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WO2017041536A1 - Composé oxo-dihydroimidazo pyridine et ses applications - Google Patents

Composé oxo-dihydroimidazo pyridine et ses applications Download PDF

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Publication number
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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Prior art keywords
amino
imidazo
compound
pyridin
dihydro
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Chinese (zh)
Inventor
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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Dongguan Zhengxing-Beite Medicine Technology Co Ltd
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Dongguan Zhengxing-Beite Medicine Technology Co Ltd
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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).

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Abstract

La présente invention concerne un composé 2-oxo-1,3-dihydroimidazo pyridine tel que représenté par la formule (I) et les applications du composé dans la préparation d'un médicament destiné au traitement de diverses maladies impliquant la tyrosine kinase de Bruton (BTK). La recherche montre que le composé décrit est apte à inhiber efficacement l'activité de la BTK, et ainsi, par l'inhibition de la BTK, empêcher la survie, la prolifération et la métastase des cellules tumorales hématologiques malignes. En outre, l'inflammation et des maladies auto-immunes peuvent être atténuées au moyen de l'inhibition de la BTK. Par conséquent, le composé de la présente invention peut être utilisé pour traiter les diverses maladies impliquant la BTK, cette invention s'applique particulièrement au traitement des tumeurs hématologiques malignes, de l'inflammation et des maladies auto-immunes, et présente une forte valeur d'application.
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US10456403B2 (en) 2014-02-21 2019-10-29 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
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US10919899B2 (en) 2017-01-16 2021-02-16 Dongguan Zhenxing-Beite Medicine Technology Co., Ltd. Imidazopyrazine compounds, preparation methods and uses thereof
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US12178818B2 (en) 2019-10-14 2024-12-31 Principia Biopharma Inc. Methods for treating immune thrombocytopenia by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile
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US12049463B2 (en) 2020-12-10 2024-07-30 Genzyme Corporation Crystalline form of Tolebrutinib
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