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WO2019088159A1 - Composé purine substituée - Google Patents

Composé purine substituée Download PDF

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Publication number
WO2019088159A1
WO2019088159A1 PCT/JP2018/040479 JP2018040479W WO2019088159A1 WO 2019088159 A1 WO2019088159 A1 WO 2019088159A1 JP 2018040479 W JP2018040479 W JP 2018040479W WO 2019088159 A1 WO2019088159 A1 WO 2019088159A1
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Prior art keywords
group
methyl
substituted
alkyl
different
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Japanese (ja)
Inventor
慎吾 東城
大輔 浦辺
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • 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 pharmaceutically useful substituted purine derivatives and pharmaceutically acceptable salts thereof, and agents for preventing and / or treating autoimmune diseases comprising them as an active ingredient.
  • Autoimmune diseases are disorders that occur in the innate immune system that should play a role in recognizing and eliminating foreign substances such as pathogenic microbes that originally invaded from the outside, and recognize components that constitute their own cells and tissues as foreign substances. It is a general term for diseases in which antibody and autoreactive lymphocytes are constantly produced in excess and inflammation occurs with systemic or organ-specific cytokine production, leading to tissue damage.
  • TLRs Toll-like receptors
  • TLR7 Toll-like receptors
  • compounds acting on TLRs can be expected to selectively control immune reactions elicited from pathogenic microorganisms, autoantibodies, and autoreactive lymphocytes, and can be expected to be fundamentally treated as new autoimmune disease therapeutic agents .
  • TLR9 inhibitory action may cause a decrease in drug efficacy and safety issues as a therapeutic agent for autoimmune diseases (Non-patent Document 3). , 4).
  • chloroquine hydroxychloroquine and the like are known as autoimmune disease therapeutic agents having a TLR inhibitory action (Non-patent Document 5).
  • the object of the present invention is to prevent and / or treat autoimmune diseases, specifically, diseases involving autoimmunity (collagen diseases represented by systemic lupus erythematosus, inflammation, allergy, asthma, graft rejection, graft vs. graft
  • autoimmune diseases specifically, diseases involving autoimmunity (collagen diseases represented by systemic lupus erythematosus, inflammation, allergy, asthma, graft rejection, graft vs. graft
  • Another object of the present invention is to find a compound that inhibits TLR, particularly TLR7, to provide a medicament that is particularly effective for preventing and / or treating autoimmune diseases.
  • the present inventors found that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) is It has been found that it exhibits strong TLR7 inhibitory action and is very useful for the prevention and / or treatment of autoimmune diseases, and has completed the present invention.
  • the present invention is as follows.
  • R 1 is optionally substituted C 1-6 alkoxy, optionally substituted C 3-7 cycloalkoxy, optionally substituted 4 to 7 membered saturated heterocyclic group] oxy, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 alkylthio, 4-membered optionally substituted 1-7 membered A saturated heterocyclic group, an optionally substituted amino, or a halogen atom; R 2 represents C 1-6 alkyl which may be substituted, C 3-7 cycloalkyl which may be substituted, or amino which may be substituted; W 1 represents a single bond or C 1-4 alkylene which may be substituted; Ring Q 1 represents a C 6-10 aromatic carbocyclic group, or a 5- to 10-membered aromatic heterocyclic group; n represents 1, 2, 3 or 4; In the case where there are a plurality of R 3 s , each is independently a hydrogen atom,
  • R 1 is (1) C 1-6 alkoxy (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (D) C 3-7 cycloalkyl (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (E) C 3-7 cycloalkoxy (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (F) phenyl (the group may be substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy), (G) 5- or 6-membered heteroaryl (wherein the group is
  • R 1 is (1) C 1-6 alkoxy (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (D) C 3-7 cycloalkyl (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (E) C 3-7 cycloalkoxy (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (F) phenyl (the group may be substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy), (G) 5- or 6-membered heteroaryl (wherein the group is
  • R 1 is (1) C 1-6 alkoxy (the same group is selected from the group consisting of a halogen atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl, and a 4- to 7-membered saturated heterocyclic group Or 1 to 3 different groups) or (2) a 4- to 10-membered saturated heterocyclic group-oxy (wherein the group is a halogen atom, and C 1-6 alkyl)
  • R 2 is C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms), C 3-7 cycloalkyl or amino, [1 ] The compound or its pharmaceutically acceptable salt as described in any one of-[4].
  • R 3 When there are a plurality of R 3 's, each independently, a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms Or C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), described in any one of [1] to [9] A compound or a pharmaceutically acceptable salt thereof.
  • Q 1 -X 1 is, Q 1 - single bond, Q 1 - (CH 2) m -O-, Q 1 - (CH 2) m -C (O) -, Q 1 - (CH 2) m -NR a- , or Q 1- (CH 2 ) m -C (O) NR a- (wherein, R a is a hydrogen atom or C 1-6 alkyl; m is 0, 1 or 2 Or a pharmaceutically acceptable salt thereof according to any one of [1] to [10].
  • R 4 is (1) -OR b (wherein R b represents C 1-6 alkyl or C 1-6 alkylsulfonyl), (2) —NR c R d (wherein R c and R d each independently represent a hydrogen atom or C 1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms) And (4) a 4- to 10-membered saturated heterocyclic group (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkyl (wherein the group is a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl And may be substituted with 1 to 3 identical or different groups selected from the group consisting of sulfonyl), (D) C 1-6 alkoxy (the group may be substituted with one to three groups of the same or different groups
  • R 5 is (1) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (2) C 1-8 alkyl (the group is (A) halogen atom, (B) cyano (c) hydroxy, (D) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (E) C 3-7 cycloalkyl (the group is the same or different 1 to 4 groups selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (F) C 3-7 cycloalkoxy (the group is a homogeneous or different 1-4 group selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (G) amino (wherein the group is a C 1-6 alkyl (the group is a halogen
  • R 11 is (1) C 1-6 alkoxy (the same group selected from the group consisting of a halogen atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl and a 4- to 7-membered saturated heterocyclic group) And may be substituted with one to three different groups), (2) 4- to 10-membered saturated heterocyclic group-oxy (wherein the group is substituted with a halogen atom, and the same or different 1 to 4 group selected from the group consisting of C 1-6 alkyl May represent); R 12 represents C 1-6 alkyl, or amino; Ring Q 11 represents a benzene ring group or a 5- or 6-membered aromatic heterocyclic group; When there are a plurality of R 13 's , they are each independently (1) Hydrogen atom, (2) halogen atom, (3) Hydroxy, (4) C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms), or (5) C
  • R 11 is C 1-6 alkoxy (the group is substituted with 1 to 3 identical or different groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy; Or a pharmaceutically acceptable salt thereof, according to [16] or [17].
  • R 14 is (1) -NR c R d (wherein R c and R d each independently represent a hydrogen atom or C 1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms) Or (2) a 4- to 10-membered nitrogen-containing saturated heterocyclic group (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkyl (wherein the group is a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl And may be substituted with 1 to 3 identical or different groups selected from the group consisting of sulfonyl), (D) C 1-6 alkoxy (the group may be substituted with one to three groups of the same or different groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy), (E) C 3-7
  • a medicament comprising the compound of any one of [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for an autoimmune disease which comprises the compound according to any one of [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a TLR7 inhibitor comprising, as an active ingredient, the compound according to any one of [1] to [21] or a pharmaceutically acceptable salt thereof.
  • [25] Systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, spontaneous thrombocytopenia comprising the compound according to any one of [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient
  • a therapeutic agent for systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, spontaneous thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, multiple sclerosis or pemphigus Use of a compound according to any one of [1] to [21] or a pharmaceutically acceptable salt thereof for the purpose.
  • Systemic lupus erythematosus in a mammal comprising administering to the mammal an effective amount of a compound according to any one of [1] to [21] or a pharmaceutically acceptable salt thereof,
  • a method of treating lupus nephritis, Sjögren's syndrome, sudden thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, multiple sclerosis or pemphigus A method of treating lupus nephritis, Sjögren's syndrome, sudden thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, multiple sclerosis or pemphigus.
  • the compounds of the present invention exhibit excellent TLR7 inhibitory activity.
  • it is useful as a preventive and / or therapeutic agent for orally administrable autoimmune diseases because of high bioavailability at the time of oral administration. .
  • the number of carbons in the definition of “substituent” may be represented as, for example, “C 1-6 ” or the like.
  • the notation “C 1-6 alkyl” has the same meaning as an alkyl group having 1 to 6 carbon atoms.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is "C 1-4 alkyl". Specific examples of “C 1-6 alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-8 alkyl means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. Preferably, it is “C 1-6 alkyl”, more preferably “C 1-4 alkyl”. Specific examples of “C 1-8 alkyl” include, in addition to the above “C 1-6 alkyl”, for example, heptyl, isoheptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylpropane, octyl, Isooctyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
  • C 2-3 alkenylene means a linear or branched divalent hydrocarbon group having 2 to 3 carbon atoms, containing one or two carbon-carbon double bonds .
  • Examples of “C 2-3 alkenylene” include, for example, ethenylene, propenylene, 1-methylethenylene and the like. Preferably, it is ethenylene.
  • C 3-7 cycloalkyl means a 3 to 7 membered monocyclic saturated or partially unsaturated hydrocarbon group. Preferably, it is "C 3-6 cycloalkyl”. Examples of “C 3-7 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
  • C 3-12 cycloalkyl means a 3- to 12-membered monocyclic or polycyclic saturated or partially unsaturated hydrocarbon group. Preferably, it is "C 3-10 cycloalkyl". Specific examples of “C 3-12 cycloalkyl” include cycloheptyl, cyclooctyl, cycloheptenyl, cyclooctenyl, adamantyl and the like in addition to the above “C 3-7 cycloalkyl”.
  • C 1-8 alkylene is a divalent saturated hydrocarbon group containing a linear or branched divalent saturated hydrocarbon group having 1 to 8 carbon atoms, or a cyclic structure having 3 to 8 carbon atoms It means a hydrocarbon group.
  • linear or branched “C 1-8 alkylene” include, for example, methylene, ethylene, trimethylene, tetramethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene And 2-methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
  • Specific examples of “C 3-8 alkylene” containing a cyclic structure include, for example, groups represented by the following group and the like.
  • C 1-4 alkylene is a divalent saturated hydrocarbon group having a linear or branched divalent saturated hydrocarbon group having 1 to 4 carbon atoms, or a cyclic structure having 3 to 4 carbon atoms It means a hydrocarbon group.
  • Specific examples of the “C 1-4 alkylene” containing a linear, branched or cyclic structure include, for example, an alkylene having 1 to 4 carbon atoms among the above “C 1-8 alkylene”.
  • C 1-6 alkyl portion of “C 1-6 alkoxy” is the same as the above “C 1-6 alkyl”. Preferably, it is "C 1-4 alkoxy”. Examples of “C 1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 3-7 cycloalkoxy is synonymous with “C 3-7 cycloalkyloxy", “C 3-7 cycloalkyl” moiety is the same as defined in the “C 3-7 cycloalkyl”.
  • Specific examples of “C 3-7 cycloalkoxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 1-6 alkyl moiety of the "C 1-6 alkylthio” is the same as defined in the “C 1-6 alkyl". Preferably, it is “C 1-4 alkylthio”. Specific examples of "C 1-6 alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.
  • C 1-6 alkyl portion of “C 1-6 alkylcarbonyl” is the same as the above “C 1-6 alkyl”. Preferably, it is "C 1-4 alkylcarbonyl”. Specific examples of “C 1-6 alkylcarbonyl” include, for example, methylcarbonyl (acetyl), ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, pentylcarbonyl or hexylcarbonyl and the like.
  • C 1-6 alkoxycarbonyl is the same as “C 1-6 alkyloxycarbonyl”, and the “C 1-6 alkyl” moiety is the same as the above “C 1-6 alkyl”. Preferably, it is "C 1-4 alkoxycarbonyl”. Specific examples of “C 1-6 alkoxycarbonyl” include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl and the like.
  • C 1-6 alkyl moiety of the - "mono- or di -C 1-6 alkylamino" is the same as defined in the "C 1-6 alkyl”. Preferred is "mono- or di-C 1-4 alkylamino".
  • mono- or di-C 1-6 alkylamino include, for example, methylamino, dimethylamino, ethylamino, diethylamino, diethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino, methylethylamino , Methylpropylamino, ethylpropylamino or dipropylamino and the like.
  • C 1-6 alkyl moiety of the - "mono- or di -C 1-6 alkylaminocarbonyl” is the same as defined in the "C 1-6 alkyl".
  • di-C 1-6 alkylaminocarbonyl two C 1-6 alkyls may form a ring together with the nitrogen atom to which they are attached.
  • it is "mono- or di-C 1-4 alkylaminocarbonyl".
  • “mono- or di-C 1-6 alkylaminocarbonyl” include, for example, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, pentyl And aminocarbonyl, hexylaminocarbonyl, methylethylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl, azetidine carbonyl, pyrrolidine carbonyl or piperidine carbonyl and the like.
  • C 1-6 alkyl portion of “C 1-6 alkylsulfonyl” is the same as the above “C 1-6 alkyl”. Preferably, it is “C 1-4 alkylsulfonyl”. Specific examples of “C 1-6 alkylsulfonyl” include methylsulfonyl (mesyl), ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl or hexylsulfonyl and the like.
  • C 6-10 aryl means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is “C 6 aryl” (phenyl). Specific examples of “C 6-10 aryl” include, for example, phenyl, 1-naphthyl or 2-naphthyl and the like.
  • a group fused to a 5- to 7-membered saturated hydrocarbon ring cyclopentane or cyclohexane
  • the group etc. which are represented by a following formula are mentioned, for example.
  • a bond crossing the ring means that the “group” is bonded at a substitutable position on the ring.
  • the “C 6-10 aromatic carbocyclic group” in ring Q 1 means an aromatic carbocyclic group having 6 to 10 carbon atoms. Preferably, it is a benzene ring group (phenylene).
  • one or more hetero atoms selected from a benzene ring and a 5- to 7-membered nitrogen atom, a sulfur atom or an oxygen atom are the same or different
  • a ring containing 1 to 4 or a group fused to a 5- to 7-membered saturated hydrocarbon ring (cyclopentane, cyclohexane or cycloheptane) is also included.
  • W 1 bonds only to the aromatic ring.
  • X 1 and R 3 can be bonded at substitutable positions on an aromatic ring or non-aromatic ring.
  • this group the group etc. which are represented by a following formula are mentioned, for example.
  • Examples of “5- to 10-membered heteroaryl” include 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic groups and the like, which include a nitrogen atom, a sulfur atom and oxygen It contains one or more (for example, 1 to 4) same or different hetero atoms selected from atoms.
  • the bicyclic heteroaryl group also includes a fused one of the monocyclic heteroaryl group and an aromatic ring (such as benzene or pyridine) or a nonaromatic ring (such as cyclohexane or piperidine).
  • aromatic ring such as benzene or pyridine
  • nonaromatic ring such as cyclohexane or piperidine
  • a bond that crosses a ring means that the “group” is bonded at a substitutable position on the ring.
  • group is bonded at a substitutable position on the ring.
  • heteroaryl it is meant that it is 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • heteroaryl is a bicyclic group
  • 1-benzoimidazolyl or 2-benzoimidazolyl it may be 4-, 5-, 6- or 7-benzoimidazolyl.
  • Examples of the “5- to 10-membered aromatic heterocyclic group” in the ring Q 1 include 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic groups and the like, and the group is It contains one or more (for example, 1 to 4) same or different hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom.
  • the bicyclic aromatic heterocycle also includes a fused one of the monocyclic aromatic heterocycle and an aromatic ring (such as benzene or pyridine) or a nonaromatic ring (such as cyclohexane or piperidine).
  • ring Q 1 is an aromatic heterocyclic group in which a monocyclic aromatic heterocycle and an aromatic ring or a nonaromatic ring are fused:
  • W 1 bind only to the aromatic ring.
  • X 1 and R 3 can be bonded at substitutable positions on an aromatic ring or non-aromatic ring.
  • the “4- to 10-membered saturated heterocyclic group” is, for example, a 4- to 10-membered monocyclic group having 1 to 3 same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom or Polycyclic saturated heterocyclic groups and the like can be mentioned.
  • the nitrogen atom, the oxygen atom and the sulfur atom are all atoms constituting a ring.
  • the heterocyclic group may be either saturated or partially unsaturated. It is preferably a saturated heterocyclic group, and more preferably a 5- or 6-membered saturated heterocyclic group.
  • the “4- to 10-membered saturated heterocyclic group” contains one or more (for example, 1 to 3) same or different hetero atoms selected from nitrogen atom, sulfur atom or oxygen atom, and is saturated or partially unsaturated
  • a (preferably saturated) 4-membered to 6-membered monocyclic heterocyclic ring and a group in which a benzene ring is fused are also included, but in this case only the monocyclic heterocyclic ring has a “group” bond.
  • the “4- to 10-membered saturated heterocyclic group” include pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuryl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, thiomorpholinyl, dioxothio Morpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoxazolidyl, dioxooxazolidinyl, dioxothiazolidinyl, 5-oxo-1,2,4-oxadiazol-3-yl, 5-oxo-1,2,4-thiadiazol-3-yl, or 5-thioxo-1,2,4-oxadiazol-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, Or
  • the “4- to 7-membered saturated heterocyclic group” means a 4- to 7-membered ring group among the above-mentioned “4- to 10-membered saturated heterocyclic group”.
  • the “4- to 10-membered nitrogen-containing saturated heterocyclic group” has, for example, 1 to 3 nitrogen atoms, and has 1 to 2 same or different atoms optionally selected from oxygen and sulfur atoms And 4-membered to 10-membered monocyclic or polycyclic saturated heterocyclic groups and the like.
  • the nitrogen atom, the oxygen atom and the sulfur atom are all atoms constituting a ring.
  • the ring may be either saturated or partially unsaturated.
  • the bond of the group may be any of a carbon
  • the “4- to 10-membered nitrogen-containing saturated heterocyclic group” includes a saturated bicyclo ring, a saturated fused ring group, and a saturated spiro-ring group having the “4- to 10-membered nitrogen-containing saturated heterocyclic group” as a basic skeleton Is also included.
  • the "group” etc. which are represented by the following group are mentioned.
  • Optionally substituted C 1-6 alkyl “Optionally substituted C 1-6 alkyl”, “optionally substituted C 1-6 alkoxy”, “optionally substituted C 1-6 alkylthio”, “optionally substituted C 1-6 alkylcarbonyl “,” optionally substituted C 1-6 alkoxycarbonyl “,” optionally substituted C 1-6 alkylsulfonyl “,” optionally substituted C 1-8 alkylene " Examples of the substituent of “optionally substituted C 1-4 alkylene” include hydroxy, a halogen atom, C 1-6 alkoxy and the like, with preference given to a halogen atom.
  • Optionally substituted C 3-7 cycloalkyl “optionally substituted C 3-7 cycloalkoxy”, “optionally substituted 4 to 7 membered saturated heterocyclic group”, “optionally substituted Examples of the substituent of the optionally substituted 4- to 7-membered saturated heterocyclic group -oxy ”include a halogen atom, C 1-6 alkyl, C 1-6 alkoxy and the like.
  • substituents of “optionally substituted amino” or “optionally substituted aminocarbonyl” include C 1-6 alkyl and the like.
  • examples of the substituent in “optionally substituted C 1-6 alkoxy” include (A) halogen atom, (B) hydroxy, (C) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (D) C 3-7 cycloalkyl (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (E) C 3-7 cycloalkoxy (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (F) phenyl (the group may be substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy), (G) 5- or 6-membered heteroaryl (where
  • examples of the substituent in the “4- to 10-membered saturated heterocyclic group” include (A) halogen atom, (B) hydroxy, (C) cyano, (D) C 1-6 alkyl (the group is selected from the group consisting of a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl and C 1-6 alkoxy May be substituted with 1 to 3 groups of the same or different types), (E) C 1-6 alkoxy (the group is substituted with 1 to 3 identical or different groups selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be), (F) C 3-7 cycloalkyl (the group may be substituted with one to three identical or different groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy) , (G) C 1-6 alkylcarbonyl (the
  • substituent of “ optionally substituted C 1-8 alkyl” include (A) halogen atom, (B) cyano (c) hydroxy, (D) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (E) C 3-7 cycloalkyl (the group is the same or different 1 to 4 groups selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (F) C 3-7 cycloalkoxy (the group is a homogeneous or different 1-4 group selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (G) amino (wherein the group is a C 1-6 alkyl (the group is a halogen atom, cyano, hydroxy, and C 3-7 cycloalkyl, selected from the group consist
  • Examples of the substituent of “ optionally substituted C 3-12 cycloalkyl” include (A) halogen atom, (B) cyano, (C) hydroxy, (D) C 1-6 alkyl (the group may be substituted with one to three groups of the same or different groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy), (E) C 1-6 alkoxy (the group may be substituted with one to three groups of the same or different groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy), (F) mono- or di-C 1-6 alkylamino, (G) C 1-6 alkylsulfonyl (the group may be substituted with the same or different 1 to 3 halogen atoms), or (h) mono- or di-C 1-6 alkylaminocarbonyl It can be mentioned.
  • R 1 , R 2 , R 3 , R 4 , R 5 , W 1 , W 2 , X 1 , X 2 and ring Q 1 are preferable.
  • the technical scope of this invention is not limited to the range of the compound listed below.
  • the preferred embodiments of the corresponding R 11 , R 12 , R 13 , R 14 , R 15 , W 12 , X 11 , X 12 and ring Q 12 are also according to the following description.
  • R 1 is (1) C 1-6 alkoxy (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (D) C 3-7 cycloalkyl (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (E) C 3-7 cycloalkoxy (the group is substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy May), (F) phenyl (the group may be substituted with one to four groups of the same or different groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy), (G) 5- or 6-membered heteroaryl (wherein the group is
  • R 1 is C 1-6 alkoxy (wherein the group is a halogen atom, hydroxy, C 1-6 alkoxy, C 3-7 cycloalkyl, and a 4- to 7-membered saturated heterocyclic group) And C 1 -C 6 alkoxy (more preferably, it is a halogen atom, hydroxy, and C 1 -C 6 alkoxy). And C 1 -6 alkoxy (which may be substituted with C 1 -6 alkoxy), and more preferably, it may be substituted with one to three groups of the same or different type selected from the group consisting of Is also good).
  • R 2 examples include C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms), C 3-7 cycloalkyl or amino. More preferably C 1-6 alkyl or amino; more preferably C 1-4 alkyl.
  • R 3 is (1) Hydrogen atom, (2) halogen atom, (3) Hydroxy, (4) C 1-6 alkyl (the group may be substituted with one to three groups of the same or different groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy) (6) C1-6 alkoxy (wherein the group is a halogen atom, hydroxy, and C1-6 alkoxy, and the same or different 1 to 3 groups selected from the group consisting of May be replaced by) Can be mentioned.
  • R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms), or C 1-6 alkoxy (the above The group is optionally substituted with the same or different 1 to 3 halogen atoms); more preferably a hydrogen atom or a halogen atom; still more preferably a hydrogen atom or a fluorine atom.
  • R 4 is (1) -OR b (wherein R b represents C 1-6 alkyl or C 1-6 alkylsulfonyl), (2) -NR c R d (wherein R c and R d each represents a hydrogen atom or C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 halogen atoms) Or (3) a 4- to 10-membered saturated heterocyclic group (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkyl (wherein the group is a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl And may be substituted with 1 to 3 identical or different groups selected from the group consisting of sulfonyl), (D) C 1-6 alkoxy (the group may be substituted with one to three groups of the same or different groups selected
  • R 4 (1) -NR c R d (wherein, R c and R d each independently represent a hydrogen atom or C 1-6 alkyl (the group is substituted with the same or different 1 to 3 halogen atoms) Or (2) a 4- to 10-membered nitrogen-containing saturated heterocyclic group (wherein the group is (A) halogen atom, (B) hydroxy, (C) C 1-6 alkyl (wherein the group is a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl And may be substituted with 1 to 3 identical or different groups selected from the group consisting of sulfonyl), (D) C 1-6 alkoxy (the group may be substituted with one to three groups of the same or different groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy), (E) C 3
  • R 4 is a group represented by the following formula (2), (3), (4), (5), (6), (7), or (8):
  • R 16 represents C 1-6 alkyl (wherein the group is a halogen atom, hydroxy, cyano, a 4- to 7-membered saturated heterocyclic group, C 3-7 cycloalkyl, C 1-6 alkoxy, and 1 to 3 groups which may be substituted with the same or different groups selected from the group consisting of C 1-6 alkylsulfonyl), C 3-7 cycloalkyl, C 1-6 alkylcarbonyl, or 4 members to Represents a 7-membered saturated heterocyclic group].
  • W 1 is C 1-4 alkylene; more preferred is methylene.
  • W 2 preferred is a single bond or C 1-8 alkylene. More preferably, it is a single bond or methylene; still more preferably a single bond.
  • Q 1 -X 1 is a Q 1 -single bond, Q 1- (CH 2 ) m -O-, Q 1- (CH 2 ) m -C (O)-, Q 1- (CH 2 ) m -NR a -, or Q 1 - (CH 2) m -C (O) NR a - ( wherein, R a represents a hydrogen atom or C 1-6 alkyl; m is 0, 1 or 2 To represent).
  • Q 1 -single bond, Q 1- (CH 2 ) m -O-, Q 1- (CH 2 ) m -C (O)-(wherein m represents 0 or 1) is Mention may be made, more preferably Q 1 -single bond or Q 1- (CH 2 ) m -O- (wherein, m represents 0 or 1).
  • the ring Q 1 is preferably a benzene ring group or a 5- or 6-membered aromatic heterocyclic group, and more preferably a benzene ring group.
  • X 2 -R 5 is a single bond -R 5 , C 2-3 alkenylene-R 5 , C 2-3 alkenylene-C (O) -R 5 , or-(CH 2 ) k -C (O) -R 5 (wherein k represents 0, 1 or 2), and more preferably a single bond -R 5 , C 2-3 alkenylene-R 5 , or C 2-3 alkenylene-C O) -R 5 is mentioned, More preferably, single bond -R 5 is mentioned.
  • R 5 is (1) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (2) C 1-8 alkyl (the group is (A) halogen atom, (B) cyano (c) hydroxy, (D) C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 halogen atoms), (E) C 3-7 cycloalkyl (the group is the same or different 1 to 4 groups selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (F) C 3-7 cycloalkoxy (the group is a homogeneous or different 1-4 group selected from the group consisting of halogen atoms, cyano, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy May be replaced by), (G) amino (wherein the group is a C 1-6 alkyl (the group is a halogen
  • R 1 is C 1-6 alkoxy (the group may be substituted with the same or different 1 to 3 groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy)
  • R 2 is C 1-4 alkyl
  • W 1 is methylene
  • Ring Q 1 is a benzene ring group
  • n is 1 or 2
  • R 3 is a hydrogen atom or a halogen atom
  • Q 1 -X 1 is a Q 1 -single bond
  • Q 1- (CH 2 ) m -O- Q 1- (CH 2 ) m -C (O)-(wherein m is 0 or 1) Represent)
  • W 2 is a single bond or methylene
  • R 4 is (1) -NR c R d (wherein, R c and R d each independently represent a hydrogen atom or C 1-6 alkyl (the group is substituted with the same or different 1 to 3 hal
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, solvates such as these hydrates or ethanol solvates are also included in the compounds of the present invention. Furthermore, the compounds of the present invention include all forms of crystalline forms.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include mineral acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; and acetates, Propionate, Oxalate, Succinate, Lactate, Malate, Tartrate, Citrate, Maleate, Fumarate, Methanesulfonate, p-Toluenesulfonate, Benzenesulfonate And organic acid salts such as ascorbate, etc. may be mentioned as specific examples.
  • mineral acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate
  • acetates Propionate, Oxalate, Succinate, Lactate, Malate, Tartrate, Citrate, Maleate, Fumarate, Methanesulfonate, p-Toluenesulfonate, Benzenesulfonate
  • organic acid salts such as ascorbate, etc
  • the compounds (1) represented by the formula (1) may exist as tautomers.
  • the compounds of the present invention also include tautomers of the compounds represented by formula (1).
  • the compounds represented by formula (1) may have at least one asymmetric carbon atom. Therefore, the compound of the present invention includes not only racemic forms of the compound represented by Formula (1) but also optically active forms of these compounds. In addition, a deuterium conversion product obtained by converting any one or more of 1 H of the compounds represented by the formula (1) into 2 H (D) is also encompassed in the compounds represented by the formula (1) .
  • the compound of the present invention is synthesized by the production method shown below, and a method combining a known compound and a known synthesis method.
  • Each of the compounds in the reaction formulas also includes the case of forming a salt, and examples of the salt include those similar to the salts of compound (1).
  • These reactions are merely illustrative, and the compounds of the present invention can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.
  • a protective group for example, documents (T.W. Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)), etc.
  • tert-butoxycarbonyl, benzyloxycarbonyl, dimethylformamide, p-toluenesulfonyl, o- can be used as the protecting group for amino group.
  • the Mamorumoto for example, dialkyl acetals, cyclic alkyl acetal, the protecting group of carboxyl group include, for example, tert- butyl ester, orthoester, amide, etc., respectively.
  • the introduction and removal of the protective group can be carried out by methods commonly used in synthetic organic chemistry (eg, TW Greene and PG M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons , Inc., New York (1999), etc.) or a method analogous thereto.
  • Step 1-1 Preparation Step of Compound (1-2)
  • Compound (1-2) can be obtained by reacting compound (1-1) with ammonia in the presence of a base in an inert solvent .
  • a commercially available product or a compound produced by a known synthesis method for example, WO2014127816, Bioorganic and Medicinal Chemistry Letters, 4879, (2006) etc.
  • a synthesis method analogous thereto can be used .
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and the like; Aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, etc.
  • Protonic polar solvents such as water, methanol, ethanol, isopropanol Solvents; and mixed solvents thereof and the like can be mentioned. Preferred is tetrahydrofuran or methanol.
  • the base include, for example, triethylamine, diisopropylethylamine and the like.
  • the reaction temperature is not particularly limited, but is usually selected in the range of -78 ° C to the boiling point of the solvent used. Preferably, it is -78 ° C to 0 ° C.
  • the reaction time is usually 30 minutes to 6 hours.
  • Step 1-2 Process for Producing Compound (1-4)
  • Compound (1-4) is produced by reacting compound (1-2) with compound (1-3) in the presence of a base in an inert solvent. It can be obtained by As the compound (1-3), a commercially available product or a compound produced by a known synthesis method (for example, WO200874752, WO200616178 or the like) or a synthesis method analogous thereto can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; protons such as methanol, ethanol, 1-propanol, isopropanol and 1-butanol Polar solvents; and mixed solvents thereof and the like.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane
  • protons such as methanol, ethanol, 1-propanol, isopropanol and 1-butanol Polar solvents
  • mixed solvents thereof and the like etrahydrofuran is a protic polar solvent.
  • the base include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium and sodium 1-propoxide; metal hydrides such as sodium hydride and the like.
  • the reaction temperature is not particularly limited, but is usually selected in the range of -20 ° C to the boiling point of the solvent used. Preferably, it is ⁇ 20 ° C. to 20 ° C.
  • the reaction time is usually 30 minutes to 12 hours.
  • Step 1-3 Preparation Step of Compound (1-5)
  • Compound (1-5) is prepared by reacting compound (1-4) with di-tert-butyl dicarbonate in the presence of a base in an inert solvent. It can be obtained by
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane and the like; aromatic hydrocarbon solvents such as toluene and xylene; chloroform, dichloromethane, Halogenated hydrocarbons such as 1,2-dichloroethane; Aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide and the like Examples thereof include water, protic polar solvents such as methanol, ethanol and isopropanol; mixed solvents thereof and the like. Preferred are tetrahydrofuran, chloroform and dichloromethane.
  • the base include, for example, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like. Preferred is a combination of triethylamine or diisopropylethylamine with N, N-dimethylaminopyridine.
  • the di-Boc derivative generated as a by-product in this reaction can be converted to the compound (1-5) by adding a metal alkoxide to the reaction system after confirming the disappearance of the compound (1-4).
  • a metal alkoxide sodium methoxide, sodium ethoxide, sodium, sodium 1-propoxide and the like are used.
  • the reaction temperature is not particularly limited, but is usually selected in the range of -20 ° C to the boiling point of the solvent used. Preferably, it is 0 ° C to 20 ° C.
  • the reaction time is usually 1 to 24 hours.
  • Step 1-4 Production Step of Compound (1-8)
  • the compound (1-8) is a compound (1 ⁇ 5), which is a compound (1 ⁇ ) in an inert solvent and in the presence of a Mitsunobu reagent and a phosphine reagent. It can be obtained by reacting with 6).
  • compound (1-8) can be produced by reacting compound (1-5) in a similar manner to known synthetic methods (eg, EP 1550662, (2005), Journal of Medicinal Chemistry, 2964, (2010), etc.) It can also be obtained by reacting with -7).
  • Compounds (1-6) can be used as commercially available products or those produced by known synthetic methods (for example, WO200644454, WO201428669 etc.) or synthetic methods analogous thereto.
  • the compound (1-7) may be a commercially available product or a compound produced by a known synthesis method (for example, US2013 / 1503254, EP1679308, (2006) and the like) or a synthesis method analogous thereto.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; chloroform, dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane; Aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide and the like And the like.
  • Mitsunobu reagent examples include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, tert-butyl azodicarboxylate, bis (2-methoxyethyl) azodicarboxylate, 1 '-(Azodicarbonyl) dipiperidine, 1,1'-azobis (N, N-dimethylformamide) and the like.
  • phosphine reagent examples include, for example, triphenylphosphine, trimethylphosphine, tributylphosphine, trioctylphosphine and the like. Preferably it is triphenyl phosphine and tributyl phosphine.
  • the reaction temperature is not particularly limited, but is usually selected from the range of -20 ° C to the boiling point of the solvent used. Preferably, it is ⁇ 20 ° C. to 60 ° C.
  • the reaction time is usually 5 minutes to 72 hours.
  • Step 1-5 Preparation Step of Compound (1-9)
  • Compound (1-9) can be obtained by reacting compound (1-8) with an acid in an inert solvent.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as toluene and xylene; methyl acetate, acetic acid Ester solvents such as ethyl; halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,2-dichloroethane; acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 And-nonpolar polar solvents such as pyrrolidinone and dimethylsulfoxide; mixed solvents thereof and the like.
  • Preferred is tetrahydrofuran, ethyl acetate, chloroform, dichloromethane.
  • the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as trifluoroacetic acid.
  • the reaction temperature is not particularly limited, but is usually selected in the range of -20 ° C to the boiling point of the solvent used. Preferably, it is 0 ° C to 30 ° C.
  • the reaction time is usually 30 minutes to 24 hours.
  • Step 1-6 Production Step of Compound (1-10)
  • the compound (1-10) can be obtained by reducing the nitro group of the compound (1-9). For example, reduction under acidic conditions using a metal such as zinc, iron, tin or a metal salt such as tin (III); reduction using a sulfide such as sodium dithionite; palladium / carbon under hydrogen atmosphere Catalytic reduction using a metal catalyst such as Raney nickel / carbon, platinum oxide / carbon, rhodium / carbon and the like can be applied.
  • a metal such as zinc, iron, tin or a metal salt such as tin (III)
  • reduction using a sulfide such as sodium dithionite
  • Catalytic reduction using a metal catalyst such as Raney nickel / carbon, platinum oxide / carbon, rhodium / carbon and the like can be applied.
  • the amount of the metal or metal salt to be used is generally 1 mol to 100 mol, preferably 2 mol to 20 mol, per 1 mol of compound (1-9).
  • the amount of the acid to be used is generally 1 mol to 100 mol, preferably 1 mol to 20 mol, per 1 mol of compound (1-9).
  • the reduction reaction is carried out in an inert solvent.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane
  • ester solvents such as methyl acetate and ethyl acetate
  • protic polar solvents such as water, methanol, ethanol, and isopropanol
  • mixed solvents thereof and the like The reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to 100 ° C.
  • the reaction time is usually 30 minutes to 12 hours.
  • This reaction can be carried out in the presence of an acid, if necessary.
  • the acid include organic acids such as formic acid, acetic acid and trifluoroacetic acid, and inorganic acids such as ammonium chloride.
  • the amount of the acid used is at least 0.1 mol per 1 mol of compound (1-9).
  • the amount of the metal catalyst to be used is generally 0.1 to 1000% by weight, preferably 1 to 100% by weight, relative to compound (1-9).
  • the reaction is carried out in an inert solvent.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane
  • ester solvents such as methyl acetate and ethyl acetate
  • protic polar solvents such as water, methanol, ethanol, and isopropanol
  • the hydrogen pressure is usually about 1 to about 100 atm, preferably about 1 to about 5 atm.
  • the reaction temperature is not particularly limited, but is usually 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is generally 30 minutes to 72 hours, preferably 1 hour to 24 hours.
  • This reaction can be carried out in the presence of an acid catalyst or a one-electron scavenger, as required.
  • the acid catalyst include organic acids such as formic acid, acetic acid and trifluoroacetic acid; and inorganic acids such as sulfuric acid, hydrochloric acid and hydrobromic acid.
  • the amount of the acid used is at least 0.1 mol per 1 mol of compound (1-9).
  • tetracyanoquinodimethane or the like is used as a monoelectron scavenger.
  • the amount of the one electron capturing agent to be used is at least 0.005 mol per 1 mol of compound (1-9).
  • Step 1-7 Preparation Step of Compound (1-13)
  • Compound (1-13) is reacted with compound (1-11) in the presence of an oxidizing agent in an inert solvent.
  • an oxidizing agent in an inert solvent.
  • the compound (1-11) a commercially available product or a compound produced by a known synthesis method (for example, US200619965, Journal of Medicinal Chemistry, 3680, (2003) or the like) or a synthesis method analogous thereto can be used.
  • an acetal that is an equivalent thereof can also be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; acetonitrile, propionitrile, N, N-dimethylformamide, N, N Aprotic polar solvents such as dimethylacetamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; protic polar solvents such as water, methanol, ethanol and isopropanol; mixed solvents thereof and the like.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane
  • acetonitrile, propionitrile N, N-dimethylformamide, N, N Aprotic polar solvents such as dimethylacetamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide
  • protic polar solvents such as water
  • oxidizing agent examples include, for example, iron (III) chloride, oxone and the like.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to the boiling point of the solvent used. Preferably, it is 0 ° C to 100 ° C.
  • the reaction time is usually 30 minutes to 24 hours.
  • Compound (1-13) can also be obtained by reacting compound (1-10) with compound (1-12) in an inert solvent or in the absence of a solvent.
  • compound (1-12) a commercially available product or a compound produced by a known synthesis method (for example, Tetrahedron Letters, 7179, (2002), WO2012110190 or the like) or a synthesis method analogous thereto can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; acetonitrile, propionitrile, N, N-dimethylformamide, N, N Aprotic polar solvents such as dimethylacetamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; aromatic hydrocarbon solvents such as toluene and xylene; and mixed solvents thereof.
  • it is toluene or no solvent.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to the boiling point of the solvent used. Preferably, the temperature is 50 ° C to 160 ° C.
  • the reaction time is usually 30 minutes to 24 hours.
  • This reaction can be carried out in the presence of a dehydrating agent, if necessary.
  • a dehydrating agent for example, molecular sieve 4A or the like is used.
  • the amount of dehydrating agent used is at least 5 times the weight of the compound (1-10).
  • Step 2-1 Production Step of Compound (2-3)
  • the compound (2-3) is a compound (2-1), using a condensing agent, in the presence of a base and an additive, if necessary, in an inert solvent And the compound (2-2).
  • a commercially available product or a compound produced by a known synthesis method eg, WO200870150, WO200870150 etc.
  • a synthesis method analogous thereto can be used.
  • the compound (2-1) those produced according to the method described in the production method 1 can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide and the like; mixed solvents of these, etc. may be mentioned. Preferred are N, N-dimethylacetamide and N-methyl-2-pyrrolidinone.
  • the condensing agent include, for example, dicyclohexyl carbodiimide, diisopropyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, benzotriazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphate Salt, diphenylphosphonyldiamide, N, N-carbonyldimidazole, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, O- (7 And -azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and the like.
  • additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine and the like.
  • the reaction can be performed.
  • the base include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide etc.
  • organic bases such as triethylamine, diisopropylethylamine and pyridine
  • potassium carbonate, sodium carbonate, cesium carbonate potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydro
  • the reaction temperature is not particularly limited, but is usually selected from the range of about -20 ° C to the boiling point of the solvent used. Preferably, it is 0 ° C to 20 ° C.
  • the reaction time is usually 10 minutes to 48 hours.
  • Compound (2-3) may be converted to compound (2-4) and produced under the production conditions of this step.
  • Step 2-2 Production Step of Compound (2-4)
  • the compound (2-4) is reacted with a silylating agent in an inert solvent, optionally in the presence of an additive. It is manufactured by
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane and the like A mixed solvent etc. are mentioned.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane
  • aromatic hydrocarbons such as toluene and xylene
  • acetonitrile, propionitrile Aprotic polar solvents
  • the additive include, for example, 1- (3-dimethylaminopropyl) 3-ethylurea, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,
  • the reaction can be carried out by adding an additive such as 2,3-benzotriazine, bis (trimethylsilyl) amine, pyridine, N, N-dimethyl-4-pyridine, pyridine and the like.
  • silylating agent examples include, for example, N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, trimethylchlorosilane and the like. Preferred are N, O-bis (trimethylsilyl) acetamide and N, O-bis (trimethylsilyl) trifluoroacetamide.
  • the reaction temperature is not particularly limited, but is usually selected from the range of about -20 ° C to the boiling point of the solvent used. Preferably, the temperature is 20 ° C to 150 ° C.
  • the reaction time is usually 10 minutes to 48 hours.
  • Manufacturing method 3 The compound represented by the formula (3-4) is produced, for example, by the method shown below.
  • R 3 , ring Q 1 , W 1 , W 2 and n are as defined in the above [1]; R 1b and R 2b are as defined in production method 1; and R 4b is substituted R f represents a substituted sulfonyl group (eg, a methanesulfonyl group, a p-toluenesulfonyl group, etc.) and the like; and an optionally substituted amino, 4- to 10-membered saturated heterocyclic group; ]
  • Step 3-1 Preparation Step of Compound (3-2)
  • Compound (3-2) can be obtained by reacting compound (3-1) with a base in an inert solvent.
  • compound (3-1) those produced according to the method described in Production method 1 can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; protic polar solvents such as methanol, ethanol and water; and mixtures thereof Solvent etc. are mentioned. Preferred are tetrahydrofuran, methanol and ethanol.
  • the base include, for example, inorganic bases such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium trimethylsilyl oxide, sodium trimethylsilyl oxide And organic bases such as potassium trimethylsilyl oxide.
  • inorganic bases such as lithium hydroxide, sodium hydroxide and potassium hydroxide.
  • the reaction temperature is not particularly limited, but is usually selected in the range of -20 ° C to the boiling point of the solvent used. Preferably, it is ⁇ 20 ° C. to 60 ° C.
  • the reaction time is usually 30 minutes to 48 hours.
  • Step 3-2 Step of Producing Compound (3-4)
  • Compound (3-4) is a compound (3-2) in an inert solvent in the presence of Mitsunobu reagent and phosphine reagent, or Kakuda reagent. It can be obtained by reacting (3-3).
  • the compound (3-3) a commercially available product or a compound produced by a known synthesis method (for example, US2003220341, US2003229092 or the like) or a synthesis method analogous thereto can be used.
  • As the compound (3-2) those produced according to the method described in the production method 1 can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; chloroform, dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane; Aprotic polar solvents such as acetonitrile, propionitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide and the like And the like.
  • Mitsunobu reagent examples include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, tert-butyl azodicarboxylate, bis (2-methoxyethyl) azodicarboxylate, 1 '-(Azodicarbonyl) dipiperidine, 1,1'-azobis (N, N-dimethylformamide) and the like.
  • Preferred are diethyl azodicarboxylate and diisopropyl azodicarboxylate.
  • phosphine reagent examples include, for example, triphenylphosphine, trimethylphosphine, tributylphosphine, trioctylphosphine and the like. Preferably it is triphenyl phosphine and tributyl phosphine.
  • Kakuda's reagent examples include (cyanomethylene) tributylphosphorane, (cyanomethylene) trimethylphosphorane and the like. Preferred is (cyanomethylene) tributylphosphorane.
  • the reaction temperature is not particularly limited, but is usually selected from the range of -20 ° C to the boiling point of the solvent used. Preferably, it is 0 ° C to 100 ° C.
  • the reaction time is usually 10 minutes to 72 hours.
  • Manufacturing method 4 The compound represented by the formula (4-4) is produced, for example, by the method shown below.
  • R 3 , ring Q 1 , W 1 and n are as defined in the above [1];
  • R 1b and R 2b are as defined in production method 1;
  • Hal c is a chlorine atom, a bromine atom or
  • A represents a boronic acid, boronic ester, BF 3 K, or BF 3 Na;
  • Q 3 represents an optionally substituted 4- to 10-membered partially unsaturated heterocyclic group
  • Q 4 represents a 4- to 10-membered saturated heterocyclic group which may be substituted.
  • Step 4-1 Process for producing compound (4-3)
  • the compound (4-3) is a compound (4-1) in the presence of a base and a palladium catalyst in an inert solvent, and optionally a phosphine ligand It can be obtained by reacting with the compound (4-2) below.
  • Compound (4-2) may be a commercially available product or a compound produced by a known synthesis method (eg, Journal of Organic Chemistry 7508 (1995), Angewandte Chemie International Edition 928 (2008) or the like) or a synthesis method analogous thereto It can be used.
  • As the compound (4-1) those produced according to the method described in Production method 1 can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide and the like; protic polar solvents such as water; mixed solvents thereof and the like.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane
  • aromatic hydrocarbons such as toluene and xylene
  • acetonitrile, propionitrile Aprotic polar solvents
  • protic polar solvents such as water
  • mixed solvents thereof and the like protic polar solvent
  • the palladium catalyst include, for example, tetrakistriphenylphosphinepalladium, bis (t-butylphosphine) palladium, zero-valent catalysts such as tris (dibenzylideneacetone) dipalladium; bis (triphenylphosphine) palladium dichloride, acetic acid And bivalent catalysts such as palladium and bis (diphenylphosphinoferrocene) palladium dichloride.
  • Preferred is tetrakistriphenylphosphine palladium or palladium acetate.
  • phosphine ligand examples include, for example, o-tolylphosphine, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2', 4 ', Monodentate coordination ligands such as 6'-triisopropyl-1,1'-biphenyl; 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane, 1, 3-Bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 9,9-dimethyl-4,5 And bidentate ligands such as bis (diphenylphosphino) xanthine and bis (2-diphenyl
  • the base include, for example, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, phosphoric acid Inorganic bases such as disodium hydrogen, sodium phosphate, potassium hydroxide, sodium hydroxide and the like can be mentioned.
  • Preferred is sodium carbonate, potassium carbonate or potassium phosphate.
  • the reaction temperature is not particularly limited, but is selected from the range of room temperature to the boiling point of the solvent used, preferably in the range of 60 ° C. to 140 ° C., or in the range of 80 ° C. to 140 ° C. under microwave irradiation.
  • the reaction time is usually 30 minutes to 24 hours.
  • Step 4-2 Process for producing compound (4-4)
  • Compound (4-4) can be produced by catalytically reducing compound (4-3) with a metal catalyst in a hydrogen atmosphere in an inert solvent. You can get it.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; ester solvents such as methyl acetate and ethyl acetate; water, methanol, ethanol And protic polar solvents such as isopropanol; mixed solvents thereof and the like.
  • the metal catalyst include, for example, palladium / carbon, palladium hydroxide / carbon, Raney nickel, platinum oxide / carbon, rhodium / carbon and the like. Preferred is palladium / carbon, palladium hydroxide / carbon.
  • the amount of the metal catalyst to be used is generally 0.1 to 1000% by weight, preferably 1 to 100% by weight, relative to compound (4-3).
  • This reaction can be carried out in the presence of an acid, if necessary.
  • an acid for example, an organic acid such as formic acid, acetic acid, trifluoroacetic acid or the like is used.
  • the amount of the acid used is a compound (4 It is 0.1 mol or more with respect to 1 mol of -3).
  • the hydrogen pressure is usually about 1 to about 100 atm, preferably about 1 to about 5 atm.
  • the reaction temperature is not particularly limited, but is usually 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is generally 30 minutes to 72 hours, preferably 1 hour to 24 hours.
  • Manufacturing method 5 The compound represented by the formula (5-5) is produced, for example, by the method shown below.
  • R 3 , ring Q 1 , W 1 and n are as defined in the above [1];
  • R 1b and R 2b are as defined in production method 1;
  • R 1c and R 1d are each independently Or a hydrogen atom or an optionally substituted C 1-6 alkyl;
  • R c and R d together with the nitrogen atom to which they are attached, optionally substituted 4 to 10 members And may form a saturated heterocycle of ]
  • Step 5-1 Preparation Step of Compound (5-3)
  • Compound (5-3) is a compound (5-1) in an inert solvent, in the presence of a borohydride compound and optionally an acid, It can also be obtained by reacting the compound (5-2).
  • a commercially available product or a compound produced by a known synthesis method for example, WO20073965, US2010216812 or the like
  • a synthesis method analogous thereto can be used.
  • the compound (5-1 those produced according to the method described in the production method 1 can be used.
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and the like; Examples thereof include protic polar solvents such as methanol, ethanol, 1-propanol, 2-propanol and water; mixed solvents thereof and the like. Preferred are tetrahydrofuran, dichloromethane, chloroform and methanol.
  • the acid include, for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid; and mineral acids such as hydrochloric acid.
  • borohydride compound examples include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. Preferred are sodium cyanoborohydride and sodium triacetoxyborohydride.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to the boiling point of the solvent used. Preferably, it is 0 ° C to 20 ° C.
  • the reaction time is usually from 30 minutes to 72 hours.
  • Step 5-2 Production Step of Compound (5-4)
  • the compound (5-4) is produced by subjecting the compound (5-3) to a method described in the step 1-5.
  • Step 5-3 Production Step of Compound (5-5)
  • the compound (5-5) is produced by subjecting the compound (5-4) to the method described in the step 1-6.
  • Process 6-1 Process for producing compound (6-3)
  • compound (6-1) can be synthesized by a known synthesis method (for example, EP 1550662, (2005), Journal of Medicinal Chemistry, 2964, 2010) and the like)) and the like, by reacting with the compound (6-2).
  • the compound (6-1) can be used as a commercially available product or one produced by a known synthesis method (eg, EP 1550662, (2005), EP 1728792, (2006), etc.) or a synthesis method analogous thereto.
  • a commercially available product or a compound produced by a known synthesis method eg, EP 1550662, (2005), EP 1728792, 2006 etc.
  • a synthesis method analogous thereto can be used as the compound (6-2).
  • Step 6-2 Production Step of Compound (6-4)
  • Compound (6-4) can be produced by subjecting compound (6-3) to a known synthesis method (for example, EP 1550662, (2005), Journal of Medicinal Chemistry, 2964, 2010) and the like) and produced by halogenation in a similar manner.
  • Step 6-3 Preparation Step of Compound (6-6)
  • Compound (6-6) is a compound (6-4) in the presence of a base and a palladium catalyst, optionally in the presence of a phosphine ligand, in an inert solvent. It can be obtained by reacting with the compound (6-5) below.
  • the compound (6-5) a commercially available product or a compound produced by a known synthesis method (for example, Organic Letters 632 (2014), Organic Letters 75 (2006) or the like) or a synthesis method analogous thereto can be used. .
  • the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; acetonitrile, propionitrile, Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide and the like; protic polar solvents such as water; mixed solvents thereof and the like.
  • ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane
  • aromatic hydrocarbons such as toluene and xylene
  • acetonitrile, propionitrile Aprotic polar solvents
  • protic polar solvents such as water
  • mixed solvents thereof and the like protic polar solvent
  • the palladium catalyst include, for example, tetrakistriphenylphosphinepalladium, bis (t-butylphosphine) palladium, zero-valent catalysts such as tris (dibenzylideneacetone) dipalladium; bis (triphenylphosphine) palladium dichloride, acetic acid And bivalent catalysts such as palladium and bis (diphenylphosphinoferrocene) palladium dichloride.
  • Preferred is tetrakistriphenylphosphine palladium or palladium acetate.
  • phosphine ligand examples include, for example, o-tolylphosphine, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2', 4 ', Monodentate coordination ligands such as 6'-triisopropyl-1,1'-biphenyl; 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane, 1, 3-Bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 9,9-dimethyl-4,5 And bidentate ligands such as bis (diphenylphosphino) xanthine and bis (2-diphenyl
  • the base include, for example, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, phosphoric acid Inorganic bases such as disodium hydrogen, sodium phosphate, potassium hydroxide, sodium hydroxide and the like can be mentioned.
  • Preferred is sodium carbonate, potassium carbonate or potassium phosphate.
  • the reaction temperature is not particularly limited, but is selected from the range of room temperature to the boiling point of the solvent used, preferably in the range of 60 ° C. to 140 ° C., or in the range of 80 ° C. to 160 ° C. under microwave irradiation.
  • the reaction time is usually 30 minutes to 24 hours.
  • the compound of the present invention having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above-mentioned production methods.
  • the isolation and purification of intermediates and products in the above-mentioned production methods should be carried out by combining methods as used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography and the like as appropriate. Can.
  • intermediates can also be subjected to the next reaction without purification.
  • the starting compounds or intermediates in the above-mentioned production methods may be present, for example, in the form of a salt such as hydrochloride depending on the reaction conditions and the like, but can be used as they are or in free form.
  • tautomers such as keto enol, positional isomers, geometric isomers, or isomers such as optical isomers may exist. Although there are also all possible isomers including these and mixtures of the isomers in any ratio are included in the present invention.
  • optical isomers can be separated by carrying out known separation steps such as a method using an optically active column and a fractional crystallization method at appropriate steps of the above-mentioned production method.
  • an optically active substance can also be used as a starting material.
  • a salt of compound (1) When it is desired to obtain a salt of compound (1), purification may be carried out as it is when a salt of compound (1) is obtained, and when compound (1) is obtained in free form, compound (1) may be suitably used. It may be dissolved or suspended in a solvent, and an acid or a base may be added to form a salt.
  • Compound (1) or a pharmaceutically acceptable salt thereof may be present in the form of water or a solvate with various solvents, and these solvates are also included in the present invention.
  • Autoimmune diseases are disorders that occur in the innate immune system that should play a role in recognizing and eliminating foreign substances such as pathogenic microbes that originally invaded from the outside, and recognize components that constitute their own cells and tissues as foreign substances. It is a generic term for diseases in which antibody and lymphocytes are produced in excess, inflammation occurs with systemic and organ-specific cytokine production and the like, leading to tissue damage.
  • autoimmune hemolytic anemia, sporadic thrombocytopenia etc. psoriasis (eg psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, pustular psoriasis), pemphigus (eg pemphigus vulgaris, varicella) Pemphigus vulgaris, rheumatoid arthritis, antiphospholipid antibody syndrome, Ecardy-Gutieres syndrome, IgG4-related disease, polymyositis, der
  • the pharmaceutical preparation according to the present invention is manufactured by mixing the active ingredient with one or more pharmaceutically acceptable carriers and any method well known in the pharmaceutical arts.
  • pharmaceutical carriers used include lactose, mannitol, glucose, starch, magnesium stearate, glycerate ester, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol and the like.
  • the pharmaceutical preparation according to the present invention may contain other various excipients, lubricants, lubricants, binders, disintegrants, tonicity agents, emulsifiers and the like.
  • oral or parenteral such as intravenous, application, inhalation and eye drop can be mentioned, preferably oral administration.
  • the administration form include tablets, injections and the like, and preferably tablets.
  • the dosage and frequency of administration of these pharmaceutical compositions vary depending on the administration form, the disease and symptoms of the patient, the age and weight of the patient, etc., and can not be generally specified, but are generally effective for adults per day
  • the amount of the component is in the range of about 0.0001 to about 5000 mg, preferably in the range of about 0.001 to about 1000 mg, more preferably in the range of about 0.1 to about 500 mg, particularly preferably in the range of about 1 to about 300 mg.
  • the administration can be divided into several times a day, preferably 1 to 3 times a day.
  • the compounds of the present invention can be used in combination with other drugs for the purpose of enhancing their effects and / or reducing their side effects.
  • the compound of the present invention can be used in combination with a drug such as a steroid drug, an immunosuppressant, a drug for targeting B cells, or a drug for inhibiting TLR.
  • a drug such as a steroid drug, an immunosuppressant, a drug for targeting B cells, or a drug for inhibiting TLR.
  • the “agent that targets B cells” refers to an antibody drug that targets B cells.
  • the "agent that inhibits TLR” include hydroxychloroquine, chloroquine and the like.
  • drugs that can be used in combination with the compound of the present invention are abbreviated as concomitant drugs.
  • Combination drugs include, for example, steroids, immunosuppressants, drugs that target B cells, TLR inhibitors, and other therapeutic agents for autoimmune diseases
  • the administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered simultaneously to the administration subject, or may be administered with a time lag. In addition, it may be a combination of the compound of the present invention and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the dose clinically used.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used based on 1 part by weight of the compound of the present invention.
  • drugs such as an antiemetic agent, a sleep inducing agent, an anticonvulsant, etc., for the purpose of the side effect suppression.
  • the dose varies depending on the individual compound and depending on the disease, age, body weight, sex, symptoms, administration route etc. of the patient, but usually 0.1 to 1000 mg of the compound of the present invention for an adult (body weight 50 kg) / Day, preferably 0.1 to 300 mg / day, administered once or twice to three times a day. It can also be administered once every several days to several weeks.
  • Example 1 9-[(4- ⁇ [(3S) -1-azabicyclo [2.2.2] octan-3-yl] oxy ⁇ -2-fluorophenyl) methyl] -2-methoxy-6-methyl-8- ( 2-Methylpropyl) -9H-Purine
  • 3-methylbutanal (0.030 ml) and iron (III) chloride 90.0 mg were added and the reaction mixture was heated to reflux did.
  • the reaction mixture was stirred for 5.5 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol.
  • Example 2 9-[(4- ⁇ [(3S) -1-azabicyclo [2.2.2] octan-3-yl] oxy ⁇ -2-fluorophenyl) methyl] -N- (4-chlorophenyl) -2-methoxy -6-Methyl-9H-purine-8-carboxamide
  • N N, O-bis (trimethylsilyl) acetamide (0.030 ml) at room temperature, and the reaction mixture was heated to 85 ° C. The reaction mixture was stirred for 5 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol.
  • Examples 3 to 26 The compounds of Examples 3 to 26 were obtained according to the methods described in Example 1 and Example 2 and using the corresponding starting compounds.
  • Example 27 3- (3- ⁇ 9-[(4- ⁇ [(3S) -1-azabicyclo [2.2.2] octan-3-yl] oxy ⁇ -2-fluorophenyl) methyl] -2-methoxy-6 -Methyl-9H-purin-8-yl ⁇ azetidin-1-yl) ethane-1-one
  • acetic anhydride 0.015 ml
  • Example 28 ⁇ 9-[(4- ⁇ [(3S) -1-Azabicyclo [2.2.2] octan-3-yl] oxy ⁇ -2-fluorophenyl) methyl] -2-methoxy-6-methyl-9H- Purin-8-yl ⁇ (phenyl) methanone EDCI.HCl (173 mg), HOBt (122 mg), benzoylformic acid (152 mg), diisopropylethylamine (0.31 mL) were added to a chloroform solution (2 mL) of the compound of Reference Example 26 and stirred at room temperature for 2 hours After that, it was left to stand overnight.
  • the reaction mixture was directly purified twice by silica gel column chromatography (chloroform / methanol and ethyl acetate / methanol), and the fractions containing the desired product were concentrated. Ethyl acetate was added to the residue, and the mixture was extracted with 1 mol / L hydrochloric acid aqueous solution. The target product was extracted with chloroform from the aqueous phase, dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (26 mg).
  • Example 29 9-[(2-Fluoro-4- ⁇ [(1R, 3R, 5S) -8-methyl-8-azabicyclo [3.2.1] octan-3-yl] oxy ⁇ phenyl) methyl] -2-methoxy -6-Methyl-8- (2-methylpropyl) -9H-purine
  • a 36% aqueous formaldehyde solution (0.022 mL) is added to a methanol solution (5 mL) of the compound of Example 26 (66 mg) and stirred at room temperature for 15 minutes, sodium borohydride (24 mg) is added and the mixture is stirred at room temperature for 2 hours did.
  • Example 30 3- (9- ⁇ [4- (1-Azabicyclo [2.2.2] octan-3-yl) -2-fluorophenyl] methyl ⁇ -2-methoxy-6-methyl-9H-purin-8-yl ) Propane nitrile
  • 2-propanol (3 mL) 2-propanol (3 mL)
  • 4,4-dimethoxybutanenitrile 51.7 mg
  • iron (III) chloride 97.0 mg
  • Example 31 9- ⁇ [4- (1-Azabicyclo [2.2.2] octan-3-yl) -2-fluorophenyl] methyl ⁇ -2-methoxy-6-methyl-8-[(oxane-4-yl) Methyl] -9H-Purine Tetrahydropyranyl-4-acetic acid (433 mg) was added to a toluene solution (2 mL) of the compound of Reference Example 22 (111 mg) at room temperature, and the reaction mixture was heated to reflux. The reaction mixture was stirred for 5 hours, then toluene (2 mL) was added and stirred for another 8 hours.
  • Example 32-72 According to the methods described in Example 1, Example 2, Example 30, and Example 31, the corresponding starting compounds were used to obtain the compounds of Examples 32-72.
  • Example 73 9-[(2-Fluoro-4- ⁇ [(1R, 4R) -5- (2-methoxyethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl] methyl ⁇ phenyl) methyl ] -2-Methoxy-6-methyl-8- (2-methylpropyl) -9H-purine
  • 2-chloroethyl methyl ether 28.4 mg
  • cesium carbonate (163 mg
  • KI 49.8 mg
  • Examples 74 to 87 The compounds of Examples 74 to 87 were obtained according to the methods described in Example 29 and Example 73, using the corresponding starting materials.
  • Example 88 9- ⁇ [4- (1-Azabicyclo [2.2.2] octan-3-yl) -2-fluorophenyl] methyl ⁇ -2-methoxy-6-methyl-8- [2- (oxolane-2-) Yl) ethyl]-9H-pudding
  • ethyl acetate 4 mL
  • 10% palladium carbon 12 mg
  • the residue was purified by amino silica gel column chromatography (ethyl acetate / methanol), but the target substance could not be isolated, so all fractions containing the target substance were collected and concentrated.
  • To a solution of the obtained residue in ethanol (4 mL) was added 10% palladium carbon (12 mg) at room temperature. After stirring under a hydrogen atmosphere at room temperature for 6.5 hours, the reaction mixture was filtered through celite and concentrated under reduced pressure.
  • the residue was purified by amino silica gel column chromatography (chloroform / methanol), but since the target substance could not be isolated, all fractions containing the target substance were collected and concentrated.
  • Examples 89 to 90 The compounds of Examples 89 to 90 were obtained according to the method described in Example 88, using the corresponding starting materials.
  • Example 92 The compound of Example 92 was obtained according to the method described in Example 91 using the corresponding raw material compounds.
  • Examples 93 to 97 The compounds of Examples 93 to 97 were obtained according to the method of de-Boc reaction described in Reference Example 15 using the corresponding starting materials.
  • Example 98 2- ⁇ (1R, 4R) -5-[(4- ⁇ [2-ethoxy-6-methyl-8- (2-methylpropyl) -9H-purin-9-yl] methyl ⁇ -3-fluorophenyl) Methyl] -2,5-diazabicyclo [2.2.1] heptan-2-yl ⁇ ethan-1-ol (Tert-Butyldimethylsiloxy) acetaldehyde (0.038 mL) and sodium triacetoxyborohydride (41 mg) were added to a tetrahydrofuran solution (5 mL) of the compound of Example 97 (54 mg) under ice cooling, and the mixture was stirred at room temperature for 3 days did.
  • reaction mixture was added with 1 M hydrochloric acid, stirred for 1 hour, and extracted with chloroform.
  • the reaction mixture was basified by adding ammonia water to saturate the aqueous layer, and extracted with chloroform-methanol.
  • the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • the residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (53 mg).
  • Examples 99 to 102 The compounds of Examples 99 to 102 were obtained according to the method of reductive amination described in Reference Example 14 using the corresponding starting materials.
  • Example 103 The compound of Example 103 was obtained according to the method described in Example 1 using the corresponding raw material compounds.
  • Example 104 9-[(2-Fluoro-4- ⁇ [(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] methyl ⁇ phenyl) methyl] -8- ( 2-Fluoro-2-methylpropyl) -2-methoxy-6-methyl-9H-purine
  • bis (2-methoxyethyl) aminosulfur trifluoride (0.156 mL) was added to a dichloromethane solution (5 mL) of the compound of Example 103 (91 mg) at -78.degree. C., the mixture was stirred at -78.degree. C. for 7 hours .
  • Example 105 The compound of Example 105 was obtained according to the method described in Example 73 using the corresponding raw material compounds.
  • Reference Example 7 According to the method described in Reference Example 6, the corresponding starting compound was used to obtain Reference Example 7 compound.
  • Reference Example 9 The compound of Reference Example 9 was obtained according to the method described in Reference Example 8 using the corresponding raw material compounds.
  • Reference Example 10 4- ⁇ [(tert-butoxycarbonyl) (2-methoxy-6-methyl-5-nitropyrimidin-4-yl) amino] methyl ⁇ -3-fluorophenyl methanesulfonate
  • a compound (1 g) of Reference Example 9 and 3-fluoro-4- (hydroxymethyl) phenyl methanesulfonate (0.75 g) in a toluene solution (10 mL) was prepared using 1,1′-azobis (N, N-dimethylformamide) (0 71 g) and tributylphosphine (0.83 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hours.
  • Reference Examples 11 to 13 The compounds of Reference Examples 11 to 13 were obtained according to the method described in Reference Example 10, using the corresponding starting compounds.
  • Reference Examples 16-19 The compounds of Reference Examples 16 to 19 were obtained according to the method described in Reference Example 15 using the corresponding starting compounds.
  • the compound of Reference Example 19 can also be obtained by using the compound of Reference Example 18 according to the method described in Reference Example 2.
  • Reference Example 21 4- ⁇ [(5-amino-2-methoxy-6-methylpyrimidin-4-yl) amino] methyl ⁇ -3-fluorophenyl methanesulfonate 7,7,8,8-Tetracyanoquinodimethane (5.3 mg) and 10% palladium carbon (0.1 g) were added to a solution of the compound of Reference Example 15 (1 g) in ethyl acetate (8 mL) at room temperature. . The reaction mixture was stirred at room temperature under normal pressure hydrogen atmosphere for 7 hours. After adding ethanol (8 mL) and stirring under a hydrogen atmosphere at normal pressure for 8 hours at room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.99 g). LC-MS [M + H] + / Rt (min): 357.1 / 0.414 (Method B).
  • Reference Examples 22-24 The compounds of Reference Examples 22 to 24 were obtained according to the method described in Reference Example 21 using the corresponding raw material compounds.
  • Reference Example 25 4- ⁇ [(5-amino-2-methoxy-6-methylpyrimidin-4-yl) amino] methyl ⁇ -3-fluorophenol
  • a solution of the compound of Reference Example 21 (3.5 g) in methanol (14 mL) / tetrahydrofuran (14 mL) was added 5 mol / L aqueous sodium hydroxide solution (9.8 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours.
  • saturated aqueous ammonium chloride solution and saturated brine was extracted with ethyl acetate.
  • Reference Examples 30 to 31 The compounds of Reference Examples 30 to 31 were obtained according to the method described in Reference Example 29 using the corresponding raw material compounds.
  • Reference Examples 32 to 33 The compounds of Reference Examples 32-33 were obtained according to the method described in Reference Example 10, using the corresponding starting compounds.
  • Reference Examples 34 to 35 The compounds of Reference Examples 34 to 35 were obtained using the corresponding starting compounds according to the method described in Reference Example 15.
  • Reference Examples 36 to 37 The compounds of Reference Examples 36 to 37 were obtained according to the method described in Reference Example 21 using the corresponding starting compounds.
  • Reference Example 39 The compound of Reference Example 39 was obtained according to the method described in Reference Example 38 using the corresponding raw material compounds.
  • Reference Example 40 4-[(6-Amino-2-methoxy-9H-purin-9-yl) methyl] -3-fluorophenol
  • a solution of the compound of Reference Example 38 (1.08 g) in methanol (12 mL) / tetrahydrofuran 15 mL was added 4 mol / L aqueous sodium hydroxide solution (4.43 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours.
  • Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with chloroform / methanol (10/1). The organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • Reference Example 42 The compound of Reference Example 42 was obtained according to the method described in Reference Example 2 using the corresponding raw material compounds.
  • Reference Example 43 The compound of Reference Example 43 was obtained according to the method described in Reference Example 3 using the corresponding raw material compounds.
  • Reference Example 45 The compound of Reference Example 45 was obtained according to the method described in Reference Example 44 using the corresponding raw material compounds.
  • Reference Example 51 The compound of Reference Example 51 was obtained according to the method described in Reference Example 14 using the corresponding raw material compounds.
  • Reference Example 52 The compound of Reference Example 52 was obtained according to the method described in Reference Example 15 using the corresponding raw material compounds.
  • Reference Example 53 The compound of Reference Example 53 was obtained according to the method described in Reference Example 20 using the corresponding raw material compounds.
  • Reference Example 54 The compound of Reference Example 54 was obtained according to the method described in Reference Example 21 using the corresponding raw material compounds.
  • Test Example 1 Human TLR7 Activation Inhibition Test
  • a human TLR7-expressing cell line is a human fetal kidney cell line that is a human TLR7 gene and a secreted alkaline phosphatase (SEAP) gene downstream of a transcriptional response element of NF- ⁇ B.
  • SEAP secreted alkaline phosphatase
  • TLR7 / NF- ⁇ B / SEAPorter TM HEK293 cells with 10% fetal bovine serum (FBS), using a 10 [mu] g / mL blasticidin S-containing DMEM medium, 37 ° C., and cultured in the presence of 5% CO 2.
  • the TLR7 / NF- ⁇ B / SEAPorter TM HEK293 cells were seeded in 96-well microtiter plates in 5 ⁇ 10 4 / 90 ⁇ L / well , 37 °C in CO 2 incubator, and cultured overnight.
  • Test compounds diluted in culture medium (10 ⁇ L / well) are added to a final concentration of 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 ⁇ mol / L, or 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 ⁇ mol / L.
  • R-848, a TLR7 / 8 ligand was added to a final concentration of 200 nmol / L (10 ⁇ L / well).
  • SEAP activity was measured as TLR7 activity after incubation in a CO 2 incubator for 20 ⁇ 1 h, for a total of 110 ⁇ L / well.
  • pNPP p-nitro-phenyl phosphate
  • Invitrogen 50 ⁇ l / well of p-nitro-phenyl phosphate (pNPP) (Invitrogen) is added, and after 15 minutes, the reaction is stopped by adding 50 ⁇ l / well of 4 mol / L sodium hydroxide solution (Nacalai Tesque). Evaluation was made by measuring absorbance at 405 nm with a microplate reader Elx 808 (BioTek). The 50% inhibitory concentration (IC 50 value) of each test compound was calculated, assuming that the SEAP activity when no test compound was added was 100%.
  • pNPP p-nitro-phenyl phosphate
  • Test Example 1 The test shown in Test Example 1 was performed for each compound obtained in the examples.
  • concentrations for suppressing 50% cell growth IC 50 values; ⁇ mol / L
  • IC 50 values ⁇ mol / L
  • the compounds of the present invention showed strong TLR7 inhibitory action in the TLR7 activation inhibition test.
  • the compounds of 75, 76, 77, 79, 80, 81, 82, 83, 85, 87, 90, 92, 94, 95, 96, 97, 98 and 104 exhibited particularly strong TLR7 inhibitory action.
  • Test Example 2 Human TLR8 Activation Inhibition Test
  • the human TLR8-expressing cell line is a human fetal kidney cell line that is a human TLR8 gene and a secreted alkaline phosphatase (SEAP) gene downstream of a transcription response element of NF- ⁇ B.
  • cell lines were stably expressed in HEK293 obtained by purchased from IMGENEX Corporation (TLR8 / NF- ⁇ B / SEAPorter TM HEK293 cells).
  • the TLR8 / NF- ⁇ B / SEAPorter TM HEK293 cells were seeded in 96-well microtiter plates at 5 ⁇ 10 4 / 90 ⁇ L / well , 37 °C in CO 2 incubator and cultured overnight.
  • test compound (10 ⁇ L / well) diluted with the medium is added to a final concentration of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 100 ⁇ mol / L.
  • R-848 which is a TLR7 / 8 ligand, is added to a final concentration of 30 ⁇ mol / L (10 ⁇ L / well).
  • SEAP activity is measured as TLR8 activity after incubation in a CO 2 incubator for 20 ⁇ 1 h, for a total of 110 ⁇ L / well.
  • pNPP p-nitro-phenyl phosphate
  • IC 50 value 50% inhibitory concentration
  • Test Example 3 Human TLR9 Activation Inhibition Test
  • the human TLR9-expressing cell line is a human fetal kidney cell line that is a human TLR9 gene and a secreted alkaline phosphatase (SEAP) gene downstream of a transcription response element of NF--B.
  • cell lines were stably expressed in HEK293 obtained by purchased from IMGENEX Corporation (TLR9 / NF- ⁇ B / SEAPorter TM HEK293 cells).
  • test compound (10 ⁇ L / well) diluted with the medium is added to a final concentration of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 ⁇ mol / L.
  • TLR9 ligand CpG-B DNA CpG2006, Hokkaido System Science
  • SEAP activity is measured as TLR9 activity after incubation in a CO 2 incubator for 20 ⁇ 1 h, for a total of 110 ⁇ L / well.
  • pNPP p-nitro-phenyl phosphate
  • 4 mol / L sodium hydroxide solution Nacalai Tesque
  • the compound of the present invention is useful for the prevention and / or treatment of autoimmune diseases because it has a TLR inhibitory action.

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Abstract

L'invention fournit un composé purine substituée représenté par la formule (1) présentant une action inhibitrice de TLR7, et se révélant avantageux dans le traitement, ou similaire, de la maladie auto-immune , et fournit également un sel pharmaceutiquement acceptable de ce composé. [Dans la formule, Ｒ１ représente un alcoxy Ｃ１－６, ou similaire, éventuellement substitué, Ｒ２ représente un alkyle Ｃ１－６, ou similaire, éventuellement substitué, le cycle Ｑ１ représente un groupe carbocyclique aromatique, ou similaire, Ｗ１ représente un alkylène Ｃ１－４, ou similaire, éventuellement substitué, n représente 1, 2, 3 ou 4, Ｒ３ représente un atome d'hydrogène, un atome d'halogène, ou similaire, Ｑ１－Ｘ１ représente Ｑ１－（ＣＨ２）ｍ－Ｏ－, ou similaire, m représente 0, 1 ou 2, Ｗ２ représente une liaison simple, ou similaire, Ｒ４ représente un hétérocycle saturé de 4 à 10 membres, éventuellement substitué, Ｘ２ représente une liaison simple, ou similaire, Ｒ５ représente un groupe alkyle Ｃ１－８, éventuellement substitué, un groupe hétérocyclique saturé de 4 à 10 membres, éventuellement substitué, ou similaire.]
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11661431B2 (en) 2021-04-16 2023-05-30 Gilead Sciences, Inc. Thienopyrrole compounds
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12070455B2 (en) 2021-09-10 2024-08-27 Gilead Sciences, Inc. Thienopyrrole compounds
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024432A1 (fr) * 1997-11-12 1999-05-20 Mitsubishi Chemical Corporation Derives de purine et medicament les renfermant en tant qu'ingredient actif
WO2000068231A1 (fr) * 1999-05-11 2000-11-16 Mitsubishi Chemical Corporation Dihydrate derive de purine, medicaments le contenant comme principe actif et intermediaire utilise dans sa preparation
WO2004029054A1 (fr) * 2002-09-27 2004-04-08 Sumitomo Pharmaceuticals Company, Limited Nouveau compose d'adenine et son application
WO2007034817A1 (fr) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé de l'adénine
WO2007034917A1 (fr) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé adénine
WO2008114817A1 (fr) * 2007-03-20 2008-09-25 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé d'adénine
JP2009504803A (ja) * 2005-08-22 2009-02-05 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Ｔｌｒアゴニスト
JP2009542697A (ja) * 2006-07-07 2009-12-03 ギリアード サイエンシーズ， インコーポレイテッド ｔｏｌｌ様レセプター７の調節因子
WO2009144632A1 (fr) * 2008-05-30 2009-12-03 Pfizer Limited Nouveaux composés
JP2010532353A (ja) * 2007-06-29 2010-10-07 ギリアード サイエンシーズ， インコーポレイテッド トール様受容体７の調節物質としてのプリン誘導体およびその使用
WO2011134669A1 (fr) * 2010-04-30 2011-11-03 Telormedix Sa Procédés d'induction d'une réponse immunitaire
JP2013508373A (ja) * 2009-10-22 2013-03-07 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様受容体の調節因子
JP2015522058A (ja) * 2012-07-13 2015-08-03 ヤンセン・アールアンドデイ・アイルランド ウイルス感染症の処置のための大環状プリン
WO2017056494A1 (fr) * 2015-09-29 2017-04-06 Sumitomo Dainippon Pharma Co., Ltd. Composés conjugués de l'adénine et leur utilisation comme adjuvants de vaccins
WO2017188287A1 (fr) * 2016-04-26 2017-11-02 大日本住友製薬株式会社 Dérivé substitué de purine

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024432A1 (fr) * 1997-11-12 1999-05-20 Mitsubishi Chemical Corporation Derives de purine et medicament les renfermant en tant qu'ingredient actif
WO2000068231A1 (fr) * 1999-05-11 2000-11-16 Mitsubishi Chemical Corporation Dihydrate derive de purine, medicaments le contenant comme principe actif et intermediaire utilise dans sa preparation
WO2004029054A1 (fr) * 2002-09-27 2004-04-08 Sumitomo Pharmaceuticals Company, Limited Nouveau compose d'adenine et son application
JP2009504803A (ja) * 2005-08-22 2009-02-05 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Ｔｌｒアゴニスト
WO2007034817A1 (fr) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé de l'adénine
WO2007034917A1 (fr) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé adénine
JP2009542697A (ja) * 2006-07-07 2009-12-03 ギリアード サイエンシーズ， インコーポレイテッド ｔｏｌｌ様レセプター７の調節因子
WO2008114817A1 (fr) * 2007-03-20 2008-09-25 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé d'adénine
JP2010532353A (ja) * 2007-06-29 2010-10-07 ギリアード サイエンシーズ， インコーポレイテッド トール様受容体７の調節物質としてのプリン誘導体およびその使用
WO2009144632A1 (fr) * 2008-05-30 2009-12-03 Pfizer Limited Nouveaux composés
JP2013508373A (ja) * 2009-10-22 2013-03-07 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様受容体の調節因子
WO2011134669A1 (fr) * 2010-04-30 2011-11-03 Telormedix Sa Procédés d'induction d'une réponse immunitaire
JP2015522058A (ja) * 2012-07-13 2015-08-03 ヤンセン・アールアンドデイ・アイルランド ウイルス感染症の処置のための大環状プリン
WO2017056494A1 (fr) * 2015-09-29 2017-04-06 Sumitomo Dainippon Pharma Co., Ltd. Composés conjugués de l'adénine et leur utilisation comme adjuvants de vaccins
WO2017188287A1 (fr) * 2016-04-26 2017-11-02 大日本住友製薬株式会社 Dérivé substitué de purine

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 7 November 2013 (2013-11-07), retrieved from STN Database accession no. 1469980-76-4 *
DATABASE REGISTRY Database accession no. 1469980- 78-6 *
DATABASE REGISTRY Database accession no. 1469980-77-5 *
DATABASE REGISTRY Database accession no. 1469980-79-7 *
DATABASE REGISTRY Database accession no. 1469980-80-0 *
DATABASE REGISTRY Database accession no. 930294-09-0 *
DATABASE REGISTRY Database accession no. 930294-12-5 *
DATABASE REGISTRY Database accession no. 930785-30-1 *
ZHU, JIANG ET AL.: "Local administration of a novel Toll-like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a marine model of T cell lymphoma", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 8, 2015, pages 1 - 10, XP021218354 *

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US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12275717B2 (en) 2020-05-06 2025-04-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11661431B2 (en) 2021-04-16 2023-05-30 Gilead Sciences, Inc. Thienopyrrole compounds
US12070455B2 (en) 2021-09-10 2024-08-27 Gilead Sciences, Inc. Thienopyrrole compounds
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2

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