[go: up one dir, main page]

WO2011096490A1 - Dérivé d'imidazopyridin-2-one - Google Patents

Dérivé d'imidazopyridin-2-one Download PDF

Info

Publication number
WO2011096490A1
WO2011096490A1 PCT/JP2011/052278 JP2011052278W WO2011096490A1 WO 2011096490 A1 WO2011096490 A1 WO 2011096490A1 JP 2011052278 W JP2011052278 W JP 2011052278W WO 2011096490 A1 WO2011096490 A1 WO 2011096490A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pyridin
dihydro
pyrrolo
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2011/052278
Other languages
English (en)
Japanese (ja)
Inventor
雅己 大塚
憲康 萩野谷
正則 市川
大典 松永
博直 斉藤
憲宏 柴田
智之 常深
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Publication of WO2011096490A1 publication Critical patent/WO2011096490A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound having an inhibitory activity on mTOR kinase activity, a pharmacologically acceptable salt thereof, or an immunosuppressant containing them as an active ingredient.
  • Mammalian target of rapamaycin is a 289 kD serine-threonine kinase identified as a target for the macrolide antibacterial rapamycin.
  • Rapamycin is known to have an immunosuppressive effect, and its mechanism of action is to bind to FKBP12 (FK-506 binding protein) in the cell to form a complex, and the rapamycin / FKBP12 complex is converted to mTOR. By binding, it is believed to inhibit the kinase activity of mTOR and inhibit protein synthesis and further proliferation in immune system cells, particularly T cells.
  • FKBP12 FK-506 binding protein
  • MTOR also referred to as FRAP, RAPT1, or RAFT1
  • FRAP FRAP
  • RAPT1 RAFT1
  • RAFT1 RAFT1
  • mTOR is associated with rejection after transplantation surgery, rheumatoid arthritis, systemic lupus erythematosus, discoid lupus erythematosus, polymyositis, scleroderma, mixed connective tissue disease, Hashimoto's disease, primary myxedema, thyrotoxicosis, Pernicious anemia, Good-pasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid, insulin resistant diabetes, type I diabetes, Addison's disease, atrophic gastritis, male infertility , Premature menopause, lens uveitis, multiple sclerosis, ulcerative colitis, Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, autoimmune hematologic disease, autoimmune hemolytic anemia , Idiopathic thrombocytopenia
  • Known compounds having mTOR inhibitory activity include pyridopyrimidine derivatives and imidazopyrazine derivatives (Patent Documents 1 to 3).
  • the inventors of the present invention show that the compound of the present invention represented by the formula (I) potently inhibits the kinase activity of mTOR, and IL- The present invention was completed by finding an excellent growth inhibitory effect against 2-dependent growth.
  • an object of the present invention is to prevent rejection after transplantation surgery containing a compound having excellent mTOR inhibitory activity, or a pharmacologically acceptable salt thereof as an active ingredient, and diseases caused by abnormal immune system and To provide a therapeutic agent, that is, to provide an immunosuppressive agent.
  • A is an 8- to 10-membered partially saturated or aromatic fused bicyclic nitrogen-containing heterocyclic group having 1 to 3 nitrogen atoms, A may have the same or different n R 1 as a substituent, R 1 is a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group (the C 1-4 alkyl group is a C 1-4 alkoxy group or —NR 7a R 7b , or 2 may be the same or different and may be substituted two), a C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, —NR 7a R 7b , —C (O) R 8 , and —C (O) A substituent selected from the group consisting of NR 9a R 9b , n is an integer from 0 to 3, R 7a , R 7b , R 9a , and R 9b are the same or different and each represents a hydrogen
  • R 8 is a hydrogen atom, a hydroxy group, a C 1-4 alkyl group, or a C 1-4 alkoxy group
  • B is a 3- to 7-membered monocyclic saturated or partially saturated cyclic hydrocarbon group, and one or two oxygen atom, sulfur atom, nitrogen atom, sulfinyl group, or sulfonyl group as a ring component May contain, B may have the same or different m R 2 as a substituent, R 2 is a substituent present on the carbon atom or nitrogen atom constituting B;
  • R 2 is a substituent present on the carbon atom that constitutes B, a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group (the C 1-4 alkyl group is C 1 -4 1 to alkoxy groups may be two substituents), C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, C 1-4 alky
  • A is the following condensed bicyclic nitrogen-containing heterocyclic group having 1 to 3 nitrogen atoms, (a) directly connected to the imidazopyridine ring The ring on the side is a partially saturated or aromatic 6-membered ring containing 0 to 2 nitrogen atoms; (B) a condensed bicyclic nitrogen-containing heterocyclic group, wherein the ring not directly connected to the imidazopyridine ring is a partially saturated or aromatic 5-membered ring containing 1 or 2 nitrogen atoms, (3) A is indolyl group, isoindolyl group, indazolyl group, pyrrolopyridyl group, pyrazolopyridyl group, imidazopyridyl group, pyrrolopyrida
  • Therapeutic agent (5) The prevention according to any one of (1) to (4) above, wherein R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, or a methyl group, and R 4 is a hydrogen atom.
  • therapeutic agent (6) The preventive and / or therapeutic agent according to any one of (1) to (5), wherein Q is a bond or a methylene group, (7) The prophylactic and / or therapeutic agent according to any one of (1) to (6) above, wherein R 5 and R 6 are the same or different and are a hydrogen atom, a halogen atom, or a C 1-4 alkyl group.
  • (8) B is a C 3-7 cycloalkyl group, a tetrahydrofuryl group, a dihydropyranyl group, a tetrahydropyranyl group, a dioxanyl group, a piperidyl group, a piperazinyl group, or a 1,1-dioxide tetrahydrothiopyranyl group.
  • R 2 is a substituent present on the carbon atom constituting B
  • R 2 is a hydroxy group, halogen atom, cyano group, oxo group, C 1-4 alkyl group, C 1-4 alkoxy
  • R 2 is a C 1-4 alkyl group, a C 1-4 alkylsulfonyl group, or a C 1-4 alkylcarbonyl group
  • m is an integer from 0 to 2, 1)
  • the present invention also comprises administering to a warm-blooded animal (preferably a human) the compound described in any one of (1) to (21) above or a pharmacologically acceptable salt thereof.
  • a warm-blooded animal preferably a human
  • the compound described in any one of (1) to (21) above or a pharmacologically acceptable salt thereof is provided.
  • a method for preventing and / or treating a disease caused by rejection after transplantation surgery and an abnormality of the immune system is provided.
  • R 1a , R 1b , and R 1c are the same or different and each represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a C 1-4 alkyl group (the C 1-4 alkyl group is a C 1-4 alkoxy group) Or may be substituted by -NR 7a R 7b , or by the same or different two), a C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, -NR 7a R 7b , -C (O) R 8 and a substituent selected from the group consisting of —C (O) NR 9a R 9b , Z is C—R 1d or a nitrogen atom; R 1d is a hydrogen atom, a halogen atom, or a C 1-4 alkyl group, R 7a , R 7b , R 9a , and R 9b are the same or different and each represents a hydrogen atom or
  • R 8 is a hydrogen atom, a hydroxy group, a C 1-4 alkyl group, or a C 1-4 alkoxy group
  • B is a 3- to 7-membered monocyclic saturated or partially saturated cyclic hydrocarbon group, and one or two oxygen atom, sulfur atom, nitrogen atom, sulfinyl group, or sulfonyl group as a ring component May contain, B may have the same or different m R 2 as a substituent, R 2 is a substituent present on the carbon atom or nitrogen atom constituting B;
  • R 2 is a substituent present on the carbon atom that constitutes B, a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group (the C 1-4 alkyl group is C 1 -4 1 to alkoxy groups may be two substituents), C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, C 1-4 alky
  • a pharmacologically acceptable salt thereof as an active ingredient a preventive and / or therapeutic agent for diseases caused by rejection after transplantation surgery and abnormalities of the immune system
  • a preventive and / or therapeutic agent for diseases caused by rejection after transplantation surgery and abnormalities of the immune system (26) The prevention according to the above (25), wherein R 1a , R 1b and R 1c are the same or different and each is a hydrogen atom, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group. / Or therapeutic agent, (27) The preventive and / or therapeutic agent according to the above (25) or (26), wherein R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, or a methyl group, and R 4 is a hydrogen atom.
  • (30) B is a C 3-7 cycloalkyl group, a tetrahydrofuryl group, a dihydropyranyl group, a tetrahydropyranyl group, a dioxanyl group, a piperidyl group, a piperazinyl group, or a 1,1-dioxide tetrahydrothiopyranyl group.
  • R 2 is a substituent present on the carbon atom constituting B
  • R 2 is a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group, or a C 1-4 alkoxy group
  • R 2 is a C 1-4 alkyl group, a C 1-4 alkylsulfonyl group, or a C 1-4 alkylcarbonyl group
  • m is an integer from 0 to 2, 25
  • the present invention also provides administration of a compound described in any one of (25) to (31) above or a pharmacologically acceptable salt thereof to a warm-blooded animal (preferably a human).
  • a warm-blooded animal preferably a human.
  • the present invention provides a method for preventing or treating a disease caused by rejection after transplantation surgery and an immune system abnormality.
  • the compound having the general formula (I) or a pharmacologically acceptable salt thereof has a strong mTOR inhibitory activity and suppressed IL-2-dependent proliferation of T cells. Therefore, it is useful as a preventive and / or therapeutic agent for diseases caused by rejection after transplantation surgery and abnormalities of the immune system, particularly as an immunosuppressant.
  • the “C 1-4 alkyl group” in the present specification is a linear or branched alkyl group having 1 to 4 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, Examples thereof include a sec-butyl group and a tert-butyl group.
  • the “C 3-8 cycloalkyl group” is an alicyclic hydrocarbon group having 3 to 8 carbon atoms
  • the “C 3-7 cycloalkyl group” is an alicyclic group having 3 to 7 carbon atoms.
  • hydrocarbon group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “halogeno C 1-4 alkyl group” is a group in which 1 to 3 identical or different halogen atoms are substituted on the C 1-4 alkyl group, and includes a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.
  • Chloromethyl group dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, 2-trifluoroethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, 1,1 , 2-trichloroethyl group, 1,2,2-trichloroethyl group, 2,2,2-trichloroethyl group and the like.
  • the “C 1-4 alkoxy group” is a group composed of the “C 1-4 alkyl group” and an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
  • the “C 1-4 alkylcarbonyl group” is a group composed of the “C 1-4 alkyl group” and a carbonyl group, and examples thereof include an acetyl group, an ethylcarbonyl group, and a propylcarbonyl group.
  • the “C 1-4 alkylsulfonyl group” is a group in which the C 1-4 alkyl group is substituted with a sulfonyl group, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group.
  • the “C 1-4 alkylene group” is a linear or branched alkylene group having 1 to 4 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, and a methylmethylene group.
  • 8 to 10-membered partially saturated or aromatic condensed bicyclic nitrogen-containing heterocyclic group in the definition of A means 8 to 10-membered partially saturated containing 1 to 3 nitrogen atoms. It may be a bicyclic aromatic ring.
  • the two monocycles constituting the bicyclic nitrogen-containing heterocyclic group are selected from the same or different from a 5-membered ring or a 6-membered ring.
  • fused bicyclic nitrogen-containing heterocyclic groups include indolizinyl group, isoindolyl group, indolyl group, indolinyl group, indazolyl group, pyrrolopyridyl group, pyrazolopyridyl group, imidazolopyridyl group, pyrazolopyrimidinyl group, purinyl group, quinolidinyl group Group, isoquinolyl group, quinolyl group, naphthidinyl group and the like.
  • the “3- to 7-membered monocyclic saturated or partially saturated cyclic hydrocarbon group” in the definition of B is any of a nitrogen atom, an oxygen atom, a sulfur atom, a sulfoxide group, or a sulfonyl group as a ring component. These are the same or different and each represents a 3- to 7-membered saturated or partially saturated cyclic hydrocarbon group which may contain one or two.
  • Examples of such a cyclic hydrocarbon group include a C 3-7 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, Examples include dihydrofuryl group, tetrahydrofuryl group, dihydropyranyl group, tetrahydropyranyl group, dioxanyl group, tetrahydrothienyl group, 1-oxidetetrahydrothiopyranyl group, and 1,1-dioxidetetrahydrothiopyranyl group. .
  • A is an 8- to 10-membered partially saturated or aromatic fused bicyclic nitrogen-containing heterocyclic group containing 1 to 3 nitrogen atoms.
  • the ring directly connected to the imidazopyridine ring is a partially saturated or aromatic 6-membered ring containing 0 to 2 nitrogen atoms, and directly connected to the imidazopyridine ring.
  • the ring not on the side is a partially saturated or aromatic 5-membered ring containing 1 or 2 nitrogen atoms.
  • A may have a nitrogen atom at the condensation site.
  • A More specific examples of A are indolyl group, isoindolyl group, indazolyl group, pyrrolopyridyl group, pyrazolopyridyl group, imidazopyridyl group, pyrrolopyridazinyl group, pyrazolopyridazinyl group, imidazopyridazinyl group Group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, imidazopyrimidinyl group, pyrrolopyrazinyl group, pyrazolopyrazinyl group, or imidazopyrazinyl group, preferably indolyl group, indazolyl group, pyrrolopyridyl group, pyrazolopyridyl group , An imidazopyridyl group, a pyrrolopyridazinyl group, a pyrazolopyrimidinyl group, or a pyrrolopyraziny
  • — (R 1 ) n represents that n identical or different R 1 are substituted with A.
  • R 1 is preferably substituted on the carbon atom constituting A.
  • R 1 represents a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group (the C 1-4 alkyl group is a C 1-4 alkoxy group or —NR 7a R 7b , or , The same or different two may be substituted), a C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, —NR 7a R 7b , —C (O) R 8 , and —C (O) A substituent selected from the group consisting of NR 9a R 9b .
  • R 7a , R 7b , R 9a , and R 9b are the same or different and each represents a hydrogen atom or a C 1-4 alkyl group (the C 1-4 alkyl group may be substituted with one or two hydroxy groups).
  • they are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, or a hydroxyethyl group, and particularly preferably the same or different, a hydrogen atom, a methyl group, or a hydroxyethyl group It is a group.
  • R 8 is a hydrogen atom, a hydroxy group, a C 1-4 alkyl group, or a C 1-4 alkoxy group, preferably a hydrogen atom, a hydroxy group, or a C 1-4 alkoxy group, more preferably A hydroxy group, a methoxy group, or an ethoxy group.
  • R 1 is preferably a fluorine atom, chlorine atom, cyano group, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, trifluoromethyl group, methoxymethyl group, ethoxymethyl group, amino group, methylamino group , Dimethylamino group, methylethylamino group, propylamino group, (2-hydroxyethyl) (methyl) amino group, formyl group, acetyl group, ethylcarbonyl group, ethoxycarbonyl group, carboxyl group, carbamoyl group, and methylcarbamoyl group Substituents selected from the group consisting of the same or different. More preferably, they are the same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group.
  • N is preferably an integer of 0 to 3, more preferably an integer of 0 to 2.
  • 1H-pyrrolo [2,3-b] pyridin-5-yl group 3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl group, 4-chloro-1H-pyrrolo [ 2,3-b] pyridin-5-yl, 3-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yl group, 4-fluoro-1H-pyrrolo [2,3-b] pyridine-5 -Yl group, 3-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl, 4-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl group, 3,4-dimethyl -1H-pyrrolo [2,3-b] pyridin-5-yl, 3-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl group, or 3-chloro-4- Methyl-1H-pyrrolo [2,3-b]
  • B is a 3- to 7-membered monocyclic saturated or partially saturated cyclic hydrocarbon group, and one or two oxygen atom, sulfur atom, nitrogen atom, sulfinyl group, or sulfonyl group as a ring component If a structure having a stereoisomeric relationship exists, these are also included.
  • B are C 3-7 cycloalkyl group, furyl group, pyranyl group, dioxanyl group, piperidyl group, piperazinyl group, thiopyranyl group, 1-oxidethiopyranyl group, or 1,1-di
  • An oxidethiopyranyl group preferably a C 3-7 cycloalkyl group, a tetrahydrofuryl group, a dihydropyranyl group, a tetrahydropyranyl group, a dioxanyl group, a piperidyl group, a piperazinyl group, or a 1,1-dioxide Tetrahydrothiopyranyl group.
  • cyclohexyl group tetrahydro-2H-pyran-2-yl group, tetrahydro-2H-pyran-3-yl group, tetrahydro-2H-pyran-4-yl group, 5,6-dihydro-2H-pyran- It is a 3-yl group or a 1,4-dioxane-2-yl group.
  • — (R 2 ) m represents that m identical or different R 2 are substituted with B.
  • R 2 is substituted for B, a structure having a stereoisomeric relationship is also included.
  • R 2 is a substituent present on a carbon atom or a nitrogen atom constituting B, and when R 2 is substituted on a carbon atom, two identical or different R 2 are substituted on the carbon atom. Also good.
  • R 2 is a substituent present on the carbon atom constituting B
  • R 2 is a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group (the C 1-4 alkyl group). the C 1-4 1 or may be two substituted with an alkoxy group), C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, C 1-4 alkylsulfonyl group, C 1-4 alkylcarbonyl group And a substituent selected from the group consisting of —NR 10a R 10b .
  • R 10a and R 10b are the same or different and are a hydrogen atom or a C 1-4 alkyl group, preferably the same or different and are a hydrogen atom, a methyl group, or an ethyl group, and more preferably both are hydrogen atoms. Is an atom.
  • R 2 substituted on the carbon atom constituting B is preferably a hydroxy group, a halogen atom, a cyano group, an oxo group, a C 1-4 alkyl group, a C 1-4 alkoxy C 1-4 alkyl group, C 1- 4 alkoxy group, C 1-4 alkylsulfonyl group, or C 1-4 alkylcarbonyl group, more preferably hydroxy group, fluorine atom, chlorine atom, cyano group, oxo group, methyl group, ethyl group, methoxy group A methyl group, a methoxy group, an ethoxy group, a methylsulfonyl group, an ethylsulfonyl group, or an acetyl group, particularly preferably a hydroxy group, a fluorine atom, a cyano group, a methyl group, a methoxymethyl group, or a methoxy group.
  • R 2 is a substituent present on the nitrogen atom constituting ring B
  • R 2 is a hydroxy group, a C 1-4 alkyl group (the C 1-4 alkyl group is a C 1-4 alkoxy group). 1 to 2 optionally substituted), C 1-4 alkoxy group, halogeno C 1-4 alkyl group, C 1-4 alkylsulfonyl group, C 1-4 alkylcarbonyl group, and —NR 10a R 10b
  • a substituent selected from the group consisting of R 10a and R 10b are the same as described above.
  • R 2 substituted on the nitrogen atom constituting B is preferably a C 1-4 alkyl group, a C 1-4 alkylsulfonyl group, or a C 1-4 alkylcarbonyl group, and more preferably a methyl group, a methyl group A sulfonyl group or an acetyl group.
  • M represents an integer of 0 to 3, preferably an integer of 0 to 2, and more preferably 0 or 1.
  • the partial structure represented by the formula (IV) is preferably a cyclopropyl group, a cyclohexyl group, a 4-hydroxycyclohexyl group, a 3-methoxycyclohexyl group, a 4-methoxycyclohexyl group, a 4,4-difluorocyclohexyl group, tetrahydrofuran- 3-yl group, 4-hydroxytetrahydrofuran-3-yl group, 4-methoxytetrahydrofuran-3-yl group, tetrahydro-2H-pyran-2-yl group, tetrahydro-2H-pyran-3-yl group, tetrahydro-2H -Pyran-4-yl group, 4-hydroxytetrahydro-2H-pyran-2-yl group, 5-hydroxytetrahydro-2H-pyran-2-yl group, 5-hydroxytetrahydro-2H-pyran-3-yl group, 4-cyanotetrahydro-2
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a halogeno C 1-4 alkyl group, or a cyano group.
  • R 3 is a hydrogen atom or a fluorine atom.
  • R 5 and R 6 are the same or different and represent a hydrogen atom, a halogen atom, or a C 1-4 alkyl group, or R 5 and R 6 form an oxo group together, or, with R 5 It indicates that R 6 may be combined with the carbon atom to which R 6 is bonded to form a C 3-8 cycloalkyl group.
  • R 5 and R 6 are preferably the same or different and each represents a hydrogen atom, a halogen atom, or a C 1-4 alkyl group. More preferably, R 5 is a hydrogen atom, a fluorine atom, or a methyl group, and R 6 is a hydrogen atom or a fluorine atom. Particularly preferably, R 5 is a hydrogen atom, a fluorine atom or a methyl group, and R 6 is a hydrogen atom.
  • Q is a bond or a C 1-4 alkylene group, preferably a bond, a methylene group or an ethylene group, and particularly preferably a bond or a methylene group.
  • the partial structure represented by the formula (V) is preferably a cyclohexylmethyl group, 4-hydroxycyclohexylmethyl group, 3-methoxycyclohexylmethyl group, 4-methoxycyclohexylmethyl group, 4,4-difluorocyclohexylmethyl group, tetrahydro -2H-pyran-2-ylmethyl group, tetrahydro-2H-pyran-3-ylmethyl group, tetrahydro-2H-pyran-4-ylmethyl group, 2- (tetrahydro-2H-pyran-4-yl) ethyl group, 2- Fluoro-2- (tetrahydro-2H-pyran-4-yl) ethyl group, 2- (tetrahydro-2H-pyran-4-yl) propyl group, tetrahydro-2H-pyran-3-ylmethyl group, 4-hydroxytetrahydro- 2H-pyran-2-ylmethyl group, 5-hydroxytetra Dro
  • a preferred combination of the partial structures represented by the formulas (III) and (V) is that the partial structure represented by the formula (III) is a 1H-indol-5-yl group, 4-fluoro -1H-indol-5-yl group, 6-fluoro-1H-indol-5-yl group, 7-fluoro-1H-indol-5-yl group, 7-fluoro-3-methyl-1H-indole-5 Yl group, 7-fluoro-4-methyl-1H-indol-5-yl group, 3,4-dimethyl-7-fluoro-1H-indol-5-yl group, 1H-indazol-5-yl group, 1H- Pyrrolo [2,3-b] pyridin-5-yl group, 3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl group, 4-chloro-1H-pyrrolo [2,3-b] Pyridin
  • Z is C—R 1d or a nitrogen atom.
  • R 1d is a hydrogen atom, a halogen atom, or a C 1-4 alkyl group, preferably a hydrogen atom, a fluorine atom, or a methyl group.
  • R 1a , R 1b , and R 1c are the same or different and each represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a C 1-4 alkyl group (the C 1-4 alkyl group is a C 1-4 alkoxy group) Or may be substituted with -NR 7a R 7b , or one, or the same or different, may be substituted two), a C 1-4 alkoxy group, a halogeno C 1-4 alkyl group, -NR 7a R 7b , -C (O) R 8 and a substituent selected from the group consisting of —C (O) NR 9a R 9b .
  • R 7a , R 7b , R 8 , R 9a , and R 9b are the same as described above.
  • Preferred R 1a , R 1b , and R 1c are the same or different and are a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a C 1-4 alkoxy group, and more preferably a hydrogen atom, a fluorine atom, A chlorine atom, a methyl group, or a methoxy group.
  • R 1a , R 1b and R 1c are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and R 1c is a hydrogen atom or a fluorine atom. It is.
  • Preferred compounds of the present invention represented by the general formulas (I) and (II) are 6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydro-2H-pyran-4 -Ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one, 6- (7-fluoro-1H-indol-5-yl) -1- (tetrahydro-2H-pyran -4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one, 6- (4-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl ) -1- (Tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one, 6- (3-methyl-1H-pyrrolo [2, 3-b] pyridin-5
  • More preferred compounds include 1-[(2S) -1,4-dioxane-2-ylmethyl] -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-imidazo [4,5-b] pyridin-2-one, 1-[(2S) -1,4-dioxane-2-ylmethyl] -6- (4-methyl-1H-pyrrolo [2,3-b] pyridine- 5-yl) -1,3-dihydro-imidazo [4,5-b] pyridin-2-one, 6- (3,4-dimethyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1-[(2S) -1,4-dioxane-2-ylmethyl] -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one, 6- (3-chloro-4- Methyl-1H-pyrrolo [2,
  • the pharmacologically acceptable salt thereof means a compound having a basic substituent among compounds having the formula (I) of the present invention and A and / or B containing a nitrogen atom.
  • a compound refers to such a salt, if desired, and can be converted into a salt according to a commonly used method. . *
  • salts include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, maleate, oxalate, malonic acid Salts of carboxylic acids such as succinate, citrate, malate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate; glutamate, asparagine Examples include salts of amino acids such as acid salts.
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, maleate, oxalate, malonic acid Salts of carboxylic acids such as succinate, citrate, malate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, tol
  • the compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also encompassed by the present invention.
  • the compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof may be solvated by being left in a solvent or recrystallized. Japanese products are also included in the present invention.
  • stereoisomers may exist, and any of these isomers and mixtures of these isomers may be present in the present invention. Is included.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • rejection after transplantation refers to liver, kidney, heart, lung, small intestine, skin, cornea, bone, fetal tissue, bone marrow cell, hematopoietic stem cell, peripheral blood stem cell, umbilical cord blood stem cell, islet cell, It refers to acute rejection that occurs within 3 months after transplantation of transplants such as hepatocytes, nerve cells, and intestinal epithelial cells, and chronic rejection that occurs thereafter, and graft-versus-host disease.
  • Diseases caused by immune system abnormalities include rheumatoid arthritis, systemic lupus erythematosus, discoid lupus erythematosus, polymyositis, scleroderma, mixed connective tissue disease, Hashimoto's disease, primary myxedema, thyroid poisoning, pernicious anemia , Good-pasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid, insulin resistant diabetes, type I diabetes, Addison's disease, atrophic gastritis, male infertility, premature Onset menopause, lensogenic uveitis, multiple sclerosis, ulcerative colitis, Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, autoimmune hematologic disease, autoimmune hemolytic anemia, sudden onset Thrombocytopenia, paroxysmal hemoglobinuria, i
  • the compound having the formula (I) of the present invention can be easily produced according to the processes 1 to 3 described below. Moreover, it can also manufacture without implementing a protective group introduction
  • Process 1 Among the compounds represented by the formula (I), the following compounds can be produced, for example, according to the following reaction formula.
  • R 1 , R 4 , R 5 , Q, A, B and m and n are the same as described above.
  • the conversion from Compound 1 to Compound 2 is performed by subjecting Compound 1 to a reductive amination reaction of a carbonyl compound using a known organic chemical technique.
  • a suitable acid such as acetic acid, hydrochloric acid, or trifluoroacetic acid
  • compound 1 and carbonyl compound in a suitable solvent for example, methanol, dichloromethane, acetic acid, etc.
  • a suitable solvent for example, methanol, dichloromethane, acetic acid, etc.
  • the carbonyl compound may be used in an amount of 1 to excess moles, preferably 1 to 5 moles, relative to 1 mole of Compound 1.
  • the reaction time is 5 minutes to 150 hours, usually 15 minutes to 100 hours.
  • compound 2 can be obtained by subjecting compound 1 to an alkylation reaction using a known organic chemical technique.
  • a suitable solvent for example, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or acetonitrile
  • a suitable solvent for example, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or acetonitrile
  • a suitable solvent for example, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or acetonitrile
  • an appropriate additive eg, triethylbenzylammonium chloride
  • the alkyl halide compound or methanesulfonyl is added at 0 to 300 ° C., preferably at room temperature to 150 ° C. It is performed by treating with an oxyalkyl compound or the like. 1 to excess moles, preferably 1 to 5 moles, may be
  • Conversion from compound 1 to compound 3 is carried out by subjecting compound 1 to an amidation reaction using a known organic chemical technique.
  • an appropriate solvent that does not adversely influence the reaction for example, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, or N, N-dimethylformamide
  • the carboxylic acid compound is reacted at 0 to 50 ° C.
  • a suitable condensing agent such as N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, or diethyl cyanophosphate.
  • the condensing agent may be used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of Compound 1.
  • a base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.
  • a catalytic amount or an excess amount can be used.
  • the reaction time is 10 minutes to 72 hours, usually 30 minutes to 24 hours.
  • an appropriate solvent for example, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, dichloromethane, etc.
  • a mixed solvent thereof that does not adversely affect the reaction with respect to Compound 1.
  • the reaction can also be carried out by reacting a carboxylic acid halogen compound in the presence of an appropriate base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) preferably at 0 to 100 ° C.
  • an appropriate base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.
  • the reaction time is 10 minutes to 72 hours, usually 30 minutes to 24 hours.
  • it can be carried out by reacting Compound 1 with a carboxylic acid compound in an acidic solvent (for example, polyphosphoric acid or the like) from 0 ° C. to the boiling point of the solvent used in the reaction, preferably at 10 ° C. to 120 ° C.
  • the reaction time is 10 minutes to 72 hours, usually 30 minutes to 24 hours.
  • Q 1 represents a methylene group.
  • Conversion from compound 3 to compound 2 is carried out by subjecting compound 3 to a reduction reaction using a known organic chemical technique.
  • a known organic chemical technique for example, in an appropriate solvent (dichloromethane, tetrahydrofuran, dichloromethane, toluene, etc.) that does not adversely affect the compound 3 or a mixed solvent thereof, from ⁇ 78 ° C. to the boiling point used for the reaction, preferably 0 ° C. to 100 ° C.
  • the reaction is carried out by treatment with a suitable reducing agent (for example, lithium aluminum hydride, diborane, lithium borohydride, borane-tetrahydrofuran complex, or borane-dimethyl sulfide complex).
  • a suitable reducing agent for example, lithium aluminum hydride, diborane, lithium borohydride, borane-tetrahydrofuran complex, or borane-dimethyl sulfide complex.
  • the reducing agent may be used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of Compound 3.
  • Lewis acid tin chloride, trifluoroborane ether complex, etc.
  • the reaction time is 1 minute to 60 hours, usually 5 minutes to 24 hours.
  • the conversion from Compound 2 to Compound 4 is performed by introducing a carbonyl group into Compound 2 using a known organic chemical technique.
  • a suitable solvent that does not adversely influence the compound 2 for example, 1,4-dioxane, tetrahydrofuran, dichloromethane, etc.
  • a mixed solvent thereof from ⁇ 10 ° C. to the boiling point of the solvent used in the reaction, preferably 0 ° C.
  • 1,1′-carbonyldiimidazole, N, N′-disuccinimidyl carbonate, triphosgene or the like 1 to excess moles, preferably 1 to 5 moles, may be used per mole of Compound 2.
  • the reaction time is 5 minutes to 60 hours, usually 1 hour to 24 hours.
  • Conversion from compound 4 to compound 5 is carried out by subjecting compound 4 to a coupling reaction with a compound constituting a partial structure containing A represented by formula (III) using a known organic chemical method. Is called.
  • a suitable organoboronic acid, organoboronate, organotin, organozinc, or organomagnesium compound and a suitable transition metal catalyst such as a palladium compound
  • compound 4 in the presence of a suitable organoboronic acid, organoboronate, organotin, organozinc, or organomagnesium compound and a suitable transition metal catalyst (such as a palladium compound), for example, compound 4 can be converted to an organic or inorganic base (for example, Sodium bicarbonate, tripotassium phosphate or diisopropylethylamine), a ligand (for example, triphenylphosphine) and a known reaction promoting additive (for example, lithium chloride or copper iodide).
  • organic or inorganic base
  • the reaction is carried out using an appropriate solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, or water) or a mixed solvent thereof.
  • the temperature is from 0 ° C to 300 ° C, preferably from room temperature to 200 ° C.
  • the above reaction is also carried out by treatment in a sealed tube or under microwave irradiation.
  • the organic boronic acid and the like and the base may be used in an amount of 1 to excess moles, preferably 1 to 5 moles relative to 1 mole of Compound 3.
  • the reaction time is 1 minute to 60 hours, usually 5 minutes to 24 hours.
  • R 1 , R 4 , R 5 , Q, A, B and m and n are the same as described above.
  • M refers to alkyl tin, borate ester or the like.
  • the conversion from compound 4 to compound 6 is performed by subjecting compound 4 to a halogen-metal exchange reaction using a known organic chemical technique.
  • a halogen-metal exchange reaction using a known organic chemical technique.
  • an appropriate diboronic acid ester, an alkylditin compound, etc. and an appropriate transition metal catalyst eg, a palladium compound
  • an organic or inorganic base eg, potassium acetate, sodium carbonate, diisopropylethylamine, etc.
  • a ligand for example, triphenylphosphine
  • a known reaction promoting additive for example, lithium chloride or copper iodide.
  • an appropriate solvent that does not adversely influence the reaction for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, or water
  • the reaction temperature is It is carried out from 0 ° C. to 300 ° C., preferably from room temperature to 200 ° C.
  • the above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation.
  • the diboronic acid ester and the like and the base may be used in an amount of 1 to excess moles, preferably 1 to 5 moles relative to 1 mole of Compound 4.
  • the reaction time is 1 minute to 60 hours, usually 5 minutes to 24 hours.
  • an appropriate solvent that does not adversely affect the reaction with respect to compound 4 for example, benzene, toluene, diethyl ether, tetrahydrofuran, or the like
  • it is ⁇ 100 ° C. to 50 ° C., preferably ⁇ 85 ° C. to 10 ° C.
  • a metal halide or trialkyl such as tributyltin chloride It is performed by reacting with boric acid ester or the like.
  • the reaction time is 1 minute to 24 hours, usually 10 minutes to 8 hours.
  • Conversion from compound 6 to compound 5 is carried out by subjecting compound 6 to a coupling reaction with a compound constituting a partial structure containing A represented by formula (III) using a known organic chemical method.
  • a suitable organic halogen compound or the like and a suitable transition metal catalyst such as a palladium compound
  • the compound 6 may be an organic or inorganic base (such as sodium bicarbonate, tripotassium phosphate, or diisopropylethylamine) as necessary.
  • a ligand for example, triphenylphosphine
  • a known reaction promoting additive for example, lithium chloride or copper iodide.
  • the reaction is carried out using an appropriate solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, or water) or a mixed solvent thereof.
  • the temperature is from 0 ° C to 300 ° C, preferably from room temperature to 200 ° C.
  • the above reaction is carried out by treatment in a sealed tube or under microwave irradiation.
  • the organic boronic acid and the like and the base are used in an amount of 1 to excess moles, preferably 1 to 5 moles relative to 1 mole of Compound 3.
  • the reaction time is 1 minute to 60 hours, preferably 5 minutes to 24 hours.
  • R 1 , R 4 , R 5 , Q, A, B and m and n are the same as described above.
  • Pro refers to a protecting group.
  • a protective group for example, cyclohexene group, trimethylsilylethoxymethyl group, trimethylsilylethyl group, cyanoethyl group, etc.
  • a protective group for example, cyclohexene group, trimethylsilylethoxymethyl group, trimethylsilylethyl group, cyanoethyl group, etc.
  • Pro is a cyclohexene group
  • it is carried out by treating Compound 1 with ethyl 2-cyclohexanonecarboxylate under heating and refluxing in an appropriate solvent (toluene, benzene, xylene, etc.) that does not adversely influence the reaction.
  • 1 to excess moles preferably 1 to 5 moles of ethyl 2-cyclohexanonecarboxylate is used per mole of Compound 1.
  • the reaction time is 5 minutes to 150 hours, preferably 60 minutes to 100 hours.
  • the conversion from compound 7 to compound 8 can be carried out according to the method of alkylation shown in Process 1. It can also be carried out by subjecting compound 7 to Mitsunobu reaction using a known organic chemical technique.
  • an appropriate solvent that does not adversely influence the reaction for example, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, etc.
  • a mixed solvent thereof from ⁇ 30 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 50 ° C.
  • the reaction is carried out by reacting an alcohol compound in the presence of cyanomethylenetributylphosphorane or triphenylphosphine and a suitable Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate.
  • a suitable Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate.
  • the triphenylphosphine and Mitsunobu reagent are used in an amount of 1 to excess moles, preferably 1 to 5 moles per mole of Compound 7.
  • the reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • the conversion from compound 8 to compound 9 can be carried out according to the halogen-metal exchange reaction method shown in Process 2.
  • the conversion from Compound 8 to Compound 10 can be carried out according to the coupling reaction method shown in Process 1.
  • Conversion from Compound 9 to Compound 10 and from Compound 6 to Compound 5 can be carried out according to the method of coupling reaction shown in Process 2.
  • Conversion from compound 9 to compound 6 and from compound 10 to compound 5 is carried out by carrying out a deprotection group reaction on compound 9 or 10 using a known organic chemical technique.
  • the reaction temperature is 0 ° C. to 200 ° C. in an appropriate solvent (for example, ethanol, methanol, propanol, or water) that does not adversely affect the compound 9 or 10 or a mixed solvent thereof.
  • a suitable acid eg sulfuric acid, hydrochloric acid, trifluoroacetic acid
  • the acid is used in an amount of 1 to an excess mole per mole of the compound 9 or 10.
  • the reaction time is 1 minute to 500 hours, preferably 5 minutes to 200 hours.
  • the compound having the formula (I) of the present invention can also be produced by using an intermediate described in International Patent Publication No. 2008/051493 pamphlet.
  • the compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof, is used as the above therapeutic agent or prophylactic agent, it is itself or an appropriate pharmacologically acceptable excipient. It can be mixed with an agent, a diluent and the like, and can be administered orally, for example, by tablet, capsule, granule, powder or syrup, or parenterally by injection or suppository.
  • excipients eg, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, converted aluminum silicate, calcium silicate, magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Colloidal silica; Veagam Waxes such as gay wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fume,
  • the dose of the compound of the present invention can vary greatly depending on various conditions such as drug activity, symptoms of patients (warm-blooded animals, particularly humans), age, weight, etc. 0.01 mg / kg body weight as the lower limit, 5000 mg / kg body weight as the upper limit, and once for intravenous administration, 0.001 mg / kg body weight as the lower limit and 5000 mg / kg body weight as the upper limit from 1 per day It is desirable to administer several times depending on the symptoms.
  • a preferred dosage is 0.1 mg / kg body weight to 100 mg / kg body weight per day.
  • the prophylactic and / or therapeutic agent of the present invention can be administered to mammals in combination with one or more drugs such as immunosuppressive drugs, antibodies used for immunosuppression, rejection drugs, antibiotics, steroid drugs and the like. . In this case, it may be administered as a mixture in which both components are mixed in one preparation, or may be administered as separate preparations. When administered as separate formulations, each formulation may be administered at the same time or may be administered at a time lag. Moreover, the administration method of each formulation may be the same or different.
  • These pharmaceutical compositions are one or more selected from the prophylactic and / or therapeutic agent of the present invention, an immunosuppressive agent, an antibody used for immunosuppression, a rejection therapeutic agent, an antibiotic and a steroid drug. A kit combining the agent may be used.
  • immunosuppressive agents examples include cyclosporin A, tacrolimus (FK506), azathioprine, mizoribine, methotrexate, mycophenolate mofetil, cyclophosphamide, sirolimus, everolimus, prednisolone, methyl
  • immunosuppressive agents examples include prednisolone, infliximab, orthoclone OKT3, anti-human lymphocyte globulin, and deoxyspargarine.
  • Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmycin sulfate, sisomycin sulfate, ceftibbutene, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, cephetamethopivoxil hydrochloride, etc. Can be mentioned.
  • steroid drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, diflucortron valerate, amsinonide, harsinonide Dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisolone valerate acetate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide Flumethasone, alcrometasone propionate, clobetasone butyrate, prednisolone, Pe
  • Example 1 (Cyclopropylmethyl) -6- (1H-indol-5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Process 2 6- (1H-Indol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one Above step 1 The compound (50 mg) obtained in 1 was suspended in 1,4-dioxane (2 ml), and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H was suspended.
  • Example 4 Using the compound (46 mg) obtained in Step 1 of Example 4, the title compound (34 mg) was obtained in the same manner as in Step 1 of Example 1.
  • Example 6 1- (Cyclohexylmethyl) -6- (1H-ind
  • Example 7 6- (1H-Indol-5-yl) -5-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridine-2- on
  • Example 4 Using the compound obtained in Step 1 (60 mg) and 5,6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline (54 mg) The title compound (54 mg) was obtained in the same manner as in Example 1, Step 3.
  • Example 4 The title compound (40 mg) was obtained in the same manner as in Example 1, Step 3, using the compound (60 mg) obtained in Step 1, and isoquinolin-4-ylboronic acid (37 mg).
  • Example 4 The title compound (6 mg) was obtained in the same manner as in Example 1, Step 3, using the compound (60 mg) obtained in Step 1, and quinolin-4-ylboronic acid (37 mg).
  • Example 4 The title compound (45 mg) was obtained in the same manner as in Example 1, Step 3, using the compound (60 mg) obtained in Step 1, and quinolin-5-ylboronic acid (37 mg).
  • Example 4 Compound (75 mg) obtained in Step 1 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (45 mg) was obtained in the same manner as in Step 4 of Example 4 using pyridine (59 mg).
  • Example 4 Compound (110 mg) obtained in Step 1 and tert-butyl 6-methyl-5- (4,4,5,5-tetramethyl-1,3,2) obtained by the method described in WO2007 / 135398 -Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylate (151 mg) was used to give the title compound (44 mg) in the same manner as in Step 1 of Example 1.
  • HRMS (ESI) [(M + H) + ] Calculated: C 20 H 22 N 5 O 2 364.17735; Found: 364.17844.
  • Example 7 Compound (80 mg) obtained in Step 4 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (47 mg) was obtained in the same manner as in Step 1 of Example 1 using pyridine (66 mg).
  • Example 8 Compound (88 mg) obtained in Step 4 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (64 mg) was obtained in the same manner as in Step 1 of Example 1 using pyridine (72 mg).
  • Example 2 Compound (61 mg) obtained in Step 2 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (46 mg) was obtained in the same manner as in Step 1 of Example 1 using pyridine (55 mg).
  • Example 3 Compound (60 mg) obtained in Step 2 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (36 mg) was obtained in the same manner as in Step 1 of Example 1 using pyridine (49 mg).
  • Example 1 Compound (60 mg) obtained in Step 2 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (51 mg) was obtained in the same manner as in Step 1 of Example 1 using pyridine (60 mg).
  • Example 4 Using the compound obtained in Step 1 (60 mg) and [1- (tert-butoxycarbonyl) -1H-indol-2-yl] boric acid (55 mg) in the same manner as Example 1 Step 3 The title compound (23 mg) was obtained.
  • Example 9 Compound (28 mg) obtained in Step 3 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (4.3 mg) was obtained in the same manner as in Step 4 of Example 4 using pyridine (21 mg).
  • Example 27 6- (4-Fluoro-1H-indol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridine-2- on
  • Process 2 6- (7-Fluoro-1H-indol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-
  • the title compound (41 mg) was obtained as a colorless amorphous solid.
  • HRMS (ESI) [(M + H) + ] Calculated: C 20 H 20 FN 4 O 2 367.15703; Found: 367.15743.
  • Example 4 Compound obtained in Step 1 (60 mg) and Tetrahedron. Lett. (45), 2317-2319, 2004 [4-Chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl] boric acid (75 mg) ) To give the title compound (26 mg) in the same manner as in Step 1 of Example 1.
  • HRMS (ESI) [(M + H) + ] Calculated: C 19 H 19 Cl1N 5 O 2 C 19 H 19 Cl1N 5 O 2 ; Found: 384.12663.
  • Process 5 6- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-cyclohex-1-en-1-yl-1- (tetrahydro-2H-pyran-4-ylmethyl)- 1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Example 1 using the compound obtained in Step 4 above (120 mg) and the compound obtained in Step 1 above (95 mg) The title compound (60 mg) was obtained by the same method as in Step 3.
  • Step 6 6- (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4 5-b] Pyridin-2-one
  • Distilled water 1.5 ml was added to an ethanol solution (5 ml) of the compound (58 mg) obtained in the above Step 5, and concentrated sulfuric acid (1.5 ml) was added under ice cooling. It was.
  • the reaction solution was stirred at 70 ° C. for 89 hours. After cooling to room temperature, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and unnecessary substances were filtered.
  • Step 6 6- (4-Methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5 -B] Pyridin-2-one
  • HRMS (ESI) [(M + H) + ] Calculated: C 20 H 22 N 5 O 2 364.17735; Found: 364.17525.
  • Example 48 Using the compound obtained in Step 4 (92 mg) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (33 mg) The title compound (42 mg) was obtained by a method similar to that in Example 1, Step 3. MS (ESI) m / z: 361 (M + H) + . HRMS (ESI) [M + H] + Calculated: C 20 H 20 N 4 O 2 361.16645; Found: 361.16597.
  • methyl iodide (2.2 ml) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes, then warmed to room temperature and stirred for 3 hours. Under ice-cooling, 1N hydrochloric acid aqueous solution was added, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane development) to give the title compound (4.0 g) as a colorless oil.
  • Example 52 Compound (65 mg) obtained in Step 4 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b The title compound (53 mg) was obtained as a colorless solid in the same manner as in Step 1 of Example 1 using pyridine (54 mg). MS (ESI) m / z: 393 (M + H) + . HRMS (ESI) [M + H] + Calculated: C 21 H 24 N 6 O 2 393.20390; Found: 393.20452.
  • Process 3 1- [2- (4-Acetylpiperazin-1-yl) ethyl] -6-bromo-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one obtained in step 2 above
  • the compound (100 mg) was dissolved in chloroform (10 ml), triethylamine (0.128 ml) and acetyl chloride (0.026 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for 1.5 hours.
  • the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol: chloroform development) to give the title compound (114 mg) as a colorless solid.
  • Process 2 1- ⁇ 2- [4- (Methylsulfonyl) piperazin-1-yl] ethyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the compound obtained in Step 1 above (82 mg) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
  • the title compound (68 mg) was obtained as a colorless solid in the same manner as in Step 1 of Example 1 using -1H-pyrrolo [2,3-b] pyridine (59 mg).
  • Methyl 4-oxotetrahydrofuran-3-carboxylate 55% sodium hydride (1.9 g) was suspended in tetrahydrofuran (30 ml), and methyl glycolate (3.6 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes. After stirring at room temperature for 30 minutes, the solvent was distilled off to obtain a colorless solid. This was suspended in dimethyl sulfoxide (20 ml), methyl acrylate (4.3 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 45 minutes.
  • Step 6 1- ⁇ [trans-4- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ tetrahydrofuran-3-yl] methyl ⁇ -3-cyclohex-1-en-1-yl-6- (1H-pyrrolo [2, 3-b] Pyridin-5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Step 7 1- ⁇ [trans-4-hydroxytetrahydrofuran-3-yl] methyl ⁇ -3-cyclohex-1-en-1-yl-6- (1H-pyrrolo [2,3-b] pyridin-5-yl)- 1,3-Dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the title compound (61 mg) was prepared in the same manner as in Example 35, Step 6 using the compound (191 mg) obtained in Step 6 above. Was obtained as a light brown powder.
  • HRMS (ESI) [M + H] + Calculated: C 18 H 17 N 5 O 3 352.14096; Found: 352.14065.
  • Step 6 3-Cyclohex-1-en-1-yl-1- ⁇ [cis-4- (tetra-2H-pyran-2-yloxy) tetrahydrofuran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3 -B] pyridin-5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the compound (91 mg) obtained in Step 5 above and 5- (4,4,4) 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (69 mg) was used in the same manner as in Step 1 of Example 1 to give the title compound ( 82 mg) as a pale yellow oil.
  • Step 7 1- ⁇ [cis-4-hydroxytetrahydrofuran-3-yl] methyl ⁇ -3-cyclohex-1-en-1-yl-6- (1H-pyrrolo [2,3-b] pyridin-5-yl)- 1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the title compound (22 mg) was prepared in the same manner as in Example 35, step 6, using the compound (82 mg) obtained in Step 6 above. Was obtained as a light brown powder.
  • HRMS (ESI) [M + H] + Calculated: C 18 H 17 N 5 O 3 352.14096; Found: 352.14081.
  • Step 6 3-Cyclohex-1-en-1-yl-1- ⁇ [trans-4-methoxytetrahydrofuran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridin-5-yl)- 1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the compound (119 mg) obtained in the above Step 5 and 5- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (197 mg) was used to give the title compound (102 mg) as a pale yellow solid in the same manner as in Step 1 of Example 1.
  • Step 7 1- ⁇ [trans-4-methoxytetrahydrofuran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H-imidazo [4 5-b] pyridin-2-one
  • HRMS (ESI) [M + H] + Calculated: C 19 H 19 N 5 O 3 366.15661; Found: 366.15599.
  • Methyl 4-anilino-2,5-dihydrofuran-3-carboxylate The compound obtained in Step 1 of Example 61 (1.0 g) was dissolved in toluene (20 ml), and aniline (0.76 ml) and p- Toluenesulfonic acid (0.011 g) was added, and the mixture was heated to reflux for 17 hours while dehydrating. After cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane development) to give the title compound (1.2 g) as a pale yellow solid.
  • Step 6 [Cis-5- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ tetrahydro-2H-pyran-3-yl] methanol
  • the compound (267 mg) obtained in the above Step 5 was dissolved in tetrahydrofuran (10 ml) and ice-cooled. Under the above conditions, triethylamine (0.214 ml) and ethyl chloroformate (0.118 ml) were added, and the mixture was stirred at the same temperature for 30 minutes. To the filtrate was added dropwise an aqueous solution (2 ml) of sodium borohydride (77.7 mg) under ice cooling, followed by stirring at room temperature for 22 hours.
  • Tetrahydrofuran was distilled off, saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol: chloroform development) to give the title compound (251 mg) as a colorless oil.
  • Step 7 6-Bromo-1- ⁇ [cis-5- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ tetrahydro-2H-pyran-3-yl] methyl ⁇ -3-cyclohex-1-en-1-yl-1 , 3-Dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Example 35 Using the compound obtained in Step 2 (200 mg) and the compound obtained in Step 6 above (251 mg) The title compound (405 mg) was obtained in the same manner as in Step 35.
  • Process 8 1- ⁇ [cis-5- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ tetrahydro-2H-pyran-3-yl] methyl ⁇ -3-cyclohex-1-en-1-yl-6- (1H- Pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Step 9 1- ⁇ [cis-5-hydroxytetrahydro-2H-pyran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H- Imidazo [4,5-b] pyridin-2-one
  • HRMS (ESI) [M + H] + Calculated: C 19 H 19 N 5 O 3 366.15661; Found: 366.15645.
  • Step 6 3-Cyclohex-1-en-1-yl-1- ⁇ [cis-5-methoxytetrahydro-2H-pyran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridine-5 -Yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Step 7 1- ⁇ [cis-5-methoxytetrahydro-2H-pyran-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H- Imidazo [4,5-b] pyridin-2-one
  • the title compound (68 mg) was obtained as a pale brown powder by the same method as in Example 35, Step 6 using the compound (113 mg) obtained in Step 6 above.
  • Step 6 1-[(2,2-Dimethyltetrahydro-2H-pyran-4-yl) methyl] -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H- Imidazo [4,5-b] pyridin-2-one
  • HRMS (ESI) [(M + H) + ] Calculated: C 21 H 23 N 5 O 2 378.19300; Found: 378.19044.
  • Process 2 6- (3-Amino-1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2- ON
  • the compound (52 mg) obtained in the above Step 1 was made into an ethanol solution (3 ml), hydrazine monohydrate (36 ⁇ l) was added thereto, and the mixture was heated to reflux for 3 hours. Further, hydrazine monohydrate (72 ⁇ l) was added, and the mixture was heated to reflux for 24 hours. Further, hydrazine monohydrate (144 ⁇ l) was added, and the mixture was heated to reflux for 24 hours.
  • Process 1 6- (Trimethylstannyl) pyrazolo [1,5-a] pyrimidine 6-Bromopyrazolo [1,5-a] pyrimidine (150 mg) was dissolved in toluene (3 ml), hexamethylditine (0.188 ml) and tetrakis Triphenylphosphine palladium (92 mg) was added, and the mixture was stirred with heating at 115 ° C. for 2 hr. The reaction mixture was cooled to room temperature, the solvent was evaporated, and the obtained residue was purified by thin layer chromatography (ethyl acetate: hexane development) to give the title compound (145 mg).
  • Step 6 3-Cyclohex-1-en-1-yl-6- (7H-pyrrolo [2,3-c] pyridazin-3-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3- Dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • Example 1 Step 3 using the compound obtained in Step 5 above (40 mg) and the compound obtained in Example 35 Step 4 (100 mg) The title compound (41 mg) was obtained as a pale yellow oily substance by the same procedure as described above.
  • Step 7 6- (7H-pyrrolo [2,3-c] pyridazin-3-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] Pyridin-2-one
  • the title compound (8 mg) was obtained as a green solid in the same manner as in Example 35, Step 6 using the compound (40 mg) obtained in Step 6 above.
  • HRMS (ESI) [M + H] + Calculated: C 18 H 19 N 6 O 2 351.15695; Found: 351.15944.
  • Step 6 6- (6-Chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1,3-dihydro-2H-imidazo [4 5-b] pyridin-2-one
  • HRMS (ESI) [M + H] + Calculated: C 19 H 19 ClN 5 O 2 384.12273; Found: 384.12511.
  • Process 1 (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) ethanone
  • dichloromethane 5 ml
  • Aluminum trichloride (846 mg) was added at room temperature over 10 minutes, followed by acetyl chloride (135 ⁇ l) and stirred at room temperature for 5 hours.
  • the reaction solution was poured into ice-cold water, and dichloromethane was added to carry out a liquid separation operation. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Process 2 6- (3-Acetyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -3-cyclohexyl-1-en-1-yl-1- (tetrahydro-2H-pyran-4-ylmethyl)- 1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one Using the compound obtained in Step 1 above (65 mg) and the compound obtained in Example 35 Step 4 (113 mg), the reaction was carried out. The title compound (26 mg) was obtained in the same manner as in Example 1, Step 3. MS (ESI) m / z: 472 (M + H) + .
  • Step 6 5- [3-Cyclohex-1-en-1yl-2-oxo-1- (tetrahydro-2H-pyran-4-ylmethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridine- 6-yl] -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile
  • Example 35 Using the compound obtained in Step 4 of Step 35 (163 mg) and the compound obtained in Step 5 above (108 mg) The title compound (125 mg) was obtained in the same manner as in Example 1, Step 3.
  • Step 7 5- [2-oxo-1- (tetrahydro-2H-pyran-4-ylmethyl) -2,3-dihydro-1H-imidazo [4,5-b] pyridin-6-yl] -1H-pyrrolo [2, 3-b] pyridine-4-carbonitrile
  • the title compound (54 mg) was obtained in the same manner as in Step 35 of Example 35 using the compound (125 mg) obtained in the above Step 6.
  • HRMS (ESI) [(M + H) + ] Calculated: C 20 H 19 N 6 O 2 375.15695; Found: 375.15940.
  • the reaction solution was cooled again to ⁇ 78 ° C., hexamethylphosphoric triamide (452 ⁇ l) was added, then ethyl cyanoformate (280 ⁇ l) was added at the same temperature, and the mixture was stirred while raising the temperature to 0 ° C. over 1 hour. Distilled water and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane development) to obtain the title compound (210 mg).
  • reaction solution was cooled to ⁇ 15 ° C., trimethylsilyl trifluoromethanesulfonate (92 ⁇ l) was added, and the mixture was stirred for 2 hours while raising the temperature to 0 ° C., and further stirred at room temperature for 3 and a half hours.
  • pyridine 0.2 ml
  • dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added to carry out a liquid separation operation.
  • the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 6 1-[(4-Oxotetrahydro-2H-pyran-3-yl) methyl] -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1,3-dihydro-2H-imidazo [ 4,5-b] pyridin-2-one
  • MS (ESI) m / z: 346 (M + H) + .
  • HRMS (ESI) [M + H] + Calculated: C 19 H 17 N 5 O 3 364.14096; Found: 364.114502.
  • Example 10-7 6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (tetrahydrofuran-3-ylmethyl) -1,3-dihydro-2H-imidazo [4,5-b] pyridine-2- on
  • Step 6 3-Cyclohex-1-en-1-yl-1- ⁇ [(3S) -4-methyl-5-oxomorpholin-3-yl] methyl ⁇ -6- (1H-pyrrolo [2,3-b] pyridine -5-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the title compound (133 mg) was obtained in the same manner as in Step 1 of Example 1 using tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (107 mg). It was.
  • 2,6-anhydro-1-O- [tert-butyl (diphenyl) silyl] -3,4-dideoxy-DL-erythro-hexitol (542 mg) obtained by the method described in 1) was dissolved in methylene chloride (15 ml) Under ice-cooling, pyridine (236 ⁇ l) and benzoyl chloride (255 ⁇ l) were sequentially added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and saturated brine in that order, and the obtained organic layer was dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane development) to obtain the title compound (285 mg) as a brown solid.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Reproductive Health (AREA)
  • Otolaryngology (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un agent prophylactique et/ou thérapeutique, pour rejet après intervention chirurgicale de transplantation, et pour des maladies provoquées par des anomalies du système immunitaire, comprenant un composé représenté par la formule (I) ou un sel pharmacologiquement acceptable de ce dernier. Dans la formule générale (I), A représente un groupe hétérocyclique azoté bicyclique, partiellement saturé ou condensé à un noyau aromatique, ayant 8 à 10 chaînons, et ayant 1 à 3 atomes d'azote ; A peut avoir, en tant que substituants, n substituants R1, identiques ou différents ; n est un entier de 0 à 3 ; B représente un groupe hydrocarboné monocyclique saturé ou partiellement saturé à 3 à 7 chaînons et peut contenir 1 ou 2 atomes d'oxygène, atomes de soufre, atomes d'azote, groupes sulfinyle ou groupes sulfonyle en tant que constituants du noyau ; B peut avoir, en tant que substituants, m substituants R2, identiques ou différents ; R2 représente un substituant présent sur un atome de carbone ou sur un atome d'azote qui forme B ; et Q représente une liaison ou un groupe alkylène en C1-4.
PCT/JP2011/052278 2010-02-04 2011-02-03 Dérivé d'imidazopyridin-2-one Ceased WO2011096490A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010022643 2010-02-04
JP2010-022643 2010-02-04

Publications (1)

Publication Number Publication Date
WO2011096490A1 true WO2011096490A1 (fr) 2011-08-11

Family

ID=44355483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/052278 Ceased WO2011096490A1 (fr) 2010-02-04 2011-02-03 Dérivé d'imidazopyridin-2-one

Country Status (1)

Country Link
WO (1) WO2011096490A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308877A4 (fr) * 2008-08-05 2012-03-14 Daiichi Sankyo Co Ltd Dérivé d'imidazopyridin-2-one
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
JP2021143175A (ja) * 2020-03-12 2021-09-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物
RU2776844C1 (ru) * 2018-09-13 2022-07-27 Киссеи Фармасьютикал Ко., Лтд. Соединение имидазопиридинона
US12083114B2 (en) 2018-12-19 2024-09-10 Disarm Therapeutics, Inc. Inhibitors of SARM1 in combination with neuro-protective agents
US12448374B2 (en) 2018-06-07 2025-10-21 Disarm Therapeutics, Inc. Inhibitors of SARM1

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006108103A1 (fr) * 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
WO2008051493A2 (fr) * 2006-10-19 2008-05-02 Signal Pharmaceuticals, Llc Composés hétéroaryle, compositions contenant ces composés et procédés de traitement faisant appel à ces composés
US20080119496A1 (en) * 2006-11-16 2008-05-22 Pharmacopeia Drug Discovery, Inc. 7-Substituted Purine Derivatives for Immunosuppression
WO2010008777A2 (fr) * 2008-06-23 2010-01-21 Ligand Pharmaceuticals Inc. Pyridines azabicycliques condensées

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006108103A1 (fr) * 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
WO2008051493A2 (fr) * 2006-10-19 2008-05-02 Signal Pharmaceuticals, Llc Composés hétéroaryle, compositions contenant ces composés et procédés de traitement faisant appel à ces composés
US20080119496A1 (en) * 2006-11-16 2008-05-22 Pharmacopeia Drug Discovery, Inc. 7-Substituted Purine Derivatives for Immunosuppression
WO2010008777A2 (fr) * 2008-06-23 2010-01-21 Ligand Pharmaceuticals Inc. Pyridines azabicycliques condensées

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308877A4 (fr) * 2008-08-05 2012-03-14 Daiichi Sankyo Co Ltd Dérivé d'imidazopyridin-2-one
US8436012B2 (en) 2008-08-05 2013-05-07 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
US8785438B2 (en) 2008-08-05 2014-07-22 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
US12448374B2 (en) 2018-06-07 2025-10-21 Disarm Therapeutics, Inc. Inhibitors of SARM1
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
JPWO2020054788A1 (ja) * 2018-09-13 2021-08-30 キッセイ薬品工業株式会社 イミダゾピリジノン化合物
RU2776844C1 (ru) * 2018-09-13 2022-07-27 Киссеи Фармасьютикал Ко., Лтд. Соединение имидазопиридинона
JP7458987B2 (ja) 2018-09-13 2024-04-01 キッセイ薬品工業株式会社 イミダゾピリジノン化合物
US12077531B2 (en) 2018-09-13 2024-09-03 Kissei Pharmaceutical Co., Ltd. Imidazopyridinone compound
US12083114B2 (en) 2018-12-19 2024-09-10 Disarm Therapeutics, Inc. Inhibitors of SARM1 in combination with neuro-protective agents
JP2021143175A (ja) * 2020-03-12 2021-09-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物
JP7504822B2 (ja) 2020-03-12 2024-06-24 キッセイ薬品工業株式会社 イミダゾピリジノン化合物を含む医薬組成物

Similar Documents

Publication Publication Date Title
JP5630867B2 (ja) イミダゾピリジン−２−オン誘導体
AU2021200951B2 (en) Benzolactam compounds as protein kinase inhibitors
JP7700196B2 (ja) Ａ２ａ／ａ２ｂ阻害剤としての縮合ピラジン誘導体
JP6192839B2 (ja) ピロロ［２，３−ｄ］ピリミジニル、ピロロ［２，３−ｂ］ピラジニル、およびピロロ［２，３−ｄ］ピリジニルアクリルアミド
ES2664985T3 (es) Compuestos y métodos para modulación de quinasa, e indicaciones de los mismos
TWI650319B (zh) 用於調節表皮生長因子受體（ｅｇｆｒ）活性之化合物及組合物
KR20150028999A (ko) 5-아자인다졸 화합물 및 이의 사용 방법
CN116783180A (zh) 用于降解ikzf2或ikzf4的三环配体
IL211277A (en) Imidazolidine compounds as an androgen receptor modulator
JP2015529224A (ja) キナーゼをモジュレートするための化合物および方法、ならびにその指標
CA2988502A1 (fr) Modulateurs des recepteurs nucleaires
KR20220063228A (ko) 아졸-융합된 피리다진-3(2h)-온 유도체
JP2024500378A (ja) 多環状ｉｒａｋ及びｆｌｔ３阻害化合物、並びにその使用
WO2011096490A1 (fr) Dérivé d'imidazopyridin-2-one
JP2011178779A (ja) イミダゾピリジン−２−オン誘導体
RU2779018C1 (ru) Бензолактамы в качестве ингибиторов протеинкиназ

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11739838

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11739838

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP