroxymethyl phenoxy-phenoxy)-2,3-dihydro-1 -H-imidazo[4,5-c]pyridin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester) (Compound 307-23)
往烧瓶里加入(3R)-3-[4-胺基-2-氧代-3-(4-羟基苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(502-19)(737mg，1.73mmol，1当量)，Cs2CO3(1.13g，3.46mmol，2当量)，加入NMP(10ml)搅拌呈棕色悬浮液，加入4-氟苯甲醛(258mg，2.076mmol，1.2当量)，80℃反应过夜。将反应体系冷却，过滤，母液加入20ml水并加入醋酸调节pH至偏酸性，DCM(10ml)萃取两次，有机相最后再用水(20ml)洗涤2次，浓缩，柱层析(甲醇∶DCM＝1∶40)得到(3R)-3-[4-胺基-2-氧代-3-(4-甲醛基苯氧基-苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(500mg，收率55％)，TLC：Rf 0.4(甲醇∶二氯甲烷＝1∶40)，浅棕色浆状物，LCMS(ESI)：m/z 530[M+1]+。将上述化合物(500mg，0.945mmol，1当量)，溶于甲醇/四氢呋喃(3ml/3ml)，加入硼氢化钠(179mg，4.73mmol，5当量)和氯化锂(200mg，4.73mmol，5当量)。加入水(20ml)搅拌，DCM(10ml x 2)萃取，浓缩，柱层析(甲醇∶DCM＝1∶40)得到(3R)-3-[4-胺基-2-氧代-3-(4-羟甲基苯氧基-苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(220mg，收率44％)，TLC：Rf 0.3(甲醇∶二氯甲烷＝1∶40)，浅黄色浆状物，LCMS(ESI)：m/z 532[M+1]+。(3R)-3-[4-Amino-2-oxo-3-(4-hydroxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine was added to the flask. tert-Butyl 1-phenyl]piperidine-1-carboxylate (502-19) (737 mg, 1.73 mmol, 1 eq.), Cs 2 CO 3 (1.13 g, 3.46 mmol, 2 eq.). In a brown suspension, 4-fluorobenzaldehyde (258 mg, 2.076 mmol, 1.2 eq.) was added and allowed to react at 80 ° C overnight. The reaction system was cooled, filtered, and the mother liquid was added with 20 ml of water and acetic acid was added to adjust the pH to acidity. The mixture was extracted twice with DCM (10 ml), and then the organic phase was washed twice with water (20 ml), concentrated, and column chromatography (methanol: DCM = 1:40) to give (3R)-3-[4-amino-2-oxo-3-(4-carbaldehydephenoxy-phenyl)-2,3-dihydro-1H-imidazo[4 , 5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (500 mg, yield 55%), TLC: Rf 0.4 (methanol: methylene chloride = 1: 40), light brown LCMS (ESI): m/z 530[M+1] + . The above-mentioned compound (500 mg, 0.945 mmol, 1 eq.) was dissolved in methanol / THF (3 ml / 3 ml), sodium borohydride (179 mg, 4.73 mmol, 5 eq.) and lithium chloride (200 mg, 4.73 mmol, 5 eq.) . Add water (20 ml), stir, DCM (10 ml x 2), EtOAc (EtOAc: EtOAc) 4-hydroxymethylphenoxy-phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (220 mg, rate 44%), TLC: Rf 0.3 ( methanol: dichloromethane = 1:40), a light yellow syrup, LCMS (ESI): m / z 532 [m + 1] +.
步骤24b：(3R)-4-胺基-3-[4-(4-羟甲基苯氧基-苯基)]-1-哌啶-3-基-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(4-Amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1-piperidin-3-yl-1，3-dihydro-imidazo[4，5-c]pyridin-2-one)(化合物308-23)的制备Step 24b: (3R)-4-Amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo[ 4,5-c]pyridin-2-one (4-Amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1-piperidin-3-yl-1,3-dihydro-imidazo[4, Preparation of 5-c]pyridin-2-one) (Compound 308-23)
往烧瓶里加入(3R)-3-[4-胺基-2-氧代-3-[4-(4-羟甲基苯氧基-苯基)]-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基]哌啶-1-甲酸叔丁酯(307-23)(0.22g，0.41mmol，1当量)，溶于DCM(2ml)，加入TFA(1ml)，室温反应1h。反应液浓缩，再用饱和碳酸氢钠中和至稍偏碱性，用5ml DCM萃取，干燥，浓缩，甲醇/DCM/三乙胺(1∶10∶0.1)柱层析得(3R)-4-胺基-3-[4-(4-羟甲基苯氧基-苯基)] -1-哌啶-3-基-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.092g，收率52％)，类白色油状物，TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)；LCMS(ESI)：m/z 432[M+1]+1 (3R)-3-[4-Amino-2-oxo-3-[4-(4-hydroxymethylphenoxy-phenyl)]-2,3-dihydro-1H- was added to the flask. tert-Butyl imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylate (307-23) (0.22 g, 0.41 mmol, 1 eq.), dissolved in DCM (2 mL) 1 ml), reacted at room temperature for 1 h. The reaction mixture was concentrated, then neutralized with saturated sodium bicarbonate to a little basic, extracted with 5 ml of DCM, dried, concentrated, and then purified by methanol/DCM/triethylamine (1:10:0.1) column (3R)-4 -amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo[4,5-c]pyridine- 2- one (0.092 g, yield 52%) as an off-white oil, TLC: Rf 0.2 (methylene chloride: methanol = 10:1); LCMS (ESI) : m / z 432 [m + 1] +1
步骤24c：(3R)-1-(1-丙烯酰基-哌啶-3-基)-4-氨基-3-[4-(4-羟甲苯氧基)-苯基]-1，3-2H-咪唑[4，5-c]吡啶-2-酮(1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1，3-dihydro-imidazo[4，5-c]pyridin-2-one)(化合物23)的制备Step 24c: (3R)-1-(1-acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethylphenyloxy)-phenyl]-1,3-2H -Imidazo[4-,4-c-yl]-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1 , 3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 23) Preparation
往烧瓶里加入(3R)-4-胺基-3-[4-(4-羟甲基苯氧基-苯基)]-1-哌啶-3-基-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(308-23)(80mg，0.1854mmol，1当量)，溶于DCM(2ml)/Et3N(56mg)，冰浴下加入丙烯酸(15mg，0.2039mmol，1.1当量)和HATU(92mg，0.241mmol，1.3当量)，反应0.5小时。反应完毕，柱层析纯化(洗脱剂：甲醇∶二氯甲烷＝1∶20)得白色固体4-胺基-1-[(3R)-1-(2-丁烯酰基)二甲胺-3-基]-3-[4-(4-羟甲基苯氧基-苯基)]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(20mg，收率22％)；纯度95.3％；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)；熔点∶99～100℃；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)。(3R)-4-Amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazole was added to the flask. [4,5-c]pyridin-2-one (308-23) (80 mg, 0.1854 mmol, 1 eq.), dissolved in EtOAc (EtOAc) 1.1 equivalents) and HATU (92 mg, 0.241 mmol, 1.3 equivalents) were reacted for 0.5 hours. After completion of the reaction, purification by column chromatography (eluent: methanol: methylene chloride = 1: 20) afforded 4-amino-1-[(3R)-1-(2-butenoyl)dimethylamine as a white solid. 3-yl]-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (20 mg , yield: 22%); purity: 95.3%; TLC: Rf 0.4 (dichloromethane: methanol = 20:1); m.p.: 99 to 100 ° C; LCMS (ESI): m/z 486[M+1] +1 ; 1 H NMR (600 MHz, CDCl 3 ): δ 1.64 (m, 1H), 1.89 (m, 2H), 2.10 (s, 1H), 2.64 (m, 1.5H), 3.12 (t, 0.5H, J = 12.12) Hz), 3.46 (t, 0.5H, J = 11.04 Hz), 3.85 (s, 0.5H), 4.21 (m, 4H), 4.82 (dd, 1H, 1 J = 8.04 Hz, 2 J = 11.22 Hz), 5.74 (d, 1H, J = 9.84 Hz), 6.34 (m, 1H), 6.62 (m, 2H), 7.11 (dd, 4H, 1 J = 8.52 Hz, 2 J = 8.34 Hz), 7.39 (t, 4H) , J = 6.36 Hz), 7.86 (s, 1H).
实施例25：(R)-1-(3-(1-丙烯酰基)哌啶基)-4-氨基-3-(4-(4-氟苄氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物25)的制备Example 25: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1,3-2H -(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 25)
步骤25a：4-(4-氟苄氧基)苯硼酸((4-((4-fiuorobenzyl)oxy)phenyl)boronic acid)(化合物601-25)的制备Step 25a: Preparation of 4-(4-tetrazobenzyloxy)phenyl)boronic acid) (Compound 601-25)
往反应瓶中加入对溴苯酚(3.0g，17.34mmol，1.0当量)，对氟苄溴(3. 93g，20.81mmol，1.2当量)，碳酸钾(4.79g，34.68mmol，2.0当量)和N，N-二甲基甲酰胺(20ml)，室温反应过夜。反应液加水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用柱层析法纯化(石油醚∶乙酸乙酯＝20∶1)得到4-(4-氟苄氧基)溴苯(4.48g，收率：92％)。LCMS(ESI)：m/z 281[M+1]+，白色固体；TLC：Rf 0.5(石油醚∶乙酸乙酯＝10∶1)。将上述得到的化合物(3.16g，11.24mmol，1.0当量)溶于无水四氢呋喃(40mL)中，用干冰丙酮浴冷却到-78℃，然后缓慢地滴加正丁基锂(2.5M，5.4mL，13.49mmol，1.2当量)，滴加完毕后在-78℃下搅拌1小时。把硼酸三甲酯(2.55mL，22.48mmol，2.0当量)加进去然后缓慢升到室温并搅拌过夜。加入2N盐酸水溶液(20mL)并搅拌2小时。水层用乙酸乙酯(50mL×3)萃取，合并有机层后用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(石油醚∶乙酸乙酯＝1∶1)纯化得4-(4-氟苄氧基)苯硼酸(0.92g，收率：33％)。LCMS(ESI)：m/z 247[M+1]+，白色固体；TLC：Rf 0.2(石油醚∶乙酸乙酯＝2∶1)。To the reaction flask were added p-bromophenol (3.0 g, 17.34 mmol, 1.0 eq.), p-fluorobenzyl bromide (3.93 g, 20.81 mmol, 1.2 eq.), potassium carbonate (4.79 g, 34.68 mmol, 2.0 eq.) and N. N-dimethylformamide (20 ml) was reacted overnight at room temperature. The reaction mixture was diluted with water (100 mL), EtOAc (EtOAc m. 4-(4-Fluorobenzyloxy)bromobenzene (4.48 g, yield: 92%). LCMS (ESI): m / z 281 [M + 1] +, as a white solid; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10). The compound obtained above (3.16 g, 11.24 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (40 mL), cooled to -78 ° C with dry ice acetone bath, and then n-butyl lithium (2.5 M, 5.4 mL) was slowly added dropwise. 13.49 mmol, 1.2 eq.) After completion of the dropwise addition, the mixture was stirred at -78 ° C for 1 hour. Trimethyl borate (2.55 mL, 22.48 mmol, 2.0 eq.) was added and then slowly warmed to room temperature and stirred overnight. A 2N aqueous hydrochloric acid solution (20 mL) was added and stirred for 2 hr. The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) -(4-Fluorobenzyloxy)benzeneboronic acid (0.92 g, yield: 33%). LCMS (ESI): m / z 247 [M + 1] +, as a white solid; TLC: Rf 0.2 (petroleum ether: ethyl acetate = 2).
步骤25b：(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(4-氟苄氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(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)piperidin e-1-carboxylate)(化合物602-25)的制备Step 25b: (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridine) piperidine (tert-butyl(R)-3-(4-amino-3-(4-(4-fluorobenzyl)oxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin e-1-carboxylate) (Compound 602-25)
将(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(0.85g，2.55mmol，1.0当量)、4-(4-氟苄氧基)苯硼酸(0.82g，3.32mmol，1.3当量)和吡啶(0.62mL，7.65mmol，3.0当量)溶于N，N-二甲基甲酰胺(8mL)中，再加入醋酸铜(0.51g，2.81mmol，1.1当量)和
Figure PCTCN2016084057-appb-000021
分子筛(1g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(100mL)稀释，过滤，滤液用半饱和食盐水(50mL×2)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(4-氟苄氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(0.27g，收率：32％)。LCMS(ESI)：m/z 534[M+1]+，棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) piperidine (0.85 g, 2.55 mmol, 1.0 eq.), 4-(4-fluorobenzyloxy)benzeneboronic acid (0.82 g, 3.32 mmol, 1.3 eq.) and pyridine (0.62 mL, 7.65 mmol, 3.0 eq.) dissolved in N,N-dimethyl In formamide (8 mL), additional copper acetate (0.51 g, 2.81 mmol, 1.1 equivalents) and
Figure PCTCN2016084057-appb-000021
Molecular sieves (1 g) were then reacted overnight at 50 ° C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with a half-saturated brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated.]]]]]]] 3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.27 g, Rate: 32%). LCMS (ESI): m / z 534 [M + 1] +, a brown solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤25c：(R)-4-氨基-3-(4-(4-氟苄氧基)苯基)-1-(3-哌啶基)-1，3- 2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物603-25)的制备Step 25c: (R)-4-Amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidinyl)-1,3- 2H-imidazo[4,5-c]pyridin-2-one ((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
将(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(4-氟苄氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(602-25)(0.27g，0.51mmol，1.0当量)溶于二氯甲烷(10mL)中，再向其中加入三氟乙酸(2mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(50mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(30mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-3-(4-(4-氟苄氧基)苯基)-1-(3-哌啶基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.20g，收率：90％)。LCMS(ESI)：m/z 434[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridine)piperidine (602-25) (0.27 g, 0.51 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). The reaction was carried out for 2 hours at room temperature. The reaction mixture was diluted with methylene chloride (50 mL), washed sequentially with saturated sodium carbonate (30 mL×2) and brine (30 mL), and then, Purification of (R)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidyl) (dichloromethane:methanol:triethylamine=100:10:1) Pyridyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (0.20 g, yield: 90%). LCMS (ESI): m / z 434 [M + 1] +, as a pale yellow solid; TLC: Rf 0.2 (methylene chloride: methanol = 10).
步骤25d：(R)-1-(3-(1-丙烯酰基)哌啶基)-4-氨基-3-(4-(4-氟苄氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物25)的制备Step 25d: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1,3-2H- Iso[4,5-c]pyridin-2-one ((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) (Compound 25) Preparation
将(R)-4-氨基-3-(4-(4-氟苄氧基)苯基)-1-(3-哌啶基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(603-25)(0.20g，0.46mmol，1.0当量)、丙烯酸(43mg，0.60mmol，1.3当量)、DCC(124mg，0.60mmol，1.3当量)和DMAP(5.6mg，0.046mmol，0.1当量)溶于二氯甲烷(10mL)，然后在0℃下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物6-7(110mg，收率：49％)。白色固体，熔点：69.7-71.7℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝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)。(R)-4-Amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidinyl)-1,3-2H-imidazo[4,5-c Pyridin-2-one (603-25) (0.20 g, 0.46 mmol, 1.0 eq.), acrylic acid (43 mg, 0.60 mmol, 1.3 eq.), DCC (124 mg, 0.60 mmol, 1.3 eq.) and DMAP (5.6 mg, 0.046) Methyl, 0.1 eq.) was dissolved in dichloromethane (10 mL) and then reacted at 0 ° C for 1 hour. After completion of the reaction, the crude product was evaporated, mjjjjjjj White solid, melting point: 69.7-71.7 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m/z 488 [M+1] + , 1 H NMR (CDCl 3 , 500 MHz): δ 7.86 (s, 1H), 7.44-7.41 (m, 2H), 7.38-7.35 (m, 2H) ), 7.11-7.08 (m, 4H), 6.64-6.57 (m, 2H), 6.34-6.30 (m, 1H), 5.72 (s, 1H), 5.08 (s, 2H), 4.90-4.82 (m, 1H) ), 4.25-4.05 (m, 4H), 3.90-3.46 (m, 1H), 3.16-2.50 (m, 2H), 2.18-2.10 (m, 1H), 2.02-1.95 (m, 1H), 1.70-1.60 (m, 1H).
实施例26：(R)-1-(3-(1-丙烯酰基)哌啶基)-4-氨基-3-(4-(2-吡啶氧基) 苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物28)的制备Example 26: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(2-pyridyloxy) Phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4- Preparation of (pyridin-2-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 28)
步骤26a：4-(2-吡啶氧基)苯硼酸((4-(pyridin-2-yloxy)phenyl)boronic acid)(化合物108-28)的制备Step 26a: Preparation of 4-(pyridin-2-yloxyphenyl)boronic acid (Compound 108-28)
往反应瓶中加入对溴苯酚(3.0g，17.34mmol，1.0当量)，2-氟吡啶(2.02g，20.81mmol，1.2当量)，碳酸钾(4.79g，34.68mmol，2.0当量)和N，N-二甲基甲酰胺(20ml)，120℃反应过夜。反应液加水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用柱层析法纯化(石油醚∶乙酸乙酯＝10∶1)得到2-(4-溴苯氧基)吡啶(1.2g，收率：28％)。LCMS(ESI)：m/z 250[M+1]+，淡黄色油状液体；TLC：Rf 0.5(石油醚∶乙酸乙酯＝4∶1)。将上述所得化合物(1.17g，4.68mmol，1.0当量)和双联频哪醇硼酸酯(1.54g，6.08mmol，1.3当量)溶于二氧六环(15mL)中，然后加入醋酸钾(1.38g，14.04mmol，3.0当量)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(0.34g，0.47mmol，0.1当量)。用氮气置换三遍然后在100℃下反应过夜。反应完成后浓缩得到粗产品，通过柱层析法(石油醚∶乙酸乙酯＝20∶1)纯化得4-(2-吡啶氧基)苯硼酸频那醇酯(1.1g，收率：79％)。LCMS(ESI)：m/z 298[M+1]+，无色油状液体；TLC：Rf 0.5(石油醚∶乙酸乙酯＝10∶1)。将上述所得的化合物(1.0g，3.37mmol，1.0当量)溶于四氢呋喃(10mL)中，然后加入高碘酸钠(1.08g，5.05mmol，1.5当量)和1N盐酸溶液(10mL)，在室温下反应3小时。反应完成后加入碳酸氢钠固体调节溶液的pH值为6-7。水层用二氯甲烷(30mL×3)萃取，有机层混合后用饱和食盐水(30mL×1)洗涤，用无水硫酸钠干燥，浓缩得到4-(2-吡啶氧基)苯硼酸(0.62g，收率：86％)。LCMS(ESI)：m/z 216[M+1]+，白色固体；TLC：Rf 0.1(石油醚∶乙酸乙酯＝4∶1)。To the reaction flask was added p-bromophenol (3.0 g, 17.34 mmol, 1.0 eq.), 2-fluoropyridine (2.02 g, 20.81 mmol, 1.2 eq.), potassium carbonate (4.79 g, 34.68 mmol, 2.0 eq.) and N, N - dimethylformamide (20 ml), reacted at 120 ° C overnight. The reaction mixture was diluted with water (100 mL), EtOAc (EtOAc m. 2-(4-Bromophenoxy)pyridine (1.2 g, yield: 28%). LCMS (ESI): m / z 250 [M + 1] +, as a pale yellow oily liquid; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 4). The compound obtained above (1.17 g, 4.68 mmol, 1.0 eq.) and bis-pinacol borate (1.54 g, 6.08 mmol, 1.3 eq.) were dissolved in dioxane (15 mL), then potassium acetate (1.38). g, 14.04 mmol, 3.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.34 g, 0.47 mmol, 0.1 eq.). It was replaced with nitrogen three times and then reacted at 100 ° C overnight. After completion of the reaction, the crude product was evaporated to purified crystals eluted eluted eluted eluted eluted eluted eluted %). LCMS (ESI): m / z 298 [M + 1] +, colorless oil; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10). The compound obtained above (1.0 g, 3.37 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), then sodium periodate (1.08 g, 5.05 mmol, 1.5 eq.) and 1N hydrochloric acid (10 mL) at room temperature Reaction for 3 hours. After the completion of the reaction, the sodium hydrogencarbonate solid regulating solution was added to have a pH of 6-7. The aqueous layer was extracted with dichloromethane (30 mL×3), and the organic layer was washed with brine, brine (30mL×1), dried over anhydrous sodium sulfate and concentrated to give 4-(2-pyridyloxy)benzeneboronic acid (0.62) g, yield: 86%). LCMS (ESI): m / z 216 [M + 1] +, as a white solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 4).
步骤26b：(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(2-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(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)(化合物307-28)的制备 Step 26b: (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-2-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-28)
将(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(306)(0.74g，2.22mmol，1.0当量)、4-(2-吡啶氧基)苯硼酸(108-28)(0.62g，2.89mmol，1.3当量)和吡啶(0.54mL，6.66mmol，3.0当量)溶于N，N-二甲基甲酰胺(10mL)中，再加入醋酸铜(0.44g，2.44mmol，1.1当量)和
Figure PCTCN2016084057-appb-000022
分子筛(1g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(100mL)稀释，过滤，滤液用半饱和食盐水(50mL×2)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(2-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(0.228g，收率：20％)。LCMS(ESI)：m/z 503[M+1]+，棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) piperidine (306) ( 0.74 g, 2.22 mmol, 1.0 eq.), 4-(2-pyridyloxy)benzeneboronic acid (108-28) (0.62 g, 2.89 mmol, 1.3 eq.) and pyridine (0.54 mL, 6.66 mmol, 3.0 eq.) In N,N-dimethylformamide (10 mL), additional copper acetate (0.44 g, 2.44 mmol, 1.1 eq.) and
Figure PCTCN2016084057-appb-000022
Molecular sieves (1 g) were then reacted overnight at 50 ° C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with a half-saturated brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated.]]]]]]] 2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.228 g, yield :20%). LCMS (ESI): m / z 503 [M + 1] +, a brown solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤26c：(R)-4-氨基-1-(3-哌啶基)-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-2-yloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-28)的制备Step 26c: (R)-4-Amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-2-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-28)
将(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(2-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(307-28)(0.228g，0.454mmol，1.0当量)溶于二氯甲烷(10mL)中，再向其中加入三氟乙酸(2mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(50mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(30mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-1-(3-哌啶基)-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.17g，收率：93％)。LCMS(ESI)：m/z 403[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazole And [4,5-c]pyridine)piperidine (307-28) (0.228 g, 0.454 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (2 mL) was then added and then The reaction was carried out for 2 hours at room temperature. The reaction mixture was diluted with methylene chloride (50 mL), washed sequentially with saturated sodium carbonate (30 mL×2) and brine (30 mL), and then, (Dichloromethane:methanol:triethylamine=100:10:1) was purified to give (R)-4-amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)benzene ))-1,3-2H-imidazo[4,5-c]pyridin-2-one (0.17 g, yield: 93%). </RTI><RTI ID =0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;
步骤26d：(R)-1-(3-(1-丙烯酰基)哌啶基)-4-氨基-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物28)的制备Step 26d: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazole And [4,5-c]pyridin-2-one ((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
将(R)-4-氨基-1-(3-哌啶基)-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(308-28)(0.17g，0.422mmol，1.0当量)、丙烯酸(40mg， 0.549mmol，1.3当量)、DCC(113mg，0.549mmol，1.3当量)和DMAP(5.2mg，0.042mmol，0.1当量)溶于二氯甲烷(10mL)，然后在0℃下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-1-(3-(1-丙烯酰基)哌啶基)-4-氨基-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(115mg，收率：60％)。白色固体，熔点：211.2-213.3℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝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)。(R)-4-Amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c] Pyridin-2-one (308-28) (0.17 g, 0.422 mmol, 1.0 equivalent), acrylic acid (40 mg, 0.549 mmol, 1.3 eq.), DCC (113 mg, 0.549 mmol, 1.3 eq.) and DMAP (5.2 mg, 0.042 mmol) , 0.1 equivalent) was dissolved in dichloromethane (10 mL) and then reacted at 0 ° C for 1 hour. After completion of the reaction, the crude product is obtained, which is purified by column chromatography (dichloromethane:methanol = 50:1) to give compound (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino -3-(4-(2-Pyridinyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (115 mg, yield: 60%). White solid, melting point: 211.2-213.3 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 457 [M + 1] +, 1 HNMR (CDCl 3 -d 1, 500MHz): δ8.23-8.22 (m, 1H), 7.88 (d, J = 5.0Hz, 1H) , 7.76-7.73 (m, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.08-7.06 (m, 1H), 6.99 (d, J = 8.5 Hz, 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) ).
实施例27：(R)-1-(3-(1-丙烯酰基)哌啶)-4-氨基-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物29)的制备Example 27: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole And [4,5-c]pyridin-2-one ((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
步骤27a：(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(3-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(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)(化合物307-29)的制备Step 27a: (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-29)
将(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(402-17)(0.8g，1.49mmol，1.0当量)、3-羟基吡啶(403-29)(0.21g，2.24mmol，1.5当量)和N，N-二甲基甘氨酸盐酸盐(39mg，0.28mmol，0.18当量)溶于二氧六环(8mL)中，再加入碘化亚铜(14.2mg，0.075mmol，0.05当量)和碳酸铯(0.97g，2.98mmol，2.0当量)，然后在氮气保护中100℃反应60小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝40∶1到20∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基- 2-氧代-3-(4-(3-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(0.24g，收率：32％)。LCMS(ESI)：m/z 503[M+1]+，淡黄色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridine) piperidine (402-17) (0.8 g, 1.49 mmol, 1.0 eq.), 3-hydroxypyridine (403-29) (0.21 g, 2.24 mmol, 1.5 eq.) and N,N-dimethylglycine Hydrochloride (39 mg, 0.28 mmol, 0.18 eq.) was dissolved in dioxane (8 mL), then cuprous iodide (14.2 mg, 0.075 mmol, 0.05 eq.) and cesium carbonate (0.97 g, 2.98 mmol, 2.0) Equivalent), then reacted at 100 ° C for 60 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature and concentrated, and the obtained crude product is purified by column chromatography (dichloromethane:methanol = 40:1 to 20:1) to give (R)-1-tert-butoxycarbonyl-3-(4- Amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.24 g, Rate: 32%). LCMS (ESI): m / z 503 [M + 1] +, as a pale yellow solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤27b：(R)-4-氨基-1-(3-哌啶基)-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-3-yloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-29)的制备Step 27b: (R)-4-Amino-1-(3-piperidinyl)-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c]pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-3-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 308-29)
合成方法如实施例26步骤26c，仅是将其中(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(2-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(307-28)替换为(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(3-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(307-29)(0.24g，0.48mmol，1.0当量)，得到(R)-4-氨基-1-(3-哌啶基)-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.18g，收率：93％)。LCMS(ESI)：m/z 403[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。The synthesis method is as in Example 26, step 26c, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl) )-2,3-Dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-28) was replaced by (R)-1-tert-butoxycarbonyl-3-(4-amino-2) -oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-29) (0.24 g , (0.88 mmol, 1.0 eq.), (R)-4-amino-1-(3-piperidinyl)-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole And [4,5-c]pyridin-2-one (0.18 g, yield: 93%). </RTI><RTI ID =0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;
步骤27c：(R)-1-(3-(1-丙烯酰基)哌啶)-4-氨基-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物29)的制备Step 27c: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole [4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(pyridin-3-yloxy)phenyl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 29)
合成方法如实施例26步骤26d，仅是将其中(R)-4-氨基-1-(3-哌啶基)-3-(4-(2-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(308-28)替换为(R)-4-氨基-1-(3-哌啶基)-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(308-29)(0.18g，0.45mmol，1.0当量)，得到(R)-1-(3-(1-丙烯酰基)哌啶)-4-氨基-3-(4-(3-吡啶氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.18g，收率：93％)。白色固体，熔点：80.5-83.8℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 457[M+1]+，1HNMR(CDCl3，500MHz)：δ8.49(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)。The synthesis procedure is as in Example 26, step 26d, except that (R)-4-amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3 -2H-imidazo[4,5-c]pyridin-2-one (308-28) was replaced by (R)-4-amino-1-(3-piperidinyl)-3-(4-(3- Pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (308-29) (0.18 g, 0.45 mmol, 1.0 eq.) afforded (R)-1 -(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridine 2-ketone (0.18 g, yield: 93%). White solid, melting point: 80.5-83.8 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 457 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ8.49 (d, J = 2.5Hz, 1H), 8.45 (d, J = 4.0Hz, 1H) , 7.88 (d, J = 5.5 Hz, 1H), 7.45-7.39 (m, 3H), 7.35-7.32 (m, 1H), 7.16 (d, J = 8.5 Hz, 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).
实施例28：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5c]吡啶-2-酮((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)(化合物30)的制备Example 28: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(pyridin-4-yloxy)phenyl Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 30)
步骤28a：(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(3-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(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)(化合物307-30)的制备Step 28a: (R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (Compound 307-30)
合成方法如实施例26步骤26b，仅是将其中4-(2-吡啶氧基)苯硼酸(108-28)替换为(4-(吡啶-4-基氧基)苯基)硼酸(108-30)(0.645g，3.0mmol，1.0当量)，得到(R)-3-(4-氨基-2-氧代-3-(4-(吡啶-4-基氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸叔丁酯(0.21g，收率：14％)。LCMS(ESI)：m/z 503[M+1]+，灰白色固体；TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。The synthesis method is as in Example 26, step 26b, except that 4-(2-pyridyloxy)benzeneboronic acid (108-28) is replaced by (4-(pyridin-4-yloxy)phenyl)boronic acid (108- 30) (0.645 g, 3.0 mmol, 1.0 eq.) afforded (R)-3-(4-amino-2-oxo-3-(4-(pyridin-4-yloxy)phenyl)-2, 3-Dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.21 g, yield: 14%). LCMS (ESI): m / z 503 [M + 1] +, an off-white solid; TLC: Rf 0.5 (methylene chloride: methanol = 20).
步骤28b：(R)-4-氨基-1-(哌啶-3-基)-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物308-30)的制备Step 28b: (R)-4-Amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazole And [4,5-c]pyridin-2-one ((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
合成方法如实施例26步骤26c，仅是将其中(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(2-吡啶氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)哌啶(307-28)替换为(R)-3-(4-氨基-2-氧代-3-(4-(吡啶-4-基氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶-1-基)哌啶-1-羧酸叔丁酯(307-30)(0.21g，0.42mmol，1.0当量)，得到(R)-4-氨基-1-(哌啶-3-基)-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(0.158g，收率：94％)。LCMS(ESI)：m/z403[M+1]+，无色固体；TLC：Rf 0.1(二氯甲烷∶甲醇＝20∶1)。The synthesis method is as in Example 26, step 26c, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl) )-2,3-Dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-28) was replaced by (R)-3-(4-amino-2-oxo-3-() 4-(Pyridin-4-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester ( 307-30) (0.21 g, 0.42 mmol, 1.0 eq) afforded (R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)benzene ))-1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.158 g, yield: 94%). LCMS (ESI): m / z403 [M + 1] +, as a colorless solid; TLC: Rf 0.1 (dichloromethane: methanol = 20).
步骤28c：(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5c]吡啶-2-酮((R)-1-(1-acryloylpiperidin-3-yl)-4-am ino-3-(4-(pyridin-4-yloxy)phenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物30)的制备Step 28c: (R)-1-(1-Aroylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro -2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-am Preparation of ino-3-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 30)
往丙烯酰氯(0.039g，0.43mmol，1.1当量)的二氯甲烷溶液(7ml)中在0℃下滴加(R)-4-氨基-1-(哌啶-3-基)-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-30)(0.158g，0.39mmol，1.0当量)的二氯甲烷溶液(10ml)，然后再滴加二异丙基乙基胺(0.075g，0.59mmol，1.5当量)的二氯甲烷溶液(1ml)，在0℃下反应10分钟。将反应液倒入水(100ml)中，用二氯甲烷(100ml×2)萃取，有机相用硅胶拌样旋干，剩余物用柱层析法纯化(二氯甲烷∶甲醇＝20∶1)得到(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-3-(4-(吡啶-4-基氧基)苯基)-1，3-二氢-2H-咪唑并[4，5c]吡啶-2-酮(0.050g，收率：28％)。无色固体，熔点：79.6-81.7℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 457[M+1]+，1HNMR(CDCl3，500MHz)：δ8.51(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)。To a solution of acryloyl chloride (0.039 g, 0.43 mmol, 1.1 eq.) in dichloromethane (7 ml), (R)-4-amino-1-(piperidin-3-yl)-3- 4-(Pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-30) (0.158 g, 0.39 mmol, A 1.0 m solution of dichloromethane (10 ml) was added dropwise a solution of diisopropylethylamine (0.075 g, 0.59 mmol, 1.5 eq.) in dichloromethane (1 ml). The reaction mixture was poured into water (100 ml), EtOAc (EtOAc) Yield (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H - Imidazo[4,5c]pyridin-2-one (0.050 g, yield: 28%). Colorless solid, melting point: 79.6-81.7 ° C. TLC: Rf 0.5 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 457 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ8.51 (d, J = 6Hz, 2H), 7.89 (d, J = 5Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 6 Hz, 2H), 6.67 (s, 1H), 6.60 (d, J = 9.5 Hz, 1H), 6.34 (d, J = 16.5 Hz, 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 = 12 Hz, 1H), 1.98 (d, J = 13.5 Hz, 1H), 1.69 (m, 1H).
实施例29：(R)-4-氨基-3-(4-苯氧苯基)-1-(3-(1-丙炔酰基哌啶))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpi peridin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物32)的制备Example 29: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(3-(1-propynylacylpiperidine))-1,3-2H-imidazo[4, 5-c]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpi peridin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one) (Compound 32) Preparation
将(R)-4-氨基-3-(4-苯氧苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-11)(0.20g，0.50mmol，1.0当量)、丙炔酸(42mg，0.60mmol，1.2当量)、DCC(123mg，0.60mmol，1.2当量)和DMAP(6mg，0.05mmol，0.1当量)溶于二氯甲烷(10mL)，然后在0℃下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物(R)-4-氨基-3-(4-苯氧苯基)-1-(3-(1-丙炔酰基哌啶))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(80mg，收率：35％)。白色固体，熔点：89.3-95.6℃。TLC：Rf 0.4(二 氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 454[M+1]+，1HNMR(CDCl3，500M Hz)：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)。(R)-4-Amino-3-(4-phenoxyphenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one ( 308-11) (0.20 g, 0.50 mmol, 1.0 eq.), propiolic acid (42 mg, 0.60 mmol, 1.2 eq.), DCC (123 mg, 0.60 mmol, 1.2 eq.) and DMAP (6 mg, 0.05 mmol, 0.1 eq.) Dichloromethane (10 mL) was then reacted at 0 ° C for 1 hour. After completion of the reaction, the crude product was concentrated, purified by column chromatography (dichloromethanol:methanol = 50:1) to give compound (R)-4-amino-3-(4-phenoxyphenyl)-1-(3) -(1-propynylacylpiperidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (80 mg, yield: 35%). White solid, melting point: 89.3-95.6 °C. TLC: Rf 0.4 (methylene chloride:methanol = 20:1). LCMS (ESI): m / z 454 [M + 1] +, 1 HNMR (CDCl 3, 500M Hz): 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).
实施例30：(R)-4-氨基-1-(3-(1-(2-丁炔酰基))哌啶基)-3-(4-苯氧苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物33)的制备Example 30: (R)-4-Amino-1-(3-(1-(2-butynyl))piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H- Imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 33)
合成方法如实施例29，仅是将其中丙炔酸替换为2-丁炔酸(52mg，0.62mmol，1.3当量)，得到(R)-4-氨基-1-(3-(1-(2-丁炔酰基))哌啶基)-3-(4-苯氧苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(60mg，收率：27％)。白色固体，熔点：84.6-89.4℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝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)。The synthesis method is as in Example 29, except that the propiolic acid is replaced with 2-butynoic acid (52 mg, 0.62 mmol, 1.3 equivalents) to give (R)-4-amino-1-(3-(1-(2) -butynoyl))piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (60 mg, yield: 27%) ). White solid, melting point: 84.6-89.4 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z468 [M + 1] +, 1 HNMR (CDCl 3, 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).
实施例31：1-(3-(1-丙烯酰基)哌啶甲基)-4-氨基-3-(4-苯氧苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物35)的制备Example 31:1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c Pyridine-2-one (1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c] Preparation of pyridin-2-one) (Compound 35)
步骤31a：1-叔丁氧羰基-3-(4-(2-氯-3-硝基)吡啶氨甲基)哌啶(tert-butyl 3-(((2-chloro-3-nitropyridin-4-yl)amino)methyl)piperidine-1-carboxylate)(化合物702-35)的制备Step 31a: 1-tert-Butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridiniumaminomethyl)piperidine (tert-butyl 3-(((chloro)-nitropyridin-4) -yl)amino)methyl)piperidine-1-carboxylate) (Compound 702-35) Preparation
往反应瓶中加入2，4-二氯-3-硝基吡啶(101)(1.0g，5.18mmol，1.0当量)，1-叔丁氧羰基-3-氨甲基哌啶(701-35)(1.11g，5.18mmol，1.0当量)，三乙胺(1.4mL，10.36mmol，2.0当量)和N，N-二甲基甲酰胺(10ml)，室温反应过 夜。反应液加水(100mL)稀释，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用柱层析法纯化(石油醚∶乙酸乙酯＝3∶1)得到1-叔丁氧羰基-3-(4-(2-氯-3-硝基)吡啶氨甲基)哌啶(1.66g，收率：86％)。LCMS(ESI)：m/z 371[M+1]+，淡黄色油状物；TLC：Rf 0.2(石油醚∶乙酸乙酯＝4∶1)。2,4-Dichloro-3-nitropyridine (101) (1.0 g, 5.18 mmol, 1.0 eq.), 1-tert-butoxycarbonyl-3-aminomethylpiperidine (701-35) was added to the reaction flask. (1.11 g, 5.18 mmol, 1.0 eq.), triethylamine (1.4 mL, 10.36 mmol, 2.0 eq.) and N,N-dimethylformamide (10 ml). The reaction mixture was diluted with water (100 mL), EtOAc (EtOAc m. 1-tert-Butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridiniumaminomethyl)piperidine (1.66 g, yield: 86%). LCMS (ESI): m / z 371 [M + 1] +, as a pale yellow oil; TLC: Rf 0.2 (petroleum ether: ethyl acetate = 4).
步骤3lb：1-叔丁氧羰基-3-(4-(2-二苄胺基-3-硝基)吡啶氨甲基)哌啶(tert-butyl 3-(((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)methyl)piperidine-1-carboxylate)(化合物703-35)的制备Step 3lb: 1-tert-Butoxycarbonyl-3-(4-(2-dibenzylamino-3-nitro)pyridinylamino)piperidine (tert-butyl 3-(((di(dibenzylamino)-) Preparation of 3-nitropyridin-4-yl)amino)methyl)piperidine-1-carboxylate) (Compound 703-35)
往反应瓶中加入1-叔丁氧羰基-3-(4-(2-氯-3-硝基)吡啶氨甲基)哌啶(702-35)(1.66g，4.48mmol，1.0当量)，二苄胺(0.95mL，4.92mmol，1.1当量)，三乙胺(1.24mL，8.96mmol，2.0当量)和乙腈(25ml)，加热回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(石油醚∶乙酸乙酯＝2∶1)得到1-叔丁氧羰基-3-(4-(2-二苄胺基-3-硝基)吡啶氨甲基)哌啶(2.13g，收率：90％)。LCMS(ESI)：m/z 532[M+1]+，黄色油状物；TLC：Rf 0.4(石油醚∶乙酸乙酯＝3∶1)。To the reaction flask was added 1-tert-butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridinylmethyl)piperidine (702-35) (1.66 g, 4.48 mmol, 1.0 eq.). Dibenzylamine (0.95 mL, 4.92 mmol, 1.1 eq.), triethylamine (1. 4 mL, 8.96 mmol, 2.0 eq.) and acetonitrile (25 mL). The reaction mixture was dried with EtOAc (EtOAc) (EtOAc) Nitro)pyridineaminomethyl)piperidine (2.13 g, yield: 90%). LCMS (ESI): m / z 532 [M + 1] +, as a yellow oil; TLC: Rf 0.4 (petroleum ether: ethyl acetate = 3).
步骤31c：1-叔丁氧羰基-3-(4-(3-氨基-2-二苄胺基)吡啶氨甲基)哌啶(tert-butyl 3-(((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)methyl)piperidine-1-carboxylate)(化合物704-35)的制备Step 31c: 1-tert-Butoxycarbonyl-3-(4-(3-amino-2-dibenzylamino)pyridinylamino)piperidine (tert-butyl 3-(((3-amino-2-) Preparation of dibenzylamino)pyridin-4-yl)amino)methyl)piperidine-1-carboxylate) (Compound 704-35)
往锌粉(2.60g，40.1mmol，10.0当量)和氯化铵(1.50g，28.07mmol，7.0当量)的甲醇溶液(40ml)中加入1-叔丁氧羰基-3-(4-(2-二苄胺基-3-硝基)吡啶氨甲基)哌啶(703-35)(2.13g，4.01mmol，1.0当量)，加热至50℃反应1小时。反应液用硅藻土过滤，滤液旋干，用二氯甲烷∶甲醇＝5∶1(50ml)溶解，过滤，有机相旋干得到粗品1-叔丁氧羰基-3-(4-(3-氨基-2-二苄胺基)吡啶氨甲基)哌啶(2.10g，收率：100％)。LCMS(ESI)：m/z 502[M+1]+，灰色固体；TLC：Rf 0.1(石油醚∶乙酸乙酯＝1∶1)。Add 1-tert-Butoxycarbonyl-3-(4-(2-) to a solution of zinc powder (2.60 g, 40.1 mmol, 10.0 eq.) and ammonium chloride (1.50 g, 28.07 mmol, 7.0 eq.) in methanol (40 ml) Dibenzylamino-3-nitro)pyridinium aminomethyl)piperidine (703-35) (2.13 g, 4.01 mmol, 1.0 eq.) was heated to 50 ° C for 1 hour. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Amino-2-dibenzylamino)pyridinylaminomethyl)piperidine (2.10 g, yield: 100%). LCMS (ESI): m / z 502 [M + 1] +, gray solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 1/1).
步骤31d：1-叔丁氧羰基-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(tert-butyl 3-((4-(dibenzylamino)-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate)(化合物705-35)的制备 Step 31d: 1-tert-Butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine ( 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
往反应瓶中加入1-叔丁氧羰基-3-(4-(3-氨基-2-二苄胺基)吡啶氨甲基)哌啶(704-35)(2.10g，4.19mmol，1.0当量)，N，N′-羰基二咪唑(1.70g，10.46mmol，2.5当量)和四氢呋喃(30ml)，将反应液加热至回流过夜。反应液用硅胶拌样旋干，用柱层析法纯化(二氯甲烷∶甲醇＝100∶1)得到1-叔丁氧羰基-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(1.87g，收率：85％)。LCMS(ESI)：m/z 528[M+1]+，淡黄色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝80∶1)。To the reaction flask was added 1-tert-butoxycarbonyl-3-(4-(3-amino-2-dibenzylamino)pyridinylmethyl)piperidine (704-35) (2.10 g, 4.19 mmol, 1.0 eq. N,N'-carbonyldiimidazole (1.70 g, 10.46 mmol, 2.5 eq.) and tetrahydrofuran (30 ml). The reaction mixture was dried with silica gel, and purified by column chromatography (dichloromethane:methanol=100:1) to give 1-t-butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2 , 3-dihydro-1H-imidazo[4,5-c]pyridinylmethyl)piperidine (1.87 g, yield: 85%). LCMS (ESI): m / z 528 [M + 1] +, as a pale yellow solid; TLC: Rf 0.4 (dichloromethane: methanol = 80:1).
步骤31e：1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(tert-butyl 3-((4-amino-2-oxo-2，3-dihydro-1H-imidazo[4，5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate)(化合物706-35)的制备Step 31e: 1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (tert-butyl) Preparation of 3-((4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate) (Compound 706-35)
往反应瓶中加入1-叔丁氧羰基-3-(4-二苄胺基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(705-35)(1.87g，3.54mmol，1.0当量)，氢氧化钯(1.6g)，乙醇(40ml)和乙酸乙酯(10ml)，反应液加热到70℃在氢气氛围中过夜。反应混合物用硅藻土过滤，滤液旋干，剩余物用柱层析法纯化(二氯甲烷∶甲醇＝20∶1)得到1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(0.8g，收率：65％)。LCMS(ESI)：m/z 348[M+1]+，白色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝20∶1)。Add 1-tert-butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridinyl) pipe to the reaction flask. Pyridine (705-35) (1.87 g, 3.54 mmol, 1.0 eq.), palladium hydroxide (1.6 g), ethanol (40 ml) and ethyl acetate (10 ml), and the reaction mixture was heated to 70 ° C overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give 1-t-butoxycarbonyl-3-(4-amino-2-oxo -2,3-Dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (0.8 g, yield: 65%). LCMS (ESI): m / z 348 [M + 1] +, as a white solid; TLC: Rf 0.2 (dichloromethane: methanol = 20).
步骤31f：1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(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)(化合物707-35)的制备Step 31f: 1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c Pyridylmethyl) piperidine (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 707-35) Preparation
将1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(706-35)(0.8g，2.30mmol，1.0当量)、对苯氧基苯硼酸(0.64g，2.99m mol，1.3当量)和吡啶(0.55g，6.90mmol，3.0当量)溶于N，N-二甲基甲酰胺(10mL)中，再加入醋酸铜(0.46g，2.53mmol，1.1当量)和
Figure PCTCN2016084057-appb-000023
分子筛(1g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(100mL)稀释，过滤，滤液用半饱和食盐水(30mL×3)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得1-叔丁氧羰基 -3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(0.45g，收率：38％)。LCMS(ESI)：m/z 516[M+1]+，淡黄色固体；TLC：Rf0.4(二氯甲烷∶甲醇＝20∶1)。1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (706-35) ( 0.8 g, 2.30 mmol, 1.0 eq.), p-phenoxybenzeneboronic acid (0.64 g, 2.99 mmol, 1.3 eq.) and pyridine (0.55 g, 6.90 mmol, 3.0 eq.) dissolved in N,N-dimethylformamide (10 mL), further adding copper acetate (0.46 g, 2.53 mmol, 1.1 equivalents) and
Figure PCTCN2016084057-appb-000023
Molecular sieves (1 g) were then reacted overnight at 50 ° C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with a half-saturated brine (30 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated.]]]~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3-(4-Phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridinylmethyl)piperidine (0.45 g, yield: 38%). LCMS (ESI): m / z 516 [M + 1] +, as a pale yellow solid; TLC: Rf0.4 (dichloromethane: methanol = 20).
步骤31g：4-氨基-3-(4-苯氧苯基)-1-(3-哌啶甲基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-ylmethyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物708-35)的制备Step 31g: 4-Amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one ( 4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 708-35) Preparation
将1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶甲基)哌啶(707-35)(0.45g，0.87mmol，1.0当量)溶于二氯甲烷(15mL)中，再向其中加入三氟乙酸(3mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(50mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(30mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得4-氨基-3-(4-苯氧苯基)-1-(3-哌啶甲基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(0.34g，收率：93％)。LCMS(ESI)：m/z 416[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine Methyl)piperidine (707-35) (0.45 g, 0.87 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL), and then trifluoroacetic acid (3 mL) was added thereto, and then reacted at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (50 mL), washed sequentially with saturated sodium carbonate (30 mL×2) and brine (30 mL), and then, (Dichloromethane:methanol:triethylamine=100:10:1) was purified to give 4-amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H - Imidazo[4,5-c]pyridin-2-one (0.34 g, yield: 93%). LCMS (ESI): m / z 416 [M + 1] +, as a pale yellow solid; TLC: Rf 0.2 (methylene chloride: methanol = 10).
步骤31h：1-(3-(1-丙烯酰基)哌啶甲基)-4-氨基-3-(4-苯氧苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物35)的制备Step 31h: 1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c] Pyridin-2-one (1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin Preparation of -2-one) (Compound 35)
将4-氨基-3-(4-苯氧苯基)-1-(3-哌啶甲基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(708-35)(0.17g，0.41mmol，1.0当量)、丙烯酸(38mg，0.53mmol，1.3当量)、DCC(110mg，0.53mmol，1.3当量)和DMAP(5.0mg，0.041mmol，0.1当量)溶于二氯甲烷(10mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物1-(3-(1-丙烯酰基)哌啶甲基)-4-氨基-3-(4-苯氧苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(55mg，收率：29％)。白色固体，熔点：68.5-70.7℃。TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。LCMS(ESI)：m/z 470[M+1]+，1HNMR(CDCl3，500MHz)：δ7.86(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)。4-Amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (708- 35) (0.17 g, 0.41 mmol, 1.0 eq.), acrylic acid (38 mg, 0.53 mmol, 1.3 eq.), DCC (110 mg, 0.53 mmol, 1.3 eq.) and DMAP (5.0 mg, 0.041 mmol, 0.1 eq.). Methane (10 mL) was then reacted at room temperature for 1 hour. After the reaction is completed, the crude product is obtained, which is purified by column chromatography (dichloromethane:methanol = 50:1) to give the compound 1-(3-(1-acryloyl)piperidinemethyl)-4-amino-3- (4-Phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (55 mg, yield: 29%). White solid, melting point: 68.5-70.7 °C. TLC: Rf 0.4 (dichloromethane:methanol = 20:1). LCMS (ESI): m / z 470 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.86 (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).
实施例32：(R，E)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物44)的制备Example 32: (R,E)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2-butene) Aceno)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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) Preparation of 44)
步骤32a：(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(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)(化合物801-44)的制备Step 32a: (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c Preparation of pyrridin-1-yl)pyrrolidine-1-carboxylate) (Compound 801-44)
将(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(107)(4.5g，14.09mmol，1.0当量)、对碘苯硼酸(401-17)(4.54g，18.32mmol，1.3当量)和吡啶(3.4mL，42.27mmol，3.0当量)溶于N，N-二甲基甲酰胺(40mL)中，再加入醋酸铜(2.82g，15.50mmol，1.1当量)和
Figure PCTCN2016084057-appb-000024
分子筛(5g)，然后在空气中50℃反应过夜。反应液冷却到室温并用乙酸乙酯(200mL)稀释，过滤，滤液用半饱和食盐水(50mL×4)洗涤。有机层用无水硫酸钠干燥，浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(3.05g，收率：41％)。LCMS(ESI)：m/z 522[M+1]+，棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (107) ( 4.5 g, 14.09 mmol, 1.0 eq.), p-iodobenzeneboronic acid (401-17) (4.54 g, 18.32 mmol, 1.3 eq.) and pyridine (3.4 mL, 42.27 mmol, 3.0 eq.) dissolved in N,N-dimethyl In formamide (40 mL), additional copper acetate (2.82 g, 15.50 mmol, 1.1 equivalents) and
Figure PCTCN2016084057-appb-000024
Molecular sieves (5 g) were then reacted overnight at 50 ° C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with a half-saturated brine (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated.]]]]]]] 3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (3.05 g, yield: 41%). LCMS (ESI): m / z 522 [M + 1] +, a brown solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤32b：(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(4-甲氧苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(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)(化合物109-44)的制备Step 32b: (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridine)pyrrolidine (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) (Compound 109-44)
将(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(801-44)(2.0g，3.84mmol，1.0当量)、对甲氧基苯酚(403-44)(1.19g，9.59mmol，2.5当量)和N，N-二甲基甘氨酸盐酸盐(1.07g，7.68mmol，2.0当量)溶于二氧六环(20mL)中，再加入碘化亚铜(0.37 g，1.92mmol，0.5当量)和碳酸铯(7.51g，23.04mmol，6.0当量)，然后在氮气保护中100℃反应20小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝40∶1到20∶1)纯化得((R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(0.61g，收率：31％)。LCMS(ESI)：m/z 518[M+1]+，灰色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridine)pyrrolidine (801-44) (2.0 g, 3.84 mmol, 1.0 equivalent), p-methoxyphenol (403-44) (1.19 g, 9.59 mmol, 2.5 equivalents) and N,N-dimethyl Glycine hydrochloride (1.07 g, 7.68 mmol, 2.0 eq.) was dissolved in dioxane (20 mL), then cuprous iodide (0.37 g, 1.92 mmol, 0.5 eq.) and cesium carbonate (7.51 g, 23.04 mmol). , 6.0 eq.), and then reacted at 100 ° C for 20 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature and concentrated, and the obtained crude product is purified by column chromatography (dichloromethane:methanol = 40:1 to 20:1) ((R)-1-tert-butoxycarbonyl-3-(4) -amino-3-(4-(4-methoxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (0.61 . g, yield: 31%) LCMS (ESI) : m / z 518 [m + 1] +, gray solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤32c：(R)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(pyrrolidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物110-44)的制备Step 32c: (R)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[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
将(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(4-甲氧苯氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(109-44)(0.61g，1.18mmol，1.0当量)溶于二氯甲烷(15mL)中，再向其中加入三氟乙酸(3mL)，然后在室温下反应2小时。将反应混合液用二氯甲烷(100mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.45g，收率：92％)。LCMS(ESI)：m/z 418[M+1]+，淡黄色固体；TLC：Rf0.2(二氯甲烷∶甲醇＝10∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(4-methoxyphenoxy)phenyl)-2,3-dihydro-1H -Imidazo[4,5-c]pyridine)pyrrolidine (109-44) (0.61 g, 1.18 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL). It was then reacted at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (100 mL), washed sequentially with saturated sodium carbonate (30 mL×2) and brine (60 mL), and then the (Dichloromethane:methanol:triethylamine=100:10:1) was purified to give (R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3- Pyrrolidine)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.45 g, yield: 92%). </RTI><RTIID=0.0></RTI></RTI><RTI ID =0.0></RTI>
步骤32d：(R，E)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物44)的制备Step 32d: (R,E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2-butene) Acyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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
将(R)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(110-44)(0.28g，0.671mmol，1.0当量)、4-二甲氨基巴豆酸盐酸盐(144mg，0.872mmol，1.3当量)、HATU(332mg，0.872mmol，1.3当量)和三乙胺(0.28mL，2.013mmol，3.0当量)溶于二氯甲烷(5mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝20∶1)纯化得化合物(R，E)-4-氨基-3-(4-(4-甲氧苯氧基)苯 基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(70mg，收率：20％)。白色固体，熔点：50.4-55.9℃。TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。LCMS(ESI)：m/z 529[M+1]+，1HNMR(CDCl3，500M Hz)：δ7.86-7.83(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)。(R)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidin)-1H-imidazo[4,5-c]pyridine-2 (3H)-ketone (110-44) (0.28 g, 0.671 mmol, 1.0 eq.), 4-dimethylamino croton hydrochloride (144 mg, 0.872 mmol, 1.3 eq.), HATU (332 mg, 0.872 mmol, 1.3 eq. And triethylamine (0.28 mL, 2.013 mmol, 3.0 eq.) was dissolved in dichloromethane (5 mL) and then reacted at room temperature for 1 hour. After the reaction is completed, it is concentrated to give a crude product which is purified by column chromatography (dichloromethane:methanol = 20:1) to give compound (R,E)-4-amino-3-(4-(4-methoxyphenoxy) Phenyl)-1-(3-(1-(4-dimethylamino-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridine-2- Ketone (70 mg, yield: 20%). White solid, melting point: 50.4-55.9 ° C. TLC: Rf 0.2 (dichloromethane:methanol = 10:1). LCMS (ESI): m / z 529 [M + 1] +, 1 HNMR (CDCl 3, 500M Hz): δ7.86-7.83 (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).
实施例33：(R，E)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物45)的制备Example 33: (R,E)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethyl) Amino-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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- Preparation of imidazo[4,5-c]pyridin-2-one) (Compound 45)
步骤33a：(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(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)(化合物109-45)的制备Step 33a: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2, 3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1,3]) Preparation of dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate) (Compound 109-45)
合成方法如实施例32步骤32b，仅是将其中对甲氧基苯酚(403-44)替换为芝麻酚(403-45)(1.21g，8.78mmol，1.5当量)，得到(R)-1-叔丁氧羰基-3-(4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(1.0g，收率：39％)。LCMS(ESI)：m/z 532[M+1]+，灰色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。The synthesis method is as in Example 32, step 32b, except that p-methoxyphenol (403-44) is replaced with sesame phenol (403-45) (1.21 g, 8.78 mmol, 1.5 eq.) to give (R)-1- Tert-Butoxycarbonyl-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazole [4,5-c]pyridine)pyrrolidine (1.0 g, yield: 39%). LCMS (ESI): m / z 532 [M + 1] +, gray solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤33b：(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((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)(化合物110-45)的制备Step 33b: (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4, 5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(pyrrolidin- Preparation of 3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 110-45)
合成方法如实施例32步骤32c，仅是将其中(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(4-甲氧苯氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯 烷(109-44)替换为(R)-1-叔丁氧羰基-3-(4-氨基-2-氧代-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-2，3-二氢-1H-咪唑并[4，5-c]吡啶)吡咯烷(109-45)(1.0g，1.88mmol，1.0当量)，得到(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.76g，收率：94％)。LCMS(ESI)：m/z 432[M+1]+，淡黄色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。The synthesis method is as in Example 32, step 32c, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(4-methoxyphenoxy)) Phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (109-44) is replaced by (R)-1-tert-butoxycarbonyl-3-(4-amino) -2-oxo-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole Alkyl (109-45) (1.0 g, 1.88 mmol, 1.0 eq.) afforded (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1 -(3-Pyrrolidine)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.76 g, yield: 94%). LCMS (ESI): m / z 432 [M + 1] +, as a pale yellow solid; TLC: Rf 0.2 (methylene chloride: methanol = 10).
步骤33c：(R，E)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物45)的制备Step 33c: (R,E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino) -2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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 Preparation of [4,5-c]pyridin-2-one) (Compound 45)
合成方法如实施例32步骤32d，仅是将其中(R)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(110-44)替换为(R)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-吡咯烷)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(110-45)(0.20g，0.464mmol，1.0当量)，得到化合物(R，E)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-(1-(4-二甲氨基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(38mg，收率：15％)。白色固体，熔点：186.3-188.5℃。TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。LCMS(ESI)：m/z 543[M+1]+，1HNMR(CDCl3，500MHz)：δ7.86-7.83(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)。The synthesis method is as in Example 32, step 32d, except that (R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H- Replacement of imidazo[4,5-c]pyridine-2(3H)-one (110-44) with (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy) Phenyl)-1-(3-pyrrolidin)-1H-imidazo[4,5-c]pyridine-2(3H)-one (110-45) (0.20 g, 0.464 mmol, 1.0 eq.) Compound (R,E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2) -butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (38 mg, yield: 15%). White solid, melting point: 186.3-188.5 °C. TLC: Rf 0.2 (dichloromethane:methanol = 10:1). LCMS (ESI): m / z 543 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.86-7.83 (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).
实施例34：(R，E)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-(1-(4-哌啶基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物46)的制备 Example 34: (R,E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butene) Aceno)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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- Preparation of one) (Compound 46)
合成方法如实施例32步骤32d，仅是将其中4-二甲氨基巴豆酸盐酸盐替换为4-哌啶基巴豆酸盐酸盐(109mg，0.529mmol，1.3当量)，得到化合物(R，E)-4-氨基-3-(4-(4-甲氧苯氧基)苯基)-1-(3-(1-(4-哌啶基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(45mg，收率：19％)。白色固体，熔点：79.9-82.4℃。TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。LCMS(ESI)：m/z 569[M+1]+，1HNMR(CDCl3，500MHz)：δ7.87-7.83(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)。Synthetic Method As in Example 32, step 32d, except that 4-dimethylamino crotonate was replaced with 4-piperidinyl croton hydrochloride (109 mg, 0.529 mmol, 1.3 eq.) to afford compound (R, E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butenoyl)pyrrolidine)) -1,3-2H-imidazo[4,5-c]pyridin-2-one (45 mg, yield: 19%). White solid, melting point: 79.9-82.4 ° C. TLC: Rf 0.2 (dichloromethane:methanol = 10:1). LCMS (ESI): m / z 569 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.87-7.83 (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).
实施例35：(R，E)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-(1-(4-哌啶基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物47)的制备Example 35: (R,E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-piperidine) Benz-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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- Preparation of dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 47)
合成方法如实施例33步骤33c，仅是将其中4-二甲氨基巴豆酸盐酸盐替换为4-哌啶基巴豆酸盐酸盐(112mg，0.542mmol，1.3当量)，得到化合物(R，E)-4-氨基-3-(4-(3，4-亚甲二氧基苯氧基)苯基)-1-(3-(1-(4-哌啶基-2-丁烯酰基)吡咯烷))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(70mg，收率：29％)。白色固体，熔点：125.2-128.3℃。TLC：Rf 0.2(二氯甲烷∶甲醇＝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)。The synthesis procedure is as follows: Step 33c of Example 33, except that 4-dimethylamino crotonate was replaced with 4-piperidinyl crotonate (112 mg, 0.542 mmol, 1.3 eq.) to give compound (R, E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butenoyl) Pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (70 mg, yield: 29%). White solid, melting point: 125.2-128.3 °C. TLC: Rf 0.2 (dichloromethane:methanol = 10:1). LCMS (ESI): m / z 583 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.85-7.83 (m, 1H), 7.36 (d, J = 8.5Hz, 2H), 7.08 ( d, J=2.5 Hz, 2H), 6.95-6.90 (m, 1H), 6.80 (d, J=8.0 Hz, 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).
实施例36：4-胺基-1-[(3R)-1-(2-丁烯酰基)哌啶-3-基]-3-(4-苯氧基 苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(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)(化合物48)的制备Example 36: 4-Amino-1-[(3R)-1-(2-butenoyl)piperidin-3-yl]-3-(4-phenoxy Phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4- Preparation of piperidin-1-yl-but-2-enoyl)-piperidin-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 48)
将4-胺基-3-(4-苯氧基苯基)-1-[(3R)-哌啶-3-基]-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(308-11)(80mg，0.2mmol，1当量)、4-(哌啶胺)-2-丁烯酸盐酸盐(49mg，0.24mmol，1.2当量)溶于DCM(5ml)，加入HATU(99mg，0.26mmol，1.3当量)和Et3N(61mg，0.6mmol，3当量)，冰浴下反应1小时。反应完毕，浓缩，甲醇/乙酸乙酯(1∶20)柱层析得白色固体4-胺基-1-[(3R)-1-(2-丁烯酰基)哌啶-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(16mg，收率15％)；纯度96.7％；TLC：Rf 0.5(二氯甲烷∶甲醇＝10∶1)；熔点：85.2～86.0℃；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)。4-Amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c Pyridin-2-one (308-11) (80 mg, 0.2 mmol, 1 eq.), 4-(piperidinamine)-2-butenoic acid salt (49 mg, 0.24 mmol, 1.2 eq. 5ml), was added HATU (99mg, 0.26mmol, 1.3 eq.) and Et 3 N (61mg, 0.6mmol, 3 eq) and the reaction under ice-cooling for 1 hour. After completion of the reaction, the residue was evaporated to mjjjjjjjjjjjjjj 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (16 mg, yield 15%); purity 96.7%; TLC: Rf 0.5 (dichloromethane:methanol = 10:1); m.p.: 85.2 - 86.0 ° C; LC-MS: 553[M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.48 (s, 3.5H) ), 1.70 (s, 1H), 1.98 (m, 2.5H), 2.10 (d, 1.5H, J = 11.56 Hz), 2.21 (t, 0.5H, J = 7.51 Hz), 2.57 (s, 5.5H) , 3.12 (t, 1H, J = 10.84 Hz), 3.27 (s, 2H), 3.48 (t, 1H, J = 10.76 Hz), 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 = 5.44 Hz).
实施例37：4-胺基-1-[(3R)-1-(2-丁烯酰基)二甲胺-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(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)(化合物49)的制备Example 37: 4-Amino-1-[(3R)-1-(2-butenoyl)dimethylamino-3-yl]-3-(4-phenoxyphenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4-piperidin-1-yl-but- Preparation of 2-enoyl)-dimethylamino-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 49)
合成方法如实施例36步骤，仅是将其中4-(哌啶胺)-2-丁烯酸盐酸盐替换为4-(二甲胺)-2-丁烯酸盐酸盐(49mg，0.24mmol，1.2当量)，得到白色固体4-胺基-1-[(3R)-1-(2-丁烯酰基)二甲胺-3-基]-3-(4-苯氧基苯基)-1，3-二氢-2H-咪唑并[4，5-c]吡啶-2-酮(20mg，收率20％)；纯度95.5％；TLC：Rf 0.4(二氯甲烷∶甲醇＝10∶1)；熔点：67～68℃；LC-MS：513[M+1]+；1HNMR(400MHz，CDCl3)：δ1.65(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，2.5 H)，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)。The synthesis procedure was as in Example 36, except that 4-(piperidinamine)-2-butyrate was replaced with 4-(dimethylamine)-2-butenoate (49 mg, 0.24). Ment, 1.2 equivalents, to give 4-amino-1-[(3R)-1-(2-butenoyl)dimethylamino-3-yl]-3-(4-phenoxyphenyl) as a white solid. -1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (20 mg, yield 20%); purity 95.5%; TLC: Rf 0.4 (dichloromethane:methanol = 10: 1); Melting point: 67-68 ° C; LC-MS: 513 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): 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, 2.5 H) , 3.46 (m, 0.5H), 3.83 (d, 0.5H, J = 10.12 Hz), 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 = 7.36 Hz), 7.40 (m, 4H), 7.86 (d, 1H, J = 5.6 Hz).
实施例38：(R)-1-(3-(1-丙烯酰基哌啶))-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物52)的制备Example 38: (R)-1-(3-(1-acryloylpiperidine)-4-amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl )-1,3-2H-imidazo[4,5-c]pyridin-2-one ((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
步骤38a：(R)-1-叔丁氧羰基-3-(4-氨基-3-(1，4-苯并二恶烷-6-氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶基)哌啶(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)(化合物307-52)的制备Step 38a: (R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(1,4-benzodioxan-6-oxy)phenyl)-2-oxo-2, 3-Dihydro-1H-imidazo[4,5-c]pyridyl)piperidine (tert-butyl(R)-3-(4-amino-3-(4-((2,3-dihydrobenzo[b] ][1,4]dioxin-6-yl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate)( Preparation of Compound 307-52)
将1-叔丁氧羰基-3-(4-氨基-3-(4-碘苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶基)哌啶(402-17)(0.65g，1.214mmol，1.0当量)、1，4-苯并二恶烷-6-酚(403-52)(0.28g，1.821mmol，1.5当量)和N，N-二甲基甘氨酸盐酸盐(67.8mg，0.486mmol，0.4当量)溶于二氧六环(8mL)中，再加入碘化亚铜(23mg，0.121mmol，0.1当量)和碳酸铯(1.19g，3.642mmol，3.0当量)，然后在氮气保护中100℃反应20小时。反应液冷却到室温并浓缩，得到的粗产品用柱层析法(二氯甲烷∶甲醇＝40∶1到20∶1)纯化得(R)-1-叔丁氧羰基-3-(4-氨基-3-(1，4-苯并二恶烷-6-氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶基)哌啶(0.26g，收率：39％)。LCMS(ESI)：m/z 560[M+1]+，棕色固体；TLC：Rf 0.4(二氯甲烷∶甲醇＝20∶1)。1-tert-Butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridyl Piperidine (402-17) (0.65 g, 1.214 mmol, 1.0 eq.), 1,4-benzodioxan-6-phenol (403-52) (0.28 g, 1.821 mmol, 1.5 eq.) and N, N-Dimethylglycine hydrochloride (67.8 mg, 0.486 mmol, 0.4 eq.) was dissolved in dioxane (8 mL), and then cuprous iodide (23 mg, 0.121 mmol, 0.1 eq.) and cesium carbonate (1.19). g, 3.642 mmol, 3.0 eq.), then reacted at 100 ° C for 20 hours under nitrogen. The reaction solution is cooled to room temperature and concentrated, and the obtained crude product is purified by column chromatography (dichloromethane:methanol = 40:1 to 20:1) to give (R)-1-tert-butoxycarbonyl-3-(4- Amino-3-(1,4-benzodioxan-6-oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridyl) Piperidine (0.26 g, yield: 39%). LCMS (ESI): m / z 560 [M + 1] +, a brown solid; TLC: Rf 0.4 (dichloromethane: methanol = 20).
步骤38b：(R)-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1-(3-哌啶基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮((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)(化合物308-52)的制备Step 38b: (R)-4-Amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl)-1-(3-piperidinyl)-1H-imidazole [4,5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)) Preparation of oxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 308-52)
将(R)-1-叔丁氧羰基-3-(4-氨基-3-(1，4-苯并二恶烷-6-氧基)苯基)-2-氧代-2，3-二氢-1H-咪唑并[4，5-c]吡啶基)哌啶(307-52)(0.26g，0.472mmol，1. 0当量)溶于二氯甲烷(10mL)中，再向其中加入三氟乙酸(2mL)，然后在室温下反应1小时。将反应混合液用二氯甲烷(100mL)稀释，依次用饱和碳酸钠溶液(30mL×2)和饱和食盐水(60mL)洗涤，然后将有机层用硅胶拌样旋干，之后用柱层析法(二氯甲烷∶甲醇∶三乙胺＝100∶10∶1)纯化得(R)-1-(3-哌啶基)-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(0.195g，收率：90％)。LCMS(ESI)：m/z 460[M+1]+，白色固体；TLC：Rf 0.2(二氯甲烷∶甲醇＝10∶1)。(R)-1-tert-Butoxycarbonyl-3-(4-amino-3-(1,4-benzodioxan-6-oxy)phenyl)-2-oxo-2,3- Dihydro-1H-imidazo[4,5-c]pyridyl)piperidine (307-52) (0.26 g, 0.472 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) Trifluoroacetic acid (2 mL) was then reacted at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride (100 mL), washed sequentially with saturated sodium carbonate (30 mL×2) and brine (60 mL), and then the (Dichloromethane:methanol:triethylamine=100:10:1) was purified to give (R)-1-(3-piperidinyl)-4-amino-3-(4-(1,4-benzo-2) Oster-6-oxy)phenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one (0.195 g, yield: 90%). LCMS (ESI): m / z 460 [M + 1] +, as a white solid; TLC: Rf 0.2 (methylene chloride: methanol = 10).
步骤38c：(R)-1-(3-(1-丙烯酰基哌啶))-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((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)(化合物52)的制备Step 38c: (R)-1-(3-(1-acryloylpiperidine)-4-amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl) -1,3-2H-imidazo[4,5-c]pyridin-2-one ((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
将(R)-1-(3-哌啶基)-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1H-咪唑并[4，5-c]吡啶-2(3H)-酮(308-52)(0.195g，0.424mmol，1.0当量)、丙烯酸(40mg，0.552mmol，1.3当量)、DCC(114mg，0.522mmol，1.3当量)和DMAP(5.1mg，0.042mmol，0.1当量)溶于二氯甲烷(8mL)，然后在室温下反应1小时。反应完成后浓缩得到粗产品，通过柱层析法(二氯甲烷∶甲醇＝20∶1)纯化得化合物(R)-1-(3-(1-丙烯酰基哌啶))-4-氨基-3-(4-(1，4-苯并二恶烷-6-氧基)苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(62mg，收率：28％)。白色固体，熔点：235.0-236.7℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝10∶1)。LCMS(ESI)：m/z 514[M+1]+，1HNMR(CDCl3，500MHz)：δ7.86(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)。(R)-1-(3-piperidinyl)-4-amino-3-(4-(1,4-benzodioxan-6-oxy)phenyl)-1H-imidazo[4 ,5-c]pyridine-2(3H)-one (308-52) (0.195 g, 0.424 mmol, 1.0 eq.), EtOAc (40 mg, 0.552 mmol, 1.3 eq.), DCC (114 mg, 0.522 mmol, 1.3 eq) DMAP (5.1 mg, 0.042 mmol, 0.1 eq.) was dissolved in dichloromethane (8 mL) and then allowed to react at room temperature for 1 hour. After completion of the reaction, the crude product was concentrated, purified by column chromatography (dichloromethane:methanol = 20:1) to give compound (R)-1-(3-(1-propionylpiperidine)-4-amino- 3-(4-(1,4-benzodioxan-6-oxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (62 mg, yield : 28%). White solid, melting point: 235.0-236.7 °C. TLC: Rf 0.5 (dichloromethane:methanol = 10:1). LCMS (ESI): m / z 514 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.86 (d, J = 5.0Hz, 1H), 7.36 (d, J = 9.0Hz, 2H) , 7.08 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 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).
实施例39：(R)-4-氨基-3-(4-苯氧苯基)-1-(3-(1-乙烯磺酰基)哌啶))-1，3-2H-咪唑并[4，5-c]吡啶-2-酮((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-(vinylsulfonyl)piperidin-3-yl)-1，3-dihydro-2H-imidazo[4，5-c]pyridin-2-one)(化合物55) 的制备Example 39: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(3-(1-vinylsulfonyl)piperidine))-1,3-2H-imidazo[4 ,5-c]pyridin-2-one ((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
将(R)-4-氨基-1-(3-哌啶基)-3-(4-苯氧基苯基)-1，3-2H-咪唑并[4，5-c]吡啶-2-酮(308-11)(0.26g，0.648mmol，1.0当量)和三乙胺(0.18mL，1.296mmol，2.0当量)溶于二氯甲烷(20mL)中，用干冰-丙酮浴冷却到-60℃，然后把氯乙基磺酰氯(158mg，0.971mmol，1.5当量)溶于二氯甲烷(5mL)中并逐滴加进去。反应液在-60℃下反应30分钟然后缓慢升到室温。用旋蒸除去溶剂得到粗产物，通过柱层析法(二氯甲烷∶甲醇＝50∶1)纯化得化合物6-53(100mg，收率：31％)。白色固体，熔点：86.3-89.4℃。TLC：Rf 0.5(二氯甲烷∶甲醇＝15∶1)。LCMS(ESI)：m/z 492[M+1]+，1HNMR(CDCl3，500MHz)：δ7.88(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)。(R)-4-Amino-1-(3-piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridine-2- Ketone (308-11) (0.26 g, 0.648 mmol, 1.0 eq.) and triethylamine (0.18 mL, 1.296 mmol, 2.0 eq.) were dissolved in dichloromethane (20 mL) and cooled to -60 ° C with dry ice-acetone bath Then, chloroethylsulfonyl chloride (158 mg, 0.971 mmol, 1.5 eq.) was dissolved in dichloromethane (5 mL) and added dropwise. The reaction solution was reacted at -60 ° C for 30 minutes and then slowly warmed to room temperature. The solvent was evaporated to give a crude crystal. White solid, melting point: 86.3-89.4 °C. TLC: Rf 0.5 (dichloromethane:methanol = 15:1). LCMS (ESI): m / z 492 [M + 1] +, 1 HNMR (CDCl 3, 500MHz): δ7.88 (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=9.5 Hz, 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).
实施例40生物活性试验Example 40 Biological Activity Test
一、BTK酶活性抑制实验I. BTK enzyme activity inhibition experiment
1、实验方法1. Experimental method
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定BTK蛋白激酶活性(参见J Biomol Screen 14：31，2009)。将上述得到的化合物用DMSO溶解后用激酶缓冲液(50mM HEPES-pH 7.5，0.0015％Brij-35，10mM MgCl2，2mM DTT)稀释10倍，在384孔板中加入5μl的10％DMSO溶解的5倍反应终浓度的化合物，无化合物对照孔和无酶活性对照孔中是5μl的10％DMSO。加入10μl 2.5倍反应终浓度的BTK酶溶液(BTK，Cat.No.08-080，Carna)，与化合物后在室温下孵育10分钟，其中无酶活对照孔中加入10μl激酶缓冲液。再加入10μl的2.5倍反应终浓度的底物FAM-labeled SRCtide peptide(Biochem，Cat.No.112394)和ATP(90μM)的底物溶液，起始反应。后在室温下孵育10分钟。28℃下孵育1小时后加25μl终止液(100mM HEPES，pH 7.5， 0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。在Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。计算抑制率，计算公式为抑制率％＝(max-转化)/(max-min)×100％。BTK protein kinase activity was determined using the Caliper mobility shift assay (see J Biomol Screen 14:31, 2009). The compound obtained above was dissolved in DMSO and diluted 10-fold with kinase buffer (50 mM HEPES-pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT), and 5 μl of 10% DMSO was added to the 384-well plate. Five times the final concentration of the compound, 5 μl of 10% DMSO in the control-free and non-enzymatically active control wells. 10 μl of a 2.5-fold final concentration of BTK enzyme solution (BTK, Cat. No. 08-080, Carna) was added, and after incubation with the compound for 10 minutes at room temperature, 10 μl of kinase buffer was added to the enzyme-free control well. Further, 10 μl of a substrate solution of 2.5 times the final concentration of the substrate FAM-labeled SRCtide peptide (Biochem, Cat. No. 112394) and ATP (90 μM) was added to initiate the reaction. After incubation for 10 minutes at room temperature. After incubation at 28 ° C for 1 hour, the reaction was stopped by adding 25 μl of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA). Conversion rate data was read on a Caliper EZ Reader II (Caliper Life Sciences). The inhibition rate was calculated, and the calculation formula was the inhibition rate % = (max - conversion) / (max - min) × 100%.
2、实验结果2, the experimental results
这类化合物能强有力的抑制BTK活性，比阳性对照化合物Ibrutinib和ONO-4059的抑制作用相当或更好。表格1中列出本发明中所述的代表性化合物在BTK检测中所具有的活性。在这些检测中，使用下述级别：对于IC50而言，I＞200nM，200nM＞II＞100nM，100nM＞III＞50nM，50nM＞IV＞10nM，V＜10nM。These compounds potently inhibit BTK activity and are comparable or better than the positive control compounds Ibrutinib and ONO-4059. The activity of representative compounds described in the present invention in the BTK assay is set forth in Table 1. In these assays, the following levels were used: for IC50, I > 200 nM, 200 nM > II > 100 nM, 100 nM > III > 50 nM, 50 nM > IV > 10 nM, V < 10 nM.
表1 BTK酶活性的抑制结果Table 1 Results of inhibition of BTK enzyme activity
Figure PCTCN2016084057-appb-000025
Figure PCTCN2016084057-appb-000025
Figure PCTCN2016084057-appb-000026
Figure PCTCN2016084057-appb-000026
注：表中的化合物编号对应于实施例1-39的化合物编号。Note: The compound numbers in the table correspond to the compound numbers of Examples 1-39.
二、肿瘤细胞增殖抑制实验Second, tumor cell proliferation inhibition experiment
1、实验方法1. Experimental method
采用CellTiter-Glo发光细胞活力检测试剂盒法(Promega，#G7572，Madison，WI)测定三磷酸腺苷(ATP)的含量来评估细胞活力。弥漫性大B细胞淋巴瘤细胞株TMD-8、大B细胞淋巴瘤细胞株SU-DHL-16购买自上海复旦IBS细胞资源中心和美国菌种保藏中心(ATCC)。用胰酶将细胞从细胞培养皿上消化和DPBS培养基重悬后用Scepter自动细胞计数仪(Millipore，#PHCC00000)计数测定细胞密度。将细胞稀释成每毫升含44,000个细胞的溶液。调整密度后的细胞溶液以每孔90μl加入细胞实验板中。孔板置于37℃、5％CO2培养箱培养24小时后加入不同浓度的待试化合物。细胞在10％胎牛血清存在下与化合物一起培养72小时。使用
Figure PCTCN2016084057-appb-000027
 Luminescent Cell Viability Assay kit(见厂家说明书)测定ATP的含量来评估细胞生长抑制。简要来讲，每个孔中加入30μl 
Figure PCTCN2016084057-appb-000028
试剂，摇板10分钟，诱导细胞裂解，用荧光/化学发光分析仪Fluoroskan Ascent FL(Thermo Scientific Fluoroskan Ascent FL)检测记录荧光信号。从二甲基亚砜(DMSO)处理72或120小时的细胞得到最大的信号值。从单独的培养基(细胞数为零)得到最小信号值定义为0。抑制率％＝(最大信号值-化合物信号值)/(最大信号值-最小信号值)×100％。使用GraphPadPrism V5.0(GraphPad Software，San Diego，CA)软件处理数据。通过S形剂量-反应曲线拟合计算IC50值。 Cell viability was assessed by measuring the amount of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI). Diffuse large B-cell lymphoma cell line TMD-8 and large B-cell lymphoma cell line SU-DHL-16 were purchased from Shanghai Fudan IBS Cell Resource Center and American Type Culture Collection (ATCC). The cells were digested with trypsin from the cell culture dish and resuspended in DPBS medium, and the cell density was determined by counting with a Scepter automatic cell counter (Millipore, #PHCC00000). The cells were diluted to a solution containing 44,000 cells per ml. The cell solution after the density adjustment was added to the cell assay plate at 90 μl per well. The plates were placed in a 37 ° C, 5% CO 2 incubator for 24 hours and then added with different concentrations of test compound. The cells were incubated with the compound for 72 hours in the presence of 10% fetal bovine serum. use
Figure PCTCN2016084057-appb-000027
The Luminescent Cell Viability Assay kit (see manufacturer's instructions) was assayed for ATP content to assess cell growth inhibition. Briefly, add 30μl to each well.
Figure PCTCN2016084057-appb-000028
The reagents were shaken for 10 minutes, cell lysis was induced, and fluorescence signals were recorded using a fluorescence/chemiluminescence analyzer Fluoroskan Ascent FL (Thermo Scientific Fluoroskan Ascent FL). The cells were treated with dimethyl sulfoxide (DMSO) for 72 or 120 hours to obtain the maximum signal value. The minimum signal value obtained from a separate medium (zero cell number) is defined as 0. Inhibition rate % = (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) × 100%. Data was processed using GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software. IC50 values were calculated by sigmoidal dose-response curve fitting.
2、实验结果2, the experimental results
这类化合物对肿瘤细胞如TMD-8、SU-DHL-16等有很强的抗细胞增殖的活性，比阳性对照化合物Ibrutinib和ONO-4059的活性相当或更好，下述的表格2中列出本发明中所述的代表性化合物在基于细胞的检测中所具有的抗细胞增殖的活性。在这些检测中，使用下述级别：对于IC50而言，I＞1uM，1uM＞II＞0.1uM，0.1uM＞III＞0.05uM，0.05uM＞IV＞0.01uM，V＜0.01uM。Such compounds have potent anti-cell proliferation activity against tumor cells such as TMD-8, SU-DHL-16, etc., which are comparable or better than the positive control compounds Ibrutinib and ONO-4059, as listed in Table 2 below. Representative compounds described in the present invention have anti-cell proliferation activity in cell-based assays. In these assays, the following levels were used: for IC50, I > 1 uM, 1 uM > II > 0.1 uM, 0.1 uM > III > 0.05 uM, 0.05 uM > IV > 0.01 uM, V < 0.01 uM.
表2 肿瘤细胞增殖的抑制结果Table 2 Inhibition results of tumor cell proliferation
Figure PCTCN2016084057-appb-000029
Figure PCTCN2016084057-appb-000029
注：表中的化合物编号对应于实施例1-39的化合物编号。Note: The compound numbers in the table correspond to the compound numbers of Examples 1-39.
三、蛋白免疫印迹(Western Blot)实验Third, Western Blot (Western Blot) experiment
1、实验方法1. Experimental method
ATCC人体套细胞淋巴瘤细胞Jeko-1和DOHH-2购买自上海拜力生物科技有限公司，悬浮培养生长，加入待试化合物或参考化合物培养1小时后，低速离心 (1200rpm；4min)收集细胞，然后用无血清培养基重悬细胞。加入Goat F(ab’)2Anti-Human IgM(10ug/ml)，2min后，用预冷的PBS洗两次，收集细胞，用生物样品均质器匀浆3次，12,000rpm于4℃离心10min，取上清液。采用Branfor法测定蛋白浓度，加入上样缓冲液(Beyotime，#P0015L)于100℃煮4min，以10％SDS-PAGE电泳分离蛋白后转移至PVDF膜，再用含5％牛血清白蛋白(BSA)(碧云天；CAT No.ST023)的TBST溶液封闭1小时，加一抗β-actin mAb(CST，#4970)、BTK(D3H5)mAb(CST，#8547)或phospho-BTK(Try223)mAb(CST，#5802)于4℃下孵育过夜，然后用TBST液洗膜3×10min。以荧光二抗IRDye@680CW Goat(polyclonal)Anti-Rabbit lgG(H+L)，Highly Cross Adsorbed(LI-COR，#926-68071)室温下避光孵育2h后再洗膜，洗涤条件同上。最后将膜置于LI-COR Odyssey红外荧光扫描成像***上检测成像。ATCC human mantle cell lymphoma cells Jeko-1 and DOHH-2 were purchased from Shanghai Baili Biotechnology Co., Ltd., grown in suspension culture, and added to the test compound or reference compound for 1 hour, then centrifuged at low speed. The cells were collected (1200 rpm; 4 min) and then resuspended in serum-free medium. Goat F(ab')2 Anti-Human IgM (10 ug/ml) was added. After 2 min, the cells were washed twice with pre-cooled PBS, and the cells were collected, homogenized three times with a biological sample homogenizer, and centrifuged at 12,000 rpm for 10 min at 4 °C. Take the supernatant. The protein concentration was determined by Branfor method, and the sample buffer (Beyotime, #P0015L) was added to cook at 100 ° C for 4 min. The protein was separated by 10% SDS-PAGE and transferred to a PVDF membrane, followed by 5% bovine serum albumin (BSA). ) (Biyuntian; CAT No.ST023) TBST solution blocked for 1 hour, plus primary anti-β-actin mAb (CST, #4970), BTK (D3H5) mAb (CST, #8547) or phospho-BTK (Try223) mAb (CST, #5802) Incubate overnight at 4 ° C, then wash the membrane with TBST solution for 3 x 10 min. The membrane was washed with a fluorescent secondary antibody IRDye@680CW Goat (polyclonal) Anti-Rabbit lgG (H+L), Highly Cross Adsorbed (LI-COR, #926-68071) at room temperature for 2 hours, and the washing conditions were the same as above. Finally, the membrane was placed on a LI-COR Odyssey infrared fluorescence scanning imaging system for imaging.
2、实验结果2, the experimental results
实施例11制备的化合物11和参照物Ibrutinib强力抑制Jeko-1和DOHH-2淋巴瘤细胞BTK蛋白磷酸化，使IgM刺激下Jeko-1和DOHH-2细胞p-BTK表达明显下降(结果如图1所示)。由图1中可以看出，本发明提供的化合物11作用于Jeko-1和DOHH-2人淋巴瘤细胞，能有效降低BTK的磷酸化。The compound 11 and the reference substance Ibrutinib prepared in Example 11 strongly inhibited the phosphorylation of BTK protein in Jeko-1 and DOHH-2 lymphoma cells, and the expression of p-BTK in Jeko-1 and DOHH-2 cells was significantly decreased under IgM stimulation (results shown in the figure). 1)). As can be seen from Figure 1, the compound 11 provided by the present invention acts on Jeko-1 and DOHH-2 human lymphoma cells, and is effective in reducing phosphorylation of BTK.
实施例41药代动力学(PK)实验Example 41 Pharmacokinetic (PK) Experiment
1、实验方法1. Experimental method
雄性SD大鼠，体重250-300克，试验前过夜禁食。待试化合物溶解在30％磺丁基-β-环糊精(SBE-β-CD)中，以20mg/kg灌胃给药。给药后15分钟、30分钟和1、2、3、4、6、8及24小时尾端断口取血，每时间点约0.3ml，置于含K2-EDTA的离心管中，离心处理(2,000g，10分钟，4℃)取血浆，储存在-80℃的超低温冰箱中。50μL的血浆样品与5微升内标(IS)混合，用乙酸乙酯萃取。真空干燥后残留物重新溶于乙腈中。对样品进行过滤，并注入到LC-MS/MS分析。Male Sprague-Dawley rats weighing 250-300 g were fasted overnight before the test. The test compound was dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and administered orally at 20 mg/kg. Blood was taken at the end of 15 minutes, 30 minutes and 1, 2, 3, 4, 6, 8 and 24 hours after administration, about 0.3 ml per time point, placed in a centrifuge tube containing K 2 -EDTA, and centrifuged. Plasma (2,000 g, 10 min, 4 ° C) was taken and stored in an ultra-low temperature freezer at -80 °C. 50 μL of the plasma sample was mixed with 5 μl of internal standard (IS) and extracted with ethyl acetate. The residue was redissolved in acetonitrile after drying in vacuo. The sample was filtered and injected into LC-MS/MS analysis.
2、实验结果 2, the experimental results
实施1制备的化合物1和实施例11制备的化合物11灌胃给药后，吸收良好，血液暴露量效高。Cmax分别为544.3和2776.7ng/ml。化合物11半衰期较短(1.2小时)，但是AUC较高(4985.5ng/ml*h)(表3)。表中Tmax是指达峰时间，Cmax是指最大血药浓度，T1/2为半衰期，AUC0-24是指0-24小时时间-浓度曲线下面积，AUCinf是指0-Inf时间-浓度曲线下面积。After the intragastric administration of Compound 1 prepared in Example 1 and Compound 11 prepared in Example 11, the absorption was good and the blood exposure was high. Cmax was 544.3 and 2776.7 ng/ml, respectively. Compound 11 had a shorter half-life (1.2 hours) but a higher AUC (4985.5 ng/ml*h) (Table 3). In the table, Tmax refers to the peak time, Cmax refers to the maximum blood concentration, T1/2 is the half-life, AUC 0-24 refers to the area under the 0-24 hour time-concentration curve, and AUC inf refers to the 0-Inf time-concentration. The area under the curve.
表3.灌胃给药(20mg/kg)药代动力学数据Table 3. Pharmacokinetic data for intragastric administration (20 mg/kg)
Figure PCTCN2016084057-appb-000030
Figure PCTCN2016084057-appb-000030
实施例42药效学实验Example 42 Pharmacodynamics Experiment
1、实验方法1. Experimental method
免疫功能严重缺陷SCAD小鼠购自北京维通利华实验动物技术有限公司，饲养于SPF动物房。培养皿中人弥漫性大B细胞淋巴瘤细胞株TMD-8达到足够数量时，收集细胞，DPBS洗2遍。最后细胞用不含血清的RPMI1640培养基和基质胶(1∶1，v/v)悬浮接种。只有大于90％的存活率(台盼蓝排斥)的单细胞悬液才可用于注射。采用1ml的注射器和25G注射器针头，将悬浮在0.2毫升不含血清的培养基和基质胶(1∶1，v/v)中500万个细胞注入每只小鼠右侧翼皮下区域并小心避开血管。在植入一周左右即可测量出肿瘤大小。使用游标卡尺测量肿瘤的大小。并用以下公式计算肿瘤体积：肿瘤体积＝(长×宽2)/2。SCAD mice with severe immunodeficiency were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. and were housed in SPF animal room. When the human diffuse large B-cell lymphoma cell line TMD-8 reached a sufficient number in the culture dish, the cells were collected and washed twice with DPBS. Finally, cells were seeded with serum-free RPMI 1640 medium and Matrigel (1:1, v/v). Only single cell suspensions with greater than 90% survival (Trypan blue exclusion) are available for injection. Using a 1 ml syringe and a 25G syringe needle, inject 5 million cells suspended in 0.2 ml of serum-free medium and Matrigel (1:1, v/v) into the right flank area of each mouse and carefully avoid Open the blood vessels. Tumor size can be measured after a week or so of implantation. The size of the tumor was measured using a vernier caliper. The tumor volume was calculated using the following formula: tumor volume = (length x width 2 )/2.
当肿瘤体积达到100-300mm3左右，将小鼠分为3个灌胃给药组，即赋形剂对照组，Ibrutinib灌胃给药组(50mg/kg，1次/日)和实施例11制备的化合物11灌胃给药组(25mg/kg，2次/日)。每组6个动物。将Ibrutinib或化合物11溶解在30％磺丁基-β-环糊精(SBE-β-CD)以及1.0摩尔等值的盐酸(pH 3-4)中， 以10ml/kg灌胃给药，连续给药14天。When the tumor volume reached about 100-300 mm 3 , the mice were divided into three intragastric administration groups, namely, vehicle control group, Ibrutinib intragastric administration group (50 mg/kg, once per day) and Example 11 Compound 11 was prepared by intragastric administration (25 mg/kg, 2 times/day). 6 animals per group. Ibrutinib or Compound 11 was dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and 1.0 molar equivalent of hydrochloric acid (pH 3-4), and administered intragastrically at 10 ml/kg continuously. Dosing for 14 days.
2、实验结果2, the experimental results
化合物11和Ibrutinib在TMD-8移植肿瘤模型的抗肿瘤活性极高。化合物11灌胃给药(剂量为25mg/kg，bid)能显著抑制弥漫性大B细胞淋巴瘤细胞株TMD-8的生长，给药14天后，移植肿瘤TMD-8缩小至消失。与给药前比较，各给药组无明显体重下降(图2)。 Compound 11 and Ibrutinib have extremely high antitumor activity in the TMD-8 transplanted tumor model. Administration of Compound 11 by intragastric administration (dose of 25 mg/kg, bid) significantly inhibited the growth of diffuse large B-cell lymphoma cell line TMD-8. After 14 days of administration, the transplanted tumor TMD-8 was reduced to disappear. There was no significant weight loss in each of the drug-administered groups compared to before administration (Fig. 2).
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments may be arbitrarily combined. For the sake of brevity of description, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be considered as the scope of this manual.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。 The above-described embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (23)

  1. 具有式(I)结构的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子：A 2-oxo1,3-dihydroimidazopyridine compound having the structure of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:
    Figure PCTCN2016084057-appb-100001
    Figure PCTCN2016084057-appb-100001
    式中：In the formula:
    X1和X2分别独立选自C或N；X 1 and X 2 are each independently selected from C or N;
    Ar选自苯环或5-6元芳香杂环；Ar is selected from a benzene ring or a 5-6 membered aromatic heterocyclic ring;
    L选自O，S，NR5，CR5R6，OCH2，CH2O；L is selected from the group consisting of O, S, NR 5 , CR 5 R 6 , OCH 2 , CH 2 O;
    Y选自(CHR5)m，C＝O，其中m选自0、1、2、3；Y is selected from (CHR 5 ) m , C=O, wherein m is selected from 0, 1, 2, 3;
    Z选自饱和的5-7元杂环或碳环；Z is selected from a saturated 5-7 membered heterocyclic ring or a carbocyclic ring;
    G选自如下基团：
    Figure PCTCN2016084057-appb-100002
    G is selected from the following groups:
    Figure PCTCN2016084057-appb-100002
    R1和R2分别独立选自：H，C1-C6烷基，卤素，硝基，羟基，C1-C6烷氧基，氰基，氨基，C1-C6烷基取代胺基，酰基，酰胺基；R 1 and R 2 are each independently selected from: H, C 1 -C 6 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, cyano, amino, C 1 -C 6 alkyl substituted amine Base, acyl group, amide group;
    R3和R4分别独立选自：H，C1-C6烷基，C3-C6环烷基，C3-C6环烷基甲基，卤素取代C1-C4烷基，羟基取代C1-C4烷基，C1-C3烷氧基取代C1-C4烷基，氨基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，卤素，硝基，羟基，C1-C6烷氧基，C1-C6烷硫基，C1-C6亚砜基，C1-C6砜基，氰基，氨基，C1-C6烷基取代胺基，酯基，酰基，酰胺基，羧基； R 3 and R 4 are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, halogen substituted C 1 -C 4 alkyl, Hydroxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 - C 4 alkyl, halogen, nitro, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 sulfoxide, C 1 -C 6 sulfonyl, cyano, Amino group, C 1 -C 6 alkyl substituted amine group, ester group, acyl group, amide group, carboxyl group;
    当R3和R4是C1-C6烷基，C1-C6烷氧基，OH或C1-C6烷基取代胺基，并且取代在Ar的相邻位置时，R3和R4可相连组成一个碳环或杂环，选自下列结构：When R 3 and R 4 are C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH or C 1 -C 6 alkyl substituted amine, and substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a carbocyclic or heterocyclic ring selected from the following structures:
    Figure PCTCN2016084057-appb-100003
    Figure PCTCN2016084057-appb-100003
    其中，n选自0、1、2；Q1和Q2分别独立选自O，NR6，CHR6；Wherein n is selected from 0, 1 , 2; Q 1 and Q 2 are each independently selected from O, NR 6 , CHR 6 ;
    R5、R6分别独立选自H，C1-C6烷基；R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl;
    R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，氨基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，杂环取代C1-C4烷基。R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, amino substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino Substituting a C 1 -C 4 alkyl group, the heterocyclic ring is substituted with a C 1 -C 4 alkyl group.
  2. 根据权利要求1所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，所述化合物具有式II所示结构：The 2-oxo 1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to claim 1, wherein the compound has Structure shown in Formula II:
    Figure PCTCN2016084057-appb-100004
    Figure PCTCN2016084057-appb-100004
    式中：X3，X4，X5，X6和X7分别独立选自C或N。Wherein: X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from C or N.
  3. 根据权利要求2所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，X3，X4，X5，X6和X7均选自C；或X3，X4，X5，X6和X7的其中一个选自N，其余选自C。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to claim 2, wherein X 3 , X 4 , X 5 , X 6 and X 7 are each selected from C; or one of X 3 , X 4 , X 5 , X 6 and X 7 is selected from N, and the remainder is selected from C.
  4. 根据权利要求1所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，G选自如下基团：The 2-oxo 1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to claim 1, wherein G is selected from the group consisting of Group:
    Figure PCTCN2016084057-appb-100005
    Figure PCTCN2016084057-appb-100005
  5. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，X1和X2均为C。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , X 1 and X 2 are both C.
  6. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，L选自O，OCH2。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , L is selected from O, OCH 2 .
  7. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，Y选自(CH2)m，其中m为0或1。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , Y is selected from (CH 2 ) m , wherein m is 0 or 1.
  8. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，Z选自如下基团：The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , Z is selected from the following groups:
    Figure PCTCN2016084057-appb-100006
    Figure PCTCN2016084057-appb-100006
  9. 根据权利要求8所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，Z选自如下基团：The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to claim 8, wherein Z is selected from the group consisting of Group:
    Figure PCTCN2016084057-appb-100007
    Figure PCTCN2016084057-appb-100007
  10. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，R3和R4分别独立选自：H，卤素，羟基，C1-C6烷氧基，羟基取代C1-C4烷基，C1-C6烷基取代胺基；The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, hydroxy, C 1 -C 6 alkoxy, hydroxy substituted C 1 -C 4 alkyl, C 1 -C 6 alkyl substituted amine;
    当R3和R4是C1-C6烷氧基或OH时，并且取代在Ar的相邻位置时，R3和 R4可相连组成一个杂环，选自下列结构：When R 3 and R 4 are C 1 -C 6 alkoxy or OH, and when substituted at an adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
    Figure PCTCN2016084057-appb-100008
    其中，n为0或1。
    Figure PCTCN2016084057-appb-100008
    Where n is 0 or 1.
  11. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，R5和R6均为H。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein R 5 and R 6 are both H.
  12. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，C1-C3烷基胺基取代C1-C4烷基，5-6元饱和氮杂环取代C1-C4烷基。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein , R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy is substituted for C 1 -C 4 alkyl, and C 1 -C 3 alkylamino is substituted for C 1 -C 4 alkyl, A 5-6 membered saturated nitrogen heterocycle is substituted for the C 1 -C 4 alkyl group.
  13. 根据权利要求1-4任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to any one of claims 1 to 4, wherein ,
    X1和X2均为C；X 1 and X 2 are both C;
    L选自O，OCH2；L is selected from O, OCH 2 ;
    Y选自(CH2)m，其中m为0或1；Y is selected from (CH 2 ) m , wherein m is 0 or 1;
    Z选自
    Figure PCTCN2016084057-appb-100009
    Z is selected from
    Figure PCTCN2016084057-appb-100009
    R1和R2均为氢；R 1 and R 2 are both hydrogen;
    R3和R4均为氢；或者其中一个为氢，另一个选自卤素或羟基或C1-C6烷氧基；或者当R3和R4为C1-C6烷氧基或OH时，并且取代在Ar的相邻位置，R3和R4可相连组成一个杂环，选自下列结构：R 3 and R 4 are both hydrogen; or one of them is hydrogen and the other is selected from halogen or hydroxy or C 1 -C 6 alkoxy; or when R 3 and R 4 are C 1 -C 6 alkoxy or OH And, in place of the adjacent position of Ar, R 3 and R 4 may be bonded to form a heterocyclic ring selected from the following structures:
    Figure PCTCN2016084057-appb-100010
    其中，n为0或1；
    Figure PCTCN2016084057-appb-100010
    Where n is 0 or 1;
    R5和R6均为H；R 5 and R 6 are both H;
    R7选自H，C1-C6烷基，C1-C3烷氧基取代C1-C4烷基，C1-C3烷基胺基取代 C1-C4烷基，5-6元饱和氮杂环取代C1-C4烷基。R 7 is selected from H, C 1 -C 6 alkyl, C 1 -C 3 alkoxy substituted C 1 -C 4 alkyl, C 1 -C 3 alkylamino substituted C 1 -C 4 alkyl, 5 A -6 member saturated nitrogen heterocycle is substituted for C 1 -C 4 alkyl.
  14. 根据权利要求1所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，其特征在于，所述化合物选自：The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, according to claim 1, wherein the compound is selected from:
    Figure PCTCN2016084057-appb-100011
    Figure PCTCN2016084057-appb-100011
    Figure PCTCN2016084057-appb-100012
    Figure PCTCN2016084057-appb-100012
    Figure PCTCN2016084057-appb-100013
    Figure PCTCN2016084057-appb-100013
    Figure PCTCN2016084057-appb-100014
    Figure PCTCN2016084057-appb-100014
  15. 权利要求1-14任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备布鲁顿酪氨酸激酶抑制剂中的应用。The 2-oxo 1,3-dihydroimidazopyridine compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, for the preparation of Bruton Application in tyrosine kinase inhibitors.
  16. 权利要求1-14任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备防治肿瘤的药物中的应用。The 2-oxo1,3-dihydroimidazopyridine compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof according to any one of claims 1 to 14, for the preparation of a tumor-controlling Application in medicine.
  17. 权利要求1-14任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备防治血液肿瘤的药物中的应用。The 2-oxo1,3-dihydroimidazopyridine compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, for preparing a blood tumor for prevention and treatment The application of the drug.
  18. 根据权利要求17所述的应用，其特征在于，所述血液肿瘤为淋巴瘤、骨髓瘤、淋巴细胞白血病或急性髓系白血病。The use according to claim 17, wherein the hematological tumor is lymphoma, myeloma, lymphocytic leukemia or acute myeloid leukemia.
  19. 权利要求1-14任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子作为布鲁顿酪氨酸激酶抑制剂在制备防治炎症或自身免疫性疾病的药物中的应用。 The 2-oxo1,3-dihydroimidazopyridine compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, as Bruton's cheese The use of a kinase inhibitor for the preparation of a medicament for the prevention or treatment of an inflammatory or autoimmune disease.
  20. 根据权利要求19所述的应用，其特征在于，所述炎症或自身免疫性疾病为类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘。The use according to claim 19, wherein the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, cholestyr's syndrome, and underlying disease asthma.
  21. 一种治疗疾病的药物组合物，其特征在于，包括作为活性成分的权利要求1-14任一项所述的2-氧代1，3-二氢咪唑并吡啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子，以及药学上可接受的载体。A pharmaceutical composition for treating a disease, comprising the 2-oxo1,3-dihydroimidazopyridine compound according to any one of claims 1 to 14 as an active ingredient or a pharmaceutically acceptable compound thereof a salt or a stereoisomer thereof or a prodrug molecule thereof, and a pharmaceutically acceptable carrier.
  22. 根据权利要求21所述的药物组合物，其特征在于，所述疾病是血液肿瘤或与布鲁顿酪氨酸激酶相关的炎症或自身免疫性疾病。The pharmaceutical composition according to claim 21, wherein the disease is a hematological tumor or an inflammatory or autoimmune disease associated with Bruton's tyrosine kinase.
  23. 根据权利要求22所述的药物组合物，其特征在于，所述血液肿瘤为淋巴瘤、骨髓瘤、淋巴细胞白血病、急性髓系白血病；所述炎症或自身免疫性疾病为类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘。 The pharmaceutical composition according to claim 22, wherein the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia; the inflammatory or autoimmune disease is rheumatoid arthritis, erythema Lupus, lupus nephritis, multiple sclerosis, Schöngren's syndrome, and underlying disease asthma.
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