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WO2011062253A1 - Nouveau dérivé fusionné de pyrimidine - Google Patents

Nouveau dérivé fusionné de pyrimidine Download PDF

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Publication number
WO2011062253A1
WO2011062253A1 PCT/JP2010/070651 JP2010070651W WO2011062253A1 WO 2011062253 A1 WO2011062253 A1 WO 2011062253A1 JP 2010070651 W JP2010070651 W JP 2010070651W WO 2011062253 A1 WO2011062253 A1 WO 2011062253A1
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optionally substituted
alkyl
group
compound
substituted
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Japanese (ja)
Inventor
成宏 浅野
克己 久保田
舞 笠井
義明 磯部
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a condensed pyrimidine derivative useful as a medicine. More specifically, the present invention relates to a fused pyrimidine derivative that is effective for the prevention and / or treatment of diseases associated with signal transduction via a Toll-like receptor (TLR). Specifically, diseases involving autoimmunity (sepsis, inflammation, allergies, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) The present invention relates to a condensed pyrimidine derivative as a prophylactic and / or therapeutic agent.
  • TLR Toll-like receptor
  • TLRs innate immunity
  • TLR 1 -TLR 10 10 human TLRs
  • TLR discriminates a specific molecular structure (pasogen-associated molecular pattern, PAMPs) typified by cell wall components and DNA of pathogenic microorganisms, induces an immune response of the host, and is responsible for biological defense ( Nature Reviews Immunology, 2001, 1, 135-145).
  • TLR 2 transmits signals such as peptidoglycan, which is a component of microbial cell wall, and zymosan of yeast
  • TLR 4 transmits a signal of lipopolysaccharide (LPS), which is a component of Gram-negative cell wall, from outside the host cell. It is transmitted into cells (Nature Immunology, 2001, 2, 675-680).
  • LPS lipopolysaccharide
  • TLR 9 expressed in endosomes in host cells has been reported to recognize DNA of pathogenic microorganisms and CpG DNA, and has attracted particular attention (Nature, 2000, 408, 740-745 or Proceedings of the National Academy of Sciences, 2001, 98, 9237-9242). Therefore, drugs and / or compositions useful for controlling innate immunity via this TLR are used in the following diseases involving autoimmunity (sepsis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease, Infectious diseases, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) can be prophylactic and / or therapeutic agents.
  • autoimmune disease is a disease that leads to tissue damage due to the continuous production of antibodies or lymphocytes that react with components that constitute the tissue of the self, and includes the following (1) organ-specific self There are two broad categories: immune diseases and (2) non-organ-specific autoimmune diseases (systemic autoimmune diseases).
  • Organ-specific autoimmune diseases Hashimoto's disease, primary myxedema, thyroid poisoning, pernicious anemia, Good-pasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris, bullous Pemphigus, insulin resistant diabetes, juvenile diabetes, type I diabetes, Addison's disease, atrophic gastritis, male infertility, premature menopause, phakogenic uveitis, multiple sclerosis, ulcerative colitis, primary Biliary cirrhosis, chronic active hepatitis, autoimmune blood diseases (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenia), paroxysmal hemoglobinuria, primary biliary cirrhosis, Guillain-Barre syndrome , Graves' disease, idiopathic thrombocytopenic purpura, interstitial pulmonary fibrosis and chronic discoid lupus erythematosus.
  • Non-organ-specific autoimmune disease (systemic autoimmune disease): rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, systemic sclerosis, polyarteritis nodosa, allergic granulation Seed vasculitis, scleroderma and mixed connective tissue disease.
  • SIRS Systemic Inflammatory Response Syndrome
  • TLR 9 can be expected to selectively control immune responses elicited from pathogenic microorganisms.
  • TLR 9 inhibitors can be expected to have further effects when used alone, in combination with TLR 2 inhibitors, in combination with TLR 4 inhibitors, or in combination with TLR 2 inhibitors and TLR 4. I can expect. Further effects on sepsis-related diseases can be expected by combination therapy in combination with existing sepsis treatment methods such as existing antibacterial agents and blood coagulants.
  • Chloroquine (a) developed as an antimalarial drug is also used for the treatment of various autoimmune diseases (such as rheumatoid arthritis and systemic lupus erythematosus), and is also useful as an anti-inflammatory drug. Recently, it has been reported that the mechanism of action of chloroquine and its analog quinacrine (b) against the autoimmune disease is due to TLR 9 antagonism (European Journal of Immunology, 2004, 34, 2541-2550). ).
  • Patent Document 1 discloses a TLR 9 inhibitor, but the structure is different from the compound of the present invention.
  • Patent Document 2 The following representative compound (c) is also disclosed as a compound having TLR 7 , TLR 8 and TLR 9 antagonism, but the structure is different from the compound of the present invention (Patent Document 2).
  • International Publication No. 2000/076982 International Publication No. 2008/030455 is also disclosed as a compound having TLR 7 , TLR 8 and TLR 9 antagonism, but the structure is different from the compound of the present invention.
  • a novel compound represented by the following formula (I) exhibits a strong TLR inhibitory action and can be a useful drug for the prevention and / or treatment of severe sepsis.
  • the present invention has been completed.
  • a condensed pyrimidine derivative represented by the following formula (I) (hereinafter also referred to as “the compound of the present invention”) is provided. That is, the present invention is as follows.
  • a 1 and A 2 represent the following formula (A) or (B), When A 1 is Formula (A), A 2 represents formula (B), When A 1 is Formula (B), A 2 represents formula (A), Q 1 represents an optionally substituted 4- to 10-membered nitrogen-containing saturated heterocyclic ring, or —NR 1 R 2 , and each of R 1 and R 2 independently represents a hydrogen atom or an optionally substituted Represents a good C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl or an optionally substituted 4-10 membered saturated heterocyclic group, Alk 3 represents a C 1-8 alkylene which may be substituted with a single bond or C 1-3 alkyl, X represents a single bond, —CO—, —NR 6 CO—, —CO 2 —, —COCO—, —CONR 6 —, —OCONR 6 —, —NR 6 CO 2 —, —NR 6 CONR 7
  • Alk 4 is C 2-4 alkylene optionally substituted with C 1-3 alkyl, wherein Ar is pyrrole, imidazole, pyrazole, triazole, indole, indazole, benzimidazole, indoline, tetrahydroquinoline , 3,4-dihydro-2H-benzo [b] [1,4] oxazine or 1H-pyrrolo [2,3-b] pyridine) and Y is bound to Y, single bond, -CO -, - NR 8 CO -, - COCO- or -NR 8 SO 2 - and is, 4 to 10-membered nitrogen-containing saturated heterocyclic ring in which Q 2 may be substituted (wherein the ring has a nitrogen atom bonded to Alk 4 ) or —NR 4 R 5 , wherein Alk 4 Is methylene optionally substituted by a single bond or C 1-3 alkyl, and when Y is bonded to a carbon
  • R 10 is a hydrogen atom, an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl-C 1-10 alkyl, a substituted 4 to 10-membered saturated heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1-5 alkylcarbonyl, optionally substituted C 1 Represents -5 alkoxycarbonyl, -CONR 13 R 14 or -SO 2 R 13 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 and R 14 each independently represents a hydrogen atom or an optionally substituted C 1-10 alkyl] Or a pharmaceutically acceptable salt thereof.
  • C 1-10 alkyl which may be substituted, C 1-5 alkoxy which may be substituted, C 1-5 alkylcarbonyl which may be substituted, C 1 1 which may be substituted
  • the alkyl part of each group of 5 alkoxycarbonyl and optionally substituted aryl-C 1-10 alkyl is (1) a halogen atom, (2) hydroxyl group, (3) Cyano, (4) carboxyl, (5) optionally substituted C 3-8 cycloalkyl, (6) aryl which may be substituted, (7) optionally substituted heteroaryl, (8) C 1-5 alkoxy, (9) optionally substituted C 3-8 cycloalkoxy, (10) C 1-5 alkoxycarbonyl, (11) -NR 15 R 16 , (12) —CONR 15 R 16 , and (13) optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of 4 to 10-membered saturated heterocyclic rings Well (wherein the groups shown in (6) and (7) above
  • the groups shown in (5), (9) and (13) are the above (a) hydroxyl group, (B) halogen, (C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, (D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, (H) -CONR 15 R 16 A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: The cycloalkyl and the saturated heterocyclic group are substituted with the same or different 1 to 5 substituents selected from the group consisting of the above (a), (b), (c), (d) and (h).
  • R 15 and R 16 are each independently a hydrogen atom, a C 1-10 alkyl which may be substituted with 1 to 5 fluorine atoms, or an optionally substituted 4 to 10 membered saturated heterocyclic ring. Or when R 15 and R 16 are bonded to the same nitrogen atom, they may together form a 4- to 10-membered saturated heterocyclic ring, Item 12.
  • Q 1 may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxyl group, —CONR 15 R 16 and C 1-6 alkyl.
  • Alk 4 is a C 1-3 alkylene optionally substituted with a single bond or C 1-2 alkyl; Y is a single bond, —O—, —NR 8 CO—, —CONR 8 —, —NR 8 CONR 9 —, —NR 8 —, —CO (CR 8 R 9 ) O— or —SO 2 NR 8 —.
  • Ar is selected from the group consisting of halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms
  • Phenylene which may be substituted with the same or different 1 to 3 substituents, or C 1-6 alkyl which may be substituted with 1 to 3 fluorine atoms and 1 to 3 fluorine atoms
  • Z is a single bond, —O—, —S— or —N (R 10 ) —
  • Alk 1 and Alk 2 are each independently, hydroxyl and C 1-5 same or different 1 to may be substituted with two substituents 1 to 2
  • C 1 is selected from the group consisting of alkoxy Methylene optionally substituted with -6 alkyl or carbonyl,
  • Alk 1 and Alk 2 are each independently methylene or carbonyl.
  • Item 4 The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
  • X is a single bond, —CO— or — (CR 6 R 7 ) m 1 O—, and Alk 3 is a single bond, C 2-6 alkylene.
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • Y is a single bond, —O—, —NR 8 CO—, —CONR 8 —, or —CO (CR 8 R 9 ) O—.
  • Item 6 The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
  • [Item 7] Z is a single bond or —N (R 10 ) —.
  • Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.
  • R 10 is a hydrogen atom; 1-3 may be substituted with a fluorine atom C 1-6 alkyl; optionally substituted with a halogen and 1 to 3 fluorine atoms C 1- Aryl-C 1-6 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 6 alkyl; optionally substituted with 1 to 3 C 1-6 alkyl Preferred 4-10 membered saturated heterocycle; substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen and C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms Optionally substituted aryl; or substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen and C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms Heteroa which may be Is a reel, Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 3 is a hydrogen atom or C 1-6 alkyl optionally substituted with one hydroxyl group.
  • Item 10 The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • a 1 is the formula (A), and A 2 is the formula (B).
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • a 1 is the formula (B), and A 2 is the formula (A).
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • Q 2 is —NR 4 R 5 .
  • Item 13 The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • Q 2 may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom, C 1-6 alkyl and —CONR 15 R 16 4 to A 10-membered nitrogen-containing saturated heterocycle, Item 13.
  • Alk 1 and Alk 2 are both methylene.
  • Item 15 The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.
  • Ar consists of halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms, and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms.
  • Q 1 is —NR 1 R 2 .
  • Item 18 The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
  • Q 1 may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxyl group, —CONR 15 R 16 and C 1-6 alkyl.
  • a membered nitrogen-containing saturated heterocycle, Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 19 or a pharmaceutically acceptable salt thereof.
  • a therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor comprising the compound according to any one of items 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compounds of the present invention prevent and / or treat autoimmune diseases, specifically diseases involving autoimmunity (inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency It is useful as a prophylactic and / or therapeutic agent for symptom or neurodegenerative disease (Alzheimer, Parkinson's disease, etc.).
  • autoimmune diseases specifically diseases involving autoimmunity (inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency
  • a prophylactic and / or therapeutic agent for symptom or neurodegenerative disease (Alzheimer, Parkinson's disease, etc.).
  • TLR inhibitor that selectively inhibits TLR, it is useful as a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis.
  • TLR inhibitor that selectively inhibits TLR, a cancer growth suppressing effect and / or a cancer cell death inducing effect can be expected, and it is also useful as a pharmaceutical effective for the prevention and / or treatment of cancer. It is.
  • the compound represented by formula (I) is referred to as compound (I).
  • the number of substituents in the “substituted” group is not particularly limited as long as it can be substituted, unless otherwise specified, and is 1 or 2 or more.
  • a group not particularly described means an unsubstituted group.
  • the description of each group also applies when the group is a part of another group or a substituent.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • Compound (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and may exist as several stereoisomers. . In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound (I) of the present invention. In addition, a deuterium converter obtained by converting any one or two or more 1 H of compound (I) to 2 H (D) is also encompassed in compound (I) of the present invention.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-6 alkyl or “C 1-10 alkyl” has 1 carbon atom. Means 6 or 1 to 10 substituents, respectively.
  • C 1-6 alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl
  • isohexyl or the like is “C 1-10 alkyl”, heptyl, octyl, isooctyl, nonyl, decyl and the like can be mentioned in addition to the above.
  • Cycloalkyl means a cyclic saturated hydrocarbon group, for example, “C 3-8 cycloalkyl” means a 3- to 8-membered cyclic saturated hydrocarbon group. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, a 5- to 7-membered cycloalkyl group is used.
  • Aryl includes 6- to 14-membered monocyclic, bicyclic, and tricyclic aryl groups. Specific examples include phenyl, naphthyl, indenyl, anthranyl and the like. Preferred examples include monocyclic or 8 to 10-membered bicyclic aryl groups having 6 carbon atoms, such as phenyl and 1- or 2-naphthyl. “Arylene” means the divalent group of the above “aryl”, and the groups listed above are likewise preferred. Moreover, as a coupling
  • Heteroaryl is a 5- to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, An 11-membered bicyclic aromatic heterocyclic group or a 12-15 membered tricyclic aromatic heterocyclic group can be mentioned.
  • a 5-membered or 6-membered monocyclic aromatic heterocyclic group or a 9-membered or 10-membered bicyclic aromatic heterocyclic group is mentioned.
  • Heteroarylene means the divalent group of the above “heteroaryl”, and the groups listed above are also preferred.
  • 1,3 substitution and 1,4 substitution on heteroarylene are preferable.
  • Halogen means each atom of fluorine, chlorine, bromine or iodine. Preferably, each atom of fluorine, chlorine or bromine is used.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is bonded via an oxygen atom.
  • C 1-5 alkoxy means a carbon atom.
  • C 1-3 alkoxy is preferable.
  • Alkylcarbonyl means a group in which linear or branched alkyl is directly linked to carbonyl, for example, “C 1-5 alkylcarbonyl” means an alkyl having 1 to 5 carbon atoms in total. Means carbonyl. Specific examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl and the like. Preferably, “C 1-4 alkylcarbonyl” is used.
  • Alkoxycarbonyl means a group in which linear or branched alkoxy is directly linked to carbonyl.
  • C 1-5 alkoxycarbonyl means alkoxy having 1 to 5 carbon atoms. Which means having an alkoxycarbonyl. Specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isoporopoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, and tert-pentoxycarbonyl.
  • C 1-3 alkoxycarbonyl is used.
  • (Ix) “4 to 10-membered saturated heterocyclic ring” means 4 to 10 atoms containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms Means a monocyclic or bicyclic saturated ring.
  • azetidine pyrrolidyl, piperidyl, morpholyl, homopiperidyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, dioxotetrahydrothiopyranyl and the like.
  • a 4- to 7-membered saturated heterocyclic ring is preferable.
  • “4- to 10-membered nitrogen-containing saturated heterocyclic ring” means a saturated ring composed of 4 to 10 atoms containing 1 to 2 nitrogen atoms in addition to carbon atoms (wherein the saturated ring is further 1 Carbon atoms may be substituted with oxygen atoms or sulfur atoms).
  • a 4- to 7-membered nitrogen-containing saturated heterocyclic ring is preferable.
  • Alkylene means a linear divalent hydrocarbon group (the group may form a cyclic hydrocarbon chain), for example, “C 1-4 alkylene” or “C 1-8 alkylene” means a hydrocarbon chain of 1 to 4 or 1 to 8 carbon atoms.
  • C 1-4 alkylene methylene, ethylene, propylene, butylene and the like can be mentioned, and in the case of “C 1-8 alkylene”, in addition to the above, pentylene, hexylene and the like Is mentioned.
  • “C 1-3 alkylene” is preferable.
  • Optionally substituted C 1-10 alkyl “optionally substituted C 1-5 alkoxy”, “optionally substituted C 1-5 alkylcarbonyl”, “optionally substituted”
  • substituent of the alkyl moiety of each group of “C 1-5 alkoxycarbonyl” and “optionally substituted aryl-C 1-10 alkyl” (1) a halogen atom, (2) hydroxyl group, (3) Cyano, (4) carboxyl, (5) optionally substituted C 3-8 cycloalkyl, (6) aryl which may be substituted, (7) optionally substituted heteroaryl, (8) C 1-5 alkoxy, (9) optionally substituted C 3-8 cycloalkoxy, (10) C 1-5 alkoxycarbonyl, (11) -NR 15 R 16 , (12) —CONR 15 R 16 , and (13) the same or different 1 to 5 substituents selected from the group consisting of optionally substituted 4 to 10 membered saturated heterocycles (in which The groups shown in the above (6)
  • the groups shown in (5), (9) and (13) are the above (a) hydroxyl group, (B) halogen, (C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, (D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, (H) -CONR 15 R 16 Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of ).
  • a substituent of (1), (2), (8), (11), (12) or (13) is preferable, and a fluorine atom, (2) or unsubstituted (8) is more preferable. Is mentioned.
  • Examples of the substituent of “ optionally substituted C 3-8 cycloalkyl” and “optionly substituted 4 to 10-membered (nitrogen-containing) saturated heterocyclic ring” include the aforementioned (a), (b), The same or different 1 to 5 substituents selected from the group consisting of (c), (d) and (h) can be mentioned. Among these, a substituent of (a), (b), (c) or (h) is preferable, and (a), a fluorine atom or (c) is more preferable.
  • Optionally substituted arylene “optionally substituted heteroarylene”, “optionally substituted aryl”, “optionally substituted heteroaryl” and “optionally substituted aryl—
  • substituents (a) to (e) are preferable, and a fluorine atom, (c) or (d) is more preferable.
  • Examples of the pharmaceutically acceptable salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citric acid, and the like. Acid addition salts such as acid salts, fumarate salts, gluconate salts, lactate salts, maleate salts, malate salts, oxalate salts, methanesulfonate salts, tartrate salts, sodium salts, potassium salts, etc.
  • inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citric acid, and the like.
  • Acid addition salts such as acid salts, fumarate salts, gluconate salts, lactate salts, maleate salts, malate salts, oxalate salts, methanesulfonate salt
  • Alkali metal salts such as alkali metal salts, magnesium salts and calcium salts, metal salts such as aluminum salts and zinc salts, ammonium salts such as ammonium and tetramethylammonium, organic amine additions such as morpholine addition salts and piperidine addition salts
  • amino acid addition salts such as glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, glutamic acid addition salts, and the like.
  • each group of A 1 , A 2 , X to Z, Q 1 , Q 2 , Ar, Alk 1 to Alk 4 and R 1 to R 16 , m Preferred groups or numerical values for 1 , m 2 , n 1 and n 2 are as follows, but the present invention is not limited to the compounds listed below.
  • a 1 is the formula (A) and A 2 is the formula (B).
  • Z is preferably a single bond, —O—, —S— or —N (R 10 ) —, more preferably a single bond, —O— or —N (R 10 ) —.
  • —N (R 10 ) — is used.
  • Alk 1 and Alk 2 are preferably 1 to 2 C 1-6 alkyls optionally substituted with the same or different 1 or 2 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy And methylene which may be substituted with, or carbonyl. More preferably, a methylene or carbonyl is mentioned, More preferably, a methylene is mentioned.
  • R 10 is preferably a hydrogen atom; a C 1-10 alkyl which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom and C 1-5 alkoxy; halogen and 1 Aryl-C 1-6 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms; same selected from the group consisting of halogen and 1 to 3 C 1-6 alkyl optionally substituted by fluorine atoms; 1-3 C 1-6 which may also be saturated heterocyclic ring substituted with an alkyl selected from the group consisting or halogen, and one to three fluorine substituents C 1-3 alkyl optionally substituted with atoms; or different one to three which may be aryl substituted with a substituent Are substituted with the same or different 1 to 3 substituents include heteroaryl optionally.
  • a hydrogen atom, C 1-10 alkyl, aryl-C 1-6 alkyl, saturated heterocyclic ring, aryl or heteroaryl is exemplified. More preferred is a hydrogen atom, aryl-C 1-6 alkyl or aryl, and most preferred is aryl-C 1-6 alkyl.
  • n 1 and n 2 are preferably 1 or 2.
  • R 1 and R 2 are preferably the same or different 1 to 3 substituents selected from the group consisting of a hydrogen atom; a fluorine atom, a hydroxyl group and —CONR 15 R 16 C 1-6 alkyl optionally substituted with C 3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom and a hydroxyl group; or C Examples thereof include a 4- to 7-membered saturated heterocyclic ring which may be substituted with 1-6 alkyl.
  • preferred rings include rings having the following structures.
  • R 17 is the above-mentioned (a), (b), (c), (d) or (h) which is a substituent of a saturated heterocyclic ring which may be substituted
  • R 18 is (c) , (D), (h) or a hydrogen atom
  • r is an integer of 0 to 5.
  • q 1 -a, q 1 -c, q 1 -d, q 1 -e, q 1 -f, q 1 -g, q 1 -h, q 1 -i, q 1 -j, q 1 -k, q 1 -l, q 1 -m, q 1 -n, q 1 -o, q 1 -p include q 1 -q and q 1 -t, more preferably, q 1 -a Q 1 -c, q 1 -d, q 1 -e, q 1 -f, q 1 -g, q 1 -h, q 1 -i, q 1 -j, q 1 -k, q 1 -l , Q 1 -m, q 1 -n, q 1 -o and q 1 -q.
  • Alk 1 and Alk 2 are preferably each independently; 1-2 identical or different C 1-10 alkyls (wherein the two alkyls are substituted with methylene, the two alkyls May combine with each other to form a ring), which may be substituted methylene; or carbonyl.
  • Alk 3 preferably includes a single bond and C 1-6 alkylene, more preferably includes a single bond and C 2-6 alkylene, more preferably includes C 2-5 alkylene, and most preferably. , C 2-4 alkylene.
  • X preferably includes a single bond, —CO—, —NR 6 CO— and — (CR 6 R 7 ) m 1 O—, more preferably a single bond, —CO— and — (CR 6 R 7 ) M 1 O—, more preferably a single bond and —O—.
  • “-” representing each substituent of X represents that “-” on the left side of X is bonded to Alk 3 and “-” on the right side of X is bonded to Q 1 Represents.
  • R 3 is preferably a hydrogen atom, or C 1-6 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and a hydroxyl group, and more preferably Includes a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms, more preferably a hydrogen atom or C 1-6 alkyl.
  • R 3 may form a 4- to 10-membered saturated heterocyclic ring which may be substituted together with one carbon atom of R 1 or Alk 3 , and preferred examples thereof include the following: Structure is mentioned.
  • R 19 is the above-mentioned (a), (b), (c), (d) or (h) which is a substituent of a saturated heterocyclic ring which may be substituted, and R 20 is (c) , (D), (h) or a hydrogen atom, and p is an integer of 0 to 5. ]
  • r 3 -a, r 3 -b, r 3 -c, r 3 -d, r 3 -e, r 3 -f, r 3 -g, r 3 -h, r 3 -i, r 3 -k, r 3 -n and r 3 -s and more preferably r 3 -a, r 3 -c, r 3 -e, r 3 -f, r 3 -h, r 3 -k. And r 3 -s.
  • R 4 and R 5 are preferably selected from the group consisting of a hydrogen atom; a fluorine atom, a hydroxyl group, C 1-5 alkoxy, —NR 15 R 16 and —CONR 15 R 16 C 1-6 alkyl or C 3-8 cycloalkyl, optionally substituted with the same or different 1 to 3 substituents as described above; or 4-7 membered optionally substituted with C 1-6 alkyl A saturated heterocyclic ring is mentioned.
  • a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl or 5- to 6-membered saturated heterocycle most preferably a hydrogen atom or C 1-6 alkyl is mentioned.
  • the C 1-6 alkyl methyl, ethyl or propyl is preferable.
  • preferred rings include ring structures below.
  • R 21 is the above-mentioned (a), (b), (c), (d) or (h) which is a substituent of a saturated heterocyclic ring which may be substituted, and R 22 is (c) , (D), (h) or a hydrogen atom, and o is an integer of 0 to 5. ]
  • q 2 -a, q 2 -c, q 2 -d, q 2 -f, q 2 -g, q 2 -i, q 2 -j, q 2 -k, q 2 -l, q 2 -m, q 2 -n, q 2 -o, q 2 -p or q 2 -q more preferably q 2 -a, q 2 -c, q 2 -d, q 2 -f , Q 2 -g, q 2 -i, q 2 -j, q 2 -k or q 2 -n.
  • Alk 4 is preferably a single bond, methylene, ethylene or propylene.
  • Ar is preferably selected from the group consisting of halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms, and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms. Phenylene optionally substituted with 1 to 3 identical or different substituents selected, or C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms and 1 to 3 fluorines And heteroarylene containing 1 to 2 nitrogen atoms optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of optionally substituted C 1-5 alkoxy .
  • phenylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen, C 1-6 alkyl and C 1-5 alkoxy, or C 1-6 alkyl And heteroarylene containing 1 to 2 nitrogen atoms optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy. More preferably, phenylene or heteroarylene is mentioned.
  • the arylene and heteroarylene the following structures can be exemplified as preferred structures, and bonds at the described substitution positions are preferred. [Wherein, R 23 is the above-mentioned (a) to (i), which is an optionally substituted heteroaryl substituent, and q is an integer of 0 to 4. ]
  • Y is preferably a single bond, —O—, —NR 8 CO—, —CONR 8 —, —NR 8 CONR 9 —, —NR 8 —, —CO (CR 8 R 9 ) O— or —SO 2 NR 8 -, and the like. More preferably, a single bond, —O—, —NR 8 CO—, —CONR 8 — or —CO (CR 8 R 9 ) O— may be mentioned, and still more preferably, a single bond or —O— may be mentioned, Most preferably, a single bond is mentioned.
  • m 1 include the 0 or 1.
  • m 2 is preferably 0 or 2. More preferably, 0 is mentioned.
  • R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are preferably a hydrogen atom or C 1-6 alkyl. More preferably, a hydrogen atom or C 1-4 alkyl is used.
  • Compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il) (Im ), (In) and (Io) are compounds included in the compound (I).
  • Compound (I) can be obtained by the method shown in the following production methods 1 to 11 or a method analogous thereto.
  • the compound in the reaction formula includes a case where a salt is formed, and examples of the salt include those similar to the salt of compound (I).
  • a 1 is the formula (A)
  • a 2 is the compound (Ia) of the formula (B)
  • a 1 is the formula (B)
  • a 2 is the formula (A)
  • a certain compound (Ib) can be obtained by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 to Alk 4 , X, Y, Z, Ar, n 1 and n 2 are as defined above.
  • R a and R b are hydrogen atoms or substituted
  • An alkyl group which may be substituted, and Hal is a chlorine atom or a bromine atom.
  • Compound (III) is obtained by reacting Compound (II) with 1 to 20 equivalents, preferably 2 to 10 equivalents of urea in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in a solvent.
  • Compound (II) is a commercially available product or a known method [for example, Journal of American Chemical Society, 5779 (1958), Journal of Medicinal Chemistry, 40, 2474-2482 (1997), Journal of Organic Chemistry, 60, 1665- 1673 (1995), WO2004 / 26864, EP1552842] or a method based thereon.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, and methanol or ethanol is preferable among them.
  • the base for example, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used, and among them, sodium methoxide or sodium ethoxide is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 1 to 60 hours.
  • Compound (IV) can be obtained by reacting compound (III) obtained in step 1 with a halogenating agent in an excess amount, preferably 3 to 10 equivalents, in a solvent or without a solvent.
  • halogenating agent examples include phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide and the like.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • DCE, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, xylene, ethyl acetate , Triethylamine, pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline and the like can be used alone or as a mixture thereof.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent or halogenating agent, preferably 50 to 140 ° C., usually for 1 to 24 hours.
  • Step 3 Compound (IV) obtained in Step 2 is added in a solvent in the presence of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base, and 1 to 5 equivalents, preferably 1.2 to 3 equivalents of compound (V ) To give compound (VI-a) and / or (VI-b).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol, and the like can be used alone or as a mixture thereof.
  • 1,4-dioxane, NMP, or 2-propanol is preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine and tripropylamine.
  • Tertiary amines such as tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, particularly triethylamine or N, N-diisopropylethylamine are preferred.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C., usually for 0.5 to 24 hours.
  • Step 4 Compound (VI-a) or Compound (VI-b) obtained in Step 3 is added in a solvent in an amount of 1 to 10 equivalents, preferably 2 to 4 equivalents, and 0.01 to 1 equivalents, preferably 0.05.
  • 1 to 5 equivalents preferably 1.1 to 2 equivalents of compound (VII) in the presence or absence of ⁇ 0.2 equivalents of palladium catalyst, 0.05 to 0.2 equivalents of phosphine ligand.
  • Compound (Ia) or Compound (Ib) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone.
  • they can be used as a mixture, and among them, a mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tetrakistriphenylphosphine palladium or palladium acetate is preferred.
  • zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis
  • a divalent catalyst such as (diphenylpho
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium acetate, or inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, among which sodium carbonate and potassium carbonate. Or sodium hydroxide is preferable.
  • phosphine ligand for example, tridentate phosphine such as triphenylphosphine, tritolylphosphine, trifuranylphosphine, tri-t-butylphosphine, S-Phos, X-Phos, or BINAP, 2,2′- A bidentate phosphine such as bis (ditolylphosphino) -1,1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and S-Phos is particularly preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Alk 4 and Y are single bonds
  • Q 2 is —NR 4 R 5 or Alk
  • Compound (Ic) which is a nitrogen-containing saturated heterocyclic ring bonded to 4 by a nitrogen atom, can also be obtained from compound (VI-a) by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 to Alk 3 , X, Z, Ar, n 1 and n 2 are as defined above.
  • R a may be a hydrogen atom or substituted.
  • An alkyl group, and Hal is a chlorine atom or a bromine atom.
  • Step 5 Compound (VI-a) obtained in Step 3 is added in a solvent in an amount of 1 to 10 equivalents, preferably 2 to 4 equivalents of base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of palladium.
  • Compound (IX) can be obtained by reacting with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of Compound (VIII) in the presence of a catalyst.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone.
  • they can be used as a mixture, and among them, a mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium is particularly preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc. Among them, sodium carbonate or potassium carbonate is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • Step 6 Compound (IX) obtained in Step 5 is 1 to 10 equivalents, preferably 3 to 5 equivalents of a base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of a phosphine ligand in a solvent, and Compound (Ic) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of Compound (X) in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst. Can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene and the like are used alone or in combination. Among them, toluene or 1,4-dioxane is preferable.
  • phosphine ligand examples include monodentate phosphines such as triphenylphosphine, tolylphosphine, trifuranylphosphine, and tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino) -1, A bidentate phosphine such as 1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and among these, BINAP is preferable.
  • monodentate phosphines such as triphenylphosphine, tolylphosphine, trifuranylphosphine, and tri-t-butylphosphine
  • BINAP 2,2′-bis (ditolylphosphino) -1
  • a bidentate phosphine such as 1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and among these, BINAP
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tris (dibenzylideneacetone) dipalladium or palladium acetate is preferred.
  • zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis
  • a divalent catalyst such as (diphenylpho
  • the base for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, various alkalis such as sodium methoxide, sodium ethoxide, potassium t-butoxide, or alkaline earth metal alkoxides can be used. Of these, cesium carbonate or potassium t-butoxide is preferred.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 and 180 ° C., under heating or under microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can also be obtained from the compound (VI-b) obtained in Step 3 by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Y is —O—, —CO 2 —, —CONR 8 —, —NR 8 —, —CO
  • Compound (Id) which is (CR 8 R 9 ) O— or —SO 2 NR 8 — can also be obtained from compound (VI-a) by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 , Alk 2 , Alk 3 , Alk 4 , X, Y, Z, Ar, n 1 and n 2 are as defined above.
  • R ′ is hydrogen.
  • L is —Y—H
  • Hal is a chlorine atom, a bromine atom or an iodine atom.
  • Step 7 Compound (VI-a) obtained in Step 3 is added in a solvent in an amount of 1 to 10 equivalents, preferably 2 to 4 equivalents of base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of palladium.
  • Compound (XII) can be obtained by reacting with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of compound (XI) in the presence of a catalyst.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone.
  • they can be used as a mixture, and among them, a mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium is particularly preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc. Among them, sodium carbonate or potassium carbonate is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 and 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • Step 8 When L is a hydroxyl group, the compound (XII) obtained in step 7 is 1 to 10 equivalents, preferably 1 to 3 equivalents of phosphine, and 1 to 10 equivalents, preferably 1 to 3 equivalents of an azo compound in a solvent.
  • the compound (Id) in which Y is —O— can be obtained by reacting with the corresponding alcohol derivative in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents in the presence of the Kakuda reagent.
  • the compound (XII) obtained in Step 7 is 1 to 10 equivalents, preferably 1 to 3 equivalents of base in the presence or absence of 1 to 5 equivalents in the solvent.
  • Y is —O—, —CO 2 —, —CONR 8 —, —NR 8 —, —CO (CR 8 R 9 ) O—.
  • a compound (Id) that is —SO 2 NR 8 — can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, dichloromethane, DCE, chloroform, benzene, toluene, xylene, DMF , DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, among which THF, dichloromethane, toluene and DMF are preferable.
  • the phosphine to be used include triphenylphosphine, trimethylphosphine, tributylphosphine and the like, among which triphenylphosphine is preferable.
  • Examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, dicyclohexyl azodicarboxylate, dibenzyl azodicarboxylate, and the like, among which diethyl azodicarboxylate or diisopropyl azodicarboxylate is preferable.
  • Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine and 4-dimethylaminopyridine.
  • Tertiary amines such as N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride Of these, potassium carbonate, cesium carbonate, pyridine, N, N-diisopropylethylamine or sodium hydride is preferred.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably room temperature to 100 ° C., usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • Production method 4 Among compounds (I), compound (Ia) in which A 1 is formula (A) and A 2 is formula (B) can also be obtained by the production method shown below. (Wherein Q 1 , Q 2 , R 3 , Alk 1 to Alk 4 , X, Y, Z, Ar, n 1 and n 2 are as defined above. R c is an optionally substituted alkyl. And Hal is a chlorine atom or a bromine atom.)
  • Step 9 By reacting 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (XIII) with compound (II) in a solvent in the presence of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base, XIV) can be obtained.
  • Compound (XIII) is synthesized as a commercially available product or by a known method [for example, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol, and the like can be used alone or as a mixture thereof.
  • methanol or ethanol is preferable.
  • the base for example, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used, among which sodium methoxide or sodium ethoxide is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 1 to 60 hours.
  • Compound (XV) can be obtained by reacting Compound (XIV) obtained in Step 9 with a halogenating agent in an excess amount, preferably 3 to 10 equivalents, in a solvent or without a solvent.
  • halogenating agent for example, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxybromide is used.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • DCE, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, xylene, ethyl acetate , Triethylamine, pyridine, N, N-diisopropylethylemine, N, N-dimethylaniline, N, N-diethylaniline and the like can be used alone or as a mixture thereof.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent, preferably 50-140 ° C., usually for 1-24 hours.
  • Step 11 Compound (XV) obtained in Step 10 is added in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base, in a solvent or without solvent, in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (V ) To give compound (Ie).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, among which 1,4-dioxane is preferred.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine, N, N Tertiary amines such as diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, particularly triethylamine or N, N-diisopropylethylamine are preferred.
  • basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate
  • inorganic bases such as sodium hydroxide and potassium hydroxide
  • aromatic amines such as pyridine and luti
  • a reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Q 2 Compound (Ic) which is —NR 4 R 5 or a nitrogen-containing saturated heterocyclic ring bonded to Alk 4 by a nitrogen atom, can also be obtained, for example, from compound (II) by the production method shown below.
  • Step 12 By reacting 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (XVI) with compound (II) in a solvent in the presence of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base, XVII) can be obtained.
  • Compound (XVI) is synthesized as a commercially available product or by a known method [for example, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, n-propanol, 2-propanol and the like can be used alone or in admixture thereof, and methanol or ethanol is preferred among them.
  • the base for example, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like can be used, and among them, sodium methoxide or sodium ethoxide is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 1 to 60 hours.
  • Compound (XVIII) can be obtained by reacting compound (XVII) obtained in step 12 with an excess amount, preferably 3 to 10 equivalents of a halogenating agent in a solvent or without a solvent.
  • halogenating agent for example, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxybromide is used.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • 1,2-dichloroethane, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, Xylene, ethyl acetate, triethylamine, pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline and the like can be used alone or as a mixture thereof.
  • the reaction is carried out at 0 ° C. to the boiling point of the solvent, preferably 50 to 140 ° C., usually for 1 to 24 hours.
  • Step 14 Compound (XVIII) obtained in Step 13 is added in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base, in a solvent or without solvent, in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (V ) To give compound (XIX).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, n-propanol, 2-propanol, and the like can be used alone or as a mixture thereof.
  • 1,4-dioxane is preferred.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine, N, N Tertiary amines such as diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, among them, triethylamine and N, N-diisopropylethylamine are preferred.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 100 ° C., usually for 0.5 to 24 hours.
  • Step 15 Compound (XIX) obtained in step 14 is 1 to 10 equivalents, preferably 3 to 5 equivalents of base, and 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of a phosphine ligand in a solvent, and Compound (Ic) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of Compound (X) in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst. Can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene and the like are used alone or in combination. Among them, toluene or 1,4-dioxane is preferable.
  • the phosphine ligand include tridentate phosphine such as triphenylphosphine, tolylphosphine, trifuranylphosphine, tri-t-butylphosphine, BINAP, 2,2′-bis (ditolylphosphino) -1,1.
  • a bidentate phosphine such as' -binaphthyl, DPE-Phos, XANT-Phos and the like can be used, and among these, BINAP is preferable.
  • the palladium catalyst include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tris (dibenzylideneacetone) dipalladium or palladium acetate is preferred.
  • the base for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, various alkalis such as sodium methoxide, sodium ethoxide and potassium t-butoxide, or alkaline earth metal alkoxides can be used. Of these, cesium carbonate or potassium t-butoxide is preferred.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • X is a single bond
  • Q 1 is —NR 1 R 2 or bonded by a nitrogen atom
  • the compound (Ie) which is a nitrogen-containing saturated heterocyclic ring and Alk 3 is two or more carbon atoms, can be obtained from the compound (IV), for example, by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 , Alk 2 , Alk 4 , Y, Z, Ar, n 1 and n 2 are as defined above.
  • R c may be substituted.
  • R b is is hydrogen atom or an optionally substituted alkyl group .
  • Alk 3 ' is a good C 1-7 alkylene optionally substituted.
  • Step 16 Compound (IV) obtained in Step 2 is added in a solvent in the presence of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base, 1 to 5 equivalents, preferably 1.2 to 3 equivalents of Compound (XX ) To give compound (XXI).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, DMA, NMP, methanol , Ethanol, 1-propanol, 2-propanol and the like can be used alone or in admixture thereof, among which 1,4-dioxane, NMP or 2-propanol is preferred.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine and tripropylamine.
  • Tertiary amines such as tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, Alkali metal hydrides such as sodium hydride and potassium hydride, particularly triethylamine or N, N-diisopropylethylamine are preferred.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C., usually for 0.5 to 24 hours.
  • Compound (XXIII) can be obtained by reacting Compound (XXI) obtained in Step 16 with 0.1 to 5 equivalents, preferably 0.1 to 1 equivalents of an acid in a solvent.
  • the solvent used in this reaction may be any as long as it is inert to the reaction, and is not particularly limited.
  • acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone and the like can be used alone or in combination. Of these, acetone is preferred.
  • the acid examples include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid, organic carboxylic acids such as acetic acid and trifluoroacetic acid, mineral acids such as hydrochloric acid and sulfuric acid, scandium trifluoromethanesulfonate, indium trifluoro Lewis acids such as romethanesulfonate can be raised, and p-toluenesulfonic acid is particularly preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 80 ° C., usually for 0.5 to 24 hours.
  • Step 18 Compound (XXIII) obtained in Step 17 is added in a solvent in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of an acid, 1 to 10 equivalents, preferably 2 to 4 equivalents of a borohydride compound, and 1 Compound (XXIV) can be obtained by reacting with ⁇ 10 equivalents, preferably 1.1 to 2 equivalents of compound (XXIII).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol , N-propanol, 2-propanol and the like can be used alone or as a mixture thereof, among which 1,2-dichloroethane or methanol is preferred.
  • the acid for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which acetic acid is preferable.
  • the borohydride compound for example, sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride can be used, among which sodium cyanoborohydride or sodium triacetoxyborohydride is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 24 hours.
  • Step 18 Compound (XXIV) obtained is present in a solvent in the presence of 1 to 10 equivalents, preferably 2 to 4 equivalents of base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of palladium catalyst.
  • the compound (Ie) can be obtained by reacting with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of compound (VII).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone.
  • they can be used as a mixture, and among them, a mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium is particularly preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc. Among them, sodium carbonate or potassium carbonate is preferable.
  • reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • Production method 7 Of the compounds (I), a compound (Ig) wherein A 1 is the formula (A), A 2 is the formula (B), Z is —N (R 10 ) —, and R 10 is a hydrogen atom
  • a compound (Ih) in which R 10 is an optionally substituted alkyl group, an optionally substituted cycloalkyl, an optionally substituted saturated heterocyclic group or an optionally substituted arylalkyl Can be obtained from the compound (If) of the compound (I) wherein Z is —N (Pro) — by the production method shown below.
  • R 110 is an optionally substituted alkyl group, an optionally substituted cycloalkyl, a substituted group.
  • Compound (Ig) can be obtained by deprotecting the protecting group of compound (If).
  • the protecting group is a benzyl group, 0 to 10 equivalents, preferably 1 to 3 equivalents, in the presence of 1 to 3 equivalents of acid in a hydrogen atmosphere of 1 to 10 atmospheres, preferably 1 to 4 atmospheres in a solvent.
  • Compound (Ig) can be obtained by treatment with a catalyst such as palladium carbon on the basis of 1 to 10 equivalents, preferably 0.1 to 1 equivalents.
  • Compound (If) can be produced according to Production Methods 1-6.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, ethyl acetate, methanol, ethanol, n-propanol, 2-propanol Propanol, water or the like can be used alone or in combination, and a mixed solvent of methanol and water is preferred.
  • the catalyst for example, palladium catalysts such as palladium carbon, palladium hydroxide carbon and palladium black, nickel catalysts such as Raney nickel, and platinum catalysts such as platinum oxide can be used, among which palladium carbon is preferable.
  • the acid for example, carboxylic acids such as acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which trifluoroacetic acid or hydrochloric acid is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 50 ° C., usually for 0.5 to 24 hours.
  • Step 21 Compound (Ig) obtained in Step 20 is 1 to 10 equivalents, preferably 2 to 3 equivalents of acid in the presence of 1 to 10 equivalents, preferably 2 to 4 equivalents of borohydride compound in the solvent, and 1 Compound (Ih) can be obtained by reaction with ⁇ 10 equivalents, preferably 1.1 to 2 equivalents of the corresponding aldehyde or ketone derivative.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol , N-propanol, 2-propanol and the like can be used alone or as a mixture thereof, among which 1,2-dichloroethane or methanol is preferred.
  • the acid for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which acetic acid is preferable.
  • borohydride compound for example, sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride can be used, among which sodium cyanoborohydride or sodium triacetoxyborohydride is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Z is —N (R 10 ) —
  • R 10 is an optionally substituted alkyl
  • Compound (Ii) which is an optionally substituted cycloalkyl, an optionally substituted saturated heterocyclic ring, an optionally substituted arylalkyl or an optionally substituted heteroaryl, is obtained from compound (Ig) It can be obtained by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 to Alk 4 , X, Y, Ar, n 1 and n 2 are as defined above.
  • Hal is a chlorine atom, a bromine atom or an iodine atom.
  • R 210 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted saturated heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heteroaryl. .
  • Step 22 Compound (Ig) obtained in step 20 is added in a solvent in the presence or absence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base, 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (XXV ) To give compound (Ii).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • dichloromethane, DCE, THF, 1,4-dioxane, DME, DMF, DMA, NMP and the like can be used alone. Or they can be mixed and used, and among them, dichloromethane, THF, DMF or NMP is preferable.
  • the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, and alkali metal hydrides such as sodium hydride and potassium hydride. Among them, potassium carbonate, cesium carbonate and sodium hydride are mentioned. Is preferred.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably room temperature to 100 ° C., usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Z is —N (R 10 ) —
  • R 10 is an optionally substituted aryl Compound (Ij) which is a group or an optionally substituted heteroaryl group can be obtained from compound (Ig) by the production method shown below.
  • Q 1 , Q 2 , R 3 , Alk 1 to Alk 4 , X, Y, Ar, n 1 and n 2 are as defined above.
  • Hal ′ is a chlorine atom, a bromine atom or an iodine atom.
  • R 310 is an optionally substituted aryl group or an optionally substituted heteroaryl group.
  • Step 23 Compound (Ih) obtained by Production Method 20 is used in a solvent in an amount of 1 to 10 equivalents, preferably 3 to 5 equivalents, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of a phosphine ligand. And by reacting with 1 to 10 equivalents, preferably 1.1 to 2 equivalents of compound (XXV) in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst. (Ij) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene and the like are used alone or in combination.
  • toluene, DME or 1,4-dioxane is preferable.
  • phosphine ligand examples include monodentate phosphine such as triphenylphosphine, tolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino) -1, Bidentate phosphines such as 1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and among these, BINAP is preferable.
  • monodentate phosphine such as triphenylphosphine, tolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino) -1
  • Bidentate phosphines such as 1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and among these, BINAP is preferable
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, among which tris (dibenzylideneacetone) dipalladium or palladium acetate is preferred.
  • zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis
  • a divalent catalyst such as (diphenylpho
  • the base for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, various alkalis such as sodium methoxide, sodium ethoxide and potassium t-butoxide, or alkaline earth metal alkoxides can be used. Of these, cesium carbonate or potassium t-butoxide is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 and 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • a 1 is the formula (A)
  • a 2 is the formula (B)
  • Alk 4 is methylene
  • Y is a single bond
  • Q 2 is —NR 4 R.
  • the compound (Il) which is 5 or a nitrogen-containing saturated heterocyclic ring bonded to Alk 4 by a nitrogen atom can be obtained, for example, from the compound (VI-a) by the production method shown below.
  • R b may be a hydrogen atom or substituted.
  • An alkyl group, R d is a hydrogen atom or C 1-3 alkyl, and Hal represents a chlorine atom or a bromine atom.
  • Step 24 Compound (VI-a) obtained in Production Method 1 is added in a solvent in an amount of 1 to 10 equivalents, preferably 3 to 5 equivalents, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of palladium.
  • Compound (XXVII) can be obtained by reacting with 1 to 5 equivalents, preferably 1.1 to 1.5 equivalents of compound (XXVI) in the presence of a catalyst.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, water and the like can be used alone or A mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium is particularly preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc. Among them, sodium carbonate or potassium carbonate is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • Step 25 Compound (XXVII) obtained in Step 24 is added in a solvent in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of acid, 1 to 10 equivalents, preferably 2 to 3 equivalents of a borohydride compound, and 1 Compound (Ik) can be obtained by reacting with ⁇ 10 equivalents, preferably 1.1 to 2 equivalents of compound (X).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol , N-propanol, 2-propanol and the like can be used alone or as a mixture thereof, among which 1,2-dichloroethane or methanol is preferred.
  • the acid for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which acetic acid is preferable.
  • borohydride compound for example, sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride can be used, among which sodium cyanoborohydride or sodium triacetoxyborohydride is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 20 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • Production method 11 Among compounds (I), Q 2 is —NR 4 R 5 and R 4 is a hydrogen atom (Il), Q 2 is a 4- to 10-membered nitrogen-containing saturated heterocycle, and nitrogen-containing saturated heterocycle Compound (Im) in which at least one nitrogen atom in the ring is —NH—, Compound (In) in which Q 2 is —NR 4 R 5 , or Q 2 is a 4- to 10-membered nitrogen-containing saturated heterocyclic ring Compound (Io) can be obtained from compound (VI-a) by the production method shown below. Wherein Q 1 , R 3 to R 5 , Alk 1 to Alk 3 , X, Y, Z, Ar, n 1 and n 2 are as defined above.
  • R a is a hydrogen atom or substituted Pro is a common amine protecting group shown in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)), and Het may be substituted. 4 to 10-membered saturated heterocyclic ring, and R e is C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms.
  • Step 26 Compound (IV-a) obtained in Production Method 1 is added in a solvent in an amount of 1 to 10 equivalents, preferably 3 to 5 equivalents of base, and 0.01 to 1 equivalents, preferably 0.05 to 0.2 equivalents of palladium.
  • Compound (XXX) or Compound (XXXI) can be obtained by reaction with 1 to 5 equivalents, preferably 1.1 to 1.5 equivalents of Compound (XXVIII) or Compound (XXIX) in the presence of a catalyst. .
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, benzene, toluene, xylene, water and the like can be used alone or A mixed solvent of DME and water or 1,4-dioxane and water is preferable.
  • the palladium catalyst examples include zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis A divalent catalyst such as (diphenylphosphinoferrocene) palladium dichloride can be used, and tetrakistriphenylphosphine palladium is particularly preferable.
  • the base examples include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, etc. Among them, sodium carbonate or potassium carbonate is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or under microwave irradiation, usually for 0.5 to 24 hours.
  • Step 27 Compound (Il) or Compound (Im) can be obtained by deprotecting the protecting group of Compound (XXX) or Compound (XXXI) obtained in Step 26.
  • the protecting group is a Boc group
  • compound (Il) or compound (Im) can be obtained by reacting with an excess amount, preferably 5 to 10 equivalents, of acid in a solvent.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, diethyl ether, dichloromethane, DCE, methanol, ethanol and the like are used alone or They can be used as a mixture. Among them, 1,4-dioxane, dichloromethane or methanol is preferable.
  • the acid for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which hydrochloric acid or trifluoroacetic acid is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at room temperature to 40 ° C., usually for 0.5 to 24 hours.
  • Step 28 Compound (Il) or Compound (Im) obtained in Step 27 is hydrogenated in a solvent in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of acid, in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents.
  • Compound (Io) or Compound (Ip) can be obtained by reacting with a boron compound and 1 to 10 equivalents, preferably 1.1 to 2 equivalents of the corresponding aldehyde or ketone derivative.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol , N-propanol, 2-propanol, and the like can be used singly or as a mixture thereof, among which 1,2-dichloroethane or methanol is preferred.
  • the acid for example, carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid can be used, among which acetic acid is preferable.
  • borohydride compound for example, sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride can be used, among which sodium cyanoborohydride or sodium triacetoxyborohydride is preferable.
  • the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at a temperature between room temperature and 40 ° C., usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (B) and A 2 is the formula (A) can be obtained by the same production method.
  • Compound (IV), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below.
  • Alk 1 , Alk 2 , Z, n 1 and n 2 are as defined above.
  • Hal is a chlorine atom and a bromine atom.
  • Step 29 Compound (XXXII) is reacted with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of a carbonate or cyanate ester in the presence of 1 to 5 equivalents, preferably 1.1 to 2 equivalents of a base in a solvent.
  • a compound having an alkoxycarbonyl group introduced at the ⁇ -position of the carbonyl group can be obtained.
  • the obtained compound is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of a guanidine derivative or an acid salt thereof in the presence or absence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent.
  • compound (XXXIII) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but the first reaction is, for example, an ether solvent such as THF, 1,4-dioxane, DME, diethyl ether, Aprotic solvents such as hexane, heptane, toluene, DMF, DMSO, and acetonitrile can be used alone or as a mixture thereof.
  • an ether solvent such as THF, 1,4-dioxane, DME, diethyl ether, Aprotic solvents such as hexane, heptane, toluene, DMF, DMSO, and acetonitrile can be used alone or as a mixture thereof.
  • THF or diethyl ether is preferable.
  • the second reaction includes, for example, ether solvents such as diethyl ether, THF, 1,4-dioxane, DME, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, halogen solvents such as chloroform and chlorobenzene, toluene, Aprotic solvents such as DMF and DMSO can be used singly or as a mixture thereof, and methanol or ethanol is particularly preferable.
  • ether solvents such as diethyl ether, THF, 1,4-dioxane, DME
  • alcohol solvents such as methanol, ethanol, 2-propanol and butanol
  • halogen solvents such as chloroform and chlorobenzene, toluene
  • Aprotic solvents such as DMF and DMSO can be used singly or as a mixture thereof, and methanol or ethanol is particularly preferable.
  • Examples of the base used in the first reaction include metal amides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium t-
  • metal amides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide
  • sodium methoxide sodium ethoxide
  • Various alkali or alkaline earth metal alkoxides such as butoxide
  • metal hydrides such as lithium hydride, sodium hydride or potassium hydride can be used, and among them, lithium hexamethyldisilazide or lithium diisopropylamide is preferable.
  • Examples of the base used in the second reaction include metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, and calcium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, lithium hexamethyldioxide.
  • guanidine / acid salt used in the second reaction guanidine / carbonate, guanidine / hydrochloride, guanidine / sulfate and the like can be used, and guanidine / carbonate is preferable.
  • the first reaction is carried out at a temperature between ⁇ 100 ° C. and 50 ° C., preferably at ⁇ 80 ° C. to 0 ° C., usually for 1 to 10 hours.
  • the second reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 50-100 ° C., usually for 1-20 hours.
  • Ketone (XXXII) is, for example, J. Chem. Soc. Perkin Trans.
  • Compound (XXXIV) can be obtained by reacting Compound (XXXIII) obtained in Step 29 with a halogenating agent in an excess amount, preferably 3 to 10 equivalents, in a solvent or without a solvent.
  • halogenating agent examples include phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide and the like.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • DCE, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, xylene, ethyl acetate , Triethylamine, pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline and the like can be used alone or as a mixture thereof.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent or halogenating agent, preferably 50 to 140 ° C., usually for 1 to 24 hours.
  • Step 31 Compound (XXXIV) obtained in Step 30 is added in the presence of 1 to 30 equivalents, preferably 5 to 15 equivalents of trialkylsilyl chloride in a solvent, 1 to 20 equivalents, preferably 3 to 10 equivalents of alkyl nitrite, and 1 Compound (IV) can be obtained by reaction with ⁇ 10 equivalents, preferably 1 to 3 equivalents of alkylammonium halide.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like can be used alone or in combination. Among them, dichloromethane is preferable.
  • the trialkylsilyl chloride for example, trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride or the like can be used, among which trimethylsilyl chloride is preferable.
  • alkyl nitrite for example, isobutyl nitrite, butyl nitrite, t-butyl nitrite, isopentyl nitrite, neopentyl nitrite, pentyl nitrite and the like can be used.
  • halogenated alkylammonium for example, tetrabutylammonium chloride, triethylbenzylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium bromide and the like can be used, among which triethylbenzylammonium chloride is preferable.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0 ° C. to 30 ° C., usually for 0.5 to 20 hours.
  • Compound (XXXIII), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below.
  • Alk 1 , Alk 2 , Z, n 1 and n 2 are as defined above.
  • R a and R b are an optionally substituted alkyl group.
  • the compound (XXXVI) can be obtained by removing the diester compound (XXXV) in a solvent with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of a base.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but the first reaction is, for example, an ether solvent such as THF, 1,4-dioxane, DME, diethyl ether, Aprotic solvents such as hexane, heptane, toluene, DMF, DMSO and the like can be used alone or as a mixture thereof.
  • an ether solvent such as THF, 1,4-dioxane, DME, diethyl ether, Aprotic solvents such as hexane, heptane, toluene, DMF, DMSO and the like can be used alone or as a mixture thereof.
  • THF or diethyl ether is preferable.
  • the base examples include metal amides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide, various alkalis such as sodium methoxide, sodium ethoxide, potassium t-butoxide or the like Alkaline earth metal alkoxides, metal hydrides such as lithium hydride, sodium hydride or potassium hydride can be used, among which lithium hexamethyldisilazide or lithium diisopropylamide is preferred.
  • the reaction is carried out at a temperature between ⁇ 100 ° C. and 50 ° C., preferably at ⁇ 80 ° C.
  • the diester compound (XXXV) is prepared by a method described in, for example, J. Am. Chem. Soc. 1960, 82, 2050-2052., J. Am. Chem. Soc. 1997, 119, 4285-4291. It can be synthesized by a method according to it, or can be purchased.
  • Step 33 Compound (XXXVI) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of a guanidine derivative or an acid salt thereof in the presence or absence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent.
  • compound (XXXIII) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • ether solvents such as diethyl ether, THF, 1,4-dioxane, DME, methanol, ethanol, 2 -Alcohol solvents such as propanol and butanol, halogen solvents such as chloroform and chlorobenzene, and aprotic solvents such as toluene, DMF and DMSO can be used alone or in combination.
  • methanol or ethanol is preferred. .
  • the base examples include metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate and calcium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium hexamethyldisilazide, sodium hexamethyl Disilazide, potassium Metal amides such as hexamethyldisilazide, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydride, sodium hydride, potassium hydride, etc.
  • Organic bases such as metal hydrides, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.
  • guanidine / acid salt guanidine / carbonate, guanidine / hydrochloride, guanidine / sulfate and the like can be used, and guanidine / carbonate is preferable.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 50-100 ° C., usually for 1-20 hours.
  • Step 34 Compound (XXXVII) is reacted with 0.2 to 5 equivalents, preferably 0.5 to 2 equivalents of an aldehyde derivative or ketone derivative in the presence of 1 equivalent to a solvent amount, preferably 5 equivalents to a solvent amount of an acid in a solvent. To give compound (XXXVII).
  • sulfuric acid, nitric acid, hydrochloric acid or the like can be used alone or mixed with water, and among them, an aqueous solution of sulfuric acid and water is preferable.
  • the reaction is carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used, preferably 0 to 40 ° C., usually for 1 to 20 hours.
  • Compound (XXXIX) can be obtained by oxidizing compound (XXXVIII) with 1 to 10 equivalents, preferably 1 to 5 equivalents of an oxidizing agent in a solvent.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • ether solvents such as diethyl ether, THF, 1,4-dioxane and DME
  • dichloromethane 1,2 -Halogen solvents such as dichloroethane, chloroform, chlorobenzene, and aprotic solvents such as toluene, acetonitrile, DMF, DMSO
  • dichloromethane or DMSO can be used alone or in combination. Is preferred.
  • the oxidizing agent used in this reaction is, for example, a metal oxide such as chromic acid or a salt thereof, sulfur trioxide pyridine complex, chloric acid, hypochlorous acid or a salt thereof, etc. Or dicyclohexylcarbodiimide, acetic anhydride, a combination of trifluoroacetic anhydride and DMSO, etc., among which chromic acid or a salt thereof or Swern oxidation is preferable.
  • the reaction is carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used, preferably 0 to 40 ° C., usually for 1 to 20 hours.
  • Compound (VI-a) which is an intermediate for synthesizing compound (I) can also be obtained by the production method shown below.
  • Alk 1 , Alk 2 , Alk 3 , R 3 , Q 1 , X, Z, n 1 and n 2 are as defined above.
  • R a and R b are optionally substituted alkyl groups.
  • Hal is a chlorine atom and a bromine atom.
  • Step 36 Compound (XXXVIII) is treated with 1 to 10 equivalents, preferably 1 to 5 equivalents of a base in a solvent, reacted with carbon disulfide, and subsequently alkylated with an alkyl halide reagent to give Compound (XXXX). Obtainable.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • ether solvents such as diethyl ether, THF, 1,4-dioxane, DME, toluene, acetonitrile, DMF
  • An aprotic solvent such as DMSO can be used alone or as a mixture thereof.
  • THF is preferable.
  • Examples of the base used in this reaction include metal amides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide, various alkalis such as sodium methoxide, sodium ethoxide, and potassium t-butoxide, Alkaline earth metal alkoxides, metal hydrides such as lithium hydride, sodium hydride or potassium hydride can be used, among which sodium hydride or lithium hexamethyldisilazide is preferred.
  • alkyl halide used in this reaction examples include alkyl iodide reagents such as methyl iodide, ethyl iodide, allyl bromide, and benzyl bromide, and alkyl bromide reagents, among which methyl iodide is preferable.
  • the reaction is carried out at a temperature between ⁇ 80 ° C. and the boiling point of the solvent used, preferably at ⁇ 20 ° C. to 50 ° C., usually for 1 to 20 hours.
  • Step 37 Compound (XXXX) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of a guanidine derivative or an acid salt thereof in the presence or absence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent.
  • compound (XXXXI) can be obtained.
  • the same conditions as in step 33 in Production Example 13 can be used.
  • Compound (XXXII) can be obtained by treating compound (XXXXI) with 1 to 10 equivalents, preferably 1 to 3 equivalents, of an oxidizing agent in a solvent.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • ether solvents such as diethyl ether, THF, 1,4-dioxane, DME, dichloromethane, chloroform, 1 Halogen solvents such as 2-dichloroethane and chlorobenzene, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, and aprotic solvents such as toluene, acetonitrile and DMF may be used alone or in combination.
  • dichloromethane or 1,2-dichloroethane is preferable.
  • the oxidizing agent used in this reaction for example, peroxides such as m-chloroperbenzoic acid, peracetic acid and hydrogen peroxide, and metal oxides such as chromic acid can be used. preferable.
  • the reaction is carried out at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used, preferably 0 ° C. to 30 ° C., usually for 1 to 20 hours.
  • Step 39 Compound (XXXXII) in the presence of 1 to 30 equivalents, preferably 5 to 15 equivalents of trialkylsilyl chloride in a solvent, 1 to 20 equivalents, preferably 3 to 10 equivalents of alkyl nitrite, and 1 to 10 equivalents, Compound (XXXXIII) can be obtained by preferably reacting with 1 to 3 equivalents of an alkylammonium halide.
  • the reaction conditions the same conditions as in step 31 in Production Example 12 can be used.
  • Step 40 Compound (XXXXIII) is reacted with 1 to 5 equivalents, preferably 1.2 to 3 equivalents of Compound (V) in the presence of 1 to 5 equivalents, preferably 1.5 to 2 equivalents of a base in a solvent.
  • compound (VI-a) can be obtained.
  • the same conditions as in step 3 in Production Example 1 can be used.
  • the compound of the present invention having a desired functional group at a desired position can be obtained by appropriately combining the above production methods.
  • Isolation and purification of intermediates and products in the above production method may be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography, and the like. it can.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • the raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride depending on the reaction conditions and the like, but can be used as it is or in a free form.
  • the raw material compound or intermediate When the raw material compound or intermediate is obtained in the form of a salt and it is desired to use or obtain the raw material compound or intermediate in a free form, these are dissolved or suspended in an appropriate solvent, and a base such as an aqueous sodium hydrogen carbonate solution is obtained. It can be converted to the free form by neutralizing with, for example.
  • isomers such as tautomers such as ketoenol, positional isomers, geometric isomers or optical isomers
  • tautomers such as ketoenol, positional isomers, geometric isomers or optical isomers
  • optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method.
  • An optically active substance can also be used as a starting material.
  • the salt of compound (I) can be purified as it is, and when compound (I) is obtained in a free form, compound (I) is appropriately converted.
  • a salt may be formed by dissolving or suspending in a solvent and adding an acid or a base.
  • Compound (I) or a pharmacologically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also encompassed in the present invention.
  • the pharmaceutical preparation according to the present invention is produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmacologically acceptable carriers.
  • the pharmaceutical carrier used include lactose, mannitol, glucose, starch, magnesium ceterate, glyceric acid 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, binders, disintegrants, isotonic agents, emulsifiers and the like.
  • intravenous administration it is desirable to use the most effective treatment, and oral or parenteral such as intravenous, application, inhalation and eye drop can be mentioned, preferably intravenous administration, It is particularly preferable to administer by intravenous infusion.
  • oral or parenteral such as intravenous, application, inhalation and eye drop
  • intravenous administration It is particularly preferable to administer by intravenous infusion.
  • the dosage form include tablets, injections and the like, with injections being preferred.
  • the dosage and frequency of administration of these pharmaceutical compositions vary depending on the dosage form, the patient's disease and symptoms, the patient's age and weight, etc., and cannot be generally specified, but are usually effective for adults per day
  • the amount of the component is in the range of about 0.0001 to about 2000 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. It can be administered once or several times a day.
  • Reference Example 2-16 The corresponding starting materials were used and reacted and treated in the same manner as described in Reference Example 1 to obtain the compounds shown in Table 1.
  • cyanoformate methyl ester (4.67 ml, 47 mmol) was added. After 1.5 hours, saturated aqueous ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated with an evaporator. The residue was dissolved in methanol (90 ml), 50 ml of which was added to a mixture of sodium methoxide in methanol (28 w / w%, 6.36 g, 33 mmol) and urea (1.98 g, 33 mmol). The mixture was stirred at 60 ° C for 1 hour and at 70 ° C for 2 hours.
  • the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (43.2 mg, yield 74%).
  • Reference Example 36 1- (3- (6-Benzyl-2-chloro-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-ylamino) propyl) piperidin-4-one
  • DMSO 1.7 ml
  • sulfur trioxide / pyridine complex 253.3 mg, 1.59 mmol
  • Example 3-42 Reaction and treatment were performed in the same manner as in Example 2 using the corresponding starting compounds, and the compounds shown in Table 8 were obtained.
  • Example 43 6-Benzyl-2- ⁇ 4-[(4-methylpiperazin-1-yl) methyl] phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [ 4,3-d] pyrimidin-4-amine
  • 1-methylpiperazine (14.6 ⁇ l, 0.132 mmol
  • acetic acid 37.7 ⁇ l, 0.658 mmol
  • sodium cyanoborohydride 27.6 mg, 0.439
  • Examples 44-57 Reaction and treatment were carried out in the same manner as in Example 43 using the corresponding starting compounds, and the compounds shown in Table 9 were obtained.
  • Example 58 2- ⁇ 4- (4-Methylpiperazin-1-yl) phenyl ⁇ -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine -4-amine 6-Benzyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydro obtained in Example 6
  • pyrido [4,3-d] pyrimidin-4-amine 800 mg, 1.52 mmol
  • methanol 16 ml
  • 4.0 ml 10% palladium-carbon
  • 4 mol / l hydrochloric acid / dioxane (4.0 ml) was added, and the mixture was stirred at 40 ° C.
  • Examples 59-61 The corresponding starting materials were used and reacted in the same manner as in Example 58 to obtain the compounds shown in Table 10.
  • Example 62 6-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [4,3 -d] pyrimidin-4-amine 2- [4- (4-Methylpiperazin-1-yl) phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [4] obtained in Example 58 , 3-d] pyrimidin-4-amine (50 mg, 0.115 mmol) in methanol (1.0 ml), 35% formalin aqueous solution (27.3 ⁇ l, 0.344 mmol), acetic acid (39.4 ⁇ l, 0.689 mmol) and cyano hydrogenation Sodium boron (28.9 mg, 0.459 mmol) was added and stirred at room temperature.
  • Examples 63-71 The corresponding starting materials were used and reacted in the same manner as in Example 62 to obtain the compounds shown in Table 11.
  • Example 72 7-acetyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [3,4 -d] pyrimidin-4-amine 2- [4- (4-Methylpiperazin-1-yl) phenyl] -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [3 obtained in Example 61 , 4-d] pyrimidin-4-amine (40 mg, 0.0918 mmol) in dichloromethane (1.0 ml) was added acetyl chloride (7.8 ⁇ l, 0.110 mmol) at 0 ° C.
  • Examples 73-74 Reaction and treatment were performed in the same manner as in Example 71 using the corresponding starting compounds, and the compounds shown in Table 12 were obtained.
  • Example 75 6-Benzyl-2- [4- (piperazin-1-yl) phenyl] -N- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [4,3- d] pyrimidin-4-amine
  • tert-butyl 4- [4- (4,4,5,5, -tetramethyl-1,3, 2-borolan-2-yl) phenyl] piperazine-1-carboxylate (70.4 mg, 0.181 mmol), 3 mol / L aqueous sodium carbonate (0.13 ml, 0.390 mmol) and tetrakistriphenylphosphine palladium (15.0 mg, 0.0130 mmol) And stirred at 120 ° C.
  • Example 76 6-Benzyl-N- (3-morpholinopropyl) -2- [4- (piperazin-1-yloxy) phenyl] -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4- Amine 4- (4,4,5,5, -tetramethyl-1 synthesized in Reference Example 8 (166 mg, 0.413 mmol) in dioxane (4.0 ml) -water (0.41 ml) with reference to WO 2006/59778 , 3,2-Dioxaborolan-2-yl) phenoxy-1-tert-butoxycarbonylpiperidine (200 mg, 0.496 mmol), 3 mol / L aqueous sodium carbonate solution (0.41 ml, 1.23 mmol), tetrakistriphenylphosphine palladium (47.8 mg, 0.0413 mmol) was added, and the mixture was stirred at 120 ° C.
  • reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the resulting residue, the reaction product was subjected to liquid separation extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure.
  • the obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate) to give the title compound (32.3 mg, yield 14%).
  • LC / MS; Retention time 3.40 min, m / z 543 (M + 1)
  • Example 78 2- ⁇ 4- (4-Methylpiperazin-1-yl) phenyl ⁇ -6- (pyrimidin-2-yl) -N- ⁇ 3- (pyrrolidin-1-yl) propyl ⁇ -5,6,7,8 -Tetrahydropyrido [4,3-d] pyrimidin-4-amine 2- ⁇ 4- (4-Methylpiperazin-1-yl) phenyl ⁇ -N- (3-pyrrolidin-1-ylpropyl) -5,6,7,8-tetrahydropyrido [4] obtained in Example 58 , 3-d] pyrimidin-4-amine (43.6 mg, 0.10 mmol) in N, N-dimethylformamide (1.0 ml), 2-chloropyrimidine (13.8 mg, 0.12 mmol), potassium carbonate (27.7 mg, 0.20) mmol) was added and stirred at 60 ° C.
  • Examples 79-136 Reaction and treatment were performed in the same manner as in Example 2 using the corresponding starting compounds, and the compounds shown in Table 13 were obtained.
  • Example 138 (2- (4- (4-Methylpiperazin-1-yl) phenyl) -4- (3- (pyrrolidin-1-yl) propylamino) -7,8-dihydropyrido [4,3-d] pyrimidine -6 (5H) -Il) ethanone
  • THF 1.0 mL
  • acetyl chloride 5.3 mg, 0.068 mmol
  • triethylamine 9.5 ⁇ l, 0.068 mmol
  • Example 139 N-isopropyl-2- (4- (4-methylpiperazin-1-yl) phenyl) -4- (3- (pyrrolidin-1-yl) propylamino) -7,8-dihydropyrido [4,3-d] Pyrimidine-6 (5H) -carboxamide
  • isopropyl isocyanate (6.9 ⁇ l, 0.070 mmol) was added under ice cooling. After warming to room temperature and stirring for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Example 140 2- ⁇ 4- (4-Methylpiperazin-1-yl) ⁇ -N- ⁇ 3- (pyrrolidin-1-yl) propyl ⁇ -6,7,8,9-tetrahydro-5H-pyrimido [4,5- d] azepine-4-amine Using the compound (90.0 mg, 0.166 mmol) obtained in Example 41, the title compound was obtained as a solid (53.3 mg, 71% yield) by carrying out the reaction and treatment in the same manner as in the method described in Example 58. ).
  • Example 141 7-isopropyl-2- ⁇ 4- (4-methylpiperazin-1-yl) ⁇ -N- ⁇ 3- (pyrrolidin-1-yl) propyl ⁇ -6,7,8,9-tetrahydro-5H-pyrimido [ 4,5-d] azepine-4-amine
  • the title compound was obtained as an oil (16.9 mg, yield 39%) by carrying out the reaction and treatment in the same manner as in the method described in Example 62. ).
  • Example 142 N 1- (2-methoxyethyl) -N 1 -methyl-N 3- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5,6,7,8-tetrahydroquinazoline-4- Yl) propane-1,3-diamine
  • Acetic acid (40.0 ⁇ l, 0.706 mmol)
  • 2-methoxy-N-methylethanamine (38.0 ⁇ l, 0.354 mmol)
  • Sodium borohydride (19.0 mg, 0.449 mmol) was added. After stirring for 2.5 hours, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution.
  • Examples 143-154 Reaction and treatment were carried out in the same manner as in Example 142 using the corresponding starting compounds, and the compounds shown in Table 14 were obtained.
  • Example 157 2- [4- (4-Methylpiperazin-1-yl) phenyl] -N- (morpholin-2-ylmethyl) -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-amine
  • ammonium formate 227.0 mg, 3.60 mmol
  • 10% palladium carbon 93.0 mg
  • Example 158 N-[(4-Methylmorpholin-2-yl) methyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] -7,8-dihydro-5H-pyrano [4,3-d] Pyrimidine-4-amine
  • a solution of the compound (52.8 mg, 0.124 mmol) obtained in Example 157 in methanol (1.6 ml) under ice-cooling 35% aqueous formaldehyde solution (10.6 mg, 0.124 mmol), acetic acid (14.2 ⁇ l, 0.248 mmol), cyanohydrogen
  • sodium borohydride (15.6 mg, 0.248 mmol
  • the reaction mixture was diluted with chloroform, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as an amorphous substance (43.2 mg, yield 79%).
  • Example 159 N-[(4-Isopropylmorpholin-2-yl) methyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] -7,8-dihydro-5H-pyrano [4,3-d] Pyrimidine-4-amine
  • the title compound was obtained as a solid by carrying out the reaction and treatment in the same manner as in Example 158 using the compound (52.8 mg, 0.124 mmol) obtained in Example 157 (39.6 mg, yield 68%) .
  • Examples 160-162 Reaction and treatment were carried out in the same manner as in Example 155 using the corresponding starting compounds, and the compounds shown in Table 15 were obtained.
  • the reaction mixture was diluted with chloroform, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as an amorphous product (53.5 mg, yield 74%).
  • Example 164-168 Using the corresponding starting compounds, Example 155 and Example 163 were combined and reacted and treated in the same manner to obtain the compounds shown in Table 16.
  • t-butyl 4- (5- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -1H-indol-1-yl) piperidine-1-carboxylate (149 mg, 0.35 mmol), 2 mol / L aqueous sodium hydroxide (750 ⁇ l, 1.50 mmol), palladium acetate (6.60 mg, 0.03 mmol) and S-Phos (24.0 mg, 0.06 mmol) were added, and the mixture was stirred at 80 ° C.
  • Test Example 1 Human TLR 9 Reporter Gene Test A HEK293 cell stable human TLR 9 expression strain (human TLR 9 -293 cell) was asleep and the passage was repeated until the cell state was stabilized. The cell culture was left in a CO 2 incubator (37 ° C., 5% CO 2 ). For cell recovery, the cells were detached using trypsin-EDTA, and the cell pellet after centrifugation was suspended in a growth medium. Human TLR 9 -293 cells prepared at 3 ⁇ 10 5 cells / mL were seeded on a 6-well collagen plate and cultured overnight.
  • NF- ⁇ B-luciferase gene was introduced into the cells and cultured overnight.
  • NF- ⁇ B-luciferase gene-introduced cells were prepared at 6.25 ⁇ 10 5 cells / mL and seeded at 80 ⁇ L / well in a 96-well black plate (5 ⁇ 10 4 cells / well).
  • the cells were cultured for 6 hours.
  • a Bright-Glo preparation solution was added at 100 ⁇ L / well and left for 1 minute under light shielding. Luminescence was measured using a luminometer, and the 50% inhibition rate (IC 50 value) of each test substance was calculated and shown in Table 18.
  • the compounds of the present invention exhibited a strong inhibitory action in the NF- ⁇ B inhibition test.
  • the compounds of 129, 130, 131, 137, 141, 142, 147, 153, 154, 164, 166, 167, 168, 169 and 170 showed particularly strong inhibitory action.
  • Test Example 2 CpG-induced IL-6 production inhibition test using mouse spleen cells
  • Mouse spleen cells were prepared as follows. The spleen extracted from C57BL / 6 mice (female) was divided with surgical scissors and ground with a slide part of the slide glass. After centrifugation, hemolysis was performed using ACK (ammonium chloride-potassium) hemolysis buffer. The medium was added to stop the reaction of the ACK hemolysis buffer, and centrifugation was performed. Cells were prepared at 1 ⁇ 10 7 cells / mL and seeded at 100 ⁇ L / well in a 96-well plate (1 ⁇ 10 6 cells / well).
  • ACK ammonium chloride-potassium
  • test substance final concentration: 1, 3, 10, 30, 100, 300, 1000 nM
  • CpG1826 5'-TCC ATG ACG TTC CTG ACG TT-3 '
  • IC 50 value 50% inhibition rate
  • the compound of the present invention exhibited a strong inhibitory action in the IL-6 production inhibition test.
  • the compounds showing high activity values in the NF- ⁇ B inhibition test shown in Table 18 also have a strong IL-6 production inhibitory action as in Examples 16, 64, 67, 88, 93, 97, 106 and 141. Indicated.
  • Test Example 3 Drug efficacy evaluation test using CpG1826 administration model A CpG1826 solution was administered intraperitoneally to mice under ether anesthesia. One to six hours after CpG1826 administration, blood was collected under ether anesthesia and the peritoneal lavage fluid was collected. Blood was collected from the heart and collected in a tube containing heparin, and abdominal cavity washing was collected after injecting PBS (phosphate buffered saline) into the abdominal cavity to massage the abdomen. The compound was administered from the mouse tail vein before CpG1826 administration. Blood and peritoneal lavage fluid were centrifuged to obtain plasma and peritoneal lavage fluid supernatants, and cytokines were measured using a commercially available ELISA kit.
  • PBS phosphate buffered saline
  • IL-6 production was measured, and the inhibition rate (%) was calculated by comparison with the solvent control of each test substance, and are shown in Table 20 and Table 21.
  • Table 20 and Table 21 in Example 16, administration of 1 mg / kg 2 hours after administration of CpG1826 confirmed significant suppression of inflammatory cytokine production as compared with the solvent control group. it has been shown to inhibit TLR 9 dependent inflammatory cytokine production.
  • Test Example 4 Drug efficacy evaluation test using cecal ligation and puncture (CLP) model
  • CLP cecal ligation and puncture
  • the cecal ligation and puncture model is the most widely used animal model in sepsis research and is currently the model that most reflects human sepsis pathology.
  • CLP cecal ligation and puncture
  • the midline of the abdomen was opened several centimeters with scissors to expose the cecum and nearby organs.
  • the cecal wall was punctured and perforated using an 18-23G needle (CLP treatment).
  • CLP treatment 18-23G needle
  • the laparotomy was closed with a cyanoacrylate surgical adhesive, and the surgical field was disinfected with isodine cotton.
  • the animals were raised and a survival check was performed at least twice a day. Some were euthanized by whole blood collection several hours after the operation, and then the peritoneal lavage fluid and organs were collected and used for measurement of cytokines, organ damage markers, viable counts, and the like.
  • the compound was administered intravenously before or after CLP treatment. Some were performed in combination with subcutaneous administration of physiological saline warmed to 37 ° C. and intraperitoneal administration of an antibacterial agent.
  • Test Example 5 Cancer Cell Proliferation Inhibition Test Human myeloma cell line Ramos has been confirmed to express TLR 9 and has been reported to promote proliferation by TLR 9 ligand (Cellular Immunology 259 (2009) p90-99).
  • a Ramos cell line was prepared to 6.25 ⁇ 10 4 cells / mL, and seeded in a 96-well plate at 80 ⁇ L / well (5 ⁇ 10 3 cells / well). After adding 10 ⁇ L each of the test substance (final concentrations: 0.01, 0.1, 1, 10 ⁇ M) and CpG2006 (final concentration: 3 ⁇ g / mL), in a CO 2 incubator (37 ° C., 5% CO 2 concentration) Cultured for 3 days.
  • Inhibitory oligonucleotides (iCpG: 5′-TTT AGG GTT AGG GTT AGG GTT AGG G-3 ′), which is a human TLR 9- specific inhibitor, were set as a positive control. 80 ⁇ L of 5-bromo-2′-deoxy-uridine (BrdU) solution was added to each well and further cultured for 16 hours. BrdU incorporation into cells was measured with a luminometer. Tables 22 and 23 show the growth inhibition rate of each test substance against the promotion of cancer cell growth by CpG2006. As shown in Tables 22 and 23, the compounds of the present invention showed a strong inhibitory effect on cancer cell proliferation in a dose-dependent manner.
  • PrdU 5-bromo-2′-deoxy-uridine
  • the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof prevents and / or treats an autoimmune disease, specifically, a disease in which an autoimmune disease is involved ( It can be used as a preventive and / or therapeutic agent for inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegenerative disease (Alzheimer, Parkinson's disease, etc.). Further, by finding a TLR inhibitor that selectively inhibits TLR, it can be used as a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis.

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Abstract

La présente invention concerne un agent prophylactique et/ou thérapeutique contre des pathologies associées à l'auto-immunité, des pathologies immunodéficientes ou des pathologies neurodégénératives, ledit agent prophylactique et/ou thérapeutique incluant un nouveau dérivé fusionné de pyrimidine. La présente invention concerne particulièrement un agent prophylactique et/ou thérapeutique contre la sepsie.
PCT/JP2010/070651 2009-11-20 2010-11-19 Nouveau dérivé fusionné de pyrimidine Ceased WO2011062253A1 (fr)

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