WO2011152485A1 - Novel 4,5-fused pyrimidine derivative - Google Patents

Novel 4,5-fused pyrimidine derivative Download PDF

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WO2011152485A1
WO2011152485A1 PCT/JP2011/062674 JP2011062674W WO2011152485A1 WO 2011152485 A1 WO2011152485 A1 WO 2011152485A1 JP 2011062674 W JP2011062674 W JP 2011062674W WO 2011152485 A1 WO2011152485 A1 WO 2011152485A1
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group
optionally substituted
alkoxy
different
alkyl
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成宏 浅野
圭子 紙本
義明 磯部
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大日本住友製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel 4,5-fused pyrimidine derivative useful as a medicine. More specifically, the present invention relates to a 4,5-condensed pyrimidine derivative that is effective in 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, infections, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) The present invention relates to 4,5-condensed pyrimidine derivatives as prophylactic and / or therapeutic agents.
  • 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 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).
  • the present inventors have found that 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 4,5-condensed pyrimidine derivative (hereinafter sometimes referred to as “the compound of the present invention”) represented by the following formula (I). That is, the present invention is as follows.
  • a 1 and A 2 represent the following formula (A) Or Z, provided that When A 1 is the formula (A), A 2 represents Z, When A 1 is Z, A 2 represents formula (A); Q 1 and Q 2 are each independently a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1 -5 alkylcarbonyl; optionally substituted C 1-5 alkoxycarbonyl; carboxyl; optionally substituted aryl; optionally substituted heteroaryl; or -CONR 5 R 6 Alk represents an optionally substituted C 1-5 alkylene; Z is a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1-5 alkylcarbonyl; Optionally substituted C 1-5 alkoxycarbonyl; optionally substituted aryl
  • R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together.
  • a 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed, Item 12.
  • a 1 is the formula (A)
  • a 2 is Z
  • Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; Hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to
  • W 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group is selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom) C 2-8 alkylene optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of (optionally substituted with the same or different 1 to 3 substituents),
  • Y is phenylene which may be substituted with the same or different 1 to 3 substituents, or monocyclic or condensed heteroarylene containing 1 to 2 nitrogen atoms, and the substituent is halogen, Selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms and C 1
  • a 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed, R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed)
  • the number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring), Item 3.
  • a 1 is the formula (A)
  • a 2 is Z
  • Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; C 1-5 alkylcarbonyl- or C 1-5 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl group,
  • C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of: and wherein X is —X 1 —NR 7 CO—X In the case of 2- , -X 1 -NR 7 CONR 8 -X 2- , -X 1 -NR 7 -X 2 -or -X 1 -O-X 2- , X 1 represents a hydroxyl group, a fluorine atom and C 1- The same selected from the group consisting of 6 alkyls (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl, C 1-5 alkoxy and fluorine atoms) Or 1 to 3 different C 2-8 alkylene optionally substituted with a substituent, X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl; W is
  • a 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed, R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed)
  • the number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring), Item 4.
  • Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C 1 is selected from the group consisting of heterocyclic -10 alkyl; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) the same or different one to three optionally substituted with a substituent C 3-8 cycloalkyl is selected from the group consisting of may also be) substituted with a substituent, cyano, hydroxyl, C 1 C 1-5 alkoxy (the group
  • W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, or —O—W 1 —, Any one of the combinations of R 3 and R 9 , R 3 and W 1 and R 9 and W 1 is bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. May be, Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
  • Q 1 and Q 2 are each independently a hydrogen atom; or a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring
  • a C 1-6 alkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of: Item 7.
  • Z is hydrogen atom; hydroxyl group, fluorine atom, C 1-5 alkoxy (the group is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atom) Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxycarbonyl- and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring.
  • R 1 , R 2 , R 3 and R 4 are each independently the same or selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy and —CONR 10 R 11 C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted with 1 to 3 different substituents; or the same or different selected from the group consisting of a hydroxyl group, a fluorine atom, and C 1-6 alkyl
  • a 4- to 10-membered saturated heterocyclic ring optionally substituted by 1 to 3 substituents, R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together.
  • a 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed, Each combination of R 1 and R 2 and R 3 and R 4 may be bonded to the carbon atom of each group to form a 4- to 7-membered nitrogen-containing saturated heterocyclic ring, Item 9.
  • R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or the same or different 1 to 5 selected from the group consisting of fluorine, hydroxyl group and C 1-5 alkoxy C 1-10 alkyl optionally substituted with 3 substituents,
  • a combination of R 5 and R 6 may form a 4- to 8-membered nitrogen-containing saturated heterocycle by combining the carbon atoms of the respective groups (provided that the combination of R 5 and R 6 is formed).
  • Formula (A) is represented by the following formula: A group represented by the formula: wherein Z 1 , Z 2 , Z 4 and Z 5 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl optionally substituted by 1 to 3 fluorine atoms And the same or different substituents selected from the group consisting of C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms, wherein Het is a 5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or A 5- to 6-membered nitrogen-containing unsaturated heterocycle, Item 11.
  • Alk is hydroxyl, optionally a fluorine atom, optionally substituted by the same or different 1-2 substituents selected from the group consisting of C 1-6 alkyl and C 1-5 alkoxy C 1- 3 alkylene, Item 13.
  • Q 1 and Q 2 are each a hydrogen atom, Item 14.
  • X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -NR 7 -X 2 - or -X 1 - O—X 2 — Any one of the combinations of R 1 and X 1 , R 1 and X 2 , R 1 and R 7 and R 7 and X 2 is bonded to the carbon atom of each group to contain a 4- to 10-membered group.
  • a nitrogen-saturated heterocyclic ring may be formed, Item 15.
  • X 1 is C 1-4 alkylene
  • X 2 is C 2-4 alkylene.
  • Item 16 The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
  • a 1 is Z and A 2 is the formula (A).
  • Item 18 The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
  • X is, -X 1 -, - X 1 -CONR 7 -X 2 -, or -X 1 -O-X 2 - is and, R 1 and R 2 are each independently substituted with a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and —CONH 2 Is a good C 1-6 alkyl, Any one combination of R 1 and X 1 , R 1 and R 2 and R 1 and R 7 is bonded to the carbon atom of each group to form a 4- to 8-membered nitrogen-containing saturated heterocyclic ring. May be, Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
  • Y is phenylene, pyridylene, or thiazolylene, which may be substituted with the same or different 1 to 2 substituents, and the substituents are selected from the group consisting of halogen and C 1-6 alkyl
  • W is -W 1- , -NR 9 -W 1- , -NR 9 CO-W 1 -or -O-W 1-
  • W 1 is C 1-4 alkylene which may be substituted with one hydroxyl group, and here, when W is —NR 9 —W 1 — or —O—W 1 —, W 1 is C 2- 4 alkylene
  • R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl, Any one of the combinations of R 3 and R 9 , R 3 and W 1 , R 9 and W 1, and R 3 and R 4 is
  • Z is a hydrogen atom, C 1-6 alkyl, halogen, C 1-3 alkoxy or —NR 5 R 6 ; R 5 and R 6 are each independently a hydrogen atom or C 1-6 alkyl.
  • Item 20 The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.
  • [Item 21] Z is a hydrogen atom or C 1-3 alkyl. Item 21. The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof.
  • Alk is C 1-3 alkylene.
  • Item 20 The compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Y is phenylene or pyridylene
  • —W—NR 3 R 4 in formula (A) is A group represented by R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl, Item 23.
  • the compound represented by formula (I) is: 2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 41) 2- [4- (4-Ethylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 45) 2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 46) 2- [3- (4-Methylpiperazin-1-yl) phen
  • the compound represented by formula (I) is: N, N-dimethyl-3- ⁇ 2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ propane-1- Amine (Example 39) 2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 40) 4- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 42) (R) -N, N-dimethyl-1- (4- ⁇ 7- [3-
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 25 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 25 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for a disease associated with Toll-like receptor 7 and / or 9 comprising the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient, and / or Or prophylactic agent.
  • a Toll-like receptor comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof. A method for the treatment and / or prevention of diseases associated with the body.
  • the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with a toll-like receptor.
  • 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.
  • CLP cecal ligation and puncture
  • 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.
  • the compounds of formula (I) may have one or more than one asymmetric carbon atom, and may cause geometric isomerism and axial chirality. May exist. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
  • 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.
  • 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.
  • 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 1-10 alkyl, respectively.
  • C 1-6 alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl,
  • isohexyl and the like are “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 6-12 membered monocyclic, bicyclic aryl groups. Specific examples include phenyl, naphthyl, indenyl and the like. Preferable examples include monocyclic or 8 to 10-membered bicyclic aryl groups having 6 carbon atoms, such as phenyl and naphthyl. “Arylene” is a divalent group that can be bonded at any of the above-mentioned positions, and specifically includes phenylene and the like.
  • Heteroaryl is a 5- to 7-membered monocyclic aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include a 2-membered aromatic heterocycle having 12 members and a tricyclic aromatic heterocycle having 12 to 15 members.
  • a 5-membered or 6-membered monocyclic aromatic heterocycle or a 9-membered bicyclic aromatic heterocycle is mentioned, and specific examples include pyridyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, and tetrazolyl. It is done.
  • “5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or 5- to 6-membered nitrogen-containing unsaturated heterocyclic ring bonded to a benzene ring” means a 5- to 6-membered ring selected from the above monocyclic aromatic heterocyclic rings or A part of the ring is saturated.
  • “Heteroarylene” is a divalent group that can be bonded at any of the above-mentioned positions, and specific examples include pyridylene, thiazolylene, and the like.
  • 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, for example, “C 1-3 alkoxy” or “C 1 the -5 alkoxy "means an alkoxy of 1 to 3 or 1 to 5 carbon atoms.
  • C 1-3 alkoxy methoxy, ethoxy, propoxy, isopropoxy and the like can be mentioned, and in the case of “C 1-5 alkoxy”, butoxy, isobutoxy, Examples thereof include s-butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, t-pentoxy and the like. Among these, “C 1-3 alkoxy” is preferable.
  • Cycloalkoxy means a group in which a cyclic saturated hydrocarbon group is bonded via an oxygen atom.
  • C 3-8 cycloalkoxy means a 3- to 8-membered cyclic group.
  • Specific examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy and the like.
  • a 5- to 7-membered cycloalkoxy group is used.
  • “Saturated heterocycle” means a saturated ring containing 1 to 3 heteroatoms in addition to carbon atoms.
  • “4- to 8-membered saturated heterocycle” or “4- to 10-membered saturated heterocycle” means 4 to 8 or 4 to 10 atoms containing 1 to 3 heteroatoms in addition to carbon atoms.
  • examples of the hetero atom include the same or different nitrogen atom, oxygen atom or sulfur atom, preferably nitrogen atom or oxygen atom, more preferably nitrogen atom.
  • Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, dioxotetrahydrothiopyranyl and the like.
  • Preferred is a 4- to 7-membered saturated heterocyclic ring and specific examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, homopiperidinyl, piperazinyl, tetrahydrofuranyl and tetrahydropyranyl.
  • “5- to 6-membered nitrogen-containing saturated heterocycle” or “4- to 10-membered nitrogen-containing saturated heterocycle” means 5 to 6 or 4 to 10 containing 1 to 2 nitrogen atoms in addition to carbon atoms (Wherein the saturated ring may further have one carbon atom substituted with an oxygen atom or a sulfur atom).
  • a 4- to 6-membered nitrogen-containing saturated heterocyclic ring is preferable.
  • Alkylene means a straight hydrocarbon chain, unless otherwise defined, in which part of the methylene may be substituted with cycloalkylene.
  • C 2-4 alkylene “C 1-5 alkylene”, “C 2-8 alkylene” or “C 1-8 alkylene” has 2 to 4, 1 to 5, 2 to 8 or 1 to 8 straight hydrocarbon chains.
  • C 2-4 alkylene ethylene, propylene, butylene, cyclobutylene and the like can be mentioned, and in the case of “C 1-5 alkylene”, in addition to the above, methylene, penta
  • C 2-8 alkylene or “C 1-8 alkylene”
  • hexamethylene, heptamethylene, octamethylene and the like can be mentioned.
  • C 2-4 alkylene is preferable.
  • bonded with the same carbon atom may construct
  • C 1-5 alkylcarbonyl- include methylcarbonyl-, ethylcarbonyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, t-butylcarbonyl- and the like. It is done. “C 1-3 alkylcarbonyl-” is preferable, and methylcarbonyl- is more preferable.
  • C 1-5 alkoxycarbonyl- include methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxycarbonyl-, t-butoxycarbonyl-, etc. Is mentioned. “C 1-3 alkoxycarbonyl-” is preferable, and methoxycarbonyl- is more preferable.
  • substituent of “optionally substituted alkylene” include the above (1) to (17), and (18) a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group includes C 1-5 alkoxy and fluorine Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of atoms) and the same or different 1 to 3 selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycle Examples thereof include C 1-10 alkyl which may be substituted with 1 substituent, and may be optionally substituted with 1 to 5 of the same or different substituents.
  • the groups shown in (5), (8), (9), (10), (11) and (12) are: (A) a hydroxyl group, (B)
  • substituents of “optionally substituted cycloalkyl” and “optionally substituted saturated heterocycle” include the above (a) to (d) and (g) to (j), and are the same or It may be optionally substituted with 1 to 5 different substituents.
  • substituent of (a), (b), (c) or (j) is preferable, and (a), a fluorine atom or (c) is more preferable.
  • substituents of “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted arylene” and “optionally substituted heteroarylene”, the above-mentioned (a ) To (l), which may be optionally substituted with the same or different 1 to 5 substituents described above.
  • a substituent of (a), (b), (c) or (d) is preferable, and (a), a fluorine atom or (c) 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.
  • a 1 , A 2 , Q 1 , Q 2 , Alk, Z, Z 1 to Z 5 , X, X 1 , X 2 , W, W 1 , Preferred groups in each of Y, R 1 to R 11 and Het are as follows, but the present invention is not limited to the compounds listed below.
  • preferred rings when each group forms a ring with other groups are as described below.
  • a 1 is Z and A 2 is formula (A).
  • Q 1 and Q 2 are preferably each independently a hydrogen atom; a hydroxyl group, a fluorine atom, or a C 1-5 alkoxy (the group is the same or different selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 1 to 3 substituents optionally selected from the group consisting of C 1-5 alkoxycarbonyl- and a 4-10 membered nitrogen-containing saturated heterocyclic ring, optionally substituted with 1 to 3 substituents) C 1-10 alkyl optionally substituted with a group; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl portion of the group is selected from the group consisting of C 1-5 alkoxy and fluorine atom) Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of the same or different 1 to 3 substituents selected from the group consisting
  • Alk is preferably a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of C 1-5 alkoxy and a fluorine atom.
  • a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine atom , C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom, good C 3-8 cycloalkyl optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of may also), cyano, hydroxyl, C 1-5 alkoxy And the same or different 1 to 3 substituents in the optionally substituted C 1-5 alkylcarbonyl is selected from the group consisting of fluorine atom - and C 1-5 alkoxycarbonyl -; carboxyl; halogen, C 1- Substituted with the same or different 1 to 3 substituents selected from the group consisting of 6 alky
  • C 1-3 alkylene More preferably, it is a linear C 1-3 alkylene which may be substituted with the same or different 1-2 substituents selected from the group consisting of a fluorine atom and C 1-6 alkyl, most preferably , Unsubstituted C 1-3 alkylene.
  • Z is preferably a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) And a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine An atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is substituted by the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms; C 3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of: a halogen; a hydroxyl group and a fluorine atom And C 1-5 alkoxy which may be substituted with the same or different
  • Z 1 to Z 5 are preferably a hydrogen atom; halogen; C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms; or C optionally substituted with 1 to 3 fluorine atoms. There may be mentioned 1-5 alkoxy. More preferred are a hydrogen atom, a fluorine atom, and C 1-6 alkyl.
  • the symbol represented by “—” in each group above represents a single bond, and the single bond on the left side of each group is bonded to the nitrogen atom on the 4,5-condensed pyrimidine skeleton side, and the single bond on the right side.
  • the bond represents bonding to a nitrogen atom on the —NR 1 R 2 side.
  • —X 1 —O—X 2 — it means (4,5-condensed pyrimidine skeleton) —X 1 —O—X 2 —NR 1 R 2 .
  • X 1 is preferably C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, and more preferably , C 1-6 alkylene, more preferably C 1-4 alkylene.
  • X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X 1 —NR 7 —X 2 — or —X 1 —O—X 2 —.
  • C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl is preferable. Is C 2-6 alkylene, more preferably C 2-4 alkylene.
  • X 2 is preferably C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, and more preferably , C 2-6 alkylene, more preferably C 2-4 alkylene.
  • W is preferably —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —, more preferably —W 1 —, —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, and more preferably —W 1 —, —NR 9 —W 1 —.
  • each group above represents a single bond
  • the single bond on the left side of each group is bonded to the carbon atom or nitrogen atom on the ring of Y
  • the single bond on the right side is , Represents binding to a nitrogen atom on the —NR 3 R 4 side.
  • W 1 is preferably C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl.
  • C 1-4 alkylene which may be substituted with one hydroxyl group is exemplified, and more preferably, C 2-4 alkylene is exemplified.
  • Y 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, halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms and 1 to 3
  • bicyclic arylene or heteroarylene is also included.
  • 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 halogen, C 1-1 Heteroarylene containing 1 to 2 nitrogen atoms optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 6 alkyl and C 1-5 alkoxy. More preferred is phenylene, pyridylene or thiazolylene which may be substituted with the same or different 1 to 2 substituents selected from the group consisting of halogen and C 1-6 alkyl.
  • arylene and heteroarylene the following structure can be illustrated as a preferable structure. [Wherein, R 12 represents (c), (g), (h) of item 2 or a hydrogen atom. ]
  • R 1 , R 2 , R 3 and R 4 are preferably each independently a hydrogen atom; a group consisting of a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl- and —CONR 10 R 11 C 1-10 alkyl and C 3-8 cycloalkyl which may be substituted with the same or different 1 to 3 substituents selected from: or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 And 4- to 10-membered saturated heterocycle optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkoxycarbonyl- and C 1-5 alkylcarbonyl-.
  • a hydrogen atom; or a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-3 alkoxy may be mentioned.
  • it is a hydrogen atom or C 1-10 alkyl.
  • R 5 , R 6 , R 7 , R 8 and R 9 are each independently 1 to 3 identical or different hydrogen atoms or the same or different selected from the group consisting of fluorine, hydroxyl group and C 1-5 alkoxy Examples thereof include C 1-10 alkyl optionally substituted with a substituent, more preferably a hydrogen atom or C 1-10 alkyl, and still more preferably C 1-4 alkyl.
  • R 10 and R 11 are preferably a hydrogen atom; a C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms; or a 4 to 10 member formed by R 10 and R 11 taken together
  • a nitrogen atom-containing saturated heterocyclic ring more preferably a hydrogen atom or C 1-10 alkyl, still more preferably a hydrogen atom or C 1-4 alkyl, most preferably C 1-4. Alkyl is mentioned.
  • R 1 -R 2 R 1 -X 1 , R 1 -X 2 , R 1 -R 7 , R 7 -X 2 , R 3 -R 4 , R 3 -W 1 , R 3 -R 9 , R 9
  • Each group of —W 1 or R 5 —R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted.
  • the substituent of the ring reflects the substituent of each group constituting the ring as it is.
  • the carbon atom of the substituent may combine to form a nitrogen-containing saturated heterocyclic ring.
  • the carbon atoms of each group are bonded to form a ring means that, as shown below, each hydrogen atom bonded to each carbon atom is removed and each carbon atom is bonded. Means to form a ring. Specific rings are listed below, but are not limited to these exemplified rings. Note that the number of nitrogen-containing saturated heterocycles formed is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and when two rings are formed, for example, One group (here, X 2 ) may be commonly used for both rings so that two rings are formed from R 1 -X 2 and R 7 -X 2 .
  • Each combination of R 1 and R 2 , R 3 and R 4 and R 5 and R 6 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of the respective groups
  • Preferred examples thereof include the following structures (however, when R 5 and R 6 are combined, r 1 -d is excluded).
  • r 1 -a More preferred are r 1 -a, r 1 -b, r 1 -c, r 1 -d and r 1 -f, and more preferred are r 1 -b, r 1 -c, r 1 -d. And r 1 -f.
  • R 1 and R 7 When the combination of R 1 and R 7 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
  • More preferable examples include r 7 -a, r 7 -b, r 7 -c, r 7 -d, and r 7 -e, and more preferably r 7 -a, r 7 -b, and r 7. -E.
  • R 7 and X 2 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
  • More preferable examples include x 2 -a, x 2 -b, x 2 -c, x 2 -d, x 2 -e, x 2 -f, x 2 -g, and x 2 -j, and more preferable. Includes x 2 -a, x 2 -c, x 2 -d, x 2 -e, x 2 -f, and x 2 -j.
  • x 1 -a, x 1 -b, x 1 -c, x 1 -d, x 1 -e, x 1 -f, x 1 -g and x 1 -k are mentioned, and more preferably , X 1 -b, x 1 -c, x 1 -e and x 1 -g.
  • R 3 and R 9 When the combination of R 3 and R 9 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
  • r 3 -a, r 3 -b, r 3 -c, r 3 -d, r 3 -e, and r 3 -g are mentioned, and more preferably, r 3 -a, r 3- b, r 3 -c, and r 3 -g.
  • R 3 and W 1 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
  • w 1 -a, w 1 -c, w 1 -d, w 1 -e, w 1 -f, w 1 -g, w 1 -h, w 1 -i, w 1 -j, w 1 -k and w 1 -p are mentioned, and more preferred are w 1 -a, w 1 -c, w 1 -e, w 1 -f, w 1 -h and w 1 -j.
  • R 9 and W 1 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group
  • preferred examples thereof include the following structures: It is done.
  • r 9 -a, r 9 -c, r 9 -d, r 9 -e, r 9 -f, r 9 -g, r 9 -h, r 9 -i, r 9 -j, r 9 -k, r 9 -l, r 9 -m, r 9 -n, r 9 -o, r 9 -p and r 9 -w more preferably r 9 -a, r 9 -c , R 9 -e, r 9 -g, r 9 -h, r 9 -j, r 9 -l and r 9 -o.
  • Het is preferably a 5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or a 5- to 6-membered nitrogen-containing unsaturated heterocyclic ring, and more preferably pyridyl, dihydropyridyl, pyrazolyl, tetrahydropyridyl, tetrazolyl, thiazolyl, Examples include oxazolyl and imidazolyl. More preferred are pyridyl, dihydropyridyl, pyrazolyl and tetrahydropyridyl.
  • Compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), ( (Im), (In), (Io), (Ip) and (Iq) are compounds included in the compound (I).
  • Compound (I) can be obtained by the method shown in the following production methods 1 to 15 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 2 is the formula (A), A 1 is Z, Z is a chlorine atom or a bromine atom, and Q 2 is a hydrogen atom, and A 1 is the formula (A), A 2 is Z, Z is a chlorine atom or bromine atom, Q 2 is a hydrogen atom, compound (Ib), A 2 is formula (A), and A 1 is Z A compound (Ic) in which Z and Q 2 are hydrogen atoms, A 2 is the formula (A), A 1 is Z, and Z is an optionally substituted C 1-10 alkyl or substituted Compound (Id), which is C 3-8 cycloalkyl, Q 2 is a hydrogen atom, A 2 is Formula (A), A 1 is Z, and Z is —NR 5 R 6 , Q 2 is a hydrogen atom (Ie), and A 2 is the formula (A), A 1 is Z, and Z may be substituted Compound (If) which is C 1-5 alkoxy and Q 2 is a hydrogen atom can
  • R a is an optionally substituted alkyl.
  • R b is a hydrogen atom or an optionally substituted alkyl, Hal a is a chlorine atom or a bromine atom, Hal b is a chlorine atom, a bromine atom or an iodine atom, and Z ′ is An optionally substituted C 1-10 alkyl or an optionally substituted C 3-8 cycloalkyl, and R ′ is an optionally substituted C 1-5 alkyl.
  • Step 1 Compound (1-1) is reacted 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 to give compound (1- 2) can be obtained.
  • Compound (1-1) is synthesized as a commercially available product or by a known method [for example, WO2002 / 066482, Journal of American Chemical Society, 3854 (2001)] or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction, and examples thereof include DMF, DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol, etc. And 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, 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 (1-3) can be obtained by reacting compound (1-2) 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, triethylamine, Pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline, N, N-dimethylaminopyridine or the like can be used alone or in combination.
  • 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 The compound (1-3) obtained in Step 2 is added in an amount of 0.05 to 1 equivalent, preferably 0.05 to 0.1 equivalent of osmium tetroxide or potassium osmate (IV) dihydrate, 1 to 10 in a solvent.
  • Compound (1-4) can be obtained by reacting with an equivalent amount, preferably 1 to 3 equivalents of a base, and 1 to 10 equivalents, preferably 3 to 4 equivalents of sodium metaperiodate.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • THF, 1,4-dioxane, acetone, t-butanol, water and the like are used alone or in combination. Among them, a mixed solvent of acetone and water is preferable.
  • aliphatic tertiary amines such as triethylamine and N, N-diisopropylethylamine, aromatic amines such as pyridine, 2,6-lutidine, pyrazine, pyridazine and pyrimidine can be used, among which 2,6- Lutidine is preferred.
  • 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.
  • the compound (1-4) can also be obtained by ozonolysis in which a reducing agent such as dimethyl sulfide is reacted after passing through an oxygen stream containing ozone at room temperature or ⁇ 78 ° C. in a solvent such as dichloromethane, ethyl acetate or methanol. Obtainable.
  • Step 4 Compound (1-4) obtained in step 3 is 1 to 10 equivalents, preferably 1.2 to 4 equivalents of borohydride in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of acid in a solvent.
  • the compound (1-6) can be obtained by reacting the compound and 1 to 10 equivalents, preferably 1.1 to 2 equivalents of the compound (1-5).
  • Compound (1-5) is synthesized as a commercially available product or by a known method [eg, Chemical Abstract, 1971 (1957); Journal of the Chemical Society, 3096 (1931)] 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, 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, sodium borohydride and the like can be used, and among them, 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 5 Compound (1-6) obtained in step 4 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. Catalyst, optionally in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of a phosphine ligand, 1 to 5 equivalents, preferably 1 to 1.05 equivalents of compound (1- By reacting with 7), compound (Ia) and / or compound (Ib) can be obtained.
  • Compound (1-7) is synthesized as a commercially available product or by a known method [eg, WO2008 / 148867, WO2004 / 013134] 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, water and the like are used alone.
  • they can be used in combination, and among them, a mixed solvent of DMF and water, 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
  • phosphine ligand examples include monodentate ligands such as o-tolylphosphine, S-Phos, and X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos, DPE-Phos, and the like.
  • a bidentate ligand can be used, and among them, S-Phos or X-Phos is preferable.
  • the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or potassium phosphate, among which sodium carbonate, potassium carbonate or potassium phosphate 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 The compound (Ia) obtained in Step 5 is 0.1 to 10 equivalents, preferably 1 to 3 equivalents, in the presence of 1 to 3 equivalents of acid in a solvent under a hydrogen atmosphere of 1 to 10 atm, preferably 1 to 4 atm.
  • Compound (Ic) can be obtained by treatment with 1 to 10 equivalents, preferably 0.1 to 1 equivalents of a catalyst such as palladium on carbon.
  • Compound (Ic) is prepared by treating compound (Ia) with a catalyst such as 0.1 to 10 equivalents, preferably 0.1 to 1 equivalents of palladium carbon in the presence of 5 to 10 equivalents of ammonium formate in a solvent. Can also 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, ethyl acetate, methanol, ethanol, n-propanol, 2-propanol Propanol, water and the like can be used alone or in combination, and methanol alone or a mixed solvent with 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 acetic acid, 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.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a hydrogen atom can also be obtained from the compound (Ib) obtained in Step 5 by the same production method.
  • Step 7 Compound (Ia) obtained in Step 5 is 1 to 5 equivalents, preferably 1.1 to 2 equivalents in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst in a solvent.
  • Compound (Id) can be obtained by reacting with an equivalent amount of compound (1-8) or compound (1-9).
  • Compound (1-8) or Compound (1-9) is synthesized as a commercially available product or by a known method [eg, WO2006 / 024493, WO2008 / 083070] 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 1,4-dioxane
  • benzene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • benzene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • benzene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • DMF 1,4-dioxane
  • benzene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • DMF 1,4-dioxane
  • xylene 1,4
  • 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 or bis (t-butylphosphine) palladium is particularly preferable.
  • zero-valent catalysts such as tetrakistriphenylphosphine palladium, bis (t-butylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or bis (triphenylphosphine) palladium dichloride, palladium acetate, bis
  • a 1 is the formula (A)
  • a 2 is Z
  • Z is an optionally substituted C 1-10 alkyl or an optionally substituted C 3-8 cycloalkyl
  • Step 8 Compound (Ia) obtained in Step 5 is added in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base in a solvent, if necessary, in the presence of 1 to 20 equivalents, preferably 3 to 10 equivalents of compound (1 Compound (Ie) can be obtained by reacting with -10).
  • Compound (1-10) can be obtained as a commercially available product or by a known method.
  • 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 THF, 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 can be used, among which potassium carbonate, triethylamine or N, N-diisopropylethylamine is preferred.
  • the reaction is carried out usually at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is —NR 5 R 6 can also be obtained from the compound (Ib) obtained in Step 5 by the same production method.
  • Compound (If) can be obtained by reacting compound (Ia) obtained in step 5 with 1 to 20 equivalents, preferably 3 to 10 equivalents, of metal alkoxide (1-11) in a solvent.
  • Compound (1-11) can be obtained as a commercially available product or by a known method.
  • an alcohol solvent such as methanol or ethanol is selected depending on the type of metal alkoxide used.
  • the reaction is carried out usually at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is optionally substituted C 1-5 alkoxy by the same production method is compound (Ib) obtained in step 5. Can get more.
  • Production method 2 Among the compounds (I), the compound (Ig) in which A 2 is the formula (A), A 1 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above.
  • Hal a and Hal c are each independently a chlorine atom or A bromine atom, R a is an optionally substituted alkyl, and R b is a hydrogen atom or an optionally substituted alkyl.
  • a commercially available product or a compound (2-1) synthesized according to the method described in, for example, Bioorganic Chemistry, 34 (5), 248-273 (2006) is 1 to 5 equivalents, preferably 1.5 to 2 in a solvent.
  • Compound (2-3) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of acid anhydride (2-2) in the presence of an equivalent amount of a base.
  • Compound (2-2) is synthesized as a commercially available product or by a known method [for example, WO2008 / 001985] 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, diethyl ether, dichloromethane, benzene, toluene, xylene and the like are used alone. Or a mixture thereof, among which THF, diethyl ether or dichloromethane is preferred.
  • the base include various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, strong bases such as LDA, LHMDS and NHMDS, and alkali metal hydrogens such as sodium hydride and potassium hydride.
  • LDA, LHMDS, and sodium hydride are preferable.
  • the reaction is carried out at a temperature between ⁇ 100 ° C. and room temperature, preferably at ⁇ 78 ° C. to room temperature, usually for 0.5 to 24 hours.
  • Step 11 Compound (2-4) obtained by reacting compound (2-3) obtained in step 10 with a sulfurizing agent such as Lawesson's reagent or diphosphorus pentasulfide in 2 to 10 equivalents, preferably 3 to 5 equivalents, in a solvent. Obtainable.
  • a sulfurizing agent such as Lawesson's reagent or diphosphorus pentasulfide in 2 to 10 equivalents, preferably 3 to 5 equivalents, 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, DME, benzene, toluene, xylene and the like are used alone or in combination. Among them, toluene, THF or 1,4-dioxane 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 100 ° C., usually for 0.5 to 24 hours.
  • Step 12 By reacting the compound (2-4) obtained in Step 11 with 1 to 20 equivalents, preferably 2 to 10 equivalents of guanidine in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in a solvent.
  • Compound (2-5) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction, and examples thereof include DMF, DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol, etc. And 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, 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.
  • Step 13 Compound (2-6) can be obtained by reacting compound (2-5) obtained in step 12 in the same manner as in step 2.
  • the compound (2-7) can be obtained by reacting the compound (2-6) obtained in Step 13 with 5 to 20 equivalents of nitrite and 2 to 5 equivalents of copper halide in a solvent.
  • Compound (2-7) is prepared by reacting Compound (2-6) with 2 to 10 equivalents of trimethylsilyl halide, 5 to 10 equivalents of nitrite, and 1 to 2 equivalents of triethylbenzylammonium halide in a solvent. Can also be obtained.
  • nitrite sodium nitrite, t-butyl nitrite or the like is used.
  • solvent used in this reaction a halogen-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane is mainly used.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0 ° C. to room temperature, usually for 0.5 to 24 hours.
  • Step 15 Compound (Ig) can be obtained by reacting compound (2-7) obtained in step 14 with compound (1-7) in the same manner as in step 5.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • Hal a is substituted with a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9.
  • —NR 5 R 6, or optionally substituted C 1-5 alkoxy, and the like can also be obtained.
  • Production method 3 Among the compounds (I), the compound (Ih) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and W is —NR 9 —W 1 —
  • the compound (2-7) can be obtained by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , R 9 , Q 1 , Q 2 , W 1 , X and Y are as defined above, and R b is a hydrogen atom or substituted.
  • each of Hal a , Hal c and Hal d is independently a chlorine atom or a bromine atom.
  • Step 16 Compound (3-2) can be obtained by reacting compound (2-7) obtained in step 14 and compound (3-1) in the same manner as in step 5.
  • Compound (3-1) is synthesized as a commercially available product or by a known method [eg, Journal of Organometallic Chemistry, 2001, 640, 197-200] or a method analogous thereto.
  • Step 17 Compound (3-2) obtained in Step 16 is mixed with 1 to 10 equivalents, preferably 3 to 5 equivalents of a base, and 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of phosphine in a solvent. Reaction with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (3-3) in the presence of a ligand and 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst. Can give compound (Ih).
  • Compound (3-3) is synthesized as a commercially available product or by a known method [for example, US200429205, Journal of Medicinal Chemistry, 1997, 40 (13), 2047-2052] 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 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, tritolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino)-
  • a bidentate phosphine such as 1,1′-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, and tris (dibenzylideneacetone) dipalladium or palladium acetate is particularly preferable.
  • 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 (diphenyl
  • 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., under heating or under microwave irradiation, usually for 0.5 to 24 hours.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl, by the same production method as in Steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
  • Production method 4 Among the compounds (I), the compound (Ii) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and W is —O—W 1 — It can be obtained from compound (2-7) by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W 1 , X and Y are as defined above.
  • R b may be a hydrogen atom or substituted.
  • a good alkyl, and Hal a and Hal c are each independently a chlorine atom or a bromine atom.
  • Step 18 Compound (4-2) can be obtained by reacting Compound (2-7) obtained in Step 14 and Compound (4-1) in the same manner as in Step 5.
  • Compound (4-1) is synthesized as a commercially available product or by a known method [eg, Organic Letters, 2006, 8 (2), 261-263] or a method analogous thereto.
  • Step 19 Compound (4-2) obtained in Step 18 is present in a solvent in the presence of 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 or Kakuda reagent.
  • Compound (Ii) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of the corresponding alcohol derivative.
  • the compound (4-2) obtained in Step 18 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.
  • the compound (Ii) can also be obtained by reacting with a corresponding alkyl halogen 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, DCE, chloroform, benzene, toluene, xylene, DMF , DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol and the like can be used alone or as a mixture thereof.
  • 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 them, 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 (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl, or optionally substituted C 3-8 cycloalkyl, by the same production method as in steps 6-9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
  • Production method 5 Among compounds (I), compound (Ig) in which A 1 is Z, Z is a chlorine atom or bromine atom, and A 2 is formula (A) can also be obtained by the production method shown below. .
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, and Y are as defined above.
  • R a is an optionally substituted alkyl.
  • Hal a is a chlorine atom or a bromine atom.
  • Step 20 Compound (2-4) obtained in Step 11 and 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (5-1) are mixed with 2 to 10 equivalents, preferably 2 to 4 equivalents of a base in a solvent.
  • Compound (5-2) can be obtained by reacting in the presence.
  • Compound (5-1) is synthesized as a commercially available product or by a known method [eg, 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, 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.
  • Step 21 Compound (Ig) can be obtained by reacting compound (5-2) obtained in step 20 in the same manner as in step 2.
  • a 1 is Z
  • Z is a chlorine atom or bromine atom
  • a 2 is the formula (A)
  • W is —NR 9 —W 1 .
  • Alk, R 1 , R 2 , R 3 , R 4 , R 9 , Q 1 , Q 2 , W 1 , X, Y are as defined above, and Hal a and Hal d are independent of each other.
  • a chlorine atom or a bromine atom, and R a is an optionally substituted alkyl.
  • Compound (6-2) can be obtained by reacting compound (2-4) obtained in step 11 and compound (6-1) in the same manner as in step 20.
  • Compound (6-1) is synthesized as a commercially available product or by a known method [eg, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
  • Step 23 Compound (6-3) can be obtained by reacting compound (6-2) obtained in step 22 and compound (3-3) in the same manner as in step 17.
  • Step 24 Compound (Ih) can be obtained by reacting compound (6-3) obtained in step 23 in the same manner as in step 2.
  • Production method 7 Among the compounds (I), A 1 is Z, Z is a chlorine atom or a bromine atom, A 2 is the formula (A), Q 2 is a hydrogen atom, and X may be substituted.
  • Compound (Ij) which is C 2-8 alkylene can also be obtained, for example, from compound (1-4) by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , W, X and Y are as defined above, and R b is a hydrogen atom or an optionally substituted alkyl.
  • R c is an optionally substituted alkyl
  • X ′ is an optionally substituted C 1-7 alkylene
  • Hal a is a chlorine atom or a bromine atom.
  • Compound (7-2) can be obtained by reacting compound (1-4) obtained in step 3 with compound (7-1) in the same manner as in step 4.
  • Compound (7-1) is synthesized as a commercially available product or by a known method [eg, Journal of Heterocyclic Chemistry, 1981, 18, 941-946.] Or a method analogous thereto.
  • Compound (7-3) can be obtained by reacting compound (7-2) obtained in step 25 with 0.1 to 5 equivalents, preferably 0.1 to 1 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.
  • acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, water or the like may be used alone or in combination.
  • a mixed solvent of acetone and water is preferable.
  • 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 preferred among them.
  • 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 27 Compound (7-3) obtained in Step 26 is 1 to 10 equivalents, preferably 2 to 4 equivalents of a borohydride compound in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of an acid in a solvent, Compound (7-5) can be obtained by reacting with 1 to 10 equivalents, preferably 1.1 to 2 equivalents of Compound (7-4). Compound (7-4) is obtained as a commercial product.
  • 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, sodium borohydride and the like can be used, and among them, 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 28 Compound (Ij) can be obtained by reacting compound (7-5) obtained in Step 27 with compound (1-7) in the same manner as in Step 5.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
  • Production method 8 Among compounds (I), compound (Ik) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is formula (A), and W is methylene or methine is, for example, compound (I) From 2-7), it can be obtained by the following production method.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , X and Y are as defined above.
  • R b is a hydrogen atom or an optionally substituted alkyl.
  • R d is a hydrogen atom or C 1-3 alkyl, and Hal a and Hal c each independently represent a chlorine atom or a bromine atom.
  • Step 29 Compound (8-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (8-1) in the same manner as in Step 5.
  • Compound (8-1) is synthesized as a commercial product or by a known method [for example, Journal of Organic Chemistry, 1997, 62 (19), 6458-6459.] Or a method analogous thereto.
  • Step 30 Compound (Ik) can be obtained by reacting compound (8-2) obtained in step 29 with compound (8-3) in the same manner as in step 27.
  • Compound (8-3) is obtained as a commercial product.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl, by the same production method as in steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
  • Production method 9 Among the compounds (I), the compound (Il) or the compound (Ig) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and R 4 is a hydrogen atom.
  • Alk, R 1 , R 2 , R 3 , Q 1 , Q 2 , W, X and Y are as defined above.
  • R 4 ′ is an optionally substituted C 2-10 alkyl.
  • R b is a hydrogen atom or an optionally substituted alkyl
  • Pro is a general example shown in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)).
  • Compound (9-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (9-1) in the same manner as in Step 5.
  • Compound (9-1) is synthesized as a commercially available product or by a known method [eg, WO2007 / 126957] or a method analogous thereto.
  • Step 32 Compound (Il) can be obtained by deprotecting the protecting group of compound (9-2) obtained in step 31.
  • the protecting group is a Boc group
  • compound (Il) can be obtained by reacting with an excess amount, preferably 5 to 10 equivalents of an 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 33 Compound (Ig) can be obtained by reacting compound (Il) obtained in step 32 with the corresponding aldehyde or ketone derivative in the same manner as in step 27.
  • a compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
  • a 2 is the formula (A)
  • a 1 is Z
  • Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl
  • Compound (Im) which is an optionally substituted aryl or an optionally substituted heteroaryl can also be obtained from compound (10-1) by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above.
  • Hal a is a chlorine atom or a bromine atom
  • Z a Is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
  • Compound (10-3) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (10-2) in the presence of an equivalent amount of a base.
  • Compound (10-2) is synthesized as a commercially available product or by a known method [eg, Journal of Medicinal Chemistry, 24 (5), 496-499 (1981)] 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, diethyl ether, dichloromethane, benzene, toluene, xylene and the like are used alone. Or a mixture thereof, among which THF, diethyl ether or toluene is preferred.
  • the base include various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, strong bases such as LDA, LHMDS and NHMDS, and alkali metal hydrogens such as sodium hydride and potassium hydride.
  • LDA, LHMDS, and sodium hydride are preferable.
  • the reaction is carried out at a temperature between ⁇ 100 ° C. and room temperature, preferably at ⁇ 78 ° C. to room temperature, usually for 0.5 to 24 hours.
  • Step 35 Compound (10-3) obtained in Step 34 is added in the presence of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base in a solvent, and 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (5-1 ) To give compound (10-4).
  • 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, 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 between 50 and 180 ° C., under heating or under microwave irradiation, usually for 0.5 to 60 hours.
  • Step 36 Compound (10-5) can be obtained by reacting compound (10-4) obtained in step 35 in the same manner as in step 2.
  • Step 37 Compound (10-5) obtained in Step 36 is added in an amount of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of a phosphine ligand, and 0.01 to 1 equivalent, preferably 0.
  • Compound (Im) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (1-5) in the presence of 05 to 0.2 equivalents of a palladium 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 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, tritolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino)-
  • a bidentate phosphine such as 1,1′-binaphthyl, DPE-Phos, XANT-Phos, S-Phos and the like can be used, and S-Phos is particularly 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 palladium acetate is particularly 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., usually for 0.5 to 24 hours.
  • a 1 is the formula (A)
  • a 2 is Z
  • Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl
  • the compound (In) which is an optionally substituted aryl or an optionally substituted heteroaryl can be obtained by the production method shown below.
  • Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above.
  • R a is an optionally substituted alkyl.
  • R b is a hydrogen atom or an optionally substituted alkyl
  • Z a is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted An aryl or an optionally substituted heteroaryl
  • Hal a is a chlorine atom or a bromine atom.
  • Step 38 Compound (11-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (11-1) in the same manner as in Step 20.
  • Compound (11-1) is synthesized as a commercially available product or by a known method [eg, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
  • Step 39 Compound (11-3) can be obtained by reacting compound (11-2) obtained in Step 38 in the same manner as in Step 2.
  • Step 40 Compound (In) can be obtained by reacting compound (11-3) obtained in step 39 with compound (1-7) in the same manner as in step 5.
  • a 1 is the formula (A)
  • a 2 is Z
  • Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl
  • the compound (In) which is an optionally substituted aryl or an optionally substituted heteroaryl can also be obtained from the compound (10-1) by the production method shown below.
  • Compound (12-2) can be obtained by reacting compound (10-1) and compound (12-1) in the same manner as in Step 34.
  • Compound (12-1) is synthesized as a commercially available product or by a known method [eg, WO2007 / 099116, WO2005 / 113494] or a method analogous thereto.
  • Compound (12-3) can be obtained by reacting compound (12-2) obtained in step 40 with compound (11-1) in the same manner as in step 35.
  • Step 42 Compound (12-4) can be obtained by reacting compound (12-3) obtained in Step 41 in the same manner as in Step 36.
  • Step 43 Compound (In) can be obtained by reacting compound (12-4) obtained in step 42 with compound (1-5) in the same manner as in step 37.
  • a 2 is the formula (A), A 1 is Z, Z and Q 2 are hydrogen atoms, and Alk is methylene. Can be obtained.
  • R 1 , R 2 , R 3 , R 4 , Q 1 , W, X, and Y are as defined above.
  • R b is a hydrogen atom or an optionally substituted alkyl, and Hal a Is a chlorine atom or a bromine atom, and Hal e is a chlorine atom, a bromine atom or an iodine atom.
  • Step 44 1 to 5 equivalents of compound (13-1) in the presence of 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 or Kakuda reagent in a solvent
  • compound (13-4) can be obtained by reacting with 1 to 3 equivalents of compound (13-2).
  • Compound (13-1) is synthesized as a commercially available product or by a known method [eg, WO2009 / 026107] or a method analogous thereto.
  • Compound (13-2) is synthesized commercially or by a known method [eg, Journal of the American Chemical Society, 1936, 58, 1079] or a method analogous thereto.
  • compound (13-1) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents of the compound (13-3) in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base in a solvent.
  • compound (13-4) can be obtained.
  • Compound (13-3) is synthesized as a commercially available product or by a known method [eg, Journal of Medicinal Chemistry, 1966, 9, 191-195] 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, dichloromethane, DCE, chloroform, benzene, toluene, xylene, DMF , DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol and the like can be used alone or as a mixture thereof.
  • 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 alkali metal hydrides such as sodium hydride and potassium hydride, among which sodium hydride 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 50 ° C., usually for 0.5 to 24 hours.
  • Step 45 Compound (13-5) can be obtained by reacting compound (13-4) obtained in Step 44 with compound (1-7) in the same manner as in Step 5.
  • Step 46 Compound (Io) can be obtained by reacting compound (13-5) obtained in step 45 in the same manner as in step 6.
  • a 2 is the formula (A)
  • a 1 is Z
  • Z is a chlorine atom or a bromine atom
  • Q 1 and Q 2 are hydrogen atoms
  • Alk is methylene.
  • Compound (Ip) can be obtained by the production method shown below. (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , W, X, Y are as defined above.
  • Ra is an alkyl which may be substituted
  • Hal a is a chlorine atom or Bromine atom.
  • Compound (14-1) is optionally added in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base in a solvent in the presence of 1 to 20 equivalents, preferably 3 to 10 equivalents of Compound (1-5).
  • Compound (14-2) can be obtained by reacting with.
  • Compound (14-1) is synthesized as a commercially available product or by a known method [eg, Synthetic Communications, 28 (17), 3159-3162 (1998)] 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 in admixture thereof, among which DMF or NMP is preferred.
  • the base 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, etc.
  • triethylamine or N, N-diisopropylethylamine 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., usually for 0.5 to 24 hours.
  • Step 48 The compound (14-2) obtained in the step 47 is reacted with an acid in an amount of 0.1 to 3 equivalents, preferably 0.1 to 1 equivalents, as necessary in a solvent, to thereby give the compound (14-3). Obtainable.
  • an alcohol solvent such as methanol or ethanol is selected according to the ester to be synthesized.
  • the acid include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid, organic carboxylic acids such as acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid and sulfuric acid. 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.
  • Compound (14-4) can be obtained by reacting compound (14-3) obtained in step 48 in the same manner as in step 11.
  • Step 50 Compound (14-5) can be obtained by reacting compound (14-4) obtained in step 49 with compound (5-1) in the same manner as in step 20.
  • Step 51 Compound (Ip) can be obtained by reacting compound (14-5) obtained in step 50 in the same manner as in step 2.
  • Hal a is a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9.
  • —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc. can also be obtained.
  • Step 52 Compound (2-7) obtained by Production Method 2 is 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of palladium catalyst in a solvent, optionally 0.01 to 1 equivalent, preferably Is reacted with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of compound (15-1) in the presence of 0.05 to 0.2 equivalents of a phosphine ligand. Can be obtained.
  • Compound (15-1) is synthesized as a commercially available product or by a known method [eg, Journal of the American Chemical Society, 2004, 126, 13614-13615.] 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 1,4-dioxane
  • benzene 1,4-dioxane
  • toluene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • toluene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • benzene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • toluene 1,4-dioxane
  • xylene 1,4-dioxane
  • DMF 1,4-dioxane
  • toluene 1,4-dioxane
  • 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
  • phosphine ligands include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos or DPE-Phos.
  • the following bidentate ligands can be used, and S-Phos or X-Phos is particularly 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.
  • Compound (15-3) can be obtained by reacting compound (15-2) obtained in step 52 with a halogenating agent in an amount of 1 to 5 equivalents, preferably 1.2 to 3 equivalents 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, DME, benzene, toluene, xylene, DMF, water and the like are used alone. Or they can be mixed and used, and a mixed solvent of THF and water is particularly preferable.
  • the halogenating agent include halogenated imides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and N-iodophthalimide, bromine or iodine, among which N-bromosuccinimide is preferable.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0-40 ° C., usually for 0.5-24 hours.
  • Step 54 Compound (Iq) can be obtained by reacting compound (15-3) obtained in step 53 with 1 to 5 equivalents, preferably 1.2 to 3 equivalents, of compound (15-4) in a solvent. it can.
  • Compound (15-4) is synthesized as a commercially available product or by a known method [eg, WO2004 / 58750, Journal of Medicinal Chemistry, 2005, 48 (24), 7520-7534.] Or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • methanol, ethanol, 1-propanol, 2-propanol, THF, 1,4-dioxane, DME, benzene , Toluene, xylene, DMF, water and the like can be used alone or in admixture thereof, with ethanol being 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.
  • Hal a is a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9. , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, and the like can also be obtained.
  • Production method 16 Among compounds (I), compound (Ia) in which A 1 is Z, Z is a chlorine atom or bromine atom, and A 2 is formula (A) can also be obtained by the production method shown below. . (Wherein R 1 , R 2 , R 3 , R 4 , W, X, Y, Q 1 and Alk are as defined above. R a is an optionally substituted alkyl group, Hal a is a chlorine atom or a bromine atom.)
  • Step 55 1-10 equivalents, preferably 1-3 equivalents of compound (5-1) and compound (1-1) are reacted in a solvent in the presence of 2-10 equivalents, preferably 2-4 equivalents of a base. Can give compound (16-1).
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • diethyl ether, 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 combination, and among them, diethyl ether, methanol or ethanol is preferable.
  • the base examples include metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide, various alkalis or alkaline earths such as sodium methoxide, sodium ethoxide and potassium t-butoxide.
  • metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide
  • various alkalis or alkaline earths such as sodium methoxide, sodium ethoxide and potassium t-butoxide.
  • a metal alkoxide or the like can be used, and among them, lithium bis (trimethylsilyl) amide, 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 50-100 ° C., usually for 1-60 hours.
  • Step 56 Compound (16-2) can be obtained by reacting compound (16-1) obtained in step 55 in the same manner as in step 2.
  • Step 57 Compound (16-3) can be obtained by reacting compound (16-2) obtained in Step 56 in the same manner as in Step 3.
  • Step 58 Compound (Ia) can be obtained by reacting compound (16-3) obtained in step 57 in the same manner as in step 4.
  • Production method 17 Compound (1-3), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below. (Wherein Q 1 and Alk have the same meanings as described above.
  • R a is an optionally substituted alkyl group, Hal a is a chlorine atom or a bromine atom, and Hal b is independently , Chlorine atom, bromine atom or iodine atom.)
  • Step 59 By reacting compound (1-1) with 1 to 5 equivalents, preferably 1 to 2 equivalents of guanidine or an acid salt thereof in the presence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent, Compound (1-1-1) 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. .
  • Examples of the base 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 hexamethyldioxide.
  • Metal amides such as silazide, potassium hexamethyldisilazide, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydride, sodium hydride, potassium hydride, etc.
  • An organic base such as metal hydride, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like can be used. Among them, the reaction with sodium methoxide and lithium hexamethyldisilazide is preferable.
  • guanidine / acid salt used in this reaction guanidine / carbonate, guanidine / hydrochloride, guanidine / sulfate and the like can be used, and among them, 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 60 Compound (1-1-2) can be obtained by reacting compound (1-1-1) obtained in Step 59 in the same manner as in Step 2.
  • Step 61 The compound (1-1-2) obtained in Step 60 is added in the presence of 1 to 30 equivalents, preferably 5 to 15 equivalents of trialkylsilyl chloride in a solvent, and 1 to 20 equivalents, preferably 3 to 10 equivalents of nitrous acid.
  • the compound (1-3) can be obtained by reacting with alkyl and 1 to 10 equivalents, preferably 1 to 3 equivalents of an 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.
  • Production method 18 Compound (1-2), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below.
  • Q 1 and Alk are as defined above.
  • R a is an optionally substituted alkyl group
  • R b is a C1-C3 lower alkyl group.
  • Step 62 Compound (1-1) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (1-1-4) in the presence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent. Thus, compound (1-1-5) can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it is inert to the reaction.
  • alcohol solvents such as methanol, ethanol, 2-propanol, butanol, and water alone or water are used. It can be used by mixing, and methanol or ethanol alone or a mixed solvent with water is preferable.
  • 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, potassium hydroxide, calcium hydroxide and barium hydroxide, lithium hexamethyl Metal amides such as disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be used. Of these, sodium methoxide, sodium ethoxide and calcium hydroxide are preferred.
  • the acidic salt of O-alkylisourea used in this reaction is O-methylisourea / sulfate, O-methylisourea / 1/2 sulfate, O-methylisourea / hydrochloride, O-ethylisourea Sulfate, O-ethylisourea / 1/2 sulfate, O-ethylisourea / hydrochloride, etc. can be used, and O-methylisourea / 1/2 sulfate is preferred.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably from room temperature to 100 ° C., usually for 1 to 48 hours.
  • Step 63 Compound (1-2) can be obtained by reacting compound (1-1-5) with a solvent amount of acidic water.
  • the acidic water used in this reaction for example, a sulfuric acid aqueous solution, a hydrochloric acid aqueous solution, a hydrobromic acid aqueous solution and the like can be used.
  • 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 1 to 48 hours.
  • 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 pharmaceutically 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 stearate, glycerate ester, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol and the like.
  • the pharmaceutical preparation according to the present invention may contain other various excipients, lubricants, 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 14-21 The corresponding starting materials and reagents were used and reacted and treated in the same manner as described in Reference Example 13 to obtain the compounds shown in Table 2.
  • reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate.
  • the organic layer was dried over magnesium sulfate, filtered 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 5A as a white solid (135 mg, yield 57%).
  • reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate.
  • the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate) to obtain the title compound 7A as a yellow oil (273 mg, yield 78%).
  • Reference Example 25-36 The corresponding starting materials and reagents were used and reacted and treated in the same manner as described in Reference Example 24 to obtain the compounds shown in Table 3.
  • the organic layer was dried over magnesium sulfate and then dried under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate).
  • the obtained oil was dissolved in tetrahydrofuran (5.0 ml), sodium hydride (46 mg, 1.04 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 1.5 hr. The reaction was stopped with water, followed by liquid separation extraction with ethyl acetate.
  • the organic layer was dried over magnesium sulfate and then dried under reduced pressure.
  • the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off 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 a colorless gum (193 mg, yield 31%).
  • Reference Example 59-60 The corresponding starting materials and reagents were used and reacted and treated in the same manner as in the method described in Reference Example 58 to obtain the compounds shown in Table 5.
  • Example 2-20 The corresponding starting materials and reagents were used for the reaction and treatment in the same manner as in Example 1 to obtain the compounds shown in Table 6.
  • Example 21 4-Chloro-2- [4- (piperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] Pyrimidine
  • Examples 22-32 The corresponding starting materials and reagents were used and reacted and treated in the same manner as in Example 21 to give the compounds shown in Table 7.
  • Example 33 4- (4- ⁇ 4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl ⁇ phenyl)- 1-methylpiperidin-4-ol
  • Acetic acid 14 ⁇ l, 0.248 mmol
  • 35% aqueous formaldehyde solution 45 ⁇ l, 1.22 mmol
  • sodium borohydride in a methanol solution 1.5 ml
  • Examples 34-37 The corresponding starting materials and reagents were used and reacted and treated in the same manner as in Example 33 to give the compounds shown in Table 8.
  • Example 38 4-Chloro-2- [4- (4-ethylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine
  • acetaldehyde (17.0 ⁇ l, 0.300 mmol)
  • triacetoxyborohydride 64. 0 mg, 0.300 mmol
  • Example 39 N, N-dimethyl-3- ⁇ 2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ propane-1- Amine
  • methanol 4.0 ml
  • 10% palladium on carbon containing 50% water
  • trifluoroacetic acid 3 drops
  • the mixture was stirred at 40 ° C. After 6 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained residue was diluted with methanol, neutralized with triethylamine, and concentrated under reduced pressure.
  • Examples 40-68 Reaction and treatment were carried out in the same manner as in Example 39 using the corresponding starting materials and reagents, and the compounds shown in Table 9 were obtained.
  • Example 69 4- (2- ⁇ 2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ ethyl) morpholine
  • ammonium formate 187 mg, 2.96 mmol
  • 10% palladium carbon containing 50% water
  • trifluoroacetic acid 3 drops
  • the obtained residue was diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added for liquid separation extraction.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate ⁇ chloroform: methanol) to give the title compound as a white solid (64.6 mg, yield 53%).
  • Examples 70-74 Reaction and treatment were carried out in the same manner as in Example 69 using the corresponding starting materials and reagents, and the compounds shown in Table 10 were obtained.
  • the residue was dissolved in ethyl acetate, extracted with 1 mol / L aqueous hydrochloric acid solution, and the aqueous layer was washed with ethyl acetate.
  • the obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a white amorphous (65.0 mg, yield 46%).
  • aqueous hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was washed with ethyl acetate.
  • the organic layer was dried over magnesium sulfate and evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a pale yellow oil (51. 0 mg, 89% yield).
  • reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate.
  • the organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure.
  • the resulting residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane ⁇ chloroform) to give the title compound as a pale yellow oil. Obtained (45.0 mg, 75% yield).
  • Example 80 4- (3- ⁇ 2- [3- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ propyl) morpholine
  • t-butyl 4- (3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (121 mg, 0.400 mmol), tetrakistriphenylphosphine palladium (46.3 mg, 0.0400 mmol), 3 mol / L aqueous sodium carbonate solution (400 ⁇ l, 1.20 mmol) was added and stirred at 110 ° C.
  • Example 81 N, N-dimethyl-3- ⁇ 4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ Propan-1-amine
  • THF 2.0 ml
  • bis (tri-t-butylphosphine) dipalladium (0) 24.6 mg, 0.0482 mmol
  • 1 mol / L-dimethylzinc-THF solution (1.20 ml, 1.20 mmol
  • Examples 82-95 Reaction and treatment were carried out in the same manner as in Example 81 using the corresponding starting materials and reagents, and the compounds shown in Table 11 were obtained.
  • Examples 97-102 Reaction and treatment were carried out in the same manner as in Example 96 using the corresponding starting materials and reagents, and the compounds shown in Table 12 were obtained.
  • Example 103 2- [4- (1-Methylpiperidin-4-yloxy) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
  • a 35% aqueous formaldehyde solution (20.0 ⁇ l) and triacetoxyborohydride (24.0 ⁇ l) were added to a methanol / dichloromethane (2: 5) solution (1.0 ml) of the compound obtained in Example 96 (23.0 mg, 0.0570 mmol). 0 mg, 0.114 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Examples 104-105 Reaction and treatment were carried out in the same manner as in Example 103 using the corresponding starting materials and reagents, and the compounds shown in Table 13 were obtained.
  • Example 106 2- [3- (1-Methylpiperidin-4-yloxy) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
  • methanol 1.0 ml
  • formalin aqueous solution 15.0 ⁇ l, 0.189 mmol
  • acetic acid 16.3 ⁇ l, 0.284 mmol
  • Sodium cyanoborohydride (11.9 mg, 0.189 mmol) was added and stirred at room temperature.
  • Examples 107-117 Reaction and treatment were carried out in the same manner as in Example 106 using the corresponding starting materials and reagents, and the compounds shown in Table 14 were obtained.
  • Example 118 4-methyl-2-( ⁇ 2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ methyl) morpholine
  • acetic acid 23.0 ⁇ l, 0.402 mmol
  • formaldehyde 35% aqueous solution
  • sodium cyanoborohydride 25.3 mg, 0.402 mmol
  • Example 120 4- (3- ⁇ 2- [4- (1-Methylpiperidin-4-yloxy) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ⁇ propyl) morpholine
  • lithium aluminum hydride 49.8 mg, 1.31 mmol
  • an aqueous sodium hydroxide solution was added to stop the reaction, and the mixture was filtered through Celite.
  • Examples 121-122 Reaction and treatment were carried out in the same manner as in Example 120 using the corresponding starting compounds and reagents, and the compounds shown in Table 15 were obtained.
  • Example 123 4-Methoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine
  • methanol 2.0 ml
  • sodium methoxide / methanol solution 109 mg, 0.565 mmol
  • 120 ° C. under microwave irradiation For 5 hours. Ethyl acetate and then water were added to the reaction solution, followed by separation and extraction with ethyl acetate.
  • Example 124 N, N-dimethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2 , 3-d] pyrimidin-4-amine
  • N-methylpyrrolidinone 1.5 ml
  • 2 mol / L dimethylamine / THF solution 1.5 ml, 3.00 mmol
  • the reaction solution was put into ice water to stop the reaction, and the solution was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid (8.0 mg, yield 42%).
  • Example 130 4- (3- ⁇ 2- [4- (4-Methylpiperazin-1-yl) phenyl] -6,7-dihydropyrido [2,3-d] pyrimidin-8 (5H) -yl ⁇ propyl) morpholine Using compound 10A (100 mg, 0.302 mmol) obtained in Reference Example 39, a coupled product was obtained as a mixture (77.1 mg) in the same manner as in Example 1. The mixture was reacted in the same manner as in Example 69 to give the title compound as a pale yellow oil (56.1 mg, 43% yield).
  • reaction solution was subjected to liquid separation extraction with ethyl acetate.
  • organic layer was washed with saturated brine and concentrated under reduced pressure.
  • the obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate), and the obtained oil was added to a methanol (3.0 ml) solution with 4 mol / L hydrochloric acid / 1,4-dioxane ( 6.0 ml) was added and stirred at room temperature. After stirring for 17 hours, the solvent was removed under reduced pressure.
  • Example 140 4- (3- (2- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) morpholine
  • the title compound was obtained as a pale yellow oil by operating in the same manner as in Example 1 and Example 39 using the compound obtained in Reference Example 5 (100 mg, 0.315 mmol) and the corresponding reagent (16. 0 mg, 13% yield).
  • Example 141 4- (2- (2- (4- (4-Ethylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) ethyl) morpholine Using Reference Example 57 (80.0 mg, 0.192 mmol) and using the same methods as in Example 76 (a), Example 69, and Example 76 (b), the title compound was obtained as a pale yellow solid. It was. (33.0 mg, 31% yield).
  • Example 142 (S) -methyl 3- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -4- (pyrrolidine -1-yl) butanoate
  • the residue obtained in the same manner as in Example 1 and Example 39 was dissolved in methanol (2.0 ml), and the mixture was cooled with ice. 4 mol / L hydrochloric acid / 1,4-dioxane (1.0 ml) was added, and the mixture was stirred at room temperature.
  • Examples 143-248 Reaction and treatment were carried out using the corresponding starting compounds and reagents, and the compounds shown in Table 16 were obtained.
  • A is the same as in Example 1, B is Example 39, C is Example 69, D is Example 76, E is Example 78, F is Example 81, and 106 is Example 106.
  • G Example 119 was H, Example 129 was I, Example 133 was J, Example 134 was K, Example 139 (a) was L, and these were combined.
  • Example 249 4- (3- (2- (benzyloxy) -4- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Propyl) morpholine To a solution of the compound obtained in Reference Example 58 (191 mg, 0.491 mmol) in 1,4-dioxane (2 ml) was added 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3).
  • Examples 250-264 Reaction and treatment were carried out using the corresponding starting compounds and reagents, and the compounds shown in Table 17 were obtained.
  • A is the same as in Example 1, D is Example 76, H is Example 119, L is Example 139 (a), and M is Example 249. It was.
  • Example 266 2- (4- (4- (7- (2-morpholinoethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazin-1-yl) ethanol Using the compound obtained in Reference Example 57 (100 mg, 0.233 mmol), the title compound was obtained as a white solid in the same manner as in Example 134 (a), Example 69, and Example 126 (b). (56.0 mg, 55% yield).
  • Example 26-7 2- (1- (1-Methylpiperidin-4-yl) -1H-indol-5-yl) -7- (3- (pyrrolidin-1-yl) propyl) -6,7-dihydro-5H-pyrrolo [ 2,3-d] pyrimidine Using the compound (141 mg, 0.469 mmol) obtained in Reference Example 3, the title compound was obtained as a white solid (28.0 mg, 20% yield) in the same manner as in Examples 139 (a), 69 and 106. ).
  • Example 268 4- (3- (2- (2- (4-Cyclopropylpiperazin-1-yl) pyrimidin-5-yl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) Morpholine Using the compound obtained in Reference Example 59 (40.0 mg, 0.098 mmol) and (1-ethoxycyclopropoxy) trimethylsilane as a ketone equivalent, the same operation as in Example 106 was performed at 50 ° C., and the title was purified. The compound was obtained as a yellow solid (27.0 mg, 61% yield).
  • Example 269 4- (3- (2- (4- (4-Methylpiperazin-yl-) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl synthesized in Example 62) Morpholine can also be synthesized by the following method.
  • reaction solution was concentrated under reduced pressure, and the resulting yellow solid was crystallized from acetonitrile.
  • Example 270 4- (3- [6-Methyl-2- ⁇ 4- (4-methylpiperazin-1-yl) phenyl ⁇ -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl) morpholine
  • Example 271 4- (3- [6-Methyl-2- ⁇ 4- (piperazin-1-yl) phenyl ⁇ -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl) morpholine
  • the obtained residue was purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate) to give the title compound of a diastereomeric mixture as a yellow amorphous (340 mg, yield 45%).
  • the obtained residue was dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) piperazine (390 mg, 1.29 mmol), tetrakistriphenylphosphine palladium (123 mg, 0.11 mmol), lithium hydroxide (102 mg, 4.30 mmol) were added, and the mixture was heated to 120 ° C. And stirred. After 1 hour, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure.
  • Example 272 4- (3- (6- (2-methoxyethyl) -2- (4- (4-methoxypiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H)- Yl) propyl) morpholine
  • methylene chloride 5 ml
  • tetrafluoroboric acid 53 mg, 0.25 mmol
  • 2 mol / L trimethylsilyldiazomethanehexane solution (0. 25 ml, 0.50 mmol
  • Example 280 4- (3- (5- (methoxymethyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Propyl) morpholine Using the compound obtained in Example 276 (95 mg, 0.20 mmol), the title compound was obtained as a yellow oil (8 mg, 8% yield) in the same manner as in Example 278.
  • Example 281 (2R) -2-((5- (methoxymethyl) -2- (4- (4-methoxypiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H)- Yl) methyl) -4-methylmorpholine
  • the title compound as a yellow oil was obtained in the same manner as in Example 278 using the compound obtained in Example 277 (46 mg, 0.10 mmol) (3 mg, 6% yield).
  • Example 282 2- (2- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) morpholino) ethanol Using the compound (62.0 mg, 0.151 mmol) obtained in Example 150, the title compound was obtained as a colorless amorphous by the same method as in Example 119 (49.0 mg, yield 72%).
  • Example 283 4- (2-methoxyethyl) -2- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) morpholine
  • the title compound was obtained as a yellow oil (69.0 mg, yield 57%) by the same method as in Example 76 using the compound (106 mg, 0.259 mmol) obtained in Example 150 and the corresponding reagent. ).
  • 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 TLR9-293 cells prepared to 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).
  • 10 ⁇ L each of the test substance final concentration: 1, 3, 10, 30, 100, 300, 1000 nM
  • CpG2006 5′-TCG TCG TTT TGT GGT TTT GTC GTT-3 ′
  • Bright-Glo preparation solution was added at 100 ⁇ L / well and allowed to stand for 2 minutes in the dark.
  • 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 compound of the present invention showed a strong inhibitory action in the NF-kB inhibition test.
  • Examples 39, 40, 41, 42, 44, 45, 46, 50, 51, 59, 63, 64, 66, 76, 77, 78, 79, 81, 82, 86, 90, 91, 92, 93, 94, 95, 103, 104, 105, 107, 112, 117, 134, 137, 143, 146, 148, 151, 156, 158, 159, 161, 162, 165, 167, 174, 175, 179, 183, 207, 208, 210, 212-219, 221, 223-226, 228, 229, 235, 237, 238, 240, 242, 243, 245, 250, 251, 253-257, 267 and 274 are Strong inhibitory action was shown.
  • Test Example 2 CpG-induced IL-6 production inhibition test using mouse spleen cells
  • Mouse spleen cells were prepared as follows. The spleen removed from C57BL / 6 mice ( ⁇ ) was divided with surgical scissors and ground with a slide of a slide glass. After centrifugation, hemolysis was performed using ACK. Medium was added to stop the ACK reaction, and centrifugation was performed. The cells were prepared to 5 ⁇ 10 6 cells / mL, and seeded at 100 ⁇ L / well in a 96-well plate (5 ⁇ 10 5 cells / well).
  • test substances 20 ⁇ L each of test substances (final concentrations: 1, 3, 10, 30, 100, 300, 1000 nM) and 80 ⁇ L each of CpG1826 (5′-TCC ATG ACG TTC CTG ACG TT -3 ′) (final concentration 100 nM)
  • CpG1826 5′-TCC ATG ACG TTC CTG ACG TT -3 ′
  • IC 50 value 50% inhibition rate of each test substance
  • the compound of the present invention exhibited a strong inhibitory action in the IL-6 production inhibition test.
  • Test Example 3 Drug efficacy evaluation test using CpG1826 administration model (peritoneal administration) A CpG1826 solution was administered intraperitoneally to mice under ether anesthesia. One to six hours after administration of CpG1826, blood was collected under ether anesthesia and 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. The blood was made into plasma by centrifugation, and cytokine was measured by 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.
  • the results are shown in Table 20 and Table 21.
  • Examples 41, 45, 48, 62, 77, 84, 86, 109, 111, 117, 118, 119, 250 and 255 are administered 2 hours after the administration of CpG1826.
  • compared with the control group confirmed pronounced inflammatory cytokine production inhibitory compounds of the present invention have 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 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. As shown in FIGS. 1 and 2, Examples 62 and 86 showed significant survival rates compared to the solvent control group at 10 mg / kg dose 6 hours after CLP treatment. It was also confirmed that inflammatory cytokines and organ damage markers were significantly improved, and the compounds of the present invention were shown to be useful in clinical practice.
  • Test Example 5 Cancer Cell Growth Inhibition Test TLR 9 expression has been confirmed in the human myeloma cell line Ramos, and there has been a report of growth promotion by TLR 9 ligand (Cellular Immunology 259 (2009) p90-99).
  • a Ramos cell line was prepared to be 6.25 ⁇ 10 4 cells / mL, and seeded in a 96-well plate at 80 ⁇ L / well (5 ⁇ 10 3 cells / well).
  • 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 Table 22 and Table 23, the compounds of the present invention showed a strong inhibitory effect on cancer cell proliferation by TLR 9 ligand stimulation in a dose-dependent manner.
  • the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof prevents and / or treats an autoimmune disease, specifically, a disease involving an autoimmune disease ( It can be used as a prophylactic and / or therapeutic agent for inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.).
  • 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.
  • 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.

Abstract

Disclosed is a 4,5-fused pyrimidine derivative which is useful as a pharmaceutical product. Specifically disclosed is a pyrimidine derivative which is effective for prophylaxis and/or treatment of diseases associated with signaling mediated by a toll-like receptor (TLR).

Description

新規４，５－縮環ピリミジン誘導体Novel 4,5-fused pyrimidine derivatives
　本発明は、医薬として有用な新規４，５－縮環ピリミジン誘導体に関する。より詳しくは、トール様受容体（ＴＬＲ）を介したシグナル伝達に関連する疾患の予防および／または治療に有効な４，５－縮環ピリミジン誘導体に関する。具体的には、自己免疫が関与する疾患（セプシス、炎症、アレルギー、喘息、移植片拒絶、移植片対宿主病、感染症、癌）、免疫不全症または神経変性疾患（アルツハイマー、パーキンソン病など）の予防薬および／または治療薬としての４，５－縮環ピリミジン誘導体に関する。 The present invention relates to a novel 4,5-fused pyrimidine derivative useful as a medicine. More specifically, the present invention relates to a 4,5-condensed pyrimidine derivative that is effective in 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, infections, cancer), immunodeficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.) The present invention relates to 4,5-condensed pyrimidine derivatives as prophylactic and / or therapeutic agents.
　生体内における免疫系の刺激は、宿主に対して保護的な生理学的結果またはそれと相反する有害な生理学的結果をもたらす。近年、これら自然免疫（先天免疫）機構への関心が増大している。特に、最近発見されたＴＬＲは、自然免疫に関係し、病原微生物を認識する受容体であることが報告されている。ＴＬＲは、高度に保存されたパターン認識受容体であり、注目を集めている。現在までにヒトのＴＬＲは１０種類が同定され、ＴＬＲ１～ＴＬＲ１０と命名されている。それぞれのＴＬＲは病原微生物の細胞壁成分やＤＮＡに代表される特有の分子構造（パソジェン・アソシエーテッド・モレキュラー・パターン、ＰＡＭＰｓ）を識別して宿主の免疫反応を誘起し、生体防御を担っている（Nature Reviews Immunology, 2001, 1, 135-145）。例えば、ＴＬＲ２は、微生物細胞壁の構成成分であるペプチドグリカン、酵母のザイモザンなどのシグナルを伝達し、ＴＬＲ４は、グラム陰性菌細胞壁の構成成分であるリポ多糖（ＬＰＳ）のシグナルを宿主細胞外から細胞内へと伝達している（Nature Immunology, 2001, 2, 675-680）。また、宿主細胞内のエンドソームに発現しているＴＬＲ９は、病原微生物のＤＮＡやＣｐＧ ＤＮＡを認識することが報告されており、特に注目される（Nature, 2000, 408, 740-745 または Proceedings of the National Academy of Sciences, 2001, 98, 9237-9242）。従って、このＴＬＲを介した自然免疫の制御に有用な薬剤および／または組成物は、以下に示す自己免疫が関与する疾患（セプシス、炎症、アレルギー、喘息、移植片拒絶、移植片対宿主病、感染症、癌）、免疫不全症または神経変性疾患（アルツハイマー、パーキンソン病など）に対する予防薬および／または治療薬と成り得る。 Stimulation of the immune system in vivo results in a physiological result that is protective to the host or that is harmful to it. In recent years, interest in these innate immunity (innate immunity) mechanisms has increased. In particular, recently discovered TLRs have been reported to be involved in innate immunity and to be receptors that recognize pathogenic microorganisms. TLRs are highly conserved pattern recognition receptors and are attracting attention. To date, 10 human TLRs have been identified and named TLR 1 -TLR 10 . Each 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). For example, TLR 2 transmits signals such as peptidoglycan, which is a component of microbial cell wall, and zymosan of yeast, and 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). In addition, 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.
　「自己免疫疾患」は、自己の組織を構成する成分に反応する抗体あるいはリンパ球が体内で持続的に産生されることによって組織障害に至る疾患であり、下記に掲げる（１）臓器特異的自己免疫疾患と（２）臓器非特異的自己免疫疾患（全身性自己免疫疾患）の２つに大別される。
　（１）臓器特異的自己免疫疾患：橋本病、原発性粘液水腫、甲状腺中毒症、悪性貧血、Good－pasture症候群、急性進行性糸球体腎炎、重症筋無力症、尋常性天疱瘡、水疱性類天疱瘡、インスリン抵抗性糖尿病、若年性糖尿病、Ｉ型糖尿病、アジソン病、萎縮性胃炎、男性不妊症、早発性更年期、水晶体原性ぶどう膜炎、多発性硬化症、潰瘍性大腸炎、原発性胆汁性肝硬変、慢性活動性肝炎、自己免疫性血液性疾患（例えば、自己免疫性溶血性貧血、突発性血小板減少症等）、発作性血色素尿症、原発性胆汁性肝硬変、ギラン・バレー症候群、バセドウ病、突発性血小板減少性紫斑病、間質性肺腺維症および慢性円板状エリテマトーデス。
　（２）臓器非特異的自己免疫疾患（全身性自己免疫疾患）：関節リウマチ、全身性エリテマトーデス、シェーグレン症候群、多発性筋炎、皮膚筋炎、全身性皮膚硬化症、結節性多発動脈炎、アレルギー性肉芽種性血管炎、強皮症および混合結合組織病。 An “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).
(1) 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.
(2) 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.
　一方、セプシスは、感染症を伴う全身性炎症反応症候群（Systemic Inflammatory Response Syndrome， SIRS）と定義されている（Chest, 1992, 101, 1644-1655）。その発症原因は、病原微生物とその毒素によって誘導された炎症性メディエーターの過剰産生であり、その炎症性メディエーターが、セプティックショック、それに伴う臓器不全の発症、さらには抗炎症性メディエーターの誘導にも関与すると考えられてきた。 On the other hand, sepsis is defined as Systemic Inflammatory Response Syndrome (SIRS) with infection (Chest, 1992, 101, 1644-1655). The cause of this is the overproduction of inflammatory mediators induced by pathogenic microorganisms and its toxins. Has been thought to be involved.
　近年、このような背景の基、一酸化窒素（ＮＯ）やサイトカインなどの炎症性メディエーターを抑制する薬剤が開発され、その有効性が動物レベルで示され、重症セプシス患者を対象に炎症性メディエーターを標的とした薬物療法の臨床試験が実施された。しかし、現在までに十分な治療効果は得られておらず、複雑なネットワークを形成する炎症性メディエーターの一部を抑制するだけでは高い効果が期待できないことが示唆される（British Medical Bulletin, 1999, 55, 212-225）。このような結果から、近年は、免疫反応により発現される炎症性メディエーターと抗炎症性メディエーターとの不均衡が、セプシスの重症化、セプティックショック、それに伴う臓器不全の発症、２次感染によるセプシスの再発またはセプシスの予後不良に深く関与すると考えられるようになった。従って、自然免疫を司るＴＬＲからの免疫反応の制御が、上記セプシス関連疾患の根本的な予防および／または治療となることが期待できる。特に、ＴＬＲ９に対する阻害剤は、病原微生物から惹起される免疫反応に対して選択的な制御が期待できる。また、ＴＬＲ９阻害剤は、単独、ＴＬＲ２阻害剤と併用、ＴＬＲ４阻害剤との併用またはＴＬＲ２阻害剤およびＴＬＲ４との併用でのさらなる効果も期待でき、新しいセプシス治療として根本治療が期待できる。既存の抗菌剤、血液凝固剤等の既存のセプシス治療法との組み合わせによる併用療法により、セプシス関連疾患に対するさらなる効果も期待できる。 In recent years, drugs that suppress inflammatory mediators such as nitric oxide (NO) and cytokines have been developed based on this background, and their effectiveness has been demonstrated at the animal level. A clinical trial of targeted drug therapy was conducted. However, sufficient therapeutic effects have not been obtained so far, and it is suggested that high effects cannot be expected just by suppressing some of the inflammatory mediators that form a complex network (British Medical Bulletin, 1999, 55, 212-225). From these results, in recent years, the imbalance between inflammatory mediators and anti-inflammatory mediators expressed by the immune response has been associated with increased sepsis, septic shock, and subsequent onset of organ failure, secondary sepsis. It is thought to be deeply involved in the recurrence of the disease or poor prognosis of sepsis. Therefore, it can be expected that the control of the immune response from the TLR that controls innate immunity will be the fundamental prevention and / or treatment of the above-mentioned sepsis-related diseases. In particular, inhibitors against TLR 9 can be expected to selectively control immune responses elicited from pathogenic microorganisms. In addition, 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.
　抗マラリア薬として開発されたクロロキン（ａ）は、種々の自己免疫疾患（関節リウマチ、全身性エリトマトーデスなど）の治療にも使用されており、抗炎症薬としても有用である。最近、その自己免疫疾患に対するクロロキンおよびその類縁体であるキナクリン（ｂ）の作用機構が、ＴＬＲ９拮抗作用によるものであることが報告されている（European Journal of Immunology, 2004, 34, 2541-2550）。
Figure JPOXMLDOC01-appb-C000006
 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). ).
Figure JPOXMLDOC01-appb-C000006
　そのほかに、最近ＴＬＲ９阻害剤に関する開示があるが、本願発明の化合物とは構造が異なる（特許文献１）。また、ＴＬＲ７、ＴＬＲ８およびＴＬＲ９拮抗作用を有する化合物として、以下の代表化合物（ｃ）も開示されているが、本願発明の化合物とは構造が異なる（特許文献２）。
Figure JPOXMLDOC01-appb-C000007
 In addition, there is a recent disclosure regarding a TLR 9 inhibitor, but the structure is different from the compound of the present invention (Patent Document 1). 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).
Figure JPOXMLDOC01-appb-C000007
国際公開第２０００／０７６９８２International Publication No. 2000/076982 国際公開第２００８／０３０４５５International Publication No. 2008/030455
　本発明の課題は、自己免疫疾患の予防および／または治療、具体的には自己免疫が関与する疾患（炎症、アレルギー、喘息、移植片拒絶、移植片対宿主病、感染症、癌）、免疫不全症または神経変性疾患（アルツハイマー、パーキンソン病など）の予防薬および／または治療薬を提供することである。また、選択的にＴＬＲを阻害するようなＴＬＲ阻害剤を見出すことで、セプシス、特に重症セプシスの予防および／または治療にも有効な医薬品を提供することである。 The object of the present invention is to prevent and / or treat autoimmune diseases, specifically diseases involving autoimmunity (inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunity It is to provide preventive and / or therapeutic agents for deficiencies or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.). Another object of the present invention is to provide a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis, by finding a TLR inhibitor that selectively inhibits TLR.
　本発明者らは、鋭意検討を行った結果、下記式（Ｉ）で表される新規化合物が、強いＴＬＲ阻害作用を示し、重症セプシスの予防および／または治療に有用な医薬となり得ることを見出し、本発明を完成させた。本発明によれば、下記式（Ｉ）で表される４，５－縮環ピリミジン誘導体（以下、「本発明の化合物」と称することもある。）が提供される。即ち、本発明は以下の通りである。 As a result of intensive studies, the present inventors have found that 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. According to the present invention, there is provided a 4,5-condensed pyrimidine derivative (hereinafter sometimes referred to as “the compound of the present invention”) represented by the following formula (I). That is, the present invention is as follows.
　［項１］下記式（１）：
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ａ１およびＡ２は、下記式（Ａ）
Figure JPOXMLDOC01-appb-C000009
 またはＺを表し、但し、
　Ａ１が式（Ａ）のとき、Ａ２はＺを表し、
　Ａ１がＺのとき、Ａ２は式（Ａ）を表し、
　Ｑ１およびＱ２は、それぞれ独立して、水素原子；置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－８シクロアルキル；シアノ；置換されていてもよいＣ１－５アルキルカルボニル；置換されていてもよいＣ１－５アルコキシカルボニル；カルボキシル；置換されていてもよいアリール；置換されていてもよいヘテロアリール；または－ＣＯＮＲ５Ｒ６を表し、
　Ａｌｋは、置換されていてもよいＣ１－５アルキレンを表し、
　Ｚは、水素原子；置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－８シクロアルキル；シアノ；置換されていてもよいＣ１－５アルキルカルボニル；置換されていてもよいＣ１－５アルコキシカルボニル；置換されていてもよいアリール；置換されていてもよいヘテロアリール；ハロゲン；置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６を表し、
　Ｘは、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－を表し、
　Ｘ１は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は置換されていてもよいＣ２－８アルキレンであり、
　Ｘ２は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｘが、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ２は置換されていてもよいＣ２－８アルキレンであり、
　Ｗは、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－を表し、
　Ｗ１は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のとき、Ｗ１は置換されていてもよいＣ２－８アルキレンであり、
　Ｙは、置換されていてもよいアリーレンまたは置換されていてもよいヘテロアリーレンを表し、
　Ｒ１、Ｒ２、Ｒ３およびＲ４は、それぞれ独立して、水素原子、置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキルまたは置換されていてもよい４～１０員の飽和複素環を表し、
　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９は、それぞれ独立して、水素原子または置換されていてもよいＣ１－１０アルキルを表し、
　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせは、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）］
で表される化合物またはその製薬学的に許容される塩。 [Item 1] The following formula (1):
Figure JPOXMLDOC01-appb-C000008
 [Wherein, A 1 and A 2 represent the following formula (A)
Figure JPOXMLDOC01-appb-C000009
 Or Z, provided that
When A 1 is the formula (A), A 2 represents Z,
When A 1 is Z, A 2 represents formula (A);
Q 1 and Q 2 are each independently a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1 -5 alkylcarbonyl; optionally substituted C 1-5 alkoxycarbonyl; carboxyl; optionally substituted aryl; optionally substituted heteroaryl; or -CONR 5 R 6
Alk represents an optionally substituted C 1-5 alkylene;
Z is a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1-5 alkylcarbonyl; Optionally substituted C 1-5 alkoxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; halogen; optionally substituted C 1-5 alkoxy; —NR 5 R 6 ; or —CONR 5 R 6 represents
X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 7 CONR 8 - X 2- , -X 1 -NR 7 -X 2 -or -X 1 -O-X 2-
X 1 represents an optionally substituted C 1-8 alkylene, wherein X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X When 1 —NR 7 —X 2 — or —X 1 —O—X 2 —, X 1 is an optionally substituted C 2-8 alkylene;
X 2 represents an optionally substituted C 1-8 alkylene, wherein X is —X 1 —CONR 7 —X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X When 1 —NR 7 —X 2 — or —X 1 —O—X 2 —, X 2 is an optionally substituted C 2-8 alkylene;
W represents —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
W 1 represents an optionally substituted C 1-8 alkylene, and when W is —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, W 1 Is an optionally substituted C 2-8 alkylene;
Y represents an optionally substituted arylene or an optionally substituted heteroarylene;
R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl or a substituted Represents a 4-10 membered saturated heterocycle,
R 5 , R 6 , R 7 , R 8 and R 9 each independently represents a hydrogen atom or an optionally substituted C 1-10 alkyl;
R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1, and each combination of R 5 and R 6 may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring by combining the carbon atoms of the respective groups (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring)]
Or a pharmaceutically acceptable salt thereof.
　［項２］＜ｉ＞項１における置換されていてもよいアルキル、置換されていてもよいアルコキシおよび置換されていてもよいアルコキシカルボニル－のそれぞれの基のアルキル部分が、それぞれ独立して、
　（１）ハロゲン原子、
　（２）水酸基、
　（３）シアノ、
　（４）カルボキシル、
　（５）置換されていてもよいＣ３－８シクロアルキル、
　（６）置換されていてもよいアリール、
　（７）置換されていてもよいヘテロアリール、
　（８）置換されていてもよいＣ１－５アルコキシ、
　（９）置換されていてもよいＣ３－８シクロアルコキシ、
　（１０）置換されていてもよいＣ１－５アルコキシカルボニル－、
　（１１）置換されていてもよいＣ１－５アルキルカルボニル－、
　（１２）置換されていてもよい４～１０員の飽和複素環、
　（１３）－ＮＲ１０Ｒ１１、
　（１４）－ＣＯＮＲ１０Ｒ１１
　（１５）－Ｎ（Ｒ１０）ＣＯＲ１１
　（１６）－ＳＯ２Ｒ１０、および
　（１７）－ＳＯ２ＮＲ１０Ｒ１１
からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよく、
　置換されていてもよいアルキレンが、前記（１）～（１７）、および
　（１８）水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル
からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよく
（ここにおいて、前記（６）および（７）における置換基は、
　（ａ）水酸基、
　（ｂ）ハロゲン、
　（ｃ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－１０アルキル、
　（ｄ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－５アルコキシ、
　（ｅ）シアノ、
　（ｆ）カルボキシル、
　（ｇ）Ｃ１－５アルコキシカルボニル－、
　（ｈ）Ｃ１－５アルキルカルボニル－、
　（ｉ）－ＮＲ１０Ｒ１１、
　（ｊ）－ＣＯＮＲ１０Ｒ１１
　（ｋ）－ＳＯ２Ｒ１０、および
　（ｌ）－ＳＯ２ＮＲ１０Ｒ１１
からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味し、
　前記（５）、（８）、（９）、（１０）、（１１）および（１２）に示す基は、前記（ａ）～（ｄ）、（ｇ）～（ｊ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味する）；
　＜ｉｉ＞項１における置換されていてもよいシクロアルキルおよび置換されていてもよい飽和複素環が、それぞれ独立して、前記（ａ）～（ｄ）、（ｇ）～（ｊ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基であり；
　＜ｉｉｉ＞項１における置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいアリーレンおよび置換されていてもよいヘテロアリーレンが、それぞれ独立して、前記（ａ）～（ｌ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基であり；
　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよい、
項１に記載の化合物またはその製薬学的に許容される塩。 [Item 2] <i> The alkyl part of each group of the optionally substituted alkyl, the optionally substituted alkoxy, and the optionally substituted alkoxycarbonyl- in the item 1, each independently,
(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) optionally substituted C 1-5 alkoxy,
(9) optionally substituted C 3-8 cycloalkoxy,
(10) optionally substituted C 1-5 alkoxycarbonyl-,
(11) optionally substituted C 1-5 alkylcarbonyl-,
(12) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
(13) -NR 10 R 11 ,
(14) -CONR 10 R 11
(15) -N (R 10 ) COR 11
(16) -SO 2 R 10 , and (17) -SO 2 NR 10 R 11
May be substituted with the same or different 1 to 5 substituents selected from the group consisting of
The optionally substituted alkylene is selected from the group consisting of the above (1) to (17), and (18) hydroxyl group, fluorine atom, C 1-5 alkoxy (this group is C 1-5 alkoxy and fluorine atom). Substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycle Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of optionally substituted C 1-10 alkyl (wherein the substituents in the above (6) and (7) are ,
(A) a hydroxyl group,
(B) halogen,
(C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(E) cyano,
(F) carboxyl,
(G) C 1-5 alkoxycarbonyl-,
(H) C 1-5 alkylcarbonyl-,
(I) -NR 10 R 11 ,
(J) -CONR 10 R 11
(K) —SO 2 R 10 , and (l) —SO 2 NR 10 R 11
Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
The groups shown in (5), (8), (9), (10), (11) and (12) are selected from the group consisting of the above (a) to (d) and (g) to (j) Meaning a group which may be substituted with the same or different 1 to 5 substituents)
<Ii> The group consisting of (a) to (d) and (g) to (j) above, wherein the optionally substituted cycloalkyl and the optionally substituted saturated heterocycle in Item 1 are each independently A group which may be substituted with the same or different 1 to 5 substituents selected from;
<Iii> The aryl which may be substituted, the heteroaryl which may be substituted, the arylene which may be substituted and the heteroarylene which may be substituted in the item 1 are each independently the above (a). A group which may be substituted with 1 to 5 substituents which are the same or different selected from the group consisting of:
R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
　［項３］Ａ１が式（Ａ）のとき、Ａ２はＺであり、
　Ａ１がＺのとき、Ａ２は式（Ａ）であり、
　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールもしくはヘテロアリール；または－ＣＯＮＲ５Ｒ６であり、
　Ａｌｋが、水酸基；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールおよびヘテロアリール；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ１０Ｒ１１；並びに－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキレンであり、
　Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該アルキルおよび該アルコキシは、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；ハロゲン、Ｃ１－５アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールもしくはヘテロアリール；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６であり、
　Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
　Ｘ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－、カルボキシルおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｘ２が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－であり、
　Ｗ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｙが、同一または異なる１～３個の置換基で置換されていてもよいフェニレンまたは１～２個の窒素原子を含む単環もしくは縮環のヘテロアリーレンであり、当該置換基がハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択され、
　Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－、Ｃ１－５アルキルカルボニル－、アリール、－ＳＯ２ＮＲ１０Ｒ１１、－ＮＲ１０Ｒ１１、１～３個のＣ１－１０アルキルで置換されていてもよいヘテロアリールおよび－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルもしくはＣ３－８シクロアルキル；－ＮＲ１０ＣＯＲ１１；または水酸基、フッ素原子、Ｃ１－６アルキル、Ｃ１－５アルコキシカルボニル－およびＣ１－５アルキルカルボニル－からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせが、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
項１または２に記載の化合物またはその製薬学的に許容される塩。 [Claim 3] When A 1 is the formula (A), A 2 is Z;
When A 1 is Z, A 2 is the formula (A),
Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; Hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) C 3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of (optionally substituted with 1 substituent); cyano; hydroxyl group, C 1- C 1-5 alkylcarbonyl- or C 1-5 alkoxycarbonyl-, which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 5 alkoxy and fluorine atoms; carboxyl; halogen, C 1 to 3 substituents selected from the group consisting of 1-6 alkyl and C 1-5 alkoxy (wherein the alkyl portion may be substituted with 1 to 3 fluorine atoms) Aryl or heteroaryl optionally substituted by: or —CONR 5 R 6 ,
Alk is a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) And a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) ) identical or different one to three optionally substituted with a substituent C 3-8 cycloalkyl is selected from the group consisting of cyano, hydroxyl, C 1-5 alkoxy and fluorine atom The same or different one to three optionally substituted with a substituent C 1-5 alkylcarbonyl is selected from the group consisting of - and C 1-5 alkoxycarbonyl -; carboxyl; halogen, C 1-6 alkyl and Substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy (the alkyl portion of the group may be optionally substituted with 1 to 3 fluorine atoms) Optionally aryl and heteroaryl; halogen; C 1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; and —NR 10 R 11 ; the same or different 1-3 substituents optionally C 1-5 alkylene optionally substituted with a group selected from the group consisting of -CONR 10 R 11 Ri,
Z is a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) may be), C 1-5 alkoxycarbonyl - and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring to 10-membered or different one to three optionally substituted with a substituent C 1- 10 alkyl; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (wherein the alkyl and the alkoxy are the same or different 1 to 3 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) the same or different one to three which may be C 3-8 cycloalkyl substituted with a substituent selected from the group consisting of may also be) substituted with a substituent; cyano; Group, C 1-5 alkoxy and the same or different one to three are C 1-5 optionally alkylcarbonyl substituted with a substituent selected from the group consisting of fluorine atom - or C 1-5 alkoxycarbonyl - Identical or different 1 to 3 selected from the group consisting of halogen, C 1-5 alkyl and C 1-5 alkoxy (wherein the alkyl portion may be substituted with 1 to 3 fluorine atoms); Aryl or heteroaryl optionally substituted by 1 substituent; halogen; C 1-5 optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom Alkoxy; —NR 5 R 6 ; or —CONR 5 R 6 ,
X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 7 CONR 8 - X 2 —, —X 1 —NR 7 —X 2 — or —X 1 —O—X 2 —,
X 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group is the same or different 1 selected from the group consisting of hydroxyl group, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, carboxyl and fluorine atom) C 1-8 alkylene optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of (optionally substituted with ˜3 substituents), wherein X X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X 1 —NR 7 —X 2 —, or —X 1 —O—X 2 — 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom; Good) It is the same or different one to three good C 2-8 alkylene optionally substituted with a substituent selected from the group consisting of,
X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl;
W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
W 1 is a hydroxyl group, a fluorine atom and a C 1-6 alkyl (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a hydroxyl group, a C 1-5 alkoxy and a fluorine atom. C 1-8 alkylene optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of: and wherein W is —NR 9 —W 1 —, — In the case of CONR 9 —W 1 — or —O—W 1 —, W 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group is selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom) C 2-8 alkylene optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of (optionally substituted with the same or different 1 to 3 substituents),
Y is phenylene which may be substituted with the same or different 1 to 3 substituents, or monocyclic or condensed heteroarylene containing 1 to 2 nitrogen atoms, and the substituent is halogen, Selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms;
R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, C 1-5 alkylcarbonyl-, aryl, -SO 2 NR 10 R 11 , -NR 10 R 11 , heteroaryl optionally substituted with 1 to 3 C 1-10 alkyls, and the same or different 1 selected from the group consisting of -CONR 10 R 11 C 1-10 alkyl or C 3-8 cycloalkyl optionally substituted with 3 substituents; —NR 10 COR 11 ; or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 alkoxycarbonyl - and C 1-5 alkylcarbonyl - same is selected from the group consisting of or different one to three 4 may be substituted with a substituent ~ 1 It is a member of the saturated heterocyclic ring,
R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of fluorine, hydroxyl and C 1-5 alkoxy C 1-10 alkyl optionally substituted with
R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring),
Item 3. The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof.
　［項４］Ａ１が式（Ａ）のとき、Ａ２はＺであり、
　Ａ１がＺのとき、Ａ２は式（Ａ）であり、
　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；または－ＣＯＮＲ５Ｒ６であり、
　Ａｌｋが、水酸基；水酸基、フッ素原子、Ｃ１－５アルコキシおよび４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ１０Ｒ１１；並びに－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキレンであり、
　Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－５アルキルおよびＣ１－５アルコキシ（該アルキルおよび該アルコキシは、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６であり、
　Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
　Ｘ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｘ２が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－であり、
　Ｗ１が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１は水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
　Ｙが、同一または異なる１～３個の置換基で置換されていてもよいフェニレンまたは１～２個の窒素原子を含む単環もしくは縮環のヘテロアリーレンであり、当該置換基がハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択され、
　Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルもしくはＣ３－８シクロアルキル；または水酸基、フッ素原子、Ｃ１－６アルキル、Ｃ１－５アルコキシカルボニル－およびＣ１－５アルキルカルボニル－からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせが、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
項１～３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 4] When A 1 is the formula (A), A 2 is Z;
When A 1 is Z, A 2 is the formula (A),
Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; C 1-5 alkylcarbonyl- or C 1-5 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl group, C 1-5 alkoxy and fluorine atom Alkoxycarbonyl-; or -CONR 5 R 6 ,
Alk may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. C 1-10 alkyl; C 1-5 alkylcarbonyl- and C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom -5 alkoxycarbonyl-; halogen; C 1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; -NR 10 R 11 ; C 1-5 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of CONR 10 R 11 ;
Z is a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) may be), C 1-5 alkoxycarbonyl - and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring to 10-membered or different one to three optionally substituted with a substituent C 1- 10 alkyl; hydroxyl group, fluorine atom, C 1-5 alkyl and C 1-5 alkoxy (wherein the alkyl and alkoxy are the same or different 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) the same or different one to three which may be C 3-8 cycloalkyl substituted with a substituent selected from the group consisting of may also be) substituted with a substituent; cyano; Androgenic; hydroxyl groups and the same is selected from the group consisting of fluorine atom, or a different one to three optionally substituted with a substituent C 1-5 alkoxy; -NR 5 R 6; or -CONR 5 be R 6 ,
X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -NR 7 CONR 8 -X 2 -, - X 1 -NR 7 —X 2 — or —X 1 —O—X 2 —,
X 1 is a hydroxyl group, a fluorine atom and a C 1-6 alkyl (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a hydroxyl group, a C 1-5 alkoxy and a fluorine atom. C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of: and wherein X is —X 1 —NR 7 CO—X In the case of 2- , -X 1 -NR 7 CONR 8 -X 2- , -X 1 -NR 7 -X 2 -or -X 1 -O-X 2- , X 1 represents a hydroxyl group, a fluorine atom and C 1- The same selected from the group consisting of 6 alkyls (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl, C 1-5 alkoxy and fluorine atoms) Or 1 to 3 different C 2-8 alkylene optionally substituted with a substituent,
X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl;
W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
W 1 is C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, wherein W 1 Is —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, W 1 is the same or different selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl C 2-8 alkylene optionally substituted with 3 substituents,
Y is phenylene which may be substituted with the same or different 1 to 3 substituents, or monocyclic or condensed heteroarylene containing 1 to 2 nitrogen atoms, and the substituent is halogen, Selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms;
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl- and —CONR 10 R 11 C 1-10 alkyl or C 3-8 cycloalkyl which may be substituted with the same or different 1 to 3 substituents as described above; or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 alkoxycarbonyl A 4- to 10-membered saturated heterocyclic ring which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of-and C 1-5 alkylcarbonyl-;
R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of fluorine, hydroxyl and C 1-5 alkoxy C 1-10 alkyl optionally substituted with
R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring),
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
　［項５］
　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいフェニルおよび５または６員の含窒素ヘテロアリール；または－ＣＯＮＲ５Ｒ６である、
項１～３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Section 5]
Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C 1 is selected from the group consisting of heterocyclic -10 alkyl; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) the same or different one to three optionally substituted with a substituent C 3-8 cycloalkyl is selected from the group consisting of may also be) substituted with a substituent, cyano, hydroxyl, C 1 C 1-5 alkoxycarbonyl- which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of -5 alkoxy and fluorine atoms; carboxyl; halogen, C 1-6 alkyl and C 1 -5 alkoxy (the alkyl part of the group may be substituted with 1 to 3 fluorine atoms) may be substituted with the same or different 1 to 3 substituents selected from the group consisting of Phenyl and 5- or 6-membered nitrogen-containing heteroaryl; or -CONR 5 R 6
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
　［項６］Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－または－Ｏ－Ｗ１－であり、
　Ｒ３とＲ９、Ｒ３とＷ１およびＲ９とＷ１の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい、
項１～５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Section 6] W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, or —O—W 1 —,
Any one of the combinations of R 3 and R 9 , R 3 and W 1 and R 9 and W 1 is bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. May be,
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
　［項７］Ｑ１およびＱ２が、それぞれ独立して、水素原子；または、水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルである、
項１～６のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Claim 7] Q 1 and Q 2 are each independently a hydrogen atom; or a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring A C 1-6 alkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of:
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.
　［項８］Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６である、
項１～７のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 8] Z is hydrogen atom; hydroxyl group, fluorine atom, C 1-5 alkoxy (the group is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atom) Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxycarbonyl- and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. good C 1-10 alkyl; hydroxyl, fluorine atom, C 1-6 alkyl and C 1-5 optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of alkoxy C 3- 8 cycloalkyl, halogen, hydroxyl and optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of fluorine atom C 1-5 alkoxy; -NR 5 R 6; or It is -CONR 5 R 6,
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
　［項９］Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシおよび－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルもしくはＣ３－８シクロアルキル；または水酸基、フッ素原子、およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
　Ｒ１とＲ２およびＲ３とＲ４の各組み合わせが、それぞれの基の炭素原子が結合して、４～７員の含窒素飽和複素環を形成していてもよい、
項１～８のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 9] R 1 , R 2 , R 3 and R 4 are each independently the same or selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy and —CONR 10 R 11 C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted with 1 to 3 different substituents; or the same or different selected from the group consisting of a hydroxyl group, a fluorine atom, and C 1-6 alkyl A 4- to 10-membered saturated heterocyclic ring optionally substituted by 1 to 3 substituents,
R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
Each combination of R 1 and R 2 and R 3 and R 4 may be bonded to the carbon atom of each group to form a 4- to 7-membered nitrogen-containing saturated heterocyclic ring,
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.
　［項１０］Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
　Ｒ５とＲ６の組み合わせが、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい（ただし、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
項１～９のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 10] R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or the same or different 1 to 5 selected from the group consisting of fluorine, hydroxyl group and C 1-5 alkoxy C 1-10 alkyl optionally substituted with 3 substituents,
A combination of R 5 and R 6 may form a 4- to 8-membered nitrogen-containing saturated heterocycle by combining the carbon atoms of the respective groups (provided that the combination of R 5 and R 6 is formed). A morpholine ring as a nitrogen-containing saturated heterocyclic ring),
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
　［項１１］式（Ａ）が、下記式（Ａ’）、（Ａ’’）または（Ａ’’’）
Figure JPOXMLDOC01-appb-C000010
 で表される基であり、
　Ｙ１が、＝（－）Ｃ－Ｚ４または窒素原子であり、
　Ｚ１、Ｚ２、Ｚ３およびＺ４が、それぞれ独立して、水素原子、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキル、または１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシである、
項１～１０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 11] The formula (A) is converted into the following formula (A ′), (A ″) or (A ′ ″):
Figure JPOXMLDOC01-appb-C000010
 A group represented by
Y 1 is = (−) CZ 4 or a nitrogen atom,
Z 1 , Z 2 , Z 3 and Z 4 are each independently a hydrogen atom, halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms, or 1 to 3 fluorines C 1-5 alkoxy optionally substituted with atoms,
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
　［項１２］式（Ａ）が、下記式
Figure JPOXMLDOC01-appb-C000011
 で表される基であり、Ｚ１、Ｚ２、Ｚ４およびＺ５が、それぞれ独立して、水素原子、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択される同一または異なる置換基であり、Ｈｅｔが、５～６員の含窒素部分飽和複素環または５～６員の含窒素不飽和複素環である、
項１～１０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 12] Formula (A) is represented by the following formula:
Figure JPOXMLDOC01-appb-C000011
 A group represented by the formula: wherein Z 1 , Z 2 , Z 4 and Z 5 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl optionally substituted by 1 to 3 fluorine atoms And the same or different substituents selected from the group consisting of C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms, wherein Het is a 5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or A 5- to 6-membered nitrogen-containing unsaturated heterocycle,
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
　［項１３］Ａｌｋが、水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～２個の置換基で置換されていてもよいＣ１－３アルキレンである、
項１～１２のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Claim 13] Alk is hydroxyl, optionally a fluorine atom, optionally substituted by the same or different 1-2 substituents selected from the group consisting of C 1-6 alkyl and C 1-5 alkoxy C 1- 3 alkylene,
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
　［項１４］Ｑ１およびＱ２が、それぞれ水素原子である、
項１～１３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 14] Q 1 and Q 2 are each a hydrogen atom,
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
　［項１５］Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
　Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７およびＲ７とＸ２の各組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい、
項１～１４のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Claim 15] X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -NR 7 -X 2 - or -X 1 - O—X 2 —
Any one of the combinations of R 1 and X 1 , R 1 and X 2 , R 1 and R 7 and R 7 and X 2 is bonded to the carbon atom of each group to contain a 4- to 10-membered group. A nitrogen-saturated heterocyclic ring may be formed,
Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.
　［項１６］Ｘ１が、Ｃ１－４アルキレンであり、Ｘ２が、Ｃ２－４アルキレンである、
項１～１５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 16] X 1 is C 1-4 alkylene, and X 2 is C 2-4 alkylene.
Item 16. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
　［項１７］Ａ１がＺであり、Ａ２が式（Ａ）である、
項１～１６のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Section 17] A 1 is Z and A 2 is the formula (A).
Item 18. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
　［項１８］Ｘが、－Ｘ１－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、または－Ｘ１－Ｏ－Ｘ２－であり、
　Ｒ１およびＲ２が、それぞれ独立して、水素原子；または、水酸基、Ｃ１－５アルコキシおよび－ＣＯＮＨ２からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルであり、
　Ｒ１とＸ１、Ｒ１とＲ２およびＲ１とＲ７の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい、
項１～１７のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Claim 18] X is, -X 1 -, - X 1 -CONR 7 -X 2 -, or -X 1 -O-X 2 - is and,
R 1 and R 2 are each independently substituted with a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and —CONH 2 Is a good C 1-6 alkyl,
Any one combination of R 1 and X 1 , R 1 and R 2 and R 1 and R 7 is bonded to the carbon atom of each group to form a 4- to 8-membered nitrogen-containing saturated heterocyclic ring. May be,
Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
　［項１９］Ｙが、同一または異なる１～２個の置換基で置換されていてもよいフェニレン、ピリジレンまたはチアゾリレンであり、当該置換基が、ハロゲンおよびＣ１－６アルキルからなる群から選択され、
　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－または－Ｏ－Ｗ１－であり、
　Ｗ１が、１個の水酸基で置換されていてもよいＣ１－４アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１はＣ２－４アルキレンであり、
　Ｒ３およびＲ４が、それぞれ独立して、水素原子；または、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルであり、
　Ｒ３とＲ９、Ｒ３とＷ１、Ｒ９とＷ１およびＲ３とＲ４の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい、
項１～１１または１３～１８のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 19] Y is phenylene, pyridylene, or thiazolylene, which may be substituted with the same or different 1 to 2 substituents, and the substituents are selected from the group consisting of halogen and C 1-6 alkyl ,
W is -W 1- , -NR 9 -W 1- , -NR 9 CO-W 1 -or -O-W 1- ;
W 1 is C 1-4 alkylene which may be substituted with one hydroxyl group, and here, when W is —NR 9 —W 1 — or —O—W 1 —, W 1 is C 2- 4 alkylene,
R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl,
Any one of the combinations of R 3 and R 9 , R 3 and W 1 , R 9 and W 1, and R 3 and R 4 is bonded to the carbon atom of each group to form a 4- to 8-membered nitrogen-containing May form a saturated heterocyclic ring,
Item 19. The compound according to any one of Items 1 to 11 or 13 to 18, or a pharmaceutically acceptable salt thereof.
　［項２０］Ｚが、水素原子、Ｃ１－６アルキル、ハロゲン、Ｃ１－３アルコキシまたは－ＮＲ５Ｒ６であり、
　Ｒ５およびＲ６が、それぞれ独立して、水素原子またはＣ１－６アルキルである、
項１～１９のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 20] Z is a hydrogen atom, C 1-6 alkyl, halogen, C 1-3 alkoxy or —NR 5 R 6 ;
R 5 and R 6 are each independently a hydrogen atom or C 1-6 alkyl.
Item 20. The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.
　［項２１］Ｚが、水素原子またはＣ１－３アルキルである、
項１～２０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 21] Z is a hydrogen atom or C 1-3 alkyl.
Item 21. The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof.
　［項２２］Ａｌｋが、Ｃ１－３アルキレンである、
項１～２１のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 22] Alk is C 1-3 alkylene.
Item 20. The compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.
　［項２３］Ｙが、フェニレンまたはピリジレンであり、
　式（Ａ）の－Ｗ－ＮＲ３Ｒ４が、
Figure JPOXMLDOC01-appb-C000012
 で表される基であり、
　Ｒ３およびＲ４が、それぞれ独立して、水素原子；または、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルである、
項１～１１または１３～２２のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 23] Y is phenylene or pyridylene,
—W—NR 3 R 4 in formula (A) is
Figure JPOXMLDOC01-appb-C000012
 A group represented by
R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl,
Item 23. The compound according to any one of Items 1 to 11 or 13 to 22, or a pharmaceutically acceptable salt thereof.
　［項２４］式（Ｉ）で表される化合物が、
２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４１）
２－［４－（４－エチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４５）
２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４６）
２－［３－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４８）
４－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例６２）
４－（３－｛２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例６４）
４－（２－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エチル）モルホリン　（実施例６９）
Ｎ，Ｎ－ジエチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例７０）
Ｎ－（２－メトキシエチル）－Ｎ－メチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例７２）
２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例７７）
４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例７８）
４－（３－｛４－エチル－２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン （実施例７９）
４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８３）
４－（２－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エチル）モルホリン　（実施例８４）
４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８６）
４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８７）
４－（３－｛４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９１）
Ｎ，Ｎ－ジメチル－１－｛４－［４－メチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペリジン－４－アミン　（実施例９５）
２－［４－（１－メチルピペリジン－４－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例１０９）
（Ｒ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－３－アミン　（実施例１１０）
（Ｓ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－３－アミン　（実施例１１１）
Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－４－アミン　（実施例１１２）
４－［３－（２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル］モルホリン　（実施例１１４）
Ｎ，Ｎ－ジメチル－１－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペリジン－４－アミン　（実施例１１７）、
２－（４－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノール　（実施例１１９）、
（Ｒ）－２－（（２－（４－（４－メチルピペラジン－１―イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン　（実施例１４６）、
（Ｒ）－４－メチル－２－（（２－（４－（４－メチルピペラジン－１―イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン　（実施例１６４）、
（Ｓ）－４－メチル－２－（（２－（４－（４－メチルピペラジン－１―イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン　（実施例１６６）、
（Ｓ）－Ｎ，Ｎ－ジメチル－１－（４－（７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペリジン－３－アミン　（実施例２４２）、
４－（３－（２－メチル－４－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン　（実施例２５０）、
２－（４－（４－（２－メチル－７－（２－（ピロリジン－１－イル）エチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）フェニル）ピペラジン－１－イル）エタノール　（実施例２５５）、および
２－メチル－（４－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（２－（ピロリジン－１－イル）エチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例２５７）
からなる群から選択される項１記載の化合物又はそれらの製薬学的に許容される塩。 [Item 24] The compound represented by formula (I) is:
2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 41)
2- [4- (4-Ethylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 45)
2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 46)
2- [3- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 48)
4- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 62) )
4- (3- {2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 64) )
4- (2- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethyl) morpholine (Example 69) )
N, N-diethyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propane-1- Amine (Example 70)
N- (2-methoxyethyl) -N-methyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il} propan-1-amine (Example 72)
2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine (Example 77)
4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 78)
4- (3- {4-Ethyl-2- [4- (4-ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 79)
4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 83)
4- (2- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethyl) morpholine (Example 84)
4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 86)
4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 87)
4- (3- {4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 91)
N, N-dimethyl-1- {4- [4-methyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperidine -4-amine (Example 95)
2- [4- (1-Methylpiperidin-4-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 109)
(R) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) piperidin-3-amine (Example 110)
(S) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) piperidin-3-amine (Example 111)
N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl ) Piperidin-4-amine (Example 112)
4- [3- (2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl] Morpholine (Example 114)
N, N-dimethyl-1- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperidin-4-amine (Example 117),
2- (4- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazin-1-yl) ethanol ( Example 119),
(R) -2-((2- (4- (4-Methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl) morpholine Example 146),
(R) -4-methyl-2-((2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl ) Morpholine (Example 164),
(S) -4-Methyl-2-((2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl ) Morpholine (Example 166),
(S) -N, N-dimethyl-1- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperidine -3-amine (Example 242),
4- (3- (2-Methyl-4- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) morpholine (Example 250),
2- (4- (4- (2-Methyl-7- (2- (pyrrolidin-1-yl) ethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) Phenyl) piperazin-1-yl) ethanol (Example 255), and 2-methyl- (4- (4- (4-methylpiperazin-1-yl) phenyl) -7- (2- (pyrrolidin-1-yl) ) Ethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 257)
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
　［項２５］式（Ｉ）で表される化合物が、
Ｎ，Ｎ－ジメチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例３９）
２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４０）
４－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４２）
（Ｒ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピロリジン－３－アミン　（実施例４９）
（Ｓ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピロリジン－３－アミン　（実施例５０）
１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－４－アミン　（実施例５４）
４－（４－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝ブチル）モルホリン　（実施例６３）
２－［４－（４－メチルピペラジン－１－イル）フェニル］－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン　（実施例６６）
２－［６－（４－メチルピペラジン－１－イル）ピリジン－３－イル］－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン　（実施例６７）
２－［メチル（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）アミノ］アセトアミド　（実施例７３）
１－（４－メチルピペラジン－１－イル）－２－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エタノン　（実施例７４）
４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例７６）
Ｎ，Ｎ－ジメチル－３－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例８１）
４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８２）
２－［４－（４－メチルピペラジン－１－イル）フェニル］－４－プロピル－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８８）
４－（３－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９０）
４－（３－｛２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９２）
４－（３－｛４－エチル－２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９３）
４－（４－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝ブチル）モルホリン　（実施例９４）
２－［４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－イル］エタノール　（実施例１２５）、
２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－｛２－［２－（ピロリジン－１－イル）エトキシ］エチル｝－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例１２７）、および
４－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－６，７－ジヒドロピリド［２，３－ｄ］ピリミジン－８（５Ｈ）－イル｝プロピル）モルホリン　（実施例１３０）
からなる群から選択される項１記載の化合物又はそれらの製薬学的に許容される塩。 [Item 25] The compound represented by formula (I) is:
N, N-dimethyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propane-1- Amine (Example 39)
2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 40)
4- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 42)
(R) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Yl} phenyl) pyrrolidin-3-amine (Example 49)
(S) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) pyrrolidin-3-amine (Example 50)
1- (4- {7- [3- (Pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl) piperidin-4-amine (Example 54)
4- (4- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} butyl) morpholine (Example 63) )
2- [4- (4-Methylpiperazin-1-yl) phenyl] -8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2,3-d Pyrimidine (Example 66)
2- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] -8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2 , 3-d] pyrimidine (Example 67)
2- [Methyl (3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) amino] acetamide (Example 73)
1- (4-Methylpiperazin-1-yl) -2- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il} ethanone (Example 74)
4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 76) )
N, N-dimethyl-3- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Propan-1-amine (Example 81)
4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 82)
2- [4- (4-Methylpiperazin-1-yl) phenyl] -4-propyl-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 88)
4- (3- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 90)
4- (3- {2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 92)
4- (3- {4-Ethyl-2- [4- (4-isopropylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 93)
4- (4- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} butyl) morpholine (Example 94)
2- [4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl) piperazine- 1-yl] ethanol (Example 125),
2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- {2- [2- (pyrrolidin-1-yl) ethoxy] ethyl} -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine (Example 127) and 4- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -6,7-dihydropyrido [2,3-d] pyrimidine- 8 (5H) -yl} propyl) morpholine (Example 130)
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
　［項２６］項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を含有する医薬組成物。 [Item 26] A pharmaceutical composition comprising the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.
　［項２７］項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を有効成分とするトール様受容体が関連する疾患の治療剤および／または予防剤。 [Claim 27] 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 25 or a pharmaceutically acceptable salt thereof as an active ingredient.
　［項２８］項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を有効成分とするトール様受容体７および／または９が関連する疾患の治療剤および／または予防剤。 [Item 28] A therapeutic agent for a disease associated with Toll-like receptor 7 and / or 9 comprising the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient, and / or Or prophylactic agent.
　［項２９］トール様受容体が関連する疾患がセプシス、自己免疫疾患または神経変性疾患である項２７に記載の治療剤および／または予防剤。 [Item 29] The therapeutic and / or prophylactic agent according to item 27, wherein the disease associated with a toll-like receptor is sepsis, autoimmune disease or neurodegenerative disease.
　［項３０］トール様受容体７および／または９が関連する疾患がセプシス、自己免疫疾患または神経変性疾患である項２８に記載の治療剤および／または予防剤。
　［項３１］項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩の治療上の有効量を治療が必要な哺乳動物に投与することからなる、トール様受容体が関連する疾患の治療および／または予防方法。
　［項３２］トール様受容体が関連する疾患の治療剤および／または予防剤を製造するための、項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩の使用。
　［項３３］トール様受容体が関連する疾患の治療および／または予防に使用するための、項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 [Item 30] The therapeutic and / or prophylactic agent according to item 28, wherein the disease associated with toll-like receptor 7 and / or 9 is sepsis, autoimmune disease or neurodegenerative disease.
[Item 31] A Toll-like receptor comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof. A method for the treatment and / or prevention of diseases associated with the body.
[Item 32] Use of the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor. use.
[Item 33] The compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with a toll-like receptor.
　本発明化合物は、自己免疫疾患の予防および／または治療、具体的には自己免疫が関与する疾患（炎症、アレルギー、喘息、移植片拒絶、移植片対宿主病、感染症、癌）、免疫不全症または神経変性疾患（アルツハイマー、パーキンソン病など）の予防薬および／または治療薬として有用である。また、選択的にＴＬＲを阻害するようなＴＬＲ阻害剤を見出すことで、セプシス、特に重症セプシスの予防および／または治療にも有効な医薬品としても有用である。また、選択的にＴＬＲを阻害するようなＴＬＲ阻害剤を見出すことで、癌増殖抑制効果および／または癌細胞死誘導効果が期待でき、癌の予防および／または治療にも有効な医薬品としても有用である。 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.). In addition, by finding a TLR inhibitor that selectively inhibits TLR, it is useful as a pharmaceutical effective for the prevention and / or treatment of sepsis, particularly severe sepsis. In addition, by finding a 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.
後述の試験例４に従い、実施例６２の化合物を１０ｍｇ／ｋｇ静脈内投与した群と溶媒対照群の盲腸結紮穿刺（ＣＬＰ）処置後の生存率を示した図であり（ｎ＝８）、生存率の数値が１００％に近いほどセプシス病態からの改善を意味する。It is the figure which showed the survival rate after the cecal ligation puncture (CLP) treatment of the group which administered the compound of Example 62 intravenously at 10 mg / kg according to the below-mentioned test example 4, and a solvent control group (n = 8). The closer the rate value is to 100%, the better the sepsis condition.
後述の試験例４に従い、実施例８６の化合物を１０ｍｇ／ｋｇ静脈内投与した群と溶媒対照群の盲腸結紮穿刺（ＣＬＰ）処置後の生存率を示した図であり（ｎ＝８）、生存率の数値が１００％に近いほどセプシス病態からの改善を意味する。FIG. 8 is a graph showing the survival rate after cecal ligation and puncture (CLP) treatment between the group administered with the compound of Example 86 intravenously at 10 mg / kg and the solvent control group according to Test Example 4 (n = 8). The closer the rate value is to 100%, the better the sepsis condition.
　以下に、本発明をさらに詳細に説明する。
　以下の記載において、式（Ｉ）で表される化合物を化合物（Ｉ）という。他の式番号の化合物についても同様である。 The present invention is described in further detail below.
In the following description, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
　本発明の化合物は、水和物及び／又は溶媒和物の形で存在することもあるので、これらの水和物及び／又は溶媒和物もまた本発明の化合物に包含される。 Since 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.
　また、式（Ｉ）の化合物は、１個又は場合により２個以上の不斉炭素原子を有する場合があり、また幾何異性や軸性キラリティを生じることがあるので、数種の立体異性体として存在することがある。本発明においては、これらの立体異性体、それらの混合物及びラセミ体は本発明の式（Ｉ）で表される化合物に包含される。
　また、化合物（Ｉ）のいずれか１つまたは２つ以上の１Ｈを２Ｈ（Ｄ）に変換した重水素変換体も本発明の化合物（Ｉ）に包含される。 In addition, the compounds of formula (I) may have one or more than one asymmetric carbon atom, and may cause geometric isomerism and axial chirality. May exist. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (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.
　なお、本明細書において、「置換」された基における置換基の数は、特に記載した場合を除き、置換可能であれば特に制限はなく、１または２以上である。本明細書内の記載において、特段の記載のない基は無置換の基を意味する。また、特に記載した場合を除き、各々の基の説明はその基が他の基の一部分または置換基である場合にも該当する。 In the present specification, 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. In the description in the present specification, a group not particularly described means an unsubstituted group. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.
（ｉ）「アルキル」とは、直鎖状または分枝鎖状の飽和炭化水素基を意味し、例えば、「Ｃ１－６アルキル」または「Ｃ１－１０アルキル」とは炭素原子数が１～６または１～１０のアルキルをそれぞれ意味する。具体例的には、「Ｃ１－６アルキル」の場合には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、ｔ－ペンチル、ヘキシル、イソヘキシル等が、「Ｃ１－１０アルキル」の場合には、前記に加えて、ヘプチル、オクチル、イソオクチル、ノニル、デシル等が挙げられる。中でも好ましくは、「Ｃ１－３アルキル」が挙げられる。
（ｉｉ）「シクロアルキル」とは、環状の飽和炭化水素基を意味し、例えば、「Ｃ３－８シクロアルキル」とは３～８員の環状の飽和炭化水素基を意味する。具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。好ましくは、５～７員のシクロアルキル基が挙げられる。 (I) “Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C 1-6 alkyl” or “C 1-10 alkyl” has 1 carbon atom. Means 6 or 1-10 alkyl, respectively. Specifically, in the case of “C 1-6 alkyl”, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, When isohexyl and the like are “C 1-10 alkyl”, heptyl, octyl, isooctyl, nonyl, decyl and the like can be mentioned in addition to the above. Among these, “C 1-3 alkyl” is preferable.
(Ii) “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.
（ｉｉｉ）「アリール」としては、６～１２員の単環性、２環性のアリール基が挙げられる。具体的には、フェニル、ナフチル、インデニル等が挙げられる。好ましくは、炭素数６の単環性または８～１０員の二環性のアリール基が挙げられ、例えば、フェニルおよびナフチルが挙げられる。「アリーレン」とは、上記で挙げた任意の位置で結合可能な２価基であり、具体的にはフェニレン等が挙げられる。
（ｉｖ）「ヘテロアリール」としては、窒素原子、酸素原子および硫黄原子からなる群から選ばれる１から４個の原子を含む、５～７員環の単環性芳香族複素環、９～１１員の２環性芳香族複素環または１２～１５員の３環性芳香族複素環が挙げられる。具体的には、ピリジル、ピラジニル、ピリミジニル、ベンゾイミダゾリル、２－オキソベンゾオキサゾリル、ベンゾトリアゾリル、ベンゾフリル、ベンゾチエニル、プリニル、ベンゾオキサゾリル、ベンゾチアゾリル、イミダゾリル、インドリル、イソキノリル、ピロリニル、キナゾリニル、シンノリニル、ピラゾリル、トリアゾリル、テトラゾリル、オキサゾリル、チアゾリル、イソチアゾリル、チエニル、フリル等が挙げられる。好ましくは、５員もしくは６員の単環性芳香族複素環、または９員の２環性芳香族複素環が挙げられ、具体的には、ピリジル、イミダゾリル、ピラゾリル、チアゾリル、インドリルまたはテトラゾリルが挙げられる。「ベンゼン環に結合する５～６員の含窒素部分飽和複素環または５～６員の含窒素不飽和複素環」とは、上記単環性芳香族複素環から選ばれる５～６員環もしくはその一部が飽和された環を意味する。また、「ヘテロアリーレン」とは、上記で挙げた任意の位置で結合可能な２価基であり、具体的にはピリジレン、チアゾリレン等が挙げられる。 (Iii) “Aryl” includes 6-12 membered monocyclic, bicyclic aryl groups. Specific examples include phenyl, naphthyl, indenyl and the like. Preferable examples include monocyclic or 8 to 10-membered bicyclic aryl groups having 6 carbon atoms, such as phenyl and naphthyl. “Arylene” is a divalent group that can be bonded at any of the above-mentioned positions, and specifically includes phenylene and the like.
(Iv) “Heteroaryl” is a 5- to 7-membered monocyclic aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include a 2-membered aromatic heterocycle having 12 members and a tricyclic aromatic heterocycle having 12 to 15 members. Specifically, pyridyl, pyrazinyl, pyrimidinyl, benzimidazolyl, 2-oxobenzoxazolyl, benzotriazolyl, benzofuryl, benzothienyl, purinyl, benzoxazolyl, benzothiazolyl, imidazolyl, indolyl, isoquinolyl, pyrrolinyl, quinazolinyl, Cinnolinyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isothiazolyl, thienyl, furyl and the like. Preferably, a 5-membered or 6-membered monocyclic aromatic heterocycle or a 9-membered bicyclic aromatic heterocycle is mentioned, and specific examples include pyridyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, and tetrazolyl. It is done. “5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or 5- to 6-membered nitrogen-containing unsaturated heterocyclic ring bonded to a benzene ring” means a 5- to 6-membered ring selected from the above monocyclic aromatic heterocyclic rings or A part of the ring is saturated. “Heteroarylene” is a divalent group that can be bonded at any of the above-mentioned positions, and specific examples include pyridylene, thiazolylene, and the like.
（ｖ）「ハロゲン」とは、フッ素、塩素、臭素またはヨウ素の各原子を意味する。好ましくは、フッ素、塩素または臭素の各原子が挙げられる。
（ｖｉ）「アルコキシ」とは、直鎖状または分枝鎖状の飽和炭化水素基が酸素原子を介して結合している基を意味し、例えば、「Ｃ１－３アルコキシ」または「Ｃ１－５アルコキシ」とは炭素原子が１～３または１～５のアルコキシを意味する。具体的には、「Ｃ１－３アルコキシ」の場合には、メトキシ、エトキシ、プロポキシ、イソプロポキシ等が挙げられ、「Ｃ１－５アルコキシ」の場合には、前記に加えてブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ、ペントキシ、イソペントキシ、ネオペントキシ、ｔ－ペントキシ等が挙げられる。中でも好ましくは、「Ｃ１－３アルコキシ」が挙げられる。
（ｖｉｉ）「シクロアルコキシ」とは、環状の飽和炭化水素基が酸素原子を介して結合している基を意味し、例えば、「Ｃ３－８シクロアルコキシ」とは３～８員の環状の飽和炭化水素基が酸素原子を介して結合している基を意味する。具体的には、シクロプロポキシ、シクロブトキシ、シクロペンチルオキシ等が挙げられる。好ましくは、５～７員のシクロアルコキシ基が挙げられる。 (V) “Halogen” means each atom of fluorine, chlorine, bromine or iodine. Preferably, each atom of fluorine, chlorine or bromine is used.
(Vi) “Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is bonded via an oxygen atom, for example, “C 1-3 alkoxy” or “C 1 the -5 alkoxy "means an alkoxy of 1 to 3 or 1 to 5 carbon atoms. Specifically, in the case of “C 1-3 alkoxy”, methoxy, ethoxy, propoxy, isopropoxy and the like can be mentioned, and in the case of “C 1-5 alkoxy”, butoxy, isobutoxy, Examples thereof include s-butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, t-pentoxy and the like. Among these, “C 1-3 alkoxy” is preferable.
(Vii) “Cycloalkoxy” means a group in which a cyclic saturated hydrocarbon group is bonded via an oxygen atom. For example, “C 3-8 cycloalkoxy” means a 3- to 8-membered cyclic group. It means a group in which a saturated hydrocarbon group is bonded through an oxygen atom. Specific examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy and the like. Preferably, a 5- to 7-membered cycloalkoxy group is used.
（ｖｉｉｉ）「飽和複素環」とは、炭素原子以外に１～３個のヘテロ原子を含む飽和環を意味する。例えば、「４～８員の飽和複素環」または「４～１０員の飽和複素環」とは、炭素原子以外に１～３個のヘテロ原子を含む４～８個または４～１０個の原子で構成される飽和環を意味する。ここでヘテロ原子としては、同一または異なる窒素原子、酸素原子または硫黄原子が挙げられ、好ましくは窒素原子または酸素原子、更に好ましくは窒素原子が挙げられる。具体例としては、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、ホモピペリジニル、ピペラジニル、ホモピペラジニル、テトラヒドロフラニル、テトラヒドロピラニル、テトラヒドロチエニル、テトラヒドロチオピラニル、オキソテトラヒドロチオピラニル、ジオキソテトラヒドロチオピラニル等が挙げられる。好ましくは、４～７員の飽和複素環であり、具体的には、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、ホモピペリジニル、ピペラジニル、テトラヒドロフラニルおよびテトラヒドロピラニルが挙げられる。「５～６員の含窒素飽和複素環」または「４～１０員の含窒素飽和複素環」とは、炭素原子以外に１～２個の窒素原子を含む５～６個または４～１０個の原子で構成される飽和環（ここにおいて、該飽和環は更に１個の炭素原子が酸素原子または硫黄原子で置換されていてもよい）を意味する。好ましくは、４～６員の含窒素飽和複素環である。
（ｉｘ）「アルキレン」とは、特に他の定義がない限り、直鎖の炭化水素鎖を意味し、該基は一部のメチレンがシクロアルキレンに置換されていてもよい。例えば、「Ｃ２－４アルキレン」、「Ｃ１－５アルキレン」、「Ｃ２－８アルキレン」または「Ｃ１－８アルキレン」とは、炭素原子数が２～４、１～５、２～８または１～８の直鎖の炭化水素鎖を意味する。具体的には、「Ｃ２－４アルキレン」の場合には、エチレン、プロピレン、ブチレン、シクロブチレン等が挙げられ、「Ｃ１－５アルキレン」の場合には、前記に加えて、メチレン、ペンタメチレン等が挙げられ、「Ｃ２－８アルキレン」またはの「Ｃ１－８アルキレン」場合には、前記に加えて、ヘキサメチレン、ヘプタメチレン、オクタメチレン等が挙げられる。中でも好ましくは、「Ｃ２－４アルキレン」が挙げられる。また、上記アルキレンがアルキルを置換するとき、同一の炭素原子に結合する同一または異なる２つのアルキルは環を構築してもよい。
（ｘ）「Ｃ１－５アルキルカルボニル－」の具体例としては、メチルカルボニル－、エチルカルボニル－、プロピルカルボニル－、イソプロピルカルボニル－、ブチルカルボニル－、イソブチルカルボニル－、ｔ－ブチルカルボニル－等が挙げられる。好ましくは、「Ｃ１－３アルキルカルボニル－」が挙げられ、さらに好ましくは、メチルカルボニル－が挙げられる。
（ｘｉ）「Ｃ１－５アルコキシカルボニル－」の具体例としては、メトキシカルボニル－、エトキシカルボニル－、プロポキシカルボニル－、イソプロポキシカルボニル－、ブトキシカルボニル－、イソブトキシカルボニル－、ｔ－ブトキシカルボニル－等が挙げられる。好ましくは、「Ｃ１－３アルコキシカルボニル－」が挙げられ、さらに好ましくは、メトキシカルボニル－が挙げられる。 (Viii) “Saturated heterocycle” means a saturated ring containing 1 to 3 heteroatoms in addition to carbon atoms. For example, “4- to 8-membered saturated heterocycle” or “4- to 10-membered saturated heterocycle” means 4 to 8 or 4 to 10 atoms containing 1 to 3 heteroatoms in addition to carbon atoms. Means a saturated ring. Here, examples of the hetero atom include the same or different nitrogen atom, oxygen atom or sulfur atom, preferably nitrogen atom or oxygen atom, more preferably nitrogen atom. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, dioxotetrahydrothiopyranyl and the like. . Preferred is a 4- to 7-membered saturated heterocyclic ring, and specific examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, homopiperidinyl, piperazinyl, tetrahydrofuranyl and tetrahydropyranyl. “5- to 6-membered nitrogen-containing saturated heterocycle” or “4- to 10-membered nitrogen-containing saturated heterocycle” means 5 to 6 or 4 to 10 containing 1 to 2 nitrogen atoms in addition to carbon atoms (Wherein the saturated ring may further have one carbon atom substituted with an oxygen atom or a sulfur atom). A 4- to 6-membered nitrogen-containing saturated heterocyclic ring is preferable.
(Ix) “Alkylene” means a straight hydrocarbon chain, unless otherwise defined, in which part of the methylene may be substituted with cycloalkylene. For example, “C 2-4 alkylene”, “C 1-5 alkylene”, “C 2-8 alkylene” or “C 1-8 alkylene” has 2 to 4, 1 to 5, 2 to 8 or 1 to 8 straight hydrocarbon chains. Specifically, in the case of “C 2-4 alkylene”, ethylene, propylene, butylene, cyclobutylene and the like can be mentioned, and in the case of “C 1-5 alkylene”, in addition to the above, methylene, penta In the case of “C 2-8 alkylene” or “C 1-8 alkylene”, in addition to the above, hexamethylene, heptamethylene, octamethylene and the like can be mentioned. Among these, “C 2-4 alkylene” is preferable. Moreover, when the said alkylene substitutes alkyl, two same or different alkyl couple | bonded with the same carbon atom may construct | assemble a ring.
(X) Specific examples of “C 1-5 alkylcarbonyl-” include methylcarbonyl-, ethylcarbonyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, t-butylcarbonyl- and the like. It is done. “C 1-3 alkylcarbonyl-” is preferable, and methylcarbonyl- is more preferable.
(Xi) Specific examples of “C 1-5 alkoxycarbonyl-” include methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxycarbonyl-, t-butoxycarbonyl-, etc. Is mentioned. “C 1-3 alkoxycarbonyl-” is preferable, and methoxycarbonyl- is more preferable.
　「置換されていてもよいアルキル」、「置換されていてもよいアルコキシ」および「置換されていてもよいアルコキシカルボニル－」のそれぞれの基のアルキル部分の置換基としては、
　（１）ハロゲン原子、
　（２）水酸基、
　（３）シアノ、
　（４）カルボキシル、
　（５）置換されていてもよいＣ３－８シクロアルキル、
　（６）置換されていてもよいアリール、
　（７）置換されていてもよいヘテロアリール、
　（８）置換されていてもよいＣ１－５アルコキシ、
　（９）置換されていてもよいＣ３－８シクロアルコキシ、
　（１０）置換されていてもよいＣ１－５アルコキシカルボニル－、
　（１１）置換されていてもよいＣ１－５アルキルカルボニル－、
　（１２）置換されていてもよい４～１０員の飽和複素環、
　（１３）－ＮＲ１０Ｒ１１、
　（１４）－ＣＯＮＲ１０Ｒ１１、
　（１５）－Ｎ（Ｒ１０）ＣＯＲ１１、
　（１６）－ＳＯ２Ｒ１０、および
　（１７）－ＳＯ２ＮＲ１０Ｒ１１
が挙げられ（Ｒ１０およびＲ１１は、前記と同義である）、同一または異なる１～５個の上記置換基で適宜置換されていてもよい。
　「置換されていてもよいアルキレン」の置換基としては、前記（１）～（１７）、および
　（１８）水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル
が挙げられ、同一または異なる１～５個の上記置換基で適宜置換されていてもよい。
　ここにおいて、前記（６）および（７）に示す基は、
　（ａ）水酸基、
　（ｂ）ハロゲン、
　（ｃ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－１０アルキル、
　（ｄ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－５アルコキシ、
　（ｅ）シアノ、
　（ｆ）カルボキシル、
　（ｇ）Ｃ１－５アルコキシカルボニル－、
　（ｈ）Ｃ１－５アルキルカルボニル－
　（ｉ）－ＮＲ１０Ｒ１１
　（ｊ）－ＣＯＮＲ１０Ｒ１１、
　（ｋ）－ＳＯ２Ｒ１０、および
　（ｌ）－ＳＯ２ＮＲ１０Ｒ１１
からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味し、
　前記（５）、（８）、（９）、（１０）、（１１）および（１２）に示す基は、
　（ａ）水酸基、
　（ｂ）ハロゲン、
　（ｃ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－１０アルキル、
　（ｄ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－５アルコキシ、
　（ｇ）Ｃ１－５アルコキシカルボニル－、
　（ｈ）Ｃ１－５アルキルカルボニル－
　（ｉ）－ＮＲ１０Ｒ１１、および
　（ｊ）－ＣＯＮＲ１０Ｒ１１、
からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味する。
　中でも好ましくは、（１）、（２）、（８）、（１２）、（１３）または（１４）の置換基であり、より好ましくは、フッ素原子、（２）または無置換の（８）が挙げられる。 As the substituent of the alkyl part of each group of “optionally substituted alkyl”, “optionally substituted alkoxy” and “optionally substituted alkoxycarbonyl-”,
(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) optionally substituted C 1-5 alkoxy,
(9) optionally substituted C 3-8 cycloalkoxy,
(10) optionally substituted C 1-5 alkoxycarbonyl-,
(11) optionally substituted C 1-5 alkylcarbonyl-,
(12) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
(13) -NR 10 R 11 ,
(14) -CONR 10 R 11 ,
(15) -N (R 10 ) COR 11 ,
(16) -SO 2 R 10 , and (17) -SO 2 NR 10 R 11
(R 10 and R 11 are as defined above) and may be optionally substituted with 1 to 5 of the same or different substituents.
Examples of the substituent of “optionally substituted alkylene” include the above (1) to (17), and (18) a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group includes C 1-5 alkoxy and fluorine Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of atoms) and the same or different 1 to 3 selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycle Examples thereof include C 1-10 alkyl which may be substituted with 1 substituent, and may be optionally substituted with 1 to 5 of the same or different substituents.
Here, the groups shown in the above (6) and (7) are:
(A) a hydroxyl group,
(B) halogen,
(C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(E) cyano,
(F) carboxyl,
(G) C 1-5 alkoxycarbonyl-,
(H) C 1-5 alkylcarbonyl-
(I) -NR 10 R 11
(J) -CONR 10 R 11 ,
(K) —SO 2 R 10 , and (l) —SO 2 NR 10 R 11
Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
The groups shown in (5), (8), (9), (10), (11) and (12) are:
(A) a hydroxyl group,
(B) halogen,
(C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
(G) C 1-5 alkoxycarbonyl-,
(H) C 1-5 alkylcarbonyl-
(I) -NR 10 R 11 , and (j) -CONR 10 R 11 ,
Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
Among these, a substituent of (1), (2), (8), (12), (13) or (14) is preferable, and a fluorine atom, (2) or unsubstituted (8) is more preferable. Is mentioned.
　「置換されていてもよいシクロアルキル」および「置換されていてもよい飽和複素環」の置換基としては、前記（ａ）～（ｄ）、（ｇ）～（ｊ）が挙げられ、同一または異なる１～５個の上記置換基で適宜置換されていてもよい。中でも好ましくは、（ａ）、（ｂ）、（ｃ）または（ｊ）の置換基であり、より好ましくは、（ａ）、フッ素原子または（ｃ）が挙げられる。 Examples of the substituents of “optionally substituted cycloalkyl” and “optionally substituted saturated heterocycle” include the above (a) to (d) and (g) to (j), and are the same or It may be optionally substituted with 1 to 5 different substituents. Among these, the substituent of (a), (b), (c) or (j) is preferable, and (a), a fluorine atom or (c) is more preferable.
　「置換されていてもよいアリール」、「置換されていてもよいヘテロアリール」、「置換されていてもよいアリーレン」および「置換されていてもよいヘテロアリーレン」の置換基としては、前記（ａ）～（ｌ）が挙げられ、同一または異なる１～５個の上記置換基で適宜置換されていてもよい。中でも好ましくは、（ａ）、（ｂ）、（ｃ）または（ｄ）の置換基であり、より好ましくは、（ａ）、フッ素原子または（ｃ）が挙げられる。 As the substituents of “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted arylene” and “optionally substituted heteroarylene”, the above-mentioned (a ) To (l), which may be optionally substituted with the same or different 1 to 5 substituents described above. Among these, a substituent of (a), (b), (c) or (d) is preferable, and (a), a fluorine atom or (c) is more preferable.
　化合物（Ｉ）の製薬学的に許容される塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、ベンゼンスルホン酸塩、安息香酸塩、クエン酸塩、フマル酸塩、グルコン酸塩、乳酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、メタンスルホン酸塩、酒石酸塩等の有機酸塩等の酸付加塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等の金属塩、アンモニウム、テトラメチルアンモニウム等のアンモニウム塩、モルホリン付加塩、ピペリジン付加塩等の有機アミン付加塩、またはグリシン付加塩、フェニルアラニン付加塩、リジン付加塩、アスパラギン酸付加塩、グルタミン酸付加塩等のアミノ酸付加塩等が挙げられる。 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. 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 And 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.
　式（Ｉ）で表される本発明の化合物の中でも、Ａ１、Ａ２、Ｑ１、Ｑ２、Ａｌｋ、Ｚ、Ｚ１～Ｚ５、Ｘ、Ｘ１、Ｘ２、Ｗ、Ｗ１、Ｙ、Ｒ１～Ｒ１１およびＨｅｔの各々の基で、好ましい基は以下のとおりであるが、本発明は下記に挙げる化合物に限定されるものではない。また、各々の基が、他の基と環を形成するときの好ましい環は、後述のとおりである。 Among the compounds of the present invention represented by the formula (I), A 1 , A 2 , Q 1 , Q 2 , Alk, Z, Z 1 to Z 5 , X, X 1 , X 2 , W, W 1 , Preferred groups in each of Y, R 1 to R 11 and Het are as follows, but the present invention is not limited to the compounds listed below. In addition, preferred rings when each group forms a ring with other groups are as described below.
　Ａ１がＺであり、Ａ２が式（Ａ）である式（Ｉ）の化合物が好ましい。
　Ｑ１およびＱ２として好ましくは、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールおよびヘテロアリール；または－ＣＯＮＲ５Ｒ６が挙げられ、より好ましくは、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルであり、さらに好ましくは、水素原子である。 Preferred are compounds of formula (I) wherein A 1 is Z and A 2 is formula (A).
Q 1 and Q 2 are preferably each independently a hydrogen atom; a hydroxyl group, a fluorine atom, or a C 1-5 alkoxy (the group is the same or different selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 1 to 3 substituents optionally selected from the group consisting of C 1-5 alkoxycarbonyl- and a 4-10 membered nitrogen-containing saturated heterocyclic ring, optionally substituted with 1 to 3 substituents) C 1-10 alkyl optionally substituted with a group; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl portion of the group is selected from the group consisting of C 1-5 alkoxy and fluorine atom) Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of the same or different 1 to 3 substituents selected from the group consisting of C 3-8 cycloalkyl, cyano, hydroxyl, C 1-5 alkoxy and the same or different one to three optionally substituted with a substituent C 1-5 alkylcarbonyl is selected from the group consisting of fluorine atom - And C 1-5 alkoxycarbonyl-; carboxyl; halogen, C 1-6 alkyl and C 1-5 alkoxy (wherein the alkyl portion of the group may be substituted by 1 to 3 fluorine atoms) Aryl and heteroaryl which may be substituted with the same or different 1 to 3 substituents selected from: or —CONR 5 R 6 , more preferably a hydrogen atom; a hydroxyl group, a fluorine atom, C 1 The same or different selected from the group consisting of -5 alkoxy, C 1-5 alkoxycarbonyl- and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring; Or a C 1-10 alkyl which may be substituted with 1 to 3 substituents, more preferably a hydrogen atom.
　Ａｌｋとして好ましくは、水酸基；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールおよびヘテロアリール；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ１０Ｒ１１；並びに－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい直鎖のＣ１－５アルキレンが挙げられ、より好ましくは、水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～２個の置換基で置換されていてもよいＣ１－３アルキレンである。さらに好ましくは、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～２個の置換基で置換されていてもよい直鎖のＣ１－３アルキレンであり、もっとも好ましくは、無置換のＣ１－３アルキレンである。 Alk is preferably a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of C 1-5 alkoxy and a fluorine atom. And a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine atom , C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom, good C 3-8 cycloalkyl optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of may also), cyano, hydroxyl, C 1-5 alkoxy And the same or different 1 to 3 substituents in the optionally substituted C 1-5 alkylcarbonyl is selected from the group consisting of fluorine atom - and C 1-5 alkoxycarbonyl -; carboxyl; halogen, C 1- Substituted with the same or different 1 to 3 substituents selected from the group consisting of 6 alkyl and C 1-5 alkoxy (the alkyl portion of the group may be optionally substituted with 1 to 3 fluorine atoms) Optionally substituted aryl and heteroaryl; halogen; C 1-5 alkoxy optionally substituted by 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; —NR 10 R 11; and -CONR 10 of the same or different one to three good linear be substituted with a substituent selected from the group consisting of R 11 C 1-5 alkylene, and more preferably, it is substituted with one or two identical or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom, C 1-6 alkyl and C 1-5 alkoxy. Also good is C 1-3 alkylene. More preferably, it is a linear C 1-3 alkylene which may be substituted with the same or different 1-2 substituents selected from the group consisting of a fluorine atom and C 1-6 alkyl, most preferably , Unsubstituted C 1-3 alkylene.
　Ｚとして好ましくは、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６が挙げられる。より好ましくは、水素原子、Ｃ１－６アルキル、ハロゲン、Ｃ１－３アルコキシまたは－ＮＲ５Ｒ６が挙げられ、さらに好ましくは、水素原子またはＣ１－３アルキルが挙げられる。 Z is preferably a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) And a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine An atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is substituted by the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms; C 3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of: a halogen; a hydroxyl group and a fluorine atom And C 1-5 alkoxy which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of: —NR 5 R 6 ; or —CONR 5 R 6 . More preferred is a hydrogen atom, C 1-6 alkyl, halogen, C 1-3 alkoxy or —NR 5 R 6 , and still more preferred is a hydrogen atom or C 1-3 alkyl.
　Ｚ１～Ｚ５として好ましくは、水素原子；ハロゲン；１～３個のフッ素原子で置換されていてもよいＣ１－６アルキル；または１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシが挙げられる。より好ましくは、水素原子、フッ素原子、Ｃ１－６アルキルが挙げられる。 Z 1 to Z 5 are preferably a hydrogen atom; halogen; C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms; or C optionally substituted with 1 to 3 fluorine atoms. There may be mentioned 1-5 alkoxy. More preferred are a hydrogen atom, a fluorine atom, and C 1-6 alkyl.
　Ｘとしては、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－が好ましく、より好ましくは、－Ｘ１－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、または－Ｘ１－Ｏ－Ｘ２－であり、さらに好ましくは、－Ｘ１－または－Ｘ１－Ｏ－Ｘ２－である。なお、上記の各基の「－」で表される記号は、単結合を表し、各基の左側の単結合は、４，５－縮環ピリミジン骨格側の窒素原子と結合し、右側の単結合は、－ＮＲ１Ｒ２側の窒素原子と結合することを表す。例えば、－Ｘ１－Ｏ－Ｘ２－の場合、（４，５－縮環ピリミジン骨格）－Ｘ１－Ｏ－Ｘ２－ＮＲ１Ｒ２を意味する。
　Ｘ１としては、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンが好ましく、より好ましくは、Ｃ１－６アルキレンであり、さらに好ましくは、Ｃ１－４アルキレンである。但し、Ｘが、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、好ましくは、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンが好ましく、より好ましくは、Ｃ２－６アルキレンであり、さらに好ましくは、Ｃ２－４アルキレンである。
　Ｘ２としては、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンが好ましく、より好ましくは、Ｃ２－６アルキレンであり、さらに好ましくはＣ２－４アルキレンである。 The X, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 - or -X 1 -O-X 2 -, more preferably, -X 1- , -X 1 -CONR 7 -X 2- , or -X 1 -O-X 2- , and more preferably -X 1 -or -X 1 -O-X 2- . The symbol represented by “—” in each group above represents a single bond, and the single bond on the left side of each group is bonded to the nitrogen atom on the 4,5-condensed pyrimidine skeleton side, and the single bond on the right side. The bond represents bonding to a nitrogen atom on the —NR 1 R 2 side. For example, in the case of —X 1 —O—X 2 —, it means (4,5-condensed pyrimidine skeleton) —X 1 —O—X 2 —NR 1 R 2 .
X 1 is preferably C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, and more preferably , C 1-6 alkylene, more preferably C 1-4 alkylene. Provided that X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X 1 —NR 7 —X 2 — or —X 1 —O—X 2 —. In this case, C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl is preferable. Is C 2-6 alkylene, more preferably C 2-4 alkylene.
X 2 is preferably C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, and more preferably , C 2-6 alkylene, more preferably C 2-4 alkylene.
　Ｗとしては、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－が好ましく、より好ましくは、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－であり、さらに好ましくは－Ｗ１－、－ＮＲ９－Ｗ１－である。なお、上記の各基の「－」で表される記号は、単結合を表し、各基の左側の単結合は、Ｙの環上の炭素原子または窒素原子と結合し、右側の単結合は、－ＮＲ３Ｒ４側の窒素原子と結合することを表す。例えば、－ＮＲ９－Ｗ１－の場合、Ｙ－ＮＲ９－Ｗ１－ＮＲ３Ｒ４であることを意味する。
　Ｗ１として、好ましくは水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンが挙げられ、より好ましくは、１個の水酸基で置換されていてもよいＣ１－４アルキレンが挙げられ、さらに好ましくは、Ｃ２－４アルキレンが挙げられる。 W is preferably —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —, more preferably —W 1 —, —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, and more preferably —W 1 —, —NR 9 —W 1 —. The symbol represented by “-” in each group above represents a single bond, the single bond on the left side of each group is bonded to the carbon atom or nitrogen atom on the ring of Y, and the single bond on the right side is , Represents binding to a nitrogen atom on the —NR 3 R 4 side. For example, -NR 9 -W 1 -means Y-NR 9 -W 1 -NR 3 R 4 .
W 1 is preferably C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl. Preferably, C 1-4 alkylene which may be substituted with one hydroxyl group is exemplified, and more preferably, C 2-4 alkylene is exemplified.
　Ｙとして好ましくは、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいフェニレン、または、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい１～２個の窒素原子を含むヘテロアリーレンが挙げられ、更に二環式のアリーレンまたはヘテロアリーレンも含まれる。より好ましくは、ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいフェニレン、または、ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい１～２個の窒素原子を含むヘテロアリーレンが挙げられる。さらに好ましくは、ハロゲンおよびＣ１－６アルキルからなる群から選択される同一または異なる１～２個の置換基で置換されていてもよいフェニレン、ピリジレンまたはチアゾリレンが挙げられる。上記のアリーレンおよびヘテロアリーレンとしては、下記の構造が好ましい構造として例示できる。
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｒ１２は、項２の（ｃ）、（ｇ）、（ｈ）または水素原子である。］ Y 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, halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms and 1 to 3 A heteroarylene containing 1 to 2 nitrogen atoms optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy optionally substituted with fluorine atoms In addition, bicyclic arylene or heteroarylene is also included. More preferably, 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 halogen, C 1-1 Heteroarylene containing 1 to 2 nitrogen atoms optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of 6 alkyl and C 1-5 alkoxy. More preferred is phenylene, pyridylene or thiazolylene which may be substituted with the same or different 1 to 2 substituents selected from the group consisting of halogen and C 1-6 alkyl. As said arylene and heteroarylene, the following structure can be illustrated as a preferable structure.
Figure JPOXMLDOC01-appb-C000013
 [Wherein, R 12 represents (c), (g), (h) of item 2 or a hydrogen atom. ]
　より好ましくは、ｙ－ｂ、ｙ－ｃ、ｙ－ｄ、ｙ－ｅ、ｙ－ｌ、ｙ－ｍ、ｙ－ｒ、ｙ－ｓ、ｙ－ｖ、ｙ－ｗ、ｙ－ｘ、ｙ－ｙ、ｙ－ｚ、ｙ－ａａ、ｙ－ａｄ、ｙ－ａｅ、ｙ－ａｈ、ｙ－ａｌ、ｙ－ａｍ、ｙ－ａｎ、ｙ－ａｏ、またはｙ－ａｐが挙げられ、さらに好ましくは、ｙ－ｌ、ｙ－ｍ、ｙ－ｖ、ｙ－ｗ、ｙ－ａｄ、ｙ－ａｅ、ｙ－ａｌまたはｙ－ａｎが挙げられる。 More preferably, yb, yc, yd, ye, yl, ym, yr, ys, yv, yw, yx, y- y, yz, y-aa, y-ad, y-ae, y-ah, y-al, y-am, y-an, y-ao, or y-ap, more preferably yl, ym, yv, yw, y-ad, y-ae, y-al or y-an.
　Ｒ１、Ｒ２、Ｒ３およびＲ４として好ましくは、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルおよびＣ３－８シクロアルキル；または水酸基、フッ素原子、Ｃ１－６アルキル、Ｃ１－５アルコキシカルボニル－およびＣ１－５アルキルカルボニル－からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環が挙げられる。より好ましくは、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシおよび－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルおよびＣ３－８シクロアルキル；または水酸基、フッ素原子、およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環が挙げられる。さらに好ましくは、水素原子；または水酸基、フッ素原子およびＣ１－３アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルが挙げられる。最も好ましくは、水素原子またはＣ１－１０アルキルである。 R 1 , R 2 , R 3 and R 4 are preferably each independently a hydrogen atom; a group consisting of a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl- and —CONR 10 R 11 C 1-10 alkyl and C 3-8 cycloalkyl which may be substituted with the same or different 1 to 3 substituents selected from: or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 And 4- to 10-membered saturated heterocycle optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkoxycarbonyl- and C 1-5 alkylcarbonyl-. More preferably, a hydrogen atom; hydroxy group optionally, a fluorine atom, optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and -CONR 10 R 11 C 1- 6 alkyl and C 3-8 cycloalkyl; or 4 to 10 members optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of hydroxyl, fluorine, and C 1-6 alkyl Of the saturated heterocyclic ring. More preferably, a hydrogen atom; or a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-3 alkoxy may be mentioned. . Most preferably, it is a hydrogen atom or C 1-10 alkyl.
　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９として好ましくは、それぞれ独立して、水素原子またはフッ素、水酸基、Ｃ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルが挙げられ、より好ましくは、水素原子またはＣ１－１０アルキルが挙げられ、さらに好ましくは、Ｃ１－４アルキルが挙げられる。
　Ｒ１０およびＲ１１として好ましくは、水素原子；１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキル；または、Ｒ１０とＲ１１が一緒になって形成する４～１０員の含窒素飽和複素環が挙げられ、より好ましくは、水素原子またはＣ１－１０アルキルが挙げられ、さらに好ましくは、水素原子またはＣ１－４アルキルが挙げられ、もっとも好ましくは、Ｃ１－４アルキルが挙げられる。 Preferably, R 5 , R 6 , R 7 , R 8 and R 9 are each independently 1 to 3 identical or different hydrogen atoms or the same or different selected from the group consisting of fluorine, hydroxyl group and C 1-5 alkoxy Examples thereof include C 1-10 alkyl optionally substituted with a substituent, more preferably a hydrogen atom or C 1-10 alkyl, and still more preferably C 1-4 alkyl.
R 10 and R 11 are preferably a hydrogen atom; a C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms; or a 4 to 10 member formed by R 10 and R 11 taken together A nitrogen atom-containing saturated heterocyclic ring, more preferably a hydrogen atom or C 1-10 alkyl, still more preferably a hydrogen atom or C 1-4 alkyl, most preferably C 1-4. Alkyl is mentioned.
　Ｒ１－Ｒ２、Ｒ１－Ｘ１、Ｒ１－Ｘ２、Ｒ１－Ｒ７、Ｒ７－Ｘ２、Ｒ３－Ｒ４、Ｒ３－Ｗ１、Ｒ３－Ｒ９、Ｒ９－Ｗ１またはＲ５－Ｒ６の各組は、それぞれの基の炭素原子が結合して、置換されていてもよい４～１０員の含窒素飽和複素環を形成していてもよい。該環の置換基は、環を構成する各基の置換基がそのまま反映される。なお、各基が置換基を有する場合、その置換基の炭素原子が結合して含窒素飽和複素環を形成してもよい。「それぞれの基の炭素原子が結合して環を形成する」とは、下記に示すようにそれぞれの炭素原子に結合しているそれぞれ１個の水素原子が除かれてそれぞれの炭素原子が結合し、環を形成することを意味する。以下、具体的な環を挙げるが、これら例示の環に限定されない。なお、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個であり、２個環が形成される場合は、例えばＲ１－Ｘ２とＲ７－Ｘ２から２環が形成されるように、一つの基（ここではＸ２）が両環に共通して用いられてもよい。
Figure JPOXMLDOC01-appb-C000014
 R 1 -R 2 , R 1 -X 1 , R 1 -X 2 , R 1 -R 7 , R 7 -X 2 , R 3 -R 4 , R 3 -W 1 , R 3 -R 9 , R 9 Each group of —W 1 or R 5 —R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted. The substituent of the ring reflects the substituent of each group constituting the ring as it is. In addition, when each group has a substituent, the carbon atom of the substituent may combine to form a nitrogen-containing saturated heterocyclic ring. “The carbon atoms of each group are bonded to form a ring” means that, as shown below, each hydrogen atom bonded to each carbon atom is removed and each carbon atom is bonded. Means to form a ring. Specific rings are listed below, but are not limited to these exemplified rings. Note that the number of nitrogen-containing saturated heterocycles formed is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and when two rings are formed, for example, One group (here, X 2 ) may be commonly used for both rings so that two rings are formed from R 1 -X 2 and R 7 -X 2 .
Figure JPOXMLDOC01-appb-C000014
　Ｒ１とＲ２、Ｒ３とＲ４およびＲ５とＲ６の各組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる（ただし、Ｒ５とＲ６の組み合わせのときは、ｒ１－ｄは除かれる）。
Figure JPOXMLDOC01-appb-C000015
 Each combination of R 1 and R 2 , R 3 and R 4 and R 5 and R 6 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of the respective groups Preferred examples thereof include the following structures (however, when R 5 and R 6 are combined, r 1 -d is excluded).
Figure JPOXMLDOC01-appb-C000015
　より好ましくは、ｒ１－ａ、ｒ１－ｂ、ｒ１－ｃ、ｒ１－ｄおよびｒ１－ｆが挙げられ、さらに好ましくは、ｒ１－ｂ、ｒ１－ｃ、ｒ１－ｄおよびｒ１－ｆが挙げられる。 More preferred are r 1 -a, r 1 -b, r 1 -c, r 1 -d and r 1 -f, and more preferred are r 1 -b, r 1 -c, r 1 -d. And r 1 -f.
　Ｒ１とＲ７の組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000016
 When the combination of R 1 and R 7 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
Figure JPOXMLDOC01-appb-C000016
　より好ましくは、ｒ７－ａ、ｒ７－ｂ、ｒ７－ｃ、ｒ７－ｄ、およびｒ７－ｅが挙げられ、さらに好ましくは、ｒ７－ａ、ｒ７－ｂ、およびｒ７－ｅが挙げられる。 More preferable examples include r 7 -a, r 7 -b, r 7 -c, r 7 -d, and r 7 -e, and more preferably r 7 -a, r 7 -b, and r 7. -E.
　Ｒ７とＸ２の組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000017
 When the combination of R 7 and X 2 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
Figure JPOXMLDOC01-appb-C000017
　より好ましくは、ｘ２－ａ、ｘ２－ｂ、ｘ２－ｃ、ｘ２－ｄ、ｘ２－ｅ、ｘ２－ｆ、ｘ２－ｇ、およびｘ２－ｊが挙げられ、さらに好ましくは、ｘ２－ａ、ｘ２－ｃ、ｘ２－ｄ、ｘ２－ｅ、ｘ２－ｆ、およびｘ２－ｊが挙げられる。 More preferable examples include x 2 -a, x 2 -b, x 2 -c, x 2 -d, x 2 -e, x 2 -f, x 2 -g, and x 2 -j, and more preferable. Includes x 2 -a, x 2 -c, x 2 -d, x 2 -e, x 2 -f, and x 2 -j.
　Ｒ１とＸ１およびＲ１とＸ２の各組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000018
 Preferred examples when each combination of R 1 and X 1 and R 1 and X 2 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of the respective groups The following structures are mentioned as:
Figure JPOXMLDOC01-appb-C000018
　より好ましくは、ｘ１－ａ、ｘ１－ｂ、ｘ１－ｃ、ｘ１－ｄ、ｘ１－ｅ、ｘ１－ｆ、ｘ１－ｇおよびｘ１－ｋが挙げられ、さらに好ましくは、ｘ１－ｂ、ｘ１－ｃ、ｘ１－ｅおよびｘ１－ｇが挙げられる。 More preferably, x 1 -a, x 1 -b, x 1 -c, x 1 -d, x 1 -e, x 1 -f, x 1 -g and x 1 -k are mentioned, and more preferably , X 1 -b, x 1 -c, x 1 -e and x 1 -g.
　Ｒ３とＲ９の組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000019
 When the combination of R 3 and R 9 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
Figure JPOXMLDOC01-appb-C000019
　より好ましくは、ｒ３－ａ、ｒ３－ｂ、ｒ３－ｃ、ｒ３－ｄ、ｒ３－ｅ、およびｒ３－ｇが挙げられ、さらに好ましくは、ｒ３－ａ、ｒ３－ｂ、ｒ３－ｃ、およびｒ３－ｇが挙げられる。 More preferably, r 3 -a, r 3 -b, r 3 -c, r 3 -d, r 3 -e, and r 3 -g are mentioned, and more preferably, r 3 -a, r 3- b, r 3 -c, and r 3 -g.
　Ｒ３とＷ１の組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000020
 When the combination of R 3 and W 1 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring which may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
Figure JPOXMLDOC01-appb-C000020
　より好ましくは、ｗ１－ａ、ｗ１－ｃ、ｗ１－ｄ、ｗ１－ｅ、ｗ１－ｆ、ｗ１－ｇ、ｗ１－ｈ、ｗ１－ｉ、ｗ１－ｊ、ｗ１－ｋおよびｗ１－ｐが挙げられ、さらに好ましくは、ｗ１－ａ、ｗ１－ｃ、ｗ１－ｅ、ｗ１－ｆ、ｗ１－ｈおよびｗ１－ｊが挙げられる。 More preferably, w 1 -a, w 1 -c, w 1 -d, w 1 -e, w 1 -f, w 1 -g, w 1 -h, w 1 -i, w 1 -j, w 1 -k and w 1 -p are mentioned, and more preferred are w 1 -a, w 1 -c, w 1 -e, w 1 -f, w 1 -h and w 1 -j.
　Ｒ９とＷ１の組み合わせが、それぞれの基の炭素原子が結合して置換されていてもよい４～１０員の含窒素飽和複素環を形成するとき、その好ましい例としては下記の構造が挙げられる。
Figure JPOXMLDOC01-appb-C000021
 When the combination of R 9 and W 1 forms a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted by bonding of the carbon atoms of each group, preferred examples thereof include the following structures: It is done.
Figure JPOXMLDOC01-appb-C000021
　より好ましくは、ｒ９－ａ、ｒ９－ｃ、ｒ９－ｄ、ｒ９－ｅ、ｒ９－ｆ、ｒ９－ｇ、ｒ９－ｈ、ｒ９－ｉ、ｒ９－ｊ、ｒ９－ｋ、ｒ９－ｌ、ｒ９－ｍ、ｒ９－ｎ、ｒ９－ｏ、ｒ９－ｐおよびｒ９－ｗが挙げられ、さらに好ましくは、ｒ９－ａ、ｒ９－ｃ、ｒ９－ｅ、ｒ９－ｇ、ｒ９－ｈ、ｒ９－ｊ、ｒ９－ｌおよびｒ９－ｏが挙げられる。 More preferably, r 9 -a, r 9 -c, r 9 -d, r 9 -e, r 9 -f, r 9 -g, r 9 -h, r 9 -i, r 9 -j, r 9 -k, r 9 -l, r 9 -m, r 9 -n, r 9 -o, r 9 -p and r 9 -w, more preferably r 9 -a, r 9 -c , R 9 -e, r 9 -g, r 9 -h, r 9 -j, r 9 -l and r 9 -o.
　Ｈｅｔとして好ましくは、５～６員の含窒素部分飽和複素環または５～６員の含窒素不飽和複素環が挙げられ、より好ましくは、ピリジル、ジヒドロピリジル、ピラゾリル、テトラヒドロピリジル、テトラゾリル、チアゾリル、オキサゾリル、イミダゾリルが挙げられる。さらに好ましくは、ピリジル、ジヒドロピリジル、ピラゾリル、テトラヒドロピリジルが挙げられる。 Het is preferably a 5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or a 5- to 6-membered nitrogen-containing unsaturated heterocyclic ring, and more preferably pyridyl, dihydropyridyl, pyrazolyl, tetrahydropyridyl, tetrazolyl, thiazolyl, Examples include oxazolyl and imidazolyl. More preferred are pyridyl, dihydropyridyl, pyrazolyl and tetrahydropyridyl.
　なお、本明細書において記載の簡略化のために、次に挙げる略号を用いることもある。ｏ－：ｏｒｔｈｏ－、ｍ－：ｍｅｔａ－、ｐ－：ｐａｒａ－、ｔ－：ｔｅｒｔ－、ｓ－：ｓｅｃ－、ＴＨＦ：テトラヒドロフラン、ＤＭＥ：エチレングリコールジメチルエーテル、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＤＭＡ：ジメチルアセトアミド、ＮＭＰ：Ｎ－メチルピロリジノン、ＤＣＥ：１，２－ジクロロエタン、ＤＭＳＯ：ジメチルスルホキシド、ＣＤＣｌ３：重クロロホルム、ＤＭＳＯ－ｄ６：重ジメチルスルホキシド、ＯＭｓ：メタンスルホニルオキシ、ＯＴｓ：トルエンスルホニルオキシ、ＯＴｆ：トリフルオロメタンスルホニルオキシ、ｓ：singlet、ｄ：dublet、ｔ：triplet、ｑ：quartet、ｍ：multiplet，Ｂｏｃ：ｔ－ブトキシカルボニル、ＤＰＰＦ：１，１’－ビス（ジフェニルホスフィノ）フェロセン、ＤＰＰＥ：１，２－ビス（ジフェニルホスフィノ）エタン、ＤＰＰＰ：１，３－ビス（ジフェニルホスフィノ）プロパン、ＤＰＰＢ：１，４－ビス（ジフェニルホスフィノ）ブタン、ＢＩＮＡＰ（登録商標）：２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル、ＤＰＥ－Ｐｈｏｓ（登録商標）：ビス（２－ジフェニルホスフィノフェニル）エーテル、ＸＡＮＴ－Ｐｈｏｓ（登録商標）：９，９－ジメチル－４，５－ビス（ジフェニルホスフィノ）キサンチン、Ｓ－Ｐｈｏｓ：２－ジシクロヘキシルホスフィノ－２’、６’－ジメトキシ－１，１’－ビフェニル（登録商標）、Ｘ－Ｐｈｏｓ：２－ジシクロヘキシルホスフィノ－２’、４’、６’－トリイソプロピル－１，１’－ビフェニル（登録商標）、ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾル－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロリン酸塩、ＬＤＡ：リチウムジイソプロピルアミド、ＬＨＭＤＳ：リチウムヘキサメチルジシラジド、ＮＨＭＤＳ：ナトリウムヘキサメチルジシラジド。 Note that the following abbreviations may be used to simplify the description in this specification. o-: ortho-, m-: meta-, p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DME: ethylene glycol dimethyl ether, DMF: N, N-dimethylformamide, DMA : Dimethylacetamide, NMP: N-methylpyrrolidinone, DCE: 1,2-dichloroethane, DMSO: dimethyl sulfoxide, CDCl 3 : deuterated chloroform, DMSO-d 6 : deuterated dimethyl sulfoxide, OMs: methanesulfonyloxy, OTs: toluenesulfonyloxy OTf: trifluoromethanesulfonyloxy, s: singlelet, d: dublet, t: triplet, q: quartet, m: multiplet, Boc: t-butoxycarbonyl, DPPF: 1,1′-bis (diphenylphosphino) ferrocene, DPPE: 1, -Bis (diphenylphosphino) ethane, DPPP: 1,3-bis (diphenylphosphino) propane, DPPB: 1,4-bis (diphenylphosphino) butane, BINAP (registered trademark): 2,2'-bis ( Diphenylphosphino) -1,1′-binaphthyl, DPE-Phos®: bis (2-diphenylphosphinophenyl) ether, XANT-Phos®: 9,9-dimethyl-4,5-bis (Diphenylphosphino) xanthine, S-Phos: 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (registered trademark), X-Phos: 2-dicyclohexylphosphino-2 ′, 4 ', 6'-Triisopropyl-1,1'-biphenyl (registered trademark), HATU: O- (7-azabenzotriazole-1- Yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, LDA: lithium diisopropylamide, LHMDS: lithium hexamethyldisilazide, NHMDS: sodium hexamethyldisilazide.
　本発明の化合物（Ｉ）の製造法について以下に述べる。化合物（Ｉａ）、（Ｉｂ）、（Ｉｃ）、（Ｉｄ）、（Ｉｅ）、（Ｉｆ）、（Ｉｇ）、（Ｉｈ）、（Ｉｉ）、（Ｉｊ）、（Ｉｋ）、（Ｉｌ）、（Ｉｍ）、（Ｉｎ）、（Ｉｏ）、（Ｉｐ）および（Ｉｑ）は化合物（Ｉ）に含まれる化合物である。化合物（Ｉ）は、下記の製造法１～１５で示される方法またはそれに準じた方法により得られる。反応式中の化合物は塩を形成している場合も含み、該塩としては、例えば化合物（Ｉ）の塩と同様のものが挙げられる。 The production method of the compound (I) of the present invention is described below. Compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), ( (Im), (In), (Io), (Ip) and (Iq) are compounds included in the compound (I). Compound (I) can be obtained by the method shown in the following production methods 1 to 15 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).
製造法１：
　化合物（Ｉ）のうち、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが塩素原子又は臭素原子であり、Ｑ２が水素原子である化合物（Ｉａ）、Ａ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子又は臭素原子であり、Ｑ２が水素原子である化合物（Ｉｂ）、Ａ２が式（Ａ）であり、Ａ１がＺであり、ＺおよびＱ２が水素原子である化合物（Ｉｃ）、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキルであり、Ｑ２が水素原子である化合物（Ｉｄ）、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが－ＮＲ５Ｒ６であり、Ｑ２が水素原子である化合物（Ｉｅ）、およびＡ２が式（Ａ）であり、Ａ１がＺであり、Ｚが置換されていてもよいＣ１－５アルコキシであり、Ｑ２が水素原子である化合物（Ｉｆ）、は、以下に示す製造法によって得ることができる。
Figure JPOXMLDOC01-appb-C000022
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｑ１、Ｗ、ＸおよびＹは、前記と同義である。Ｒａは置換されていてもよいアルキルであり、Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｈａｌａは、塩素原子または臭素原子であり、Ｈａｌｂは、塩素原子、臭素原子またはヨウ素原子であり、Ｚ’は、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキルであり、Ｒ’は、置換されていてもよいＣ１－５アルキルである。） Production method 1:
Among the compounds (I), A 2 is the formula (A), A 1 is Z, Z is a chlorine atom or a bromine atom, and Q 2 is a hydrogen atom, and A 1 is the formula (A), A 2 is Z, Z is a chlorine atom or bromine atom, Q 2 is a hydrogen atom, compound (Ib), A 2 is formula (A), and A 1 is Z A compound (Ic) in which Z and Q 2 are hydrogen atoms, A 2 is the formula (A), A 1 is Z, and Z is an optionally substituted C 1-10 alkyl or substituted Compound (Id), which is C 3-8 cycloalkyl, Q 2 is a hydrogen atom, A 2 is Formula (A), A 1 is Z, and Z is —NR 5 R 6 , Q 2 is a hydrogen atom (Ie), and A 2 is the formula (A), A 1 is Z, and Z may be substituted Compound (If) which is C 1-5 alkoxy and Q 2 is a hydrogen atom can be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000022
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q 1 , W, X, and Y are as defined above. R a is an optionally substituted alkyl. R b is a hydrogen atom or an optionally substituted alkyl, Hal a is a chlorine atom or a bromine atom, Hal b is a chlorine atom, a bromine atom or an iodine atom, and Z ′ is An optionally substituted C 1-10 alkyl or an optionally substituted C 3-8 cycloalkyl, and R ′ is an optionally substituted C 1-5 alkyl.)
〔工程１〕
　化合物（１－１）を、溶媒中２～１０当量、好ましくは３～５当量の塩基の存在下、１～２０当量、好ましくは２～１０当量の尿素と反応させることにより、化合物（１－２）を得ることができる。化合物（１－１）は、市販品としてまたは公知の方法［例えば、ＷＯ２００２／０６６４８２， Journal of American Chemical Society， 3854 (2001)］もしくはそれに準じた方法によって合成される。 [Step 1]
Compound (1-1) is reacted 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 to give compound (1- 2) can be obtained. Compound (1-1) is synthesized as a commercially available product or by a known method [for example, WO2002 / 066482, Journal of American Chemical Society, 3854 (2001)] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノールが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でもナトリウムメトキシドまたはナトリウムエトキシドが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃で、通常１～６０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, and examples thereof include DMF, DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol, etc. And methanol or ethanol is preferable.
As 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.
〔工程２〕
　工程１で得られる化合物（１－２）を、溶媒中または無溶媒で過剰量、好ましくは３～１０当量のハロゲン化剤と反応させることにより、化合物（１－３）を得ることができる。 [Step 2]
Compound (1-3) can be obtained by reacting compound (1-2) obtained in step 1 with a halogenating agent in an excess amount, preferably 3 to 10 equivalents, in a solvent or without a solvent.
　ハロゲン化剤としては、例えばオキシ塩化リン、五塩化リン、オキシ臭化リン等が用いられる。本反応で用いられる溶媒としては、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＤＣＥ、ＴＨＦ、１，４－ジオキサン、ＤＭＥ、クロロホルム、ベンゼン、トルエン、キシレン、トリエチルアミン、ピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンまたはＮ，Ｎ－ジメチルアミノピリジン等を単独でまたはそれらを混合して用いることができる。
　反応は０℃から溶媒またはハロゲン化剤の沸点の間の温度、好ましくは５０～１４０℃で、通常１～２４時間行われる。 Examples of the halogenating agent 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. For example, DCE, THF, 1,4-dioxane, DME, chloroform, benzene, toluene, xylene, triethylamine, Pyridine, N, N-diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline, N, N-dimethylaminopyridine or the like can be used alone or in combination.
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.
〔工程３〕
工程２で得られる化合物（１－３）を、溶媒中０．０５～１当量、好ましくは０．０５～０．１当量の四酸化オスミウムまたはカリウム オスメート（ＩＶ）２水和物、１～１０当量、好ましくは１～３当量の塩基、および１～１０当量、好ましくは３～４当量のメタ過ヨウ素酸ナトリウムと反応させることにより、化合物（１－４）を得ることができる。 [Step 3]
The compound (1-3) obtained in Step 2 is added in an amount of 0.05 to 1 equivalent, preferably 0.05 to 0.1 equivalent of osmium tetroxide or potassium osmate (IV) dihydrate, 1 to 10 in a solvent. Compound (1-4) can be obtained by reacting with an equivalent amount, preferably 1 to 3 equivalents of a base, and 1 to 10 equivalents, preferably 3 to 4 equivalents of sodium metaperiodate.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、アセトン、ｔ－ブタノール、水等を単独でまたはそれらを混合して用いることができ、中でもアセトンと水の混合溶媒が好ましい。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどの脂肪族３級アミン、ピリジン、２，６－ルチジン、ピラジン、ピリダジン、ピリミジンなどの芳香族アミン等を用いることができ、中でも２，６－ルチジンが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～５０℃で、通常０．５～２４時間行われる。
また、化合物（１－４）は、ジクロロメタン、酢酸エチル、メタノール等の溶媒中、室温あるいは－７８℃にてオゾンを含む酸素気流を通じた後、ジメチルスルフィド等の還元剤を反応させるオゾン分解によっても得ることができる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, acetone, t-butanol, water and the like are used alone or in combination. Among them, a mixed solvent of acetone and water is preferable.
As the base, aliphatic tertiary amines such as triethylamine and N, N-diisopropylethylamine, aromatic amines such as pyridine, 2,6-lutidine, pyrazine, pyridazine and pyrimidine can be used, among which 2,6- Lutidine is preferred.
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.
The compound (1-4) can also be obtained by ozonolysis in which a reducing agent such as dimethyl sulfide is reacted after passing through an oxygen stream containing ozone at room temperature or −78 ° C. in a solvent such as dichloromethane, ethyl acetate or methanol. Obtainable.
〔工程４〕
　工程３で得られる化合物（１－４）を、溶媒中で１～１０当量、好ましくは２～３当量の酸の存在下、１～１０当量、好ましくは１．２～４当量の水素化ホウ素化合物、および１～１０当量、好ましくは１．１～２当量の化合物（１－５）と反応させることにより、化合物（１－６）を得ることができる。化合物（１－５）は、市販品としてまたは公知の方法［例えば、Chemical Abstract, 1971 (1957); Journal of the Chemical Society, 3096 (1931)］もしくはそれに準じた方法によって合成される。 [Step 4]
Compound (1-4) obtained in step 3 is 1 to 10 equivalents, preferably 1.2 to 4 equivalents of borohydride in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of acid in a solvent. The compound (1-6) can be obtained by reacting the compound and 1 to 10 equivalents, preferably 1.1 to 2 equivalents of the compound (1-5). Compound (1-5) is synthesized as a commercially available product or by a known method [eg, Chemical Abstract, 1971 (1957); Journal of the Chemical Society, 3096 (1931)] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、メタノール、エタノール、ｎ－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でも１，２－ジクロロエタンまたはメタノールが好ましい。
　酸としては、例えばギ酸、プロピオン酸、酢酸、トリフルオロ酢酸等のカルボン酸類、塩酸等の鉱酸類を用いることができ、中でも酢酸が好ましい。
　水素化ホウ素化合物としては、例えばシアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等を用いることができ、中でもシアノ水素化ホウ素ナトリウムまたはトリアセトキシ水素化ホウ素ナトリウムが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～４０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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.
As 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.
As the borohydride compound, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like can be used, and among them, 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.
〔工程５〕
　工程４で得られる化合物（１－６）を、溶媒中で１～１０当量、好ましくは２～４当量の塩基、および０．０１～１当量、好ましくは０．０５～０．２当量のパラジウム触媒、必要に応じて０．０１～１当量、好ましくは０．０５～０．２当量のホスフィン配位子の存在下、１～５当量、好ましくは１～１．０５当量の化合物（１－７）と反応させることにより、化合物（Ｉａ）および／または化合物（Ｉｂ）を得ることができる。化合物（１－７）は、市販品としてまたは公知の方法 ［例えば、ＷＯ２００８／１４８８６７，ＷＯ２００４／０１３１３４］もしくはそれに準じた方法によって合成される。 [Step 5]
Compound (1-6) obtained in step 4 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. Catalyst, optionally in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of a phosphine ligand, 1 to 5 equivalents, preferably 1 to 1.05 equivalents of compound (1- By reacting with 7), compound (Ia) and / or compound (Ib) can be obtained. Compound (1-7) is synthesized as a commercially available product or by a known method [eg, WO2008 / 148867, WO2004 / 013134] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、水等を単独でまたはそれらを混合して用いることができ、中でもＤＭＦと水、ＤＭＥと水または１，４－ジオキサンと水の混合溶媒が好ましい。
　パラジウム触媒としては、例えばテトラキストリフェニルホスフィンパラジウム、ビス（ｔ－ブチルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等の０価触媒、またはビス（トリフェニルホスフィン）パラジウム・ジクロリド、酢酸パラジウム、ビス（ジフェニルホスフィノフェロセン）パラジウム・ジクロリド等の２価触媒を用いることができ、中でもテトラキストリフェニルホスフィンパラジウムまたは酢酸パラジウムが好ましい。
　ホスフィン配位子としては、例えばｏ－トリルホスフィン、Ｓ－ＰｈｏｓまたはＸ－Ｐｈｏｓ等の単座配位型の配位子、ＤＰＰＦ、ＤＰＰＥ、ＤＰＰＰ、ＤＰＰＢ、ＢＩＮＡＰ、ＸＡＮＴ－ＰｈｏｓまたはＤＰＥ－Ｐｈｏｓ等の二座配位型の配位子を用いることができ、中でもＳ－ＰｈｏｓまたはＸ－Ｐｈｏｓが好ましい。
　塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウムまたはリン酸カリウム等の塩基性塩類が挙げられるが、中でも炭酸ナトリウム、炭酸カリウムまたはリン酸カリウムが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の加熱下もしくはマイクロ波照射下で、通常０．５～２４時間で行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone. Alternatively, they can be used in combination, and among them, a mixed solvent of DMF and water, DME and water, or 1,4-dioxane and water is preferable.
Examples of 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 tetrakistriphenylphosphine palladium or palladium acetate is preferred.
Examples of the phosphine ligand include monodentate ligands such as o-tolylphosphine, S-Phos, and X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos, DPE-Phos, and the like. A bidentate ligand can be used, and among them, S-Phos or X-Phos is preferable.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or potassium phosphate, among which sodium carbonate, potassium carbonate or potassium phosphate 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.
〔工程６〕
　工程５で得られる化合物（Ｉａ）を溶媒中で１～１０気圧、好ましくは１～４気圧の水素雰囲気下、０．１～１０当量、好ましくは１～３当量の酸の存在下、０．１～１０当量、好ましくは０．１から１当量のパラジウム炭素等の触媒で処理することにより、化合物（Ｉｃ）を得ることができる。また、化合物（Ｉｃ）は、化合物（Ｉａ）を溶媒中、５～１０当量の蟻酸アンモニウムの存在下、０．１～１０当量、好ましくは０．１から１当量のパラジウム炭素等の触媒で処理することによっても得ることができる。 [Step 6]
The compound (Ia) obtained in Step 5 is 0.1 to 10 equivalents, preferably 1 to 3 equivalents, in the presence of 1 to 3 equivalents of acid in a solvent under a hydrogen atmosphere of 1 to 10 atm, preferably 1 to 4 atm. Compound (Ic) can be obtained by treatment with 1 to 10 equivalents, preferably 0.1 to 1 equivalents of a catalyst such as palladium on carbon. Compound (Ic) is prepared by treating compound (Ia) with a catalyst such as 0.1 to 10 equivalents, preferably 0.1 to 1 equivalents of palladium carbon in the presence of 5 to 10 equivalents of ammonium formate in a solvent. Can also be obtained.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、酢酸エチル、メタノール、エタノール、ｎ－プロパノール、２－プロパノール、水等を単独でまたはそれらを混合して用いることができ、中でもメタノール単独もしくは水との混合溶媒が好ましい。
　触媒としては、例えばパラジウム炭素、水酸化パラジウム炭素、パラジウムブラック等のパラジウム触媒類、ラネーニッケル等のニッケル触媒類、酸化白金等の白金触媒類を用いることができ、中でもパラジウム炭素が好ましい。酸としては、例えば酢酸、トリフルオロ酢酸等のカルボン酸類、塩酸等の鉱酸類を用いることができ、中でも酢酸、トリフルオロ酢酸または塩酸が好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～５０℃で、通常０．５～２４時間行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが水素原子である化合物も工程５で得られる化合物（Ｉｂ）より得ることができる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, ethyl acetate, methanol, ethanol, n-propanol, 2-propanol Propanol, water and the like can be used alone or in combination, and methanol alone or a mixed solvent with water is preferred.
As 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. As 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 acetic acid, 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. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a hydrogen atom can also be obtained from the compound (Ib) obtained in Step 5 by the same production method.
〔工程７〕
　工程５で得られる化合物（Ｉａ）を、溶媒中で０．０１～１当量、好ましくは０．０５～０．２当量のパラジウム触媒の存在下、１～５当量、好ましくは１．１～２当量の化合物（１－８）または化合物（１－９）と反応させることにより、化合物（Ｉｄ）を得ることができる。化合物（１－８）または化合物（１－９）は、市販品としてまたは公知の方法［例えば、ＷＯ２００６／０２４４９３，ＷＯ２００８／０８３０７０］もしくはそれに準じた方法によって合成される。 [Step 7]
Compound (Ia) obtained in Step 5 is 1 to 5 equivalents, preferably 1.1 to 2 equivalents in the presence of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst in a solvent. Compound (Id) can be obtained by reacting with an equivalent amount of compound (1-8) or compound (1-9). Compound (1-8) or Compound (1-9) is synthesized as a commercially available product or by a known method [eg, WO2006 / 024493, WO2008 / 083070] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦが好ましい。
　パラジウム触媒としては、例えばテトラキストリフェニルホスフィンパラジウム、ビス（ｔ－ブチルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等の０価触媒、またはビス（トリフェニルホスフィン）パラジウム・ジクロリド、酢酸パラジウム、ビス（ジフェニルホスフィノフェロセン）パラジウム・ジクロリド等の２価触媒を用いることができ、中でもテトラキストリフェニルホスフィンパラジウムまたはビス（ｔ－ブチルホスフィン）パラジウムが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは２０～１００℃の加熱下もしくはマイクロ波照射下で、通常０．５～２４時間で行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキルである化合物も工程５で得られる化合物（Ｉｂ）より得ることができる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF and the like are used alone or in combination. And THF can be used.
Examples of 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, and tetrakistriphenylphosphine palladium or bis (t-butylphosphine) palladium is particularly preferable. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably at 20-100 ° C. or under microwave irradiation, usually for 0.5-24 hours. In the same production method, A 1 is the formula (A), A 2 is Z, and Z is an optionally substituted C 1-10 alkyl or an optionally substituted C 3-8 cycloalkyl Can also be obtained from compound (Ib) obtained in step 5.
〔工程８〕
　工程５で得られる化合物（Ｉａ）を、溶媒中で必要に応じて１～１０当量、好ましくは２～５当量の塩基の存在下、１～２０当量、好ましくは３～１０当量の化合物（１－１０）と反応させることにより、化合物（Ｉｅ）を得ることができる。化合物（１－１０）は、市販品としてまたは公知の方法で得られる。 [Step 8]
Compound (Ia) obtained in Step 5 is added in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base in a solvent, if necessary, in the presence of 1 to 20 equivalents, preferably 3 to 10 equivalents of compound (1 Compound (Ie) can be obtained by reacting with -10). Compound (1-10) can be obtained as a commercially available product or by a known method.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦ、１，４－ジオキサン、ＮＭＰまたは２－プロパノールが好ましい。
　塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウム等の塩基性塩類、水酸化ナトリウム、水酸化カリウム等の無機塩基類、ピリジン、ルチジン等の芳香族アミン類、トリエチルアミン、トリプロピルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン等の第３級アミン類、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物類等を用いることができ、中でも炭酸カリウム、トリエチルアミンまたはＮ，Ｎ－ジイソプロピルエチルアミンが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の加熱下もしくはマイクロ波照射下で、通常０．５～２４時間行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが－ＮＲ５Ｒ６である化合物も工程５で得られる化合物（Ｉｂ）より得ることができる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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 THF, 1,4-dioxane, NMP or 2-propanol is preferable.
Examples of the base 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 can be used, among which potassium carbonate, triethylamine or N, N-diisopropylethylamine is preferred.
The reaction is carried out usually at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or microwave irradiation, usually for 0.5 to 24 hours. A compound in which A 1 is the formula (A), A 2 is Z, and Z is —NR 5 R 6 can also be obtained from the compound (Ib) obtained in Step 5 by the same production method.
〔工程９〕
　工程５で得られる化合物（Ｉａ）を、溶媒中で１～２０当量、好ましくは３～１０当量の金属アルコキシド（１－１１）と反応させることにより、化合物（Ｉｆ）を得ることができる。化合物（１－１１）は、市販品としてまたは公知の方法で得られる。 [Step 9]
Compound (If) can be obtained by reacting compound (Ia) obtained in step 5 with 1 to 20 equivalents, preferably 3 to 10 equivalents, of metal alkoxide (1-11) in a solvent. Compound (1-11) can be obtained as a commercially available product or by a known method.
　本反応で用いられる溶媒は、用いる金属アルコキシドの種類によって、メタノール、エタノール等のアルコール溶媒が選択される。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の加熱下もしくはマイクロ波照射下で、通常０．５～２４時間行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが置換されていてもよいＣ１－５アルコキシである化合物も工程５で得られる化合物（Ｉｂ）より得ることができる。 As the solvent used in this reaction, an alcohol solvent such as methanol or ethanol is selected depending on the type of metal alkoxide used.
The reaction is carried out usually at a temperature between room temperature and the boiling point of the solvent used, preferably 50 to 180 ° C. or microwave irradiation, usually for 0.5 to 24 hours. A compound in which A 1 is the formula (A), A 2 is Z, and Z is optionally substituted C 1-5 alkoxy by the same production method is compound (Ib) obtained in step 5. Can get more.
製造法２：
　化合物（Ｉ）のうち、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが塩素原子または臭素原子である化合物（Ｉｇ）は、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000023
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、Ｘ、Ｙは前記と同義である。ＨａｌａおよびＨａｌｃは、それぞれ独立して塩素原子または臭素原子であり、Ｒａは、置換されていてもよいアルキルであり、Ｒｂは、水素原子または置換されていてもよいアルキルである。） Production method 2:
Among the compounds (I), the compound (Ig) in which A 2 is the formula (A), A 1 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000023
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above. Hal a and Hal c are each independently a chlorine atom or A bromine atom, R a is an optionally substituted alkyl, and R b is a hydrogen atom or an optionally substituted alkyl.)
〔工程１０〕
　市販品または例えばBioorganic Chemistry, 34(5), 248-273 (2006)に記載の方法に準じて合成した化合物（２－１）を、溶媒中で１～５当量、好ましくは１．５～２当量の塩基の存在下、１～５当量、好ましくは１～３当量の酸無水物（２－２）と反応させることにより、化合物（２－３）を得ることができる。化合物（２－２）は、市販品としてまたは公知の方法［例えば、ＷＯ２００８／００１９８５］もしくはそれに準じた方法によって合成される。 [Step 10]
A commercially available product or a compound (2-1) synthesized according to the method described in, for example, Bioorganic Chemistry, 34 (5), 248-273 (2006) is 1 to 5 equivalents, preferably 1.5 to 2 in a solvent. Compound (2-3) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of acid anhydride (2-2) in the presence of an equivalent amount of a base. Compound (2-2) is synthesized as a commercially available product or by a known method [for example, WO2008 / 001985] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジエチルエーテル、ジクロロメタン、ベンゼン、トルエン、キシレン等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦ、ジエチルエーテルまたはジクロロメタンが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド、ＬＤＡ、ＬＨＭＤＳ、ＮＨＭＤＳ等の強塩基、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物類等を用いることができ、中でもＬＤＡ、ＬＨＭＤＳ、水素化ナトリウムが好ましい。
　反応は－１００℃から室温の間の温度、好ましくは－７８℃～室温で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, diethyl ether, dichloromethane, benzene, toluene, xylene and the like are used alone. Or a mixture thereof, among which THF, diethyl ether or dichloromethane is preferred.
Examples of the base include various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, strong bases such as LDA, LHMDS and NHMDS, and alkali metal hydrogens such as sodium hydride and potassium hydride. In particular, LDA, LHMDS, and sodium hydride are preferable.
The reaction is carried out at a temperature between −100 ° C. and room temperature, preferably at −78 ° C. to room temperature, usually for 0.5 to 24 hours.
〔工程１１〕
　工程１０で得られる化合物（２－３）を、溶媒中２～１０当量、好ましくは３～５当量のローソン試薬または五硫化二リン等の硫化剤と反応させることにより、化合物（２－４）得ることができる。 [Step 11]
Compound (2-4) obtained by reacting compound (2-3) obtained in step 10 with a sulfurizing agent such as Lawesson's reagent or diphosphorus pentasulfide in 2 to 10 equivalents, preferably 3 to 5 equivalents, in a solvent. Obtainable.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン等を単独でまたはそれらを混合して用いることができ、中でもトルエン、ＴＨＦまたは１，４－ジオキサンが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～１００℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene and the like are used alone or in combination. Among them, toluene, THF or 1,4-dioxane 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 100 ° C., usually for 0.5 to 24 hours.
〔工程１２〕
　工程１１で得られる化合物（２－４）を、溶媒中２～１０当量、好ましくは３～５当量の塩基の存在下、１～２０当量、好ましくは２～１０当量のグアニジンと反応させることにより、化合物（２－５）を得ることができる。 [Step 12]
By reacting the compound (2-4) obtained in Step 11 with 1 to 20 equivalents, preferably 2 to 10 equivalents of guanidine in the presence of 2 to 10 equivalents, preferably 3 to 5 equivalents of a base in a solvent. Compound (2-5) can be obtained.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノールが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でもナトリウムメトキシドまたはナトリウムエトキシドが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃で、通常１～６０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, and examples thereof include DMF, DMA, NMP, methanol, ethanol, 1-propanol, 2-propanol, etc. And methanol or ethanol is preferable.
As 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.
〔工程１３〕
　工程１２で得られる化合物（２－５）を、工程２と同様の方法で反応させることにより、化合物（２－６）を得ることができる。 [Step 13]
Compound (2-6) can be obtained by reacting compound (2-5) obtained in step 12 in the same manner as in step 2.
〔工程１４〕
工程１３で得られる化合物（２－６）を溶媒中５～２０当量の亜硝酸塩、および２～５当量のハロゲン化銅と反応させることにより、化合物（２－７）を得ることができる。また、化合物（２－７）は、化合物（２－６）を溶媒中２～１０当量のハロゲン化トリメチルシリル、５～１０当量の亜硝酸塩、１～２当量のハロゲン化トリエチルベンジルアンモニウムと反応させることによっても得ることができる。 [Step 14]
The compound (2-7) can be obtained by reacting the compound (2-6) obtained in Step 13 with 5 to 20 equivalents of nitrite and 2 to 5 equivalents of copper halide in a solvent. Compound (2-7) is prepared by reacting Compound (2-6) with 2 to 10 equivalents of trimethylsilyl halide, 5 to 10 equivalents of nitrite, and 1 to 2 equivalents of triethylbenzylammonium halide in a solvent. Can also be obtained.
　亜硝酸塩としては、亜硝酸ナトリウム、亜硝酸ｔ－ブチル等が用いられる。本反応で用いられる溶媒としては、主にジクロロメタン、クロロホルム、１，２－ジクロロエタン等のハロゲン系溶媒が用いられる。反応は０℃から用いる溶媒の沸点の間の温度、好ましくは０℃～室温で、通常０．５～２４時間行われる。 As the nitrite, sodium nitrite, t-butyl nitrite or the like is used. As the solvent used in this reaction, a halogen-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane is mainly used. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0 ° C. to room temperature, usually for 0.5 to 24 hours.
〔工程１５〕
　工程１４で得られる化合物（２－７）と化合物（１－７）を工程５と同様の方法で反応させることにより、化合物（Ｉｇ）を得ることができる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。また、化合物（Ｉｇ）を用い、工程６～９と同様の製造法により、Ｈａｌａを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 [Step 15]
Compound (Ig) can be obtained by reacting compound (2-7) obtained in step 14 with compound (1-7) in the same manner as in step 5. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method. In addition, using compound (Ig), Hal a is substituted with a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9. , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, and the like can also be obtained.
製造法３：
化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｗが－ＮＲ９－Ｗ１－である化合物（Ｉｈ）は、化合物（２－７）より、以下に示す製造法によって得ることができる。
Figure JPOXMLDOC01-appb-C000024
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ９、Ｑ１、Ｑ２、Ｗ１、ＸおよびＹは、前記と同義であり、Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｈａｌａ、ＨａｌｃおよびＨａｌｄは、それぞれ独立して塩素原子または臭素原子である。） Production method 3:
Among the compounds (I), the compound (Ih) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and W is —NR 9 —W 1 — The compound (2-7) can be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000024
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , R 9 , Q 1 , Q 2 , W 1 , X and Y are as defined above, and R b is a hydrogen atom or substituted. And each of Hal a , Hal c and Hal d is independently a chlorine atom or a bromine atom.)
〔工程１６〕
　工程１４で得られる化合物（２－７）と化合物（３－１）とを用いて工程５と同様の方法で反応させることにより、化合物（３－２）を得ることができる。化合物（３－１）は、市販品としてまたは公知の方法［例えば、Journal of Organometallic Chemistry, 2001, 640, 197-200］もしくはそれに準じた方法によって合成される。 [Step 16]
Compound (3-2) can be obtained by reacting compound (2-7) obtained in step 14 and compound (3-1) in the same manner as in step 5. Compound (3-1) is synthesized as a commercially available product or by a known method [eg, Journal of Organometallic Chemistry, 2001, 640, 197-200] or a method analogous thereto.
〔工程１７〕
　工程１６で得られる化合物（３－２）を、溶媒中１～１０当量、好ましくは３～５当量の塩基、および０．０１～１当量、好ましくは０．０５～０．２当量のホスフィン配位子、および０．０１～１当量、好ましくは０．０５～０．２当量のパラジウム触媒の存在下、１～５当量、好ましくは１～２当量の化合物（３－３）と反応させることにより、化合物（Ｉｈ）を得ることができる。化合物（３－３）は、市販品としてまたは公知の方法［例えば、ＵＳ２００４２４２０５， Journal of Medicinal Chemistry, 1997, 40(13), 2047-2052］もしくはそれに準じた方法によって合成される。 [Step 17]
Compound (3-2) obtained in Step 16 is mixed with 1 to 10 equivalents, preferably 3 to 5 equivalents of a base, and 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of phosphine in a solvent. Reaction with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (3-3) in the presence of a ligand and 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalents of palladium catalyst. Can give compound (Ih). Compound (3-3) is synthesized as a commercially available product or by a known method [for example, US200429205, Journal of Medicinal Chemistry, 1997, 40 (13), 2047-2052] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン等を単独でまたはそれらを混合して用いることができ、中でもトルエンまたは１，４－ジオキサンが好ましい。
　ホスフィン配位子としては、例えばトリフェニルホスフィン、トリトリルホスフィン、トリフラニルホスフィン、トリ ｔ－ブチルホスフィン等の単座配位型ホスフィン、またはＢＩＮＡＰ、２，２’－ビス（ジトリルホスフィノ）－１，１’－ビナフチル、ＤＰＥ－Ｐｈｏｓ、ＸＡＮＴ－Ｐｈｏｓ等の２座配位型ホスフィンを用いることができ、中でもＢＩＮＡＰが好ましい。
　パラジウム触媒としては、例えばテトラキストリフェニルホスフィンパラジウム、ビス（ｔ－ブチルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等の０価触媒、またはビス（トリフェニルホスフィン）パラジウム・ジクロリド、酢酸パラジウム、ビス（ジフェニルホスフィノフェロセン）パラジウム・ジクロリド等の２価触媒を用いることができ、中でもトリス（ジベンジリデンアセトン）ジパラジウムまたは酢酸パラジウムが好ましい。
　塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウム等の塩基性塩類、ナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でも炭酸セシウムまたはカリウム ｔ－ブトキシドが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の間の温度で加熱下もしくはマイクロ波照射下で、通常０．５～２４時間で行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。また、化合物（Ｉｈ）を用い、工程６～９と同様の製造法により、Ｈａｌaを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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.
Examples of the phosphine ligand include monodentate phosphines such as triphenylphosphine, tritolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino)- A bidentate phosphine such as 1,1′-binaphthyl, DPE-Phos, XANT-Phos can be used, and among these, BINAP is preferable.
Examples of 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, and tris (dibenzylideneacetone) dipalladium or palladium acetate is particularly preferable.
As 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., under heating or under microwave irradiation, usually for 0.5 to 24 hours. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method. In addition, using compound (Ih), Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl, by the same production method as in Steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
製造法４：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｗが－Ｏ－Ｗ１－である化合物（Ｉｉ）は、化合物（２－７）より、以下に示す製造法によって得ることができる。
Figure JPOXMLDOC01-appb-C000025
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ１、ＸおよびＹは、前記と同義である。Ｒｂは、水素原子または置換されていてもよいアルキルであり、ＨａｌａおよびＨａｌｃは、それぞれ独立して塩素原子または臭素原子である。） Production method 4:
Among the compounds (I), the compound (Ii) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and W is —O—W 1 — It can be obtained from compound (2-7) by the production method shown below.
Figure JPOXMLDOC01-appb-C000025
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W 1 , X and Y are as defined above. R b may be a hydrogen atom or substituted. A good alkyl, and Hal a and Hal c are each independently a chlorine atom or a bromine atom.)
〔工程１８〕
　工程１４で得られる化合物（２－７）と化合物（４－１）とを用いて工程５と同様の方法で反応させることにより、化合物（４－２）を得ることができる。化合物（４－１）は、市販品としてまたは公知の方法［例えば、Organic Letters, 2006, 8(2), 261-263］もしくはそれに準じた方法によって合成される。 [Step 18]
Compound (4-2) can be obtained by reacting Compound (2-7) obtained in Step 14 and Compound (4-1) in the same manner as in Step 5. Compound (4-1) is synthesized as a commercially available product or by a known method [eg, Organic Letters, 2006, 8 (2), 261-263] or a method analogous thereto.
〔工程１９〕
　工程１８で得られる化合物（４－２）を、溶媒中、１～１０当量、好ましくは１～３当量のホスフィン、および１～１０当量、好ましくは１～３当量のアゾ化合物または角田試薬存在下、１～５当量、好ましくは１～３当量の対応するアルコール誘導体と反応させることにより、化合物（Ｉｉ）を得ることができる。または、工程１８で得られる化合物（４－２）を、溶媒中、１～１０当量、好ましくは１～３当量の塩基の存在下または非存在下、１～５当量、好ましくは１～３当量の対応するアルキルハロゲン誘導体等と反応させることによっても化合物（Ｉｉ）を得ることができる。 [Step 19]
Compound (4-2) obtained in Step 18 is present in a solvent in the presence of 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 or Kakuda reagent. Compound (Ii) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of the corresponding alcohol derivative. Alternatively, the compound (4-2) obtained in Step 18 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. The compound (Ii) can also be obtained by reacting with a corresponding alkyl halogen derivative.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジクロロメタン、ＤＣＥ、クロロホルム、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦ、ジクロロメタン、トルエン、ＤＭＦが好ましい。
　使用するホスフィンとしては、例えばトリフェニルホスフィン、トリメチルホスフィン、トリブチルホスフィン等が挙げられるが、中でもトリフェニルホスフィンが好ましい。
　アゾ化合物としては、ジエチルアゾジカルボキシレート、ジイソプロピルアゾジカルボキシレート、ジシクロヘキシルアゾジカルボキシレート、ジベンジルアゾジカルボキシレート等が挙げられるが、中でもジエチルアゾジカルボキシレートまたはジイソプロピルアゾジカルボキシレートが好ましい。
　塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウム等の塩基性塩類、ピリジン、ルチジン等の芳香族アミン類、トリエチルアミン、トリプロピルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン等の第３級アミン類、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物類、中でも炭酸カリウム、炭酸セシウム、ピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミンまたはが水素化ナトリウムが好ましい。反応は０℃から用いる溶媒の沸点の間の温度、好ましくは室温～１００℃で、通常０．５～２４時間行われる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。また、化合物（Ｉｉ）を用い、工程６～９と同様の製造法により、Ｈａｌaを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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 as a mixture thereof. Among them, THF, dichloromethane, toluene and DMF are preferable.
Examples of 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 them, 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 (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method. In addition, using compound (Ii), Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl, or optionally substituted C 3-8 cycloalkyl, by the same production method as in steps 6-9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
製造法５：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）である化合物（Ｉｇ）は、以下に示す製造法によっても得ることもできる。
Figure JPOXMLDOC01-appb-C000026
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、ＸおよびＹは、前記と同義である。Ｒａは、置換されていてもよいアルキルであり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 5:
Among compounds (I), compound (Ig) in which A 1 is Z, Z is a chlorine atom or bromine atom, and A 2 is formula (A) can also be obtained by the production method shown below. .
Figure JPOXMLDOC01-appb-C000026
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, and Y are as defined above. R a is an optionally substituted alkyl. , Hal a is a chlorine atom or a bromine atom.)
〔工程２０〕
　工程１１で得られる化合物（２－４）と、１～１０当量、好ましくは１～３当量の化合物（５－１）とを、溶媒中２～１０当量、好ましくは２～４当量の塩基の存在下反応させることにより、化合物（５－２）を得ることができる。化合物（５－１）は、市販品としてまたは公知の方法 ［例えば、Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)］ もしくはそれに準じた方法によって合成される。 [Step 20]
Compound (2-4) obtained in Step 11 and 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (5-1) are mixed with 2 to 10 equivalents, preferably 2 to 4 equivalents of a base in a solvent. Compound (5-2) can be obtained by reacting in the presence. Compound (5-1) is synthesized as a commercially available product or by a known method [eg, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ 、ＤＭＡ 、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノールが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でもナトリウムメトキシドまたはナトリウムエトキシドが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃で、通常１～６０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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. Among them, methanol or ethanol is preferable.
As 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.
〔工程２１〕
　工程２０で得られる化合物（５－２）を工程２と同様の方法で反応させることにより、化合物（Ｉｇ）を得ることができる。 [Step 21]
Compound (Ig) can be obtained by reacting compound (5-2) obtained in step 20 in the same manner as in step 2.
製造法６：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｗが－ＮＲ９－Ｗ１であ化合物（Ｉｈ）は、例えば化合物（２－４）より、以下に示す製造法によっても得ることができる。
Figure JPOXMLDOC01-appb-C000027
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ９、Ｑ１、Ｑ２、Ｗ１、Ｘ、Ｙは、前記と同義であり、ＨａｌａおよびＨａｌｄは、それぞれ独立して塩素原子または臭素原子であり、Ｒａは、置換されていてもよいアルキルである。） Production method 6:
Of the compounds (I), A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and W is —NR 9 —W 1 . For example, it can be obtained from the compound (2-4) by the production method shown below.
Figure JPOXMLDOC01-appb-C000027
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , R 9 , Q 1 , Q 2 , W 1 , X, Y are as defined above, and Hal a and Hal d are independent of each other. A chlorine atom or a bromine atom, and R a is an optionally substituted alkyl.)
〔工程２２〕
　工程１１で得られる化合物（２－４）と化合物（６－１）とを用いて工程２０と同様の方法で反応させることにより、化合物（６－２）を得ることができる。なお、化合物（６－１）は、市販品としてまたは公知の方法 ［例えば、Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)］ もしくはそれに準じた方法によって合成される。 [Step 22]
Compound (6-2) can be obtained by reacting compound (2-4) obtained in step 11 and compound (6-1) in the same manner as in step 20. Compound (6-1) is synthesized as a commercially available product or by a known method [eg, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
〔工程２３〕
　工程２２で得られる化合物（６－２）と化合物（３－３）とを用いて工程１７と同様の方法で反応させることにより、化合物（６－３）を得ることができる。 [Step 23]
Compound (6-3) can be obtained by reacting compound (6-2) obtained in step 22 and compound (3-3) in the same manner as in step 17.
〔工程２４〕
工程２３で得られる化合物（６－３）を工程２と同様の方法で反応させることにより、化合物（Ｉｈ）を得ることができる。 [Step 24]
Compound (Ih) can be obtained by reacting compound (6-3) obtained in step 23 in the same manner as in step 2.
製造法７：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｑ２が水素原子であり、Ｘが置換されていてもよいＣ２－８アルキレンである化合物（Ｉｊ）は、例えば化合物（１－４）より、以下に示す製造法によっても得ることができる。
Figure JPOXMLDOC01-appb-C000028
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｗ、ＸおよびＹは、前記と同義であり、Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｒｃは、置換されていてもよいアルキルであり、Ｘ’は、置換されていてもよいＣ１－７アルキレンであり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 7:
Among the compounds (I), A 1 is Z, Z is a chlorine atom or a bromine atom, A 2 is the formula (A), Q 2 is a hydrogen atom, and X may be substituted. Compound (Ij) which is C 2-8 alkylene can also be obtained, for example, from compound (1-4) by the production method shown below.
Figure JPOXMLDOC01-appb-C000028
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , W, X and Y are as defined above, and R b is a hydrogen atom or an optionally substituted alkyl. , R c is an optionally substituted alkyl, X ′ is an optionally substituted C 1-7 alkylene, and Hal a is a chlorine atom or a bromine atom.)
〔工程２５〕
　工程３で得られる化合物（１－４）と化合物（７－１）とを工程４と同様の方法で反応させることにより、化合物（７－２）を得ることができる。化合物（７－１）は、市販品としてまたは公知の方法 ［例えば、Journal of Heterocyclic Chemistry, 1981, 18, 941-946.］もしくはそれに準じた方法によって合成される。 [Step 25]
Compound (7-2) can be obtained by reacting compound (1-4) obtained in step 3 with compound (7-1) in the same manner as in step 4. Compound (7-1) is synthesized as a commercially available product or by a known method [eg, Journal of Heterocyclic Chemistry, 1981, 18, 941-946.] Or a method analogous thereto.
〔工程２６〕
　工程２５で得られる化合物（７－２）を、溶媒中で０．１～５当量、好ましくは０．１～１当量の酸と反応させることにより、化合物（７－３）を得ることができる。 [Step 26]
Compound (7-3) can be obtained by reacting compound (7-2) obtained in step 25 with 0.1 to 5 equivalents, preferably 0.1 to 1 equivalents of acid in a solvent. .
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばアセトン、メチルエチルケトン、ジエチルケトン、シクロヘキサノンまたは水等を単独でまたはそれらを混合して用いることができ、中でもアセトンと水の混合溶媒が好ましい。
　酸としては、例えばｐ－トルエンスルホン酸、ベンゼンスルホン酸、カンファースルホン酸等の有機スルホン酸類、酢酸、トリフルオロ酢酸等の有機カルボン酸類、塩酸、硫酸等の鉱酸類、スカンジウムトリフルオロメタンスルホネート、インジウムトリフルオロメタンスルホネート等のルイス酸類が上げられるが、中でもｐ－トルエンスルホン酸が好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～８０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, water or the like may be used alone or in combination. Among them, a mixed solvent of acetone and water is preferable.
Examples of the acid 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 preferred among them. 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.
〔工程２７〕
　工程２６で得られる化合物（７－３）を、溶媒中で１～１０当量、好ましくは２～３当量の酸の存在下、１～１０当量、好ましくは２～４当量の水素化ホウ素化合物、および１～１０当量、好ましくは１．１～２当量の化合物（７－４）と反応させることにより、化合物（７－５）を得ることができる。化合物（７－４）は、市販品として得られる。 [Step 27]
Compound (7-3) obtained in Step 26 is 1 to 10 equivalents, preferably 2 to 4 equivalents of a borohydride compound in the presence of 1 to 10 equivalents, preferably 2 to 3 equivalents of an acid in a solvent, Compound (7-5) can be obtained by reacting with 1 to 10 equivalents, preferably 1.1 to 2 equivalents of Compound (7-4). Compound (7-4) is obtained as a commercial product.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、メタノール、エタノール、ｎ－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でも１，２－ジクロロエタンまたはメタノールが好ましい。
　酸としては、例えばギ酸、プロピオン酸、酢酸、トリフルオロ酢酸等のカルボン酸類、塩酸等の鉱酸類を用いることができ、中でも酢酸が好ましい。
　水素化ホウ素化合物としては、例えばシアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等を用いることができ、中でもシアノ水素化ホウ素ナトリウムまたはトリアセトキシ水素化ホウ素ナトリウムが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～４０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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.
As 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.
As the borohydride compound, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like can be used, and among them, 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.
〔工程２８〕
　工程２７得られる化合物（７－５）と化合物（１－７）とを工程５と同様の方法で反応させることにより、化合物（Ｉｊ）を得ることができる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。また、化合物（Ｉｊ）を用い、工程６～９と同様の製造法により、Ｈａｌａを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 [Step 28]
Compound (Ij) can be obtained by reacting compound (7-5) obtained in Step 27 with compound (1-7) in the same manner as in Step 5. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method. In addition, using compound (Ij), Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl, by the same production method as in Steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
製造法８：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｗがメチレンまたはメチンである化合物（Ｉｋ）は、例えば化合物（２－７）より、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000029
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、ＸおよびＹは前記と同義である。Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｒｄは、水素原子またはＣ１－３アルキルであり、ＨａｌａおよびＨａｌｃは、それぞれ独立して塩素原子または臭素原子を表す。） Production method 8:
Among compounds (I), compound (Ik) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is formula (A), and W is methylene or methine is, for example, compound (I) From 2-7), it can be obtained by the following production method.
Figure JPOXMLDOC01-appb-C000029
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , X and Y are as defined above. R b is a hydrogen atom or an optionally substituted alkyl. R d is a hydrogen atom or C 1-3 alkyl, and Hal a and Hal c each independently represent a chlorine atom or a bromine atom.)
〔工程２９〕
　製造法２で得られる化合物（２－７）と化合物（８－１）とを工程５と同様の方法で反応させることにより、化合物（８－２）を得ることができる。化合物（８－１）は、市販品としてまたは公知の方法［例えば、Journal of Organic Chemistry, 1997, 62(19), 6458-6459.］もしくはそれに準じた方法によって合成される。 [Step 29]
Compound (8-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (8-1) in the same manner as in Step 5. Compound (8-1) is synthesized as a commercial product or by a known method [for example, Journal of Organic Chemistry, 1997, 62 (19), 6458-6459.] Or a method analogous thereto.
〔工程３０〕
　工程２９で得られる化合物（８－２）と化合物（８－３）とを工程２７と同様の方法で反応させることにより、化合物（Ｉｋ）を得ることができる。化合物（８－３）は、市販品として得られる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。また、化合物（Ｉｋ）を用い、工程６～９と同様の製造法により、Ｈａｌａを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 [Step 30]
Compound (Ik) can be obtained by reacting compound (8-2) obtained in step 29 with compound (8-3) in the same manner as in step 27. Compound (8-3) is obtained as a commercial product. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method. In addition, using compound (Ik), Hal a as a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl, by the same production method as in steps 6 to 9 , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
製造法９：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ａ２が式（Ａ）であり、Ｒ４が水素原子である化合物（Ｉｌ）または化合物（Ｉｇ）は、化合物（２－７）より、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000030
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｑ１、Ｑ２、Ｗ、ＸおよびＹは前記と同義である。Ｒ４’は、置換されていてもよいＣ２－１０アルキルであり、Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｐｒｏは、例えば文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)）に示されている一般的なアミンの保護基であり、ＨａｌａおよびＨａｌｃは、それぞれ独立して塩素原子または臭素原子である。）
〔工程３１〕
　製造法２で得られる化合物（２－７）と化合物（９－１）とを工程５と同様の方法で反応させることにより、化合物（９－２）を得ることができる。化合物（９－１）は、市販品としてまたは公知の方法［例えば、ＷＯ２００７／１２６９５７］もしくはそれに準じた方法によって合成される。 Production method 9:
Among the compounds (I), the compound (Il) or the compound (Ig) in which A 1 is Z, Z is a chlorine atom or bromine atom, A 2 is the formula (A), and R 4 is a hydrogen atom. Can be obtained from compound (2-7) by the following production method.
Figure JPOXMLDOC01-appb-C000030
 (Wherein, Alk, R 1 , R 2 , R 3 , Q 1 , Q 2 , W, X and Y are as defined above. R 4 ′ is an optionally substituted C 2-10 alkyl. R b is a hydrogen atom or an optionally substituted alkyl, and Pro is a general example shown in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)). (It is a protecting group for amine, and Hal a and Hal c are each independently a chlorine atom or a bromine atom.)
[Step 31]
Compound (9-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (9-1) in the same manner as in Step 5. Compound (9-1) is synthesized as a commercially available product or by a known method [eg, WO2007 / 126957] or a method analogous thereto.
〔工程３２〕
　工程３１で得られる化合物（９－２）の保護基を脱保護することで化合物（Ｉｌ）を得ることができる。例えば、保護基がＢｏｃ基である時、溶媒中で過剰量、好ましくは５～１０当量の酸と反応させることにより、化合物（Ｉｌ）を得ることができる。 [Step 32]
Compound (Il) can be obtained by deprotecting the protecting group of compound (9-2) obtained in step 31. For example, when the protecting group is a Boc group, compound (Il) can be obtained by reacting with an excess amount, preferably 5 to 10 equivalents of an acid in a solvent.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ジエチルエーテル、ジクロロメタン、ＤＣＥ、メタノール、エタノール等を単独でまたはそれらを混合して用いることができ、中でも１，４－ジオキサン、ジクロロメタンまたはメタノールが好ましい。
　酸としては、例えばギ酸、プロピオン酸、酢酸、トリフルオロ酢酸等のカルボン酸類、塩酸等の鉱酸類を用いることができ、中でも塩酸またはトリフルオロ酢酸が好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～４０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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.
As 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.
〔工程３３〕
　工程３２で得られる化合物（Ｉｌ）と対応するアルデヒドまたはケトン誘導体とを工程２７と同様の方法で反応させることにより、化合物（Ｉｇ）を得ることができる。なお、同様の製造法によりＡ１が式（Ａ）であり、Ａ２がＺであり、Ｚが塩素原子または臭素原子である化合物も得ることができる。 [Step 33]
Compound (Ig) can be obtained by reacting compound (Il) obtained in step 32 with the corresponding aldehyde or ketone derivative in the same manner as in step 27. A compound in which A 1 is the formula (A), A 2 is Z, and Z is a chlorine atom or a bromine atom can be obtained by the same production method.
製造法１０：
　化合物（Ｉ）のうち、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである化合物（Ｉｍ）は、化合物（１０－１）より、以下に示す製造法により得ることもできる。
Figure JPOXMLDOC01-appb-C000031
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、Ｘ、Ｙは前記と同義である。Ｈａｌａは、塩素原子または臭素原子であり、Ｚａは、置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。） Production method 10:
Among the compounds (I), A 2 is the formula (A), A 1 is Z, and Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl Compound (Im) which is an optionally substituted aryl or an optionally substituted heteroaryl can also be obtained from compound (10-1) by the production method shown below.
Figure JPOXMLDOC01-appb-C000031
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above. Hal a is a chlorine atom or a bromine atom, and Z a Is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
〔工程３４〕
　市販品または例えばJournal of American Chemical Society, 71, 2571-2575 (1949)に記載の方法に準じて合成した化合物（１０－１）を、溶媒中で１～５当量、好ましくは１．５～２当量の塩基の存在下、１～５当量、好ましくは１～３当量の化合物（１０－２）と反応させることにより、化合物（１０－３）を得ることができる。化合物（１０－２）は、市販品としてまたは公知の方法［例えば、Journal of Medicinal Chemistry, 24(5), 496-499 (1981)］もしくはそれに準じた方法によって合成される。 [Step 34]
A commercially available product or a compound (10-1) synthesized according to the method described in, for example, Journal of American Chemical Society, 71, 2571-2575 (1949), is 1 to 5 equivalents, preferably 1.5 to 2 in a solvent. Compound (10-3) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (10-2) in the presence of an equivalent amount of a base. Compound (10-2) is synthesized as a commercially available product or by a known method [eg, Journal of Medicinal Chemistry, 24 (5), 496-499 (1981)] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジエチルエーテル、ジクロロメタン、ベンゼン、トルエン、キシレン等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦ、ジエチルエーテルまたはトルエンが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド、ＬＤＡ、ＬＨＭＤＳ、ＮＨＭＤＳ等の強塩基、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物類等を用いることができ、中でもＬＤＡ、ＬＨＭＤＳ、水素化ナトリウムが好ましい。
　反応は－１００℃から室温の間の温度、好ましくは－７８℃～室温で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, diethyl ether, dichloromethane, benzene, toluene, xylene and the like are used alone. Or a mixture thereof, among which THF, diethyl ether or toluene is preferred.
Examples of the base include various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, strong bases such as LDA, LHMDS and NHMDS, and alkali metal hydrogens such as sodium hydride and potassium hydride. In particular, LDA, LHMDS, and sodium hydride are preferable.
The reaction is carried out at a temperature between −100 ° C. and room temperature, preferably at −78 ° C. to room temperature, usually for 0.5 to 24 hours.
〔工程３５〕
　工程３４で得られる化合物（１０－３）を、溶媒中で２～１０当量、好ましくは２～４当量の塩基の存在下、１～１０当量、好ましくは１～３当量の化合物（５－１）と反応させることにより、化合物（１０－４）を得ることができる。 [Step 35]
Compound (10-3) obtained in Step 34 is added in the presence of 2 to 10 equivalents, preferably 2 to 4 equivalents of a base in a solvent, and 1 to 10 equivalents, preferably 1 to 3 equivalents of compound (5-1 ) To give compound (10-4).
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノールが好ましい。
　塩基としては、例えばナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でもナトリウムメトキシドまたはナトリウムエトキシドが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の間の温度で加熱下もしくはマイクロ波照射下、通常０．５～６０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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. Among these, methanol or ethanol is preferable.
As 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 between 50 and 180 ° C., under heating or under microwave irradiation, usually for 0.5 to 60 hours.
〔工程３６〕
　工程３５で得られる化合物（１０－４）を工程２と同様の方法で反応させることにより、化合物（１０－５）を得ることができる。 [Step 36]
Compound (10-5) can be obtained by reacting compound (10-4) obtained in step 35 in the same manner as in step 2.
〔工程３７〕
　工程３６で得られる化合物（１０－５）を、溶媒中０．０１～１当量、好ましくは０．０５～０．２当量のホスフィン配位子、および０．０１～１当量、好ましくは０．０５～０．２当量のパラジウム触媒の存在下、１～５当量、好ましくは１～２当量の化合物（１－５）と反応させることにより、化合物（Ｉｍ）を得ることができる。 [Step 37]
Compound (10-5) obtained in Step 36 is added in an amount of 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of a phosphine ligand, and 0.01 to 1 equivalent, preferably 0. Compound (Im) can be obtained by reacting with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (1-5) in the presence of 05 to 0.2 equivalents of a palladium catalyst.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン等を単独でまたはそれらを混合して用いることができ、中でもトルエンまたは１，４－ジオキサンが好ましい。
　ホスフィン配位子としては、例えばトリフェニルホスフィン、トリトリルホスフィン、トリフラニルホスフィン、トリ ｔ－ブチルホスフィン等の単座配位型ホスフィン、またはＢＩＮＡＰ、２，２’－ビス（ジトリルホスフィノ）－１，１’－ビナフチル、ＤＰＥ－Ｐｈｏｓ、ＸＡＮＴ－Ｐｈｏｓ、Ｓ－Ｐｈｏｓ等の２座配位型ホスフィンを用いることができ、中でもＳ－Ｐｈｏｓが好ましい。
　パラジウム触媒としては、例えばテトラキストリフェニルホスフィンパラジウム、ビス（ｔ－ブチルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等の０価触媒、またはビス（トリフェニルホスフィン）パラジウム・ジクロリド、酢酸パラジウム、ビス（ジフェニルホスフィノフェロセン）パラジウム・ジクロリド等の２価触媒を用いることができ、中でも酢酸パラジウムが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の間の温度で、通常０．５～２４時間で行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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.
Examples of the phosphine ligand include monodentate phosphines such as triphenylphosphine, tritolylphosphine, trifuranylphosphine, tri-t-butylphosphine, or BINAP, 2,2′-bis (ditolylphosphino)- A bidentate phosphine such as 1,1′-binaphthyl, DPE-Phos, XANT-Phos, S-Phos and the like can be used, and S-Phos is particularly preferable.
Examples of 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, and palladium acetate is particularly 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., usually for 0.5 to 24 hours.
製造法１１：
　化合物（Ｉ）のうち、Ａ１が式（Ａ）であり、Ａ２がＺであり、Ｚが置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである化合物（Ｉｎ）は、以下に示す製造法によって得ることができる。
Figure JPOXMLDOC01-appb-C000032
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、Ｘ、Ｙは、前記と同義である。Ｒａは、置換されていてもよいアルキルであり、Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｚａは置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールであり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 11:
Among the compounds (I), A 1 is the formula (A), A 2 is Z, and Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl The compound (In) which is an optionally substituted aryl or an optionally substituted heteroaryl can be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000032
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , W, X, Y are as defined above. R a is an optionally substituted alkyl. , R b is a hydrogen atom or an optionally substituted alkyl, Z a is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted An aryl or an optionally substituted heteroaryl, and Hal a is a chlorine atom or a bromine atom.)
〔工程３８〕
　製造法２で得られる化合物（２－７）と化合物（１１－１）を、工程２０と同様の方法で反応させることにより、化合物（１１－２）を得ることができる。化合物（１１－１）は、市販品としてまたは公知の方法［例えば、Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)］もしくはそれに準じた方法によって合成される。 [Step 38]
Compound (11-2) can be obtained by reacting compound (2-7) obtained in Production Method 2 with compound (11-1) in the same manner as in Step 20. Compound (11-1) is synthesized as a commercially available product or by a known method [eg, Chemical and Pharmaceutical Bulletin, 55, 372-375 (2007)] or a method analogous thereto.
〔工程３９〕
　工程３８で得られる化合物（１１－２）を、工程２と同様の方法で反応させることにより、化合物（１１－３）を得ることができる。 [Step 39]
Compound (11-3) can be obtained by reacting compound (11-2) obtained in Step 38 in the same manner as in Step 2.
〔工程４０〕
工程３９で得られる化合物（１１－３）と化合物（１－７）とを、工程５と同様の方法で反応させることにより、化合物（Ｉｎ）を得ることができる。 [Step 40]
Compound (In) can be obtained by reacting compound (11-3) obtained in step 39 with compound (1-7) in the same manner as in step 5.
製造法１２：
　化合物（Ｉ）のうち、Ａ１が式（Ａ）であり、Ａ２がＺであり、Ｚが置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである化合物（Ｉｎ）は、化合物（１０－１）より、以下に示す製造法によっても得ることもできる。
Figure JPOXMLDOC01-appb-C000033
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、Ｘ、Ｙは前記と同義である。Ｚａは置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールであり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 12:
Among the compounds (I), A 1 is the formula (A), A 2 is Z, and Z is an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl The compound (In) which is an optionally substituted aryl or an optionally substituted heteroaryl can also be obtained from the compound (10-1) by the production method shown below.
Figure JPOXMLDOC01-appb-C000033
 (Wherein, Alk, R 1, R 2 , R 3, R 4, Q 1, Q 2, W, X, Y are as defined above .Z a good C 1-10 alkyl optionally substituted An optionally substituted C 3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl, Hal a is a chlorine atom or a bromine atom.)
〔工程４０〕
　化合物（１０－１）と化合物（１２－１）を、工程３４と同様の方法で反応させることにより、化合物（１２－２）を得ることができる。化合物（１２－１）は、市販品としてまたは公知の方法 ［例えば、ＷＯ２００７／０９９１１６，ＷＯ２００５／１１３４９４］ もしくはそれに準じた方法によって合成される。 [Step 40]
Compound (12-2) can be obtained by reacting compound (10-1) and compound (12-1) in the same manner as in Step 34. Compound (12-1) is synthesized as a commercially available product or by a known method [eg, WO2007 / 099116, WO2005 / 113494] or a method analogous thereto.
〔工程４１〕
　工程４０で得られる化合物（１２－２）と化合物（１１－１）とを、工程３５と同様の方法で反応させることにより、化合物（１２－３）を得ることができる。 [Step 41]
Compound (12-3) can be obtained by reacting compound (12-2) obtained in step 40 with compound (11-1) in the same manner as in step 35.
〔工程４２〕
　工程４１で得られる化合物（１２－３）を工程３６と同様の方法で反応させることにより、化合物（１２－４）を得ることができる。 [Step 42]
Compound (12-4) can be obtained by reacting compound (12-3) obtained in Step 41 in the same manner as in Step 36.
〔工程４３〕
　工程４２で得られる化合物（１２－４）と化合物（１－５）を、工程３７と同様の方法で反応させることにより、化合物（Ｉｎ）を得ることができる。 [Step 43]
Compound (In) can be obtained by reacting compound (12-4) obtained in step 42 with compound (1-5) in the same manner as in step 37.
製造法１３：
　化合物（Ｉ）のうち、Ａ２が式（Ａ）であり、Ａ１がＺであり、ＺおよびＱ２が水素原子であり、Ａｌｋがメチレンである化合物（Ｉｏ）は、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000034
 （式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｗ、Ｘ、Ｙは前記と同義である。Ｒｂは、水素原子または置換されていてもよいアルキルであり、Ｈａｌａは、塩素原子または臭素原子であり、Ｈａｌｅは、塩素原子、臭素原子またはヨウ素原子である。） Production method 13:
Among the compounds (I), A 2 is the formula (A), A 1 is Z, Z and Q 2 are hydrogen atoms, and Alk is methylene. Can be obtained.
Figure JPOXMLDOC01-appb-C000034
 (Wherein R 1 , R 2 , R 3 , R 4 , Q 1 , W, X, and Y are as defined above. R b is a hydrogen atom or an optionally substituted alkyl, and Hal a Is a chlorine atom or a bromine atom, and Hal e is a chlorine atom, a bromine atom or an iodine atom.)
〔工程４４〕
　化合物（１３－１）を、溶媒中、１～１０当量、好ましくは１～３当量のホスフィン、および１～１０当量、好ましくは１～３当量のアゾ化合物または角田試薬存在下、１～５当量、好ましくは１～３当量の化合物（１３－２）と反応させることにより、化合物（１３－４）を得ることができる。化合物（１３－１）は、市販品としてまたは公知の方法［例えば、ＷＯ２００９／０２６１０７］もしくはそれに準じた方法によって合成される。化合物（１３－２）は、市販品としてまたは公知の方法［例えば、Journal of the American Chemical Society, 1936, 58, 1079］もしくはそれに準じた方法によって合成される。
　または、化合物（１３－１）を、溶媒中、１～１０当量、好ましくは１～３当量の塩基存在下、１～５当量、好ましくは１～３当量の化合物（１３－３）と反応させることにより、化合物（１３－４）を得ることができる。化合物（１３－３）は、市販品としてまたは公知の方法［例えば、Journal of Medicinal Chemistry, 1966, 9, 191-195］もしくはそれに準じた方法によって合成される。 [Step 44]
1 to 5 equivalents of compound (13-1) in the presence of 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 or Kakuda reagent in a solvent Preferably, compound (13-4) can be obtained by reacting with 1 to 3 equivalents of compound (13-2). Compound (13-1) is synthesized as a commercially available product or by a known method [eg, WO2009 / 026107] or a method analogous thereto. Compound (13-2) is synthesized commercially or by a known method [eg, Journal of the American Chemical Society, 1936, 58, 1079] or a method analogous thereto.
Alternatively, the compound (13-1) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents of the compound (13-3) in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base in a solvent. Thus, compound (13-4) can be obtained. Compound (13-3) is synthesized as a commercially available product or by a known method [eg, Journal of Medicinal Chemistry, 1966, 9, 191-195] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ジクロロメタン、ＤＣＥ、クロロホルム、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦ、ジクロロメタン、トルエン、ＤＭＦが好ましい。
　使用するホスフィンとしては、例えばトリフェニルホスフィン、トリメチルホスフィン、トリブチルホスフィン等が挙げられるが、中でもトリフェニルホスフィンが好ましい。
　アゾ化合物としては、ジエチルアゾジカルボキシレート、ジイソプロピルアゾジカルボキシレート、ジシクロヘキシルアゾジカルボキシレート、ジベンジルアゾジカルボキシレート等が上げられるが、中でもジエチルアゾジカルボキシレートまたはジイソプロピルアゾジカルボキシレートが好ましい。
　塩基としては、例えば水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物類が上げられるが、中でも水素化ナトリウムが好ましい。反応は０℃から用いる溶媒の沸点の間の温度、好ましくは０℃～５０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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 as a mixture thereof. Among them, THF, dichloromethane, toluene and DMF are preferable.
Examples of 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 alkali metal hydrides such as sodium hydride and potassium hydride, among which sodium hydride 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 50 ° C., usually for 0.5 to 24 hours.
〔工程４５〕
　工程４４で得られる化合物（１３－４）と化合物（１－７）とを、工程５と同様の方法で反応させることにより、化合物（１３－５）を得ることができる。 [Step 45]
Compound (13-5) can be obtained by reacting compound (13-4) obtained in Step 44 with compound (1-7) in the same manner as in Step 5.
〔工程４６〕
　工程４５で得られる化合物（１３－５）を工程６と同様の方法で反応させることにより、化合物（Iｏ）を得ることができる。 [Step 46]
Compound (Io) can be obtained by reacting compound (13-5) obtained in step 45 in the same manner as in step 6.
製造法１４：
　化合物（Ｉ）のうち、Ａ２が式（Ａ）であり、Ａ１がＺであり、Ｚが塩素原子または臭素原子であり、Ｑ１およびＱ２が水素原子であり、Ａｌｋがメチレンである化合物（Ｉｐ）は、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000035
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｗ、Ｘ、Ｙは前記と同義である。Ｒａは置換されていてもよいアルキルであり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 14:
Among the compounds (I), A 2 is the formula (A), A 1 is Z, Z is a chlorine atom or a bromine atom, Q 1 and Q 2 are hydrogen atoms, and Alk is methylene. Compound (Ip) can be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000035
 (In the formula, Alk, R 1 , R 2 , R 3 , R 4 , W, X, Y are as defined above. Ra is an alkyl which may be substituted, and Hal a is a chlorine atom or Bromine atom.)
〔工程４７〕
　化合物（１４－１）を、溶媒中で必要に応じて１～１０当量、好ましくは２～５当量の塩基の存在下、１～２０当量、好ましくは３～１０当量の化合物（１－５）と反応させることにより、化合物（１４－２）を得ることができる。化合物（１４－１）は、市販品としてまたは公知の方法［例えば、Synthetic Communications, 28(17), 3159-3162 (1998)］もしくはそれに準じた方法によって合成される。 [Step 47]
Compound (14-1) is optionally added in the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base in a solvent in the presence of 1 to 20 equivalents, preferably 3 to 10 equivalents of Compound (1-5). Compound (14-2) can be obtained by reacting with. Compound (14-1) is synthesized as a commercially available product or by a known method [eg, Synthetic Communications, 28 (17), 3159-3162 (1998)] or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもＤＭＦまたはＮＭＰが好ましい。
　塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウム等の塩基性塩類、水酸化ナトリウム、水酸化カリウム等の無機塩基類、ピリジン、ルチジン等の芳香族アミン類、トリエチルアミン、トリプロピルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン等の第３級アミン類等を用いることができ、中でもトリエチルアミンまたはＮ，Ｎ－ジイソプロピルエチルアミンが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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 DMF or NMP is preferred.
Examples of the base 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, etc. Among them, triethylamine or N, N-diisopropylethylamine 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., usually for 0.5 to 24 hours.
〔工程４８〕
　工程４７で得られる化合物（１４－２）を、溶媒中で必要に応じて０．１～３当量、好ましくは０．１～１当量の酸と反応させることにより、化合物（１４－３）を得ることができる。 [Step 48]
The compound (14-2) obtained in the step 47 is reacted with an acid in an amount of 0.1 to 3 equivalents, preferably 0.1 to 1 equivalents, as necessary in a solvent, to thereby give the compound (14-3). Obtainable.
　本反応で用いられる溶媒は、合成するエステルに応じて、メタノール、エタノール等のアルコール溶媒が選択される。
　酸としては、例えばｐ－トルエンスルホン酸、ベンゼンスルホン酸、カンファースルホン酸等の有機スルホン酸類、酢酸、トリフルオロ酢酸等の有機カルボン酸類、塩酸、硫酸等の鉱酸類が上げられるが、中でも硫酸が好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは室温～８０℃で、通常０．５～２４時間行われる。 As a solvent used in this reaction, an alcohol solvent such as methanol or ethanol is selected according to the ester to be synthesized.
Examples of the acid include organic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid, organic carboxylic acids such as acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid and sulfuric acid. 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.
〔工程４９〕
　工程４８で得られる化合物（１４－３）を工程１１と同様の方法で反応させることにより、化合物（１４－４）を得ることができる。 [Step 49]
Compound (14-4) can be obtained by reacting compound (14-3) obtained in step 48 in the same manner as in step 11.
〔工程５０〕
　工程４９で得られる化合物（１４－４）と化合物（５－１）とを工程２０と同様の方法で反応させることにより、化合物（１４－５）を得ることができる。 [Step 50]
Compound (14-5) can be obtained by reacting compound (14-4) obtained in step 49 with compound (5-1) in the same manner as in step 20.
〔工程５１〕
　工程５０で得られる化合物（１４－５）を工程２と同様の方法で反応させることにより、化合物（Ｉｐ）を得ることができる。なお、化合物（Ｉｐ）を用い、工程６～９と同様の製造法により、Ｈａｌａを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 [Step 51]
Compound (Ip) can be obtained by reacting compound (14-5) obtained in step 50 in the same manner as in step 2. In addition, using compound (Ip), Hal a is a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9. , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, etc., can also be obtained.
製造法１５：
　化合物（Ｉ）のうち、Ｙがチアゾール、イミダゾールまたはオキサゾールの２価へテロアリールである化合物（Ｉｑ）は、化合物（２－７）より、以下に示す製造法により得ることができる。
Figure JPOXMLDOC01-appb-C000036
 （式中、Ａｌｋ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｑ１、Ｑ２、Ｗ、Ｘ、Ｙは前記と同義である。ＲｅおよびＲｆは、それぞれ独立して置換されていてもよいアルキルであり、Ｒｇは水素原子またはアルキル等の置換基であり、ＨａｌａおよびＨａｌｃは、それぞれ独立して塩素原子または臭素原子であり、Ｈａｌｅは、塩素原子、臭素原子またはヨウ素原子であり、Ｔは硫黄原子、窒素原子または酸素原子である。） Production method 15:
Among compounds (I), compound (Iq) in which Y is divalent heteroaryl of thiazole, imidazole or oxazole can be obtained from compound (2-7) by the production method shown below.
Figure JPOXMLDOC01-appb-C000036
 (Wherein, Alk, R 1, R 2 , R 3, R 4, Q 1, Q 2, W, X, Y are as defined above .R e and R f are each independently substituted R g is a hydrogen atom or a substituent such as alkyl, Hal a and Hal c are each independently a chlorine atom or a bromine atom, and Hal e is a chlorine atom, a bromine atom or (It is an iodine atom, and T is a sulfur atom, a nitrogen atom or an oxygen atom.)
〔工程５２〕
　製造法２で得られる化合物（２－７）を、溶媒中で０．０１～１当量、好ましくは０．０５～０．２当量のパラジウム触媒、必要に応じて０．０１～１当量、好ましくは０．０５～０．２当量のホスフィン配位子の存在下、１～５当量、好ましくは１．１～２当量の化合物（１５－１）と反応させることにより、化合物（１５－２）を得ることができる。化合物（１５－１）は、市販品としてまたは公知の方法［例えば、Journal of the American Chemical Society, 2004, 126, 13614-13615.］もしくはそれに準じた方法によって合成される。 [Step 52]
Compound (2-7) obtained by Production Method 2 is 0.01 to 1 equivalent, preferably 0.05 to 0.2 equivalent of palladium catalyst in a solvent, optionally 0.01 to 1 equivalent, preferably Is reacted with 1 to 5 equivalents, preferably 1.1 to 2 equivalents of compound (15-1) in the presence of 0.05 to 0.2 equivalents of a phosphine ligand. Can be obtained. Compound (15-1) is synthesized as a commercially available product or by a known method [eg, Journal of the American Chemical Society, 2004, 126, 13614-13615.] Or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、を用いることができ、中でもトルエンが好ましい。
　パラジウム触媒としては、例えばテトラキストリフェニルホスフィンパラジウム、ビス（ｔ－ブチルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等の０価触媒、またはビス（トリフェニルホスフィン）パラジウム・ジクロリド、酢酸パラジウム、ビス（ジフェニルホスフィノフェロセン）パラジウム・ジクロリド等の２価触媒を用いることができ、中でもテトラキストリフェニルホスフィンパラジウムまたは酢酸パラジウムが好ましい。
　ホスフィン配位子としては、例えばｏ－トリトリルホスフィン、Ｓ－ＰｈｏｓまたはＸ－Ｐｈｏｓ等の単座配位型の配位子、ＤＰＰＦ、ＤＰＰＥ、ＤＰＰＰ、ＤＰＰＢ、ＢＩＮＡＰ、ＸＡＮＴ－ＰｈｏｓまたはＤＰＥ－Ｐｈｏｓ等の二座配位型の配位子を用いることができ、中でもＳ－ＰｈｏｓまたはＸ－Ｐｈｏｓが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１８０℃の加熱下もしくはマイクロ波照射下で、通常０．５～２４時間で行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF can be used. Of these, toluene is preferred.
Examples of 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 tetrakistriphenylphosphine palladium or palladium acetate is preferred.
Examples of phosphine ligands include monodentate ligands such as o-tolylphosphine, S-Phos or X-Phos, DPPF, DPPE, DPPP, DPPB, BINAP, XANT-Phos or DPE-Phos. The following bidentate ligands can be used, and S-Phos or X-Phos is particularly 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.
〔工程５３〕
　工程５２で得られる化合物（１５－２）を、溶媒中で１～５当量、好ましくは１．２～３当量のハロゲン化剤と反応させることにより、化合物（１５－３）を得ることができる。 [Step 53]
Compound (15-3) can be obtained by reacting compound (15-2) obtained in step 52 with a halogenating agent in an amount of 1 to 5 equivalents, preferably 1.2 to 3 equivalents in a solvent. .
本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、水等を単独でまたはそれらを混合して用いることができ、中でもＴＨＦと水の混合溶媒が好ましい。
　ハロゲン化剤としては、例えばＮ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、Ｎ－ヨードスクシンイミド、Ｎ－ヨードフタルイミド等のハロゲン化イミド類、臭素またはヨウ素が挙げられるが、中でもＮ－ブロモスクシンイミドが好ましい。
　反応は０℃から用いる溶媒の沸点の間の温度、好ましくは０～４０℃で、通常０．５～２４時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, THF, 1,4-dioxane, DME, benzene, toluene, xylene, DMF, water and the like are used alone. Or they can be mixed and used, and a mixed solvent of THF and water is particularly preferable.
Examples of the halogenating agent include halogenated imides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and N-iodophthalimide, bromine or iodine, among which N-bromosuccinimide is preferable.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 0-40 ° C., usually for 0.5-24 hours.
〔工程５４〕
　工程５３で得られる化合物（１５－３）を、溶媒中で１～５当量、好ましくは１．２～３当量の化合物（１５－４）と反応させることにより、化合物（Ｉｑ）を得ることができる。化合物（１５－４）は、市販品としてまたは公知の方法［例えば、ＷＯ２００４／５８７５０， Journal of Medicinal Chemistry, 2005, 48(24), 7520-7534.］もしくはそれに準じた方法によって合成される。 [Step 54]
Compound (Iq) can be obtained by reacting compound (15-3) obtained in step 53 with 1 to 5 equivalents, preferably 1.2 to 3 equivalents, of compound (15-4) in a solvent. it can. Compound (15-4) is synthesized as a commercially available product or by a known method [eg, WO2004 / 58750, Journal of Medicinal Chemistry, 2005, 48 (24), 7520-7534.] Or a method analogous thereto.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばメタノール、エタノール、１－プロパノール、２－プロパノール、ＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、水等を単独でまたはそれらを混合して用いることができ、中でもエタノールが好ましい。
　反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃で、通常０．５～２４時間行われる。なお、化合物（Ｉｑ）を用い、工程６～９と同様の製造法により、Ｈａｌａを水素原子、置換されていてもよいＣ１－１０アルキルまたは置換されていてもよいＣ３－８シクロアルキル、－ＮＲ５Ｒ６または置換されていてもよいＣ１－５アルコキシ等、種々の置換基へ変換した化合物を得ることもできる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, methanol, ethanol, 1-propanol, 2-propanol, THF, 1,4-dioxane, DME, benzene , Toluene, xylene, DMF, water and the like can be used alone or in admixture thereof, with ethanol being 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. In addition, using compound (Iq), Hal a is a hydrogen atom, optionally substituted C 1-10 alkyl or optionally substituted C 3-8 cycloalkyl by the same production method as in Steps 6 to 9. , —NR 5 R 6, or optionally substituted C 1-5 alkoxy, and the like can also be obtained.
製造法１６：
　化合物（Ｉ）のうち、Ａ１がＺであり、Ｚが塩素原子又は臭素原子であり、Ａ２が式（Ａ）である化合物（Ｉａ）は、以下に示す製造法によっても得ることもできる。
Figure JPOXMLDOC01-appb-C000037
 （式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｗ、Ｘ、Ｙ、Ｑ１およびＡｌｋは、前記と同義である。Ｒａは、置換されていてもよいアルキル基であり、Ｈａｌａは、塩素原子または臭素原子である。） Production method 16:
Among compounds (I), compound (Ia) in which A 1 is Z, Z is a chlorine atom or bromine atom, and A 2 is formula (A) can also be obtained by the production method shown below. .
Figure JPOXMLDOC01-appb-C000037
 (Wherein R 1 , R 2 , R 3 , R 4 , W, X, Y, Q 1 and Alk are as defined above. R a is an optionally substituted alkyl group, Hal a is a chlorine atom or a bromine atom.)
〔工程５５〕
　１～１０当量、好ましくは１～３当量の化合物（５－１）と、化合物（１－１）とを、溶媒中２～１０当量、好ましくは２～４当量の塩基の存在下反応させることにより、化合物（１６－１）を得ることができる。 [Step 55]
1-10 equivalents, preferably 1-3 equivalents of compound (5-1) and compound (1-1) are reacted in a solvent in the presence of 2-10 equivalents, preferably 2-4 equivalents of a base. Can give compound (16-1).
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばジエチルエーテル、ＴＨＦ、１，４－ジオキサン、ＤＭＥ、ベンゼン、トルエン、キシレン、ＤＭＦ、ＤＭＡ、ＮＭＰ、メタノール、エタノール、１－プロパノール、２－プロパノール等を単独でまたはそれらを混合して用いることができ、中でもジエチルエーテル、メタノールまたはエタノールが好ましい。
　塩基としては、例えばリチウム ビス（トリメチルシリル）アミド、ナトリウム ビス（トリメチルシリル）アミドまたはカリウム ビス（トリメチルシリル）アミド等の金属アミド類、ナトリウムメトキシド、ナトリウムエトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド等を用いることができ、中でもリチウム ビス（トリメチルシリル）アミド、ナトリウムメトキシドまたはナトリウムエトキシドが好ましい。反応は室温から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃ で、通常１～６０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, diethyl ether, 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 combination, and among them, diethyl ether, methanol or ethanol is preferable.
Examples of the base include metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide, various alkalis or alkaline earths such as sodium methoxide, sodium ethoxide and potassium t-butoxide. A metal alkoxide or the like can be used, and among them, lithium bis (trimethylsilyl) amide, 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 50-100 ° C., usually for 1-60 hours.
〔工程５６〕
　工程５５で得られる化合物（１６－１）を工程２と同様の方法で反応させることにより、化合物（１６－２）を得ることができる。 [Step 56]
Compound (16-2) can be obtained by reacting compound (16-1) obtained in step 55 in the same manner as in step 2.
〔工程５７〕
　工程５６で得られる化合物（１６－２）を工程３と同様の方法で反応させることにより、化合物（１６－３）を得ることができる。 [Step 57]
Compound (16-3) can be obtained by reacting compound (16-2) obtained in Step 56 in the same manner as in Step 3.
〔工程５８〕
　工程５７で得られる化合物（１６－３）を工程４と同様の方法で反応させることにより、化合物（Ｉａ）を得ることができる。 [Step 58]
Compound (Ia) can be obtained by reacting compound (16-3) obtained in step 57 in the same manner as in step 4.
製造法１７：
　化合物（Ｉ）を合成する中間体である化合物（１－３）は、以下に示す製造法によっても得ることができる。
Figure JPOXMLDOC01-appb-C000038
 （式中、Ｑ１、Ａｌｋは前記と同義である。Ｒａは、置換されていてもよいアルキル基であり、Ｈａｌａは、塩素原子または臭素原子であり、Ｈａｌｂは、それぞれ独立して、塩素原子、臭素原子またはヨウ素原子である。） Production method 17:
Compound (1-3), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000038
 (Wherein Q 1 and Alk have the same meanings as described above. R a is an optionally substituted alkyl group, Hal a is a chlorine atom or a bromine atom, and Hal b is independently , Chlorine atom, bromine atom or iodine atom.)
〔工程５９〕
　化合物（１－１）を、溶媒中０～５当量、好ましくは１～２当量の塩基の存在下、１～５当量、好ましくは１～２当量のグアニジンまたはその酸性塩と反応させることにより、化合物（１－１－１）を得ることができる。 [Step 59]
By reacting compound (1-1) with 1 to 5 equivalents, preferably 1 to 2 equivalents of guanidine or an acid salt thereof in the presence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent, Compound (1-1-1) can be obtained.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばジエチルエーテル、ＴＨＦ、１，４－ジオキサン、ＤＭＥ等のエーテル系溶媒、メタノール、エタノール、２－プロパノール、ブタノール等のアルコール系溶媒、クロロホルム、クロロベンゼンなどのハロゲン系溶媒、トルエン、ＤＭＦ、ＤＭＳＯ等の非プロトン性溶媒を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノールが好ましい。
　塩基は、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸カルシウム等の金属炭酸塩、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の金属水酸化物、リチウム ヘキサメチルジシラジド、ナトリウム ヘキサメチルジシラジド、カリウム ヘキサメチルジシラジド等の金属アミド類、ナトリウム メトキシド、ナトリウム エトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド類、水素化リチウム、水素化ナトリウムまたは水素化カリウム等の金属水素化物、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジンなどの有機塩基等を用いることができ、中でもナトリウムメトキシド、リチウム ヘキサメチルジシラジドでの反応が好ましい。
　本反応で用いられるグアニジン・酸性塩は、グアニジン・炭酸塩、グアニジン・塩酸塩、グアニジン・硫酸塩などを用いることができ、中でもグアニジン・炭酸塩が好ましい。
　反応は０℃から用いる溶媒の沸点の間の温度、好ましくは５０～１００℃で、通常１～２０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, 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. Of these, methanol or ethanol is preferred. .
Examples of the base 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 hexamethyldioxide. Metal amides such as silazide, potassium hexamethyldisilazide, various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium hydride, sodium hydride, potassium hydride, etc. An organic base such as metal hydride, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like can be used. Among them, the reaction with sodium methoxide and lithium hexamethyldisilazide is preferable.
As the guanidine / acid salt used in this reaction, guanidine / carbonate, guanidine / hydrochloride, guanidine / sulfate and the like can be used, and among them, 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.
〔工程６０〕
　工程５９で得られる化合物（１－１－１）を、工程２と同様の方法で反応させることにより、化合物（１－１－２）を得ることができる。 [Step 60]
Compound (1-1-2) can be obtained by reacting compound (1-1-1) obtained in Step 59 in the same manner as in Step 2.
〔工程６１〕
　工程６０で得られる化合物（１－１－２）を、溶媒中１～３０当量、好ましくは５～１５当量のトリアルキルシリルクロリド存在下、１～２０当量、好ましくは３～１０当量の亜硝酸アルキル、および１～１０等量、好ましくは１～３当量のハロゲン化アルキルアンモニウムと反応させることにより、化合物（１－３）を得ることができる。 [Step 61]
The compound (1-1-2) obtained in Step 60 is added in the presence of 1 to 30 equivalents, preferably 5 to 15 equivalents of trialkylsilyl chloride in a solvent, and 1 to 20 equivalents, preferably 3 to 10 equivalents of nitrous acid. The compound (1-3) can be obtained by reacting with alkyl and 1 to 10 equivalents, preferably 1 to 3 equivalents of an alkylammonium halide.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素等を単独でまたはそれらを混合して用いることができ、中でもジクロロメタンが好ましい。
　トリアルキルシリルクロリドとしては、例えばトリメチルシリルクロリド、トリエチルシリルクロリドまたはトリプロピルシリルクロリド等を用いることができ、中でもトリメチルシリルクロリドが好ましい。
　亜硝酸アルキルとしては、例えば亜硝酸イソブチル、亜硝酸ブチル、亜硝酸ｔ－ブチル、亜硝酸イソペンチル、亜硝酸ネオペンチル、亜硝酸ペンチルなどを用いることができ、中でも亜硝酸ｔ－ブチルまたは亜硝酸イソブチルが好ましい。
　ハロゲン化アルキルアンモニウムとしては、例えば塩化テトラブチルアンモニウム、塩化トリエチルベンジルアンモニウム、塩化テトラプロピルアンモニウム、臭化テトラブチルアンモニウムなどを用いることができ、中でも塩化トリエチルベンジルアンモニウムが好ましい。
　反応は０℃から用いる溶媒の沸点の間の温度、好ましくは０℃～３０℃で、通常０．５～２０時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like can be used alone or in combination. Among them, dichloromethane is preferable.
As the trialkylsilyl chloride, for example, trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride or the like can be used, among which trimethylsilyl chloride is preferable.
As the alkyl nitrite, for example, isobutyl nitrite, butyl nitrite, t-butyl nitrite, isopentyl nitrite, neopentyl nitrite, pentyl nitrite and the like can be used. preferable.
As the 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.
製造法１８：
　化合物（Ｉ）を合成する中間体である化合物（１－２）は、以下に示す製造法によっても得ることができる。
Figure JPOXMLDOC01-appb-C000039
 （式中、Ｑ１、Ａｌｋは前記と同義である。Ｒａは、置換されていてもよいアルキル基であり、Ｒｂは、Ｃ１～Ｃ３の低級アルキル基である。） Production method 18:
Compound (1-2), which is an intermediate for synthesizing compound (I), can also be obtained by the production method shown below.
Figure JPOXMLDOC01-appb-C000039
 (In the formula, Q 1 and Alk are as defined above. R a is an optionally substituted alkyl group, and R b is a C1-C3 lower alkyl group.)
〔工程６２〕
　化合物（１－１）を、溶媒中０～５当量、好ましくは１～２当量の塩基の存在下、１～５当量、好ましくは１～２当量の化合物（１－１－４）と反応させることにより、化合物（１－１－５）を得ることができる。 [Step 62]
Compound (1-1) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (1-1-4) in the presence of 0 to 5 equivalents, preferably 1 to 2 equivalents of a base in a solvent. Thus, compound (1-1-5) can be obtained.
　本反応で用いられる溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばメタノール、エタノール、２－プロパノール、ブタノール等のアルコール系溶媒、および水を単独でまたはそれらを混合して用いることができ、中でもメタノールまたはエタノール単独、もしくは水との混合溶媒が好ましい。
　塩基は、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸カルシウム等の金属炭酸塩、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム等の金属水酸化物、リチウム ヘキサメチルジシラジド、ナトリウム ヘキサメチルジシラジド、カリウム ヘキサメチルジシラジド等の金属アミド類、ナトリウム メトキシド、ナトリウム エトキシド、カリウム ｔ－ブトキシド等の各種アルカリまたはアルカリ土類金属アルコキシド類等を用いることができ、中でもナトリウム メトキシド、ナトリウム エトキシド、水酸化カルシウムが好ましい。
　本反応で用いられるＯ－アルキルイソウレアの酸性塩は、Ｏ－メチルイソウレア・硫酸塩、Ｏ－メチルイソウレア・１／２硫酸塩、Ｏ－メチルイソウレア・塩酸塩、Ｏ－エチルイソウレア・硫酸塩、Ｏ－エチルイソウレア・１／２硫酸塩、Ｏ－エチルイソウレア・塩酸塩、などを用いることができ、中でもＯ－メチルイソウレア・１／２硫酸塩が好ましい。
　反応は０℃から用いる溶媒の沸点の間の温度、好ましくは室温～１００℃で、通常１～４８時間行われる。 The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, alcohol solvents such as methanol, ethanol, 2-propanol, butanol, and water alone or water are used. It can be used by mixing, and methanol or ethanol alone or a mixed solvent with water is preferable.
Examples of the base include metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate and calcium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide, lithium hexamethyl Metal amides such as disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and various alkali or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be used. Of these, sodium methoxide, sodium ethoxide and calcium hydroxide are preferred.
The acidic salt of O-alkylisourea used in this reaction is O-methylisourea / sulfate, O-methylisourea / 1/2 sulfate, O-methylisourea / hydrochloride, O-ethylisourea Sulfate, O-ethylisourea / 1/2 sulfate, O-ethylisourea / hydrochloride, etc. can be used, and O-methylisourea / 1/2 sulfate is preferred.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably from room temperature to 100 ° C., usually for 1 to 48 hours.
〔工程６３〕
　化合物（１－１－５）を、溶媒量の酸性水と反応させることにより、化合物（１－２）を得ることができる。 [Step 63]
Compound (1-2) can be obtained by reacting compound (1-1-5) with a solvent amount of acidic water.
　本反応で用いられる酸性水は、例えば硫酸水溶液、塩酸水溶液、臭化水素酸水溶液等を用いることができ、中でも硫酸水溶が好ましい。
　反応は、０℃から用いる溶媒の沸点の間の温度、好ましくは室温～１００℃で、通常１～４８時間行われる。 As the acidic water used in this reaction, for example, a sulfuric acid aqueous solution, a hydrochloric acid aqueous solution, a hydrobromic acid aqueous solution and the like can be used.
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 1 to 48 hours.
　上記の製造法を適宜組み合わせて実施することにより、所望の位置に所望の官能基を有する本発明の化合物を得ることができる。上記製造法における中間体および生成物の単離、精製は、通常の有機合成で用いられる方法、例えばろ過、抽出、洗浄、乾燥、濃縮、結晶化、各種クロマトグラフィー等を適宜組み合わせて行うことができる。また、中間体においては、特に精製することなく次の反応に供することもできる。
　上記の製造法における原料化合物または中間体は、反応条件等により、例えば塩酸塩等の塩の形態で存在し得るものもあるが、そのまま、または遊離の形で使用することができる。原料化合物または中間体が塩の形態で得られ、原料化合物または中間体を遊離の形で使用または取得したい場合には、これらを適当な溶媒に溶解または懸濁し、例えば炭酸水素ナトリウム水溶液等の塩基等で中和することにより遊離の形へ変換できる。 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. In addition, 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. 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.
　化合物（Ｉ）またはその薬理学的に許容される塩の中には、ケトエノール体のような互変異性体、位置異性体、幾何異性体または光学異性体のような異性体が存在し得るものもあるが、これらを含め可能な全ての異性体および該異性体のいかなる比率における混合物も本発明に包含される。
　また、光学異性体は前記製造法の適切な工程で、光学活性カラムを用いた方法、分別結晶化法などの公知の分離工程を実施することで分離することができる。また、出発原料として光学活性体を使用することもできる。 Among compounds (I) or pharmacologically acceptable salts thereof, there may exist isomers such as tautomers such as ketoenol, positional isomers, geometric isomers or optical isomers However, all possible isomers including these and mixtures in any ratio of the isomers are also encompassed by the present invention.
In addition, 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.
　化合物（Ｉ）の塩を取得したい場合は、化合物（Ｉ）の塩が得られる場合はそのまま精製すればよく、また化合物（Ｉ）が遊離の形で得られる場合は化合物（Ｉ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて塩を形成させればよい。また、化合物（Ｉ）またはその製薬学的に許容される塩は、水または各種溶媒との溶媒和物の形で存在することもあるが、それら溶媒和物も本発明に包含される。 When the salt of compound (I) is desired to be obtained, 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. In addition, Compound (I) or a pharmaceutically 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.
　本発明に関わる医薬製剤は、活性成分を薬理学的に許容される一種またはそれ以上の担体と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。使用される製剤用担体としては、例えばラクトース、マンニトール、グルコース、デンプン、ステアリン酸マグネシウム、グリセリン酸エステル、注射用蒸留水、生理食塩水、プロピレングリコール、ポリエチレングリコール、エタノール等が挙げられる。また、本発明に係わる医薬製剤は、その他の各種の賦形剤、潤滑剤、結合剤、崩壊剤、等張化剤、乳化剤等を含有していてもよい。 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. Examples of the pharmaceutical carrier used include lactose, mannitol, glucose, starch, magnesium stearate, glycerate ester, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol and the like. The pharmaceutical preparation according to the present invention may contain other various excipients, lubricants, binders, disintegrants, isotonic agents, emulsifiers and the like.
　投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口、または、静脈内、塗布、吸入および点眼等の非経口を挙げることができるが、好ましくは静脈内投与であり、特に点滴静注で投与するのが好ましい。投与形態としては、例えば錠剤、注射剤等を挙げる事ができるが、好ましくは注射剤である。これらの医薬組成物の投与量や投与回数は、投与形態、患者の疾患やその症状、患者の年齢や体重等によって異なり、一概に規定することができないが、通常は成人に対し１日あたり有効成分の量として約０．０００１～約２０００ｍｇの範囲、好ましくは約０．００１～約１０００ｍｇの範囲、さらに好ましくは約０．１～約５００ｍｇの範囲、特に好ましくは約１～約３００ｍｇの範囲を１日１回または数回に分けて投与することができる。 As the administration route, 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. Examples of 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.
　以下、本発明を実施例および参考例を挙げてさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。 Hereinafter, the present invention will be described more specifically with reference to examples and reference examples, but the scope of the present invention is not limited to these examples.
　下記、実施例中の各化合物の物理化学データは、以下の機器類によって測定した。
１ＨＮＭＲ：ＪＥＯＬ　ＪＮＭ－ＬＡ３００
　以下の実施例および参考例の項に保持時間を記載した高速液体クロマトグラフィー分析の実施条件は以下の通りである。
カラム：オクタデシル基化学結合型シリカ（ＯＤＳ）、カラム長５０ｍｍ、カラム内径４．６ｍｍ［商品名 ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ ＡＣＲ Ｓ５ ５０Ｘ４.６ｍｍ（株式会社 資生堂ファインケミカル）］
流速：３．５ｍｌ／ｍｉｎ
測定波長：２２０ｎｍ、２５４ｎｍ
移動層：Ａ液；０．０５％トリフルオロ酢酸水溶液
　　　　Ｂ液；０．０３５％トリフルオロ酢酸アセトニトリル溶液
タイムプログラム：
ステップ　時間（分）　　　　Ａ液　：　Ｂ液
　１　　　０．０－０．５　　９９　：　１
　２　　　０．５－４．８　　９９　：　１　→　　１　：　９９
　３　　　４．８－５．０　　　１　：　９９
　４　　　５．０－５．２　　　１　：　９９　→　９９　：　　１
　５　　　５．２－５．８　　９９　：　　１
　また、各化合物の精製は山善株式会社のハイフラッシュカラム（シリカゲルカラムまたはアミノシリカゲルカラム）、またはＧｉｌｓｏｎ社の分取用ＨＰＬＣを用いて行った。 The following physicochemical data of each compound in the examples was measured by the following instruments.
1 HNMR: JEOL JNM-LA300
The performance conditions of the high performance liquid chromatography analysis in which the retention time is described in the following examples and reference examples are as follows.
Column: Octadecyl group chemically bonded silica (ODS), column length 50 mm, column inner diameter 4.6 mm [trade name CAPCELL PAK C18 ACR S5 50X4.6 mm (Shiseido Fine Chemical Co., Ltd.)]
Flow rate: 3.5ml / min
Measurement wavelength: 220 nm, 254 nm
Moving layer: Liquid A; 0.05% trifluoroacetic acid aqueous solution Liquid B; 0.035% trifluoroacetic acid acetonitrile solution Time program:
Step Time (min) A liquid: B liquid 1 0.0-0.5 99: 1
2 0.5-4.8 99: 1 → 1: 99
3 4.8-5.0 1:99
4 5.0-5.2 1: 99 → 99: 1
5 5.2-5.8 99: 1
Further, each compound was purified using a high-flash column (silica gel column or amino silica gel column) manufactured by Yamazen Co., Ltd. or a preparative HPLC manufactured by Gilson.
（参考例１）
３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－Ｎ，Ｎ－ジメチルプロパン－１－アミン
Figure JPOXMLDOC01-appb-C000040
 (Reference Example 1)
3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -N, N-dimethylpropan-1-amine
Figure JPOXMLDOC01-appb-C000040
（ａ）５－アリルピリミジン－２，４，６（１Ｈ，３Ｈ，５Ｈ）－トリオン
　ジエチル ２－アリルマロネート（２００ｇ，１.０ｍｏｌ）のエタノール（５００ｍｌ）溶液に、尿素（６０ｇ，１.０ｍｏｌ）を加え後、ナトリウムエトキシド（６８ｇ，１.０ｍｏｌ）のエタノール（５００ｍｌ）溶液を滴下し、加熱還流した。３時間後、室温に冷却後アセトン（５００ｍｌ）を加え、析出している固体をろ取した。得られた固体を水（１Ｌ）に懸濁し、濃塩酸で酸性とした。析出した固体をろ過後、水およびジエチルエーテル／ヘキサンで洗浄することにより化合物１Ａを得た（１１１ｇ、収率６６％）。
1H-NMR (DMSO-d6,δ ppm): 11.23 (2H, s), 5.60-5.74 (1H, m), 4.99-5.04 (2H, m),3.67 (1H, m), 2.65 (2H, m). (A) 5-allylpyrimidine-2,4,6 (1H, 3H, 5H) -trione Diethyl 2-allylmalonate (200 g, 1.0 mol) in ethanol (500 ml) in urea (60 g, 1.0 mol) ), And a solution of sodium ethoxide (68 g, 1.0 mol) in ethanol (500 ml) was added dropwise and heated to reflux. Three hours later, after cooling to room temperature, acetone (500 ml) was added, and the precipitated solid was collected by filtration. The resulting solid was suspended in water (1 L) and acidified with concentrated hydrochloric acid. The precipitated solid was filtered and then washed with water and diethyl ether / hexane to obtain Compound 1A (111 g, yield 66%).
1 H-NMR (DMSO-d6, δ ppm): 11.23 (2H, s), 5.60-5.74 (1H, m), 4.99-5.04 (2H, m), 3.67 (1H, m), 2.65 (2H, m ).
（ｂ）５－アリル－２，４，６－トリクロロピリミジン
　オキシ塩化リン（１０ｍｌ）を０℃に冷却し、上記で得られた化合物１Ａ（３.０ｇ， １３.４ｍｍｏｌ）、Ｎ，Ｎ－ジメチルアニリン（１.１５ｍｌ）を加え、１２０℃で過熱攪拌した。２.５時間後、減圧留去し得られた残渣に氷を加え、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより化合物１Ｂを得た（３.２ｇ、収率８０％）。
1H-NMR (CDCl3,δ ppm): 5.75-5.88 (1H, m), 5.07-5.19 (2H, m), 3.59-3.62 (2H, m). (B) 5-allyl-2,4,6-trichloropyrimidine phosphorous oxychloride (10 ml) was cooled to 0 ° C., and the compound 1A obtained above (3.0 g, 13.4 mmol), N, N-dimethyl Aniline (1.15 ml) was added, and the mixture was stirred with heating at 120 ° C. After 2.5 hours, ice was added to the residue obtained by evaporation under reduced pressure, followed by separation and extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to obtain Compound 1B (3.2 g, yield 80%).
1 H-NMR (CDCl 3 , δ ppm): 5.75-5.88 (1H, m), 5.07-5.19 (2H, m), 3.59-3.62 (2H, m).
（ｃ）２－（２，４，６－トリクロロピリミジン－５－イル）アセトアルデヒド
　上記で得られた化合物１Ｂ（２.７ｇ、１２.１ｍｍｏｌ）のアセトン（３０ｍｌ）、水（３０ｍｌ）溶液に、カリウム オスメート（ＩＶ）２水和物（２２３ｍｇ、０.６０４ｍｍｏｌ）を加え、メタ過ヨウ素酸ナトリウム（１０.３ｇ、４８.３ｍｍｏｌ）を少量ずつ添加し、室温にて攪拌した。４時間後、セライトろ過し、アセトンを減圧留去後、酢酸エチルで分液抽出した。有機層を５％－チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１Ｃを得た（１.５０ｇ、収率５８％）。
1H-NMR (CDCl3,δ ppm): 9.77 (1H, d, J = 0.6 Hz), 4.11 (2H, d, J = 0.6 Hz). (C) 2- (2,4,6-trichloropyrimidin-5-yl) acetaldehyde To a solution of the compound 1B (2.7 g, 12.1 mmol) obtained above in acetone (30 ml) and water (30 ml), potassium Osmate (IV) dihydrate (223 mg, 0.604 mmol) was added, sodium metaperiodate (10.3 g, 48.3 mmol) was added in portions and stirred at room temperature. After 4 hours, the mixture was filtered through Celite, and acetone was distilled off under reduced pressure, followed by separation and extraction with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution and saturated brine, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 1C (1.50 g, yield 58%).
1 H-NMR (CDCl 3 , δ ppm): 9.77 (1H, d, J = 0.6 Hz), 4.11 (2H, d, J = 0.6 Hz).
（ｄ）３－［２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］－Ｎ，Ｎ－ジメチルプロパン－１－アミン
　上記で得られた化合物１Ｃ（５００ｍｇ、２.２２ｍｍｏｌ）のメタノール（５.０ｍｌ）溶液に、０℃にて酢酸（２５４μｌ、４.４４ｍｍｏｌ）、Ｎ１，Ｎ１－ジメチルプロパン－１，３－ジアミン（３０６μｌ、２.４４ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１９５ｍｇ、３.１０ｍｍｏｌ）を加え、室温にて攪拌した。６時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：酢酸エチル）で精製することにより表題化合物１Ｄを得た（４１５ｍｇ、収率７３％）。
1H-NMR (CDCl3,δ ppm): 3.67-3.73 (2H, m), 3.38-3.43 (2H, m), 2.97-3.03 (2H, m), 2.25-2.30 (2H, m), 2.21 (6H, s), 1.69-1.79 (2H, m). (D) 3- [2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] -N, N-dimethylpropan-1-amine Compound 1C obtained above ( 500 mg, 2.22 mmol) in methanol (5.0 ml) at 0 ° C. with acetic acid (254 μl, 4.44 mmol), N1, N1-dimethylpropane-1,3-diamine (306 μl, 2.44 mmol), cyano Sodium borohydride (195 mg, 3.10 mmol) was added and stirred at room temperature. After 6 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: ethyl acetate) to give the title compound 1D (415 mg, 73% yield).
1 H-NMR (CDCl 3 , δ ppm): 3.67-3.73 (2H, m), 3.38-3.43 (2H, m), 2.97-3.03 (2H, m), 2.25-2.30 (2H, m), 2.21 ( 6H, s), 1.69-1.79 (2H, m).
　　参考例２－１０：
　対応する原料化合物と試薬を用い、参考例１（ｄ）に記載の方法と同様に反応・処理して表１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
 Reference Example 2-10 :
Using the corresponding starting materials and reagents, the compounds shown in Table 1 were obtained by reacting and treating in the same manner as described in Reference Example 1 (d).
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
（参考例１１）
３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－Ｎ－（２－メトキシエチル）－Ｎ－メチルプロパン－１－アミン
Figure JPOXMLDOC01-appb-C000043
 (Reference Example 11)
3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -N- (2-methoxyethyl) -N-methylpropan-1-amine
Figure JPOXMLDOC01-appb-C000043
（ａ）２，４－ジクロロ－７－（３，３－ジエトキシプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　参考例１（ｃ）で得た化合物１Ｃ（３００ｍｇ、１.３３ｍｍｏｌ）のメタノール（６.０ｍｌ）溶液に、０℃にて酢酸（１６８μｌ、２.９３ｍｍｏｌ）、３，３－ジエトキシ－１－プロピルアミン（２３６μｌ、１.４６ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１１７ｍｇ、１.８６ｍｍｏｌ）を加え、室温にて攪拌した。終夜撹拌後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより表題化合物２Ａを無色ガム状物質として得た（２２１ｍｇ、収率５２％）。
1H-NMR (CDCl3,δ ppm): 4.50-4.55 (1H, m), 3.59-3.75 (4H, m), 3.37-3.54 (4H, m), 2.94-3.03 (2H, m), 1.85-1.92 (2H, m), 1.12-1.19 (6H, m). (A) 2,4-dichloro-7- (3,3-diethoxypropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine Compound 1C obtained in Reference Example 1 (c) ( 300 mg, 1.33 mmol) in methanol (6.0 ml) at 0 ° C. with acetic acid (168 μl, 2.93 mmol), 3,3-diethoxy-1-propylamine (236 μl, 1.46 mmol), cyano hydrogenation Sodium boron (117 mg, 1.86 mmol) was added and stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 2A as a colorless gum (221 mg, yield 52%).
1 H-NMR (CDCl 3 , δ ppm): 4.50-4.55 (1H, m), 3.59-3.75 (4H, m), 3.37-3.54 (4H, m), 2.94-3.03 (2H, m), 1.85- 1.92 (2H, m), 1.12-1.19 (6H, m).
（ｂ）３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロパナール
　上記で得た化合物２Ａ（２１９ｍｇ、０.６８５ｍｍｏｌ）のアセトン（６.０ｍｌ）－水（１.５ｍｌ）溶液に、ｐ－トルエンスルホン酸・１水和物（１７７ｍｇ、１.０３ｍｍｏｌ）を加え、室温にて攪拌した。６時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製することにより表題化合物２Ｂを無色ガム状物質として得た（１４３ｍｇ、収率８５％）。
1H-NMR (CDCl3,δ ppm): 9.82 (1H, s), 3.67-3.78 (4H, m), 3.00 (2H, t, J = 8.7 Hz), 2.82-2.86 (2H, m). (B) 3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propanal Compound 2A obtained above (219 mg, 0.685 mmol) in acetone (6 0.0 ml) -water (1.5 ml) solution was added p-toluenesulfonic acid monohydrate (177 mg, 1.03 mmol) and stirred at room temperature. After 6 hours, the reaction was stopped with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol) to give the title compound 2B as a colorless gum (143 mg, yield 85%).
1 H-NMR (CDCl 3 , δ ppm): 9.82 (1H, s), 3.67-3.78 (4H, m), 3.00 (2H, t, J = 8.7 Hz), 2.82-2.86 (2H, m).
（ｃ）３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－Ｎ－（２－メトキシエチル）－Ｎ－メチルプロパン－１－アミン
　上記で得た化合物２Ｂ（１３９ｍｇ、０.５６６ｍｍｏｌ）のメタノール（５.７ｍｌ）溶液に、０℃にて酢酸（６５.６μｌ、１.１３ｍｍｏｌ）、Ｎ－メチル－２－メトキシエチルアミン（６６.９μｌ、０.６２３ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（７１.０ｍｇ、１.１３ｍｍｏｌ）を加え、室温にて攪拌した。終夜撹拌後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより表題化合物２Ｃを無色ガム状物質として得た（１００ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 3.70 (2H, t, J = 8.4 Hz), 3.40-3.46 (4H, m), 3.33 (3H,s), 3.00 (2H, t, J = 8.4 Hz), 2.52-2.55 (2H, m), 2.37-2.42 (2H, m), 2.24 (3H, s), 1.71-1.81 (2H, m). (C) 3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -N- (2-methoxyethyl) -N-methylpropan-1-amine To a solution of compound 2B (139 mg, 0.566 mmol) obtained in 1) in methanol (5.7 ml) at 0 ° C., acetic acid (65.6 μl, 1.13 mmol), N-methyl-2-methoxyethylamine (66.9 μl, 0.623 mmol) and sodium cyanoborohydride (71.0 mg, 1.13 mmol) were added and stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 2C as a colorless gum (100 mg, yield 56%).
1 H-NMR (CDCl 3 , δ ppm): 3.70 (2H, t, J = 8.4 Hz), 3.40-3.46 (4H, m), 3.33 (3H, s), 3.00 (2H, t, J = 8.4 Hz) ), 2.52-2.55 (2H, m), 2.37-2.42 (2H, m), 2.24 (3H, s), 1.71-1.81 (2H, m).
（参考例１２）
２－｛［３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル］（メチル）アミノ｝アセトアミド
Figure JPOXMLDOC01-appb-C000044
 　参考例１１（ｂ）で得た化合物２Ｂを用い、参考例１１（ｃ）と同様の方法にて合成することにより、表題化合物３Ａを得た（１９０ｍｇ、収率４９％）。
1H-NMR (CDCl3,δ ppm): 5.13 (2H, m), 3.53-3.62 (4H, m), 3.00 (2H, t, J = 8.1 Hz), 2.95 (2H, s), 2.47-2.52 (2H, m), 2.24 (3H, s), 1.72-1.83 (2H, m). (Reference Example 12)
2-{[3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl] (methyl) amino} acetamide
Figure JPOXMLDOC01-appb-C000044
 The title compound 3A was obtained by synthesizing in the same manner as in Reference Example 11 (c) using Compound 2B obtained in Reference Example 11 (b) (190 mg, 49% yield).
1 H-NMR (CDCl 3 , δ ppm): 5.13 (2H, m), 3.53-3.62 (4H, m), 3.00 (2H, t, J = 8.1 Hz), 2.95 (2H, s), 2.47-2.52 (2H, m), 2.24 (3H, s), 1.72-1.83 (2H, m).
（参考例１３）
ｔ－ブチル ４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノキシ）ピペリジン－１－カルボキシレート
Figure JPOXMLDOC01-appb-C000045
 (Reference Example 13)
t-butyl 4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenoxy) piperidine- 1-carboxylate
Figure JPOXMLDOC01-appb-C000045
（ａ）２－［４－（ベンジルオキシ）フェニル］－４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　参考例３で得た化合物（１.００ｇ、３.３２ｍｍｏｌ）の１，４－ジオキサン（１３.２８ｍｌ）溶液に、４－（ベンジルオキシ）フェニルボロン酸（７９５ｍｇ、３.４９ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（３８４ｍｇ、０.３３２ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（３.３２ｍｌ、９.９６ｍｍｏｌ）を加え、マイクロウェーブ照射下１５０℃にて攪拌した。３.５時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝９とし、クロロホルムで分液抽出した。有機層を硫酸マグネシウムにより乾燥後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物４Ａを白色ガム状物質として得た（７０５ｍｇ、収率４７％）。
1H-NMR (CDCl3,δ ppm): 8.29 (2H, d, J = 8.8 Hz), 7.31-7.44 (5H, m), 6.98 (2H, d, J = 8.8 Hz), 5.10 (2H, s), 3.66 (2H, t, J = 8.5 Hz), 3.54 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 8.5 Hz), 2.56 (6H, brs), 1.81-1.92 (6H, m). (A) 2- [4- (Benzyloxy) phenyl] -4-chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] Pyrimidine To a solution of the compound obtained in Reference Example 3 (1.00 g, 3.32 mmol) in 1,4-dioxane (13.28 ml) was added 4- (benzyloxy) phenylboronic acid (795 mg, 3.49 mmol), tetrakistri Phenylphosphine palladium (384 mg, 0.332 mmol), 3 mol / L aqueous sodium carbonate solution (3.32 ml, 9.96 mmol) were added, and the mixture was stirred at 150 ° C. under microwave irradiation. After 3.5 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 9 with an aqueous sodium hydroxide solution and subjected to liquid separation extraction with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound 4A as a white gum (705 mg, yield 47%).
1 H-NMR (CDCl 3 , δ ppm): 8.29 (2H, d, J = 8.8 Hz), 7.31-7.44 (5H, m), 6.98 (2H, d, J = 8.8 Hz), 5.10 (2H, s ), 3.66 (2H, t, J = 8.5 Hz), 3.54 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 8.5 Hz), 2.56 (6H, brs), 1.81-1.92 (6H , m).
（ｂ）４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノール
　上記で得た化合物４Ａ（７０５ｍｇ、１.５７ｍｍｏｌ）のメタノール（１０.０ｍｌ）溶液に、１０％パラジウム炭素（５０％含水）（３５０ｍｇ）、トリフルオロ酢酸（５５.０μｌ）を加え、水素雰囲気下（０.３ＭＰａ）、室温にて攪拌した。６.５時間後、反応溶液をセライトろ過し、減圧濃縮した。得られた残渣をメタノールに希釈し、トリエチルアミンを加え中和後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより表題化合物４Ｂを淡黄色アモルファスとして得た（４３７ｍｇ、収率８６％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 8.8 Hz), 7.91 (1H, s), 6.82 (2H, d, J = 8.8 Hz), 3.60 (2H, t, J = 8.3 Hz), 3.54 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 8.3 Hz), 2.58-2.63 (6H, m), 1.83-1.96 (7H, m). (B) 4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenol Compound 4A obtained above (705 mg, 1.57 mmol) in a methanol (10.0 ml) solution was added 10% palladium on carbon (containing 50% water) (350 mg) and trifluoroacetic acid (55.0 μl) under a hydrogen atmosphere (0.3 MPa). Stir at room temperature. After 6.5 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained residue was diluted with methanol, neutralized with triethylamine, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound 4B as a pale yellow amorphous product (437 mg, 86% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 8.8 Hz), 7.91 (1H, s), 6.82 (2H, d, J = 8.8 Hz), 3.60 (2H, t, J = 8.3 Hz), 3.54 (2H, t, J = 7.0 Hz), 3.00 (2H, t, J = 8.3 Hz), 2.58-2.63 (6H, m), 1.83-1.96 (7H, m).
（ｃ）ｔ－ブチル ４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノキシ）ピペリジン－１－カルボキシレート
　上記で得られた化合物４Ｂ（４４.０ｍｇ、０.１３６ｍｍｏｌ）のＴＨＦ（１.０ｍｌ）溶液に、ｔ－ブチル ４－ヒドロキシピペリジン－１－カーボキシレート（５４.０ｍｇ、０.２７１ｍｍｏｌ）、トリフェニルホスフィン（７１.０ｍｇ、０.２７１ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（５３.０μｌ、０.２７１ｍｍｏｌ）を加え室温にて撹拌した。３時間後、反応溶液を減圧濃縮し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：メタノール）で精製することにより表題化合物４Ｃを淡黄色油状物として得た。（５７.０ｍｇ、収率８２％）。
1H-NMR (CDCl3,δ ppm): 8.27 (2H, d, J =9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.33 (1H, m), 3.52-3.64 (6H, m), 3.30-3.36 (2H, m), 3.01 (2H, t, J =8.4 Hz), 2.56 (6H, brs), 1.80-1.89 (10H, m), 1.45 (9H, s). (C) t-butyl 4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenoxy ) Piperidine-1-carboxylate To a solution of the compound 4B obtained above (44.0 mg, 0.136 mmol) in THF (1.0 ml) was added t-butyl 4-hydroxypiperidine-1-carboxylate (54.0 mg). , 0.271 mmol), triphenylphosphine (71.0 mg, 0.271 mmol) and diisopropyl azodicarboxylate (53.0 μl, 0.271 mmol) were added and stirred at room temperature. After 3 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate → chloroform: methanol) to give the title compound 4C as a pale yellow oil. (57.0 mg, 82% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.27 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.33 (1H, m), 3.52-3.64 (6H, m), 3.30-3.36 (2H, m), 3.01 (2H, t, J = 8.4 Hz), 2.56 (6H, brs), 1.80-1.89 (10H, m), 1.45 (9H, s).
　　参考例１４－２１：
　対応する原料化合物と試薬を用い、参考例１３に記載の方法と同様に反応・処理して表２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
 Reference Example 14-21 :
The corresponding starting materials and reagents were used and reacted and treated in the same manner as described in Reference Example 13 to obtain the compounds shown in Table 2.
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
（参考例２２）
Ｎ－（４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）－２－（ジメチルアミノ）アセトアミド
Figure JPOXMLDOC01-appb-C000048
 (Reference Example 22)
N- (4- {4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl)- 2- (Dimethylamino) acetamide
Figure JPOXMLDOC01-appb-C000048
（ａ）４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝アニリン
　参考例３で得た化合物（２００ｍｇ、０.６６４ｍｍｏｌ）の１，４－ジオキサン（２.６５ｍｌ）溶液に、４－（４、４、５、５－テトラメチル－１、３、２－ジオキサボロラン－２－イル）アニリン（１５３ｍｇ、０.６９７ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（７７.０ｍｇ、０.０６６４ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（６６４μｌ、１.９９ｍｍｏｌ）を加え、１２０℃にて攪拌した。７時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥し、ろ過後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製し、表題化合物５Ａを白色固体として得た（１３５ｍｇ、収率５７％）。
1H-NMR (CDCl3,δ ppm): 8.16 (2H, dd, J = 6.6 Hz, 2.0 Hz), 6.67 (2H, dd, J = 6.6 Hz, 2.0 Hz), 3.87 (2H, brs), 3.65 (2H, t, J = 8.6 Hz), 3.55 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 8.6 Hz), 2.60-2.71 (4H, m), 1.85-2.00 (6H, m), 1.55 (2H, brs). (A) 4- {4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} aniline Reference Example To a solution of the compound obtained in 3 (200 mg, 0.664 mmol) in 1,4-dioxane (2.65 ml), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) aniline (153 mg, 0.697 mmol), tetrakistriphenylphosphine palladium (77.0 mg, 0.0664 mmol), 3 mol / L aqueous sodium carbonate solution (664 μl, 1.99 mmol) were added and stirred at 120 ° C. After 7 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered 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 5A as a white solid (135 mg, yield 57%).
1 H-NMR (CDCl 3 , δ ppm): 8.16 (2H, dd, J = 6.6 Hz, 2.0 Hz), 6.67 (2H, dd, J = 6.6 Hz, 2.0 Hz), 3.87 (2H, brs), 3.65 (2H, t, J = 8.6 Hz), 3.55 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 8.6 Hz), 2.60-2.71 (4H, m), 1.85-2.00 (6H, m), 1.55 (2H, brs).
（ｂ）Ｎ－（４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）－２－（ジメチルアミノ）アセトアミド
　上記で得た化合物５Ａ（６０.０ｍｇ、０.１６８ｍｍｏｌ）のＤＭＦ（１.５ｍｌ）溶液に、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド・塩酸塩（６４.０ｍｇ、０.３３５ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（４.５０ｍｇ、０.０３３５ｍｍｏｌ）、Ｎ，Ｎ－ジメチルグリシン（３５.０ｍｇ、０.３３５ｍｍｏｌ）を加え、室温にて撹拌した。２４時間後１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド・塩酸塩（９６.０ｍｇ、０.５０４ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（６.７５ｍｇ、０.０５０４ｍｍｏｌ）、Ｎ，Ｎ－ジメチルグリシン（５３.０ｍｇ、０.５０４ｍｍｏｌ）を追加し、４０時間撹拌した。反応溶液に飽和食塩水を入れたのちに酢酸エチルをいれて３０分撹拌後、酢酸エチルで分液抽出した。有機層を水、続いて飽和食塩水で洗い、硫酸マグネシウムで乾燥した。減圧濃縮後、得られた残渣をアミノカラムクロマトグラフィー（溶出溶媒；クロロホルム：酢酸エチル）で精製し、表題化合物５Ｂを黄色固体として得た（４５.０ｍｇ、収率６１％）。
1H-NMR (CDCl3,δ ppm): 9.23 (1H, brs), 8.23 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 3.70 (2H, t, J = 8.0 Hz), 3.57 (2H, t, J = 6.8 Hz), 3.03-3.09 (4H, m), 2.74 (2H, brs), 2.38 (6H, s), 1.92-2.02 (6H, m), 1.59 (4H, brs). (B) N- (4- {4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} Phenyl) -2- (dimethylamino) acetamide To a solution of the compound 5A obtained above (60.0 mg, 0.168 mmol) in DMF (1.5 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (64.0 mg, 0.335 mmol), 1-hydroxybenzotriazole (4.50 mg, 0.0335 mmol), N, N-dimethylglycine (35.0 mg, 0.335 mmol) were added and stirred at room temperature. . After 24 hours, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (96.0 mg, 0.054 mmol), 1-hydroxybenzotriazole (6.75 mg, 0.0504 mmol), N, N-dimethyl Glycine (53.0 mg, 0.504 mmol) was added and stirred for 40 hours. Saturated brine was added to the reaction solution, ethyl acetate was added, and the mixture was stirred for 30 min. The organic layer was washed with water followed by saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the resulting residue was purified by amino column chromatography (elution solvent; chloroform: ethyl acetate) to give the title compound 5B as a yellow solid (45.0 mg, 61% yield).
1 H-NMR (CDCl 3 , δ ppm): 9.23 (1H, brs), 8.23 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 3.70 (2H, t, J = 8.0 Hz), 3.57 (2H, t, J = 6.8 Hz), 3.03-3.09 (4H, m), 2.74 (2H, brs), 2.38 (6H, s), 1.92-2.02 (6H, m), 1.59 (4H, brs).
（参考例２３）
Ｎ－（４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）－２－モルホリノアセトアミド
Figure JPOXMLDOC01-appb-C000049
 　参考例２２（ａ）で得られる化合物５Ａを用い、参考例２２（ｂ）と同様の方法にて合成することにより、表題化合物６Ａを淡黄色油状物として得た（３６ｍｇ、収率４２％）。
1H-NMR (CDCl3,δ ppm): 9.17 (1H, brs), 8.32 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 3.70-3.80 (6H, m), 3.59 (2H, t, J = 6.5 Hz), 3.15 (2H, s), 3.08 (2H, t, J = 8.7 Hz), 2.61-2.64 (4H, m), 2.24 (2H, m), 2.02 (2H, m), 1.54 (8H, m). (Reference Example 23)
N- (4- {4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl)- 2-morpholinoacetamide
Figure JPOXMLDOC01-appb-C000049
 The title compound 6A was obtained as a pale yellow oil by synthesis using the compound 5A obtained in Reference Example 22 (a) in the same manner as in Reference Example 22 (b) (36 mg, yield 42%). .
1 H-NMR (CDCl 3 , δ ppm): 9.17 (1H, brs), 8.32 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 3.70-3.80 (6H, m ), 3.59 (2H, t, J = 6.5 Hz), 3.15 (2H, s), 3.08 (2H, t, J = 8.7 Hz), 2.61-2.64 (4H, m), 2.24 (2H, m), 2.02 (2H, m), 1.54 (8H, m).
（参考例２４）
ｔ－ブチル ４－（４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－カルボキシレート
Figure JPOXMLDOC01-appb-C000050
 　参考例３で得た化合物（２００ｍｇ、０.６６４ｍｍｏｌ）の１，４－ジオキサン（２.６５ｍｌ）溶液に、ｔ－ブチル ４－（４－（４、４、５、５－テトラメチル－１、３、２－ジオキサボロラン－２－イル）フェニル）ピペラジン－１－カルボキシレート（２７０ｍｇ、０.６９７ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（７７.０ｍｇ、０.０６６４ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（６６４μｌ、１.９９ｍｍｏｌ）を加え、１２０℃にて攪拌した。５.５時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥し、ろ過後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：酢酸エチル）で精製し、表題化合物７Ａを黄色油状物として得た（２７３ｍｇ、収率７８％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.43-3.72 (12H, m), 3.21-3.25 (4H, m), 3.03 (2H, t, J = 8.5 Hz), 2.35-2.42 (6H, m), 1.76-1.82 (2H, m), 1.47 (9H, s). (Reference Example 24)
t-butyl 4- (4- {4-chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} Phenyl) piperazine-1-carboxylate
Figure JPOXMLDOC01-appb-C000050
 To a solution of the compound obtained in Reference Example 3 (200 mg, 0.664 mmol) in 1,4-dioxane (2.65 ml), t-butyl 4- (4- (4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (270 mg, 0.697 mmol), tetrakistriphenylphosphine palladium (77.0 mg, 0.0664 mmol), 3 mol / L aqueous sodium carbonate solution (664 μl, 1.99 mmol) was added and stirred at 120 ° C. After 5.5 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate) to obtain the title compound 7A as a yellow oil (273 mg, yield 78%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.43-3.72 (12H, m), 3.21-3.25 (4H , m), 3.03 (2H, t, J = 8.5 Hz), 2.35-2.42 (6H, m), 1.76-1.82 (2H, m), 1.47 (9H, s).
　　参考例２５－３６：
　対応する原料化合物と試薬を用い、参考例２４に記載の方法と同様に反応・処理して表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
 Reference Example 25-36 :
The corresponding starting materials and reagents were used and reacted and treated in the same manner as described in Reference Example 24 to obtain the compounds shown in Table 3.
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
（参考例３７）
１－［２－（２－｛４－クロロ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エトキシ）エチル］ピロリジン－２－オン
Figure JPOXMLDOC01-appb-C000054
 (Reference Example 37)
1- [2- (2- {4-Chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Ethoxy) ethyl] pyrrolidin-2-one
Figure JPOXMLDOC01-appb-C000054
（ａ）２－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）エタノール
　参考例１（ｃ）で得た化合物１Ｃ（３１０ｍｇ、１.３７ｍｍｏｌ）のメタノール（７.０ｍｌ）溶液に、０℃にて酢酸（１７３μｌ、３.０１ｍｍｏｌ）、２－アミノエタノール（９２.０μｌ、１.５１ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１２１ｍｇ、１.９２ｍｍｏｌ）を加え、室温にて攪拌した。５時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物８Ａを得た（２３６ｍｇ、収率７４％）。
1H-NMR (CDCl3,δ ppm): 3.79-3.89 (4H, m), 3.55 (2H, t, J = 5.0 Hz), 3.04 (2H, t, J = 8.6 Hz), 2.32 (1H, t, J = 5.5 Hz). (A) 2- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) ethanol Compound 1C obtained in Reference Example 1 (c) (310 mg, 1.37 mmol) In methanol (7.0 ml) at 0 ° C. with acetic acid (173 μl, 3.01 mmol), 2-aminoethanol (92.0 μl, 1.51 mmol), sodium cyanoborohydride (121 mg, 1.92 mmol). The mixture was added and stirred at room temperature. After 5 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 8A (236 mg, yield 74%).
1 H-NMR (CDCl 3 , δ ppm): 3.79-3.89 (4H, m), 3.55 (2H, t, J = 5.0 Hz), 3.04 (2H, t, J = 8.6 Hz), 2.32 (1H, t , J = 5.5 Hz).
（ｂ）２－｛４－クロロ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エタノール
　上記で得た化合物８Ａ（２１８ｍｇ、０.９３ｍｍｏｌ）の１，４－ジオキサン（４ｍｌ）溶液に、１－メチル－４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン（２９６ｍｇ、０.９８ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１０８ｍｇ、０.０９３ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０.９３ｍｌ、２.７９ｍｍｏｌ）を加え、マイクロウエーブ照射下１１０℃にて攪拌した。２時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１０とし、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄後、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより表題化合物８Ｂを得た（１７９ｍｇ、収率５１％）。
1H-NMR (CDCl3,δ ppm): 8.15 (2H, d, J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 3.86-3.92 (2H, m), 3.72 (2H, t, J = 8.4 Hz), 3.53-3.57 (2H, m), 3.26-3.32 (4H, m), 3.05 (2H, t, J = 8.4 Hz), 2.52-2.58 (4H, m), 2.33 (3H, s). (B) 2- {4-Chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethanol To a solution of the obtained compound 8A (218 mg, 0.93 mmol) in 1,4-dioxane (4 ml), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl] piperazine (296 mg, 0.98 mmol), tetrakistriphenylphosphine palladium (108 mg, 0.093 mmol), 3 mol / L sodium carbonate aqueous solution (0.93 ml, 2.79 mmol) were added, and the microwave was added. The mixture was stirred at 110 ° C. under irradiation. After 2 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound 8B (179 mg, yield). 51%).
1 H-NMR (CDCl 3 , δ ppm): 8.15 (2H, d, J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 3.86-3.92 (2H, m), 3.72 (2H, t , J = 8.4 Hz), 3.53-3.57 (2H, m), 3.26-3.32 (4H, m), 3.05 (2H, t, J = 8.4 Hz), 2.52-2.58 (4H, m), 2.33 (3H, s).
（ｃ）１－［２－（２－｛４－クロロ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エトキシ）エチル］ピロリジン－２－オン
　上記で得た化合物８Ｂ（１６４ｍｇ、０.４３９ｍｍｏｌ）のＤＭＦ（４ｍｌ）溶液を０℃に冷却し、水素化ナトリウム（７１.３ｍｇ、０.４８３ｍｍｏｌ）を加え、攪拌した。１５分後、１－（２－クロロエチル）ピロリジン－２－オンを加え室温にて攪拌した。３時間後、クロロホルム－水で分液抽出し、有機層を飽和食塩水で洗浄後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル：クロロホルム）で精製することにより表題化合物８Ｃを得た（１３３.１ｍｇ、収率６２％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 4.09 (2H, s), 3.69-3.83 (6H, m), 3.38-3.50 (2H, m), 3.25-3.33 (6H, m), 3.02 (2H, t, J = 8.1 Hz), 2.52-2.59 (4H, m), 2.34 (3H, s), 1.74-1.93 (4H, m). (C) 1- [2- (2- {4-Chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il} ethoxy) ethyl] pyrrolidin-2-one A solution of compound 8B obtained above (164 mg, 0.439 mmol) in DMF (4 ml) was cooled to 0 ° C. and sodium hydride (71.3 mg, 0.483 mmol). Was added and stirred. After 15 minutes, 1- (2-chloroethyl) pyrrolidin-2-one was added and stirred at room temperature. After 3 hours, the mixture was subjected to separation / extraction with chloroform-water, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate: chloroform) to obtain the title compound 8C (133.1 mg, yield 62%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 6.89 (2H, d, J = 9.0 Hz), 4.09 (2H, s), 3.69-3.83 (6H, m ), 3.38-3.50 (2H, m), 3.25-3.33 (6H, m), 3.02 (2H, t, J = 8.1 Hz), 2.52-2.59 (4H, m), 2.34 (3H, s), 1.74- 1.93 (4H, m).
（参考例３８）
２，４－ジクロロ－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000055
 (Reference Example 38)
2,4-Dichloro-8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000055
（ａ）ジエチル ２－（３－ブテニル）マロネート
　ジエチル マロネート（２２.４ｇ、０.１４０ｍｏｌ）のエタノール（１００ｍｌ）溶液に、２０％ ナトリウムエトキシド／エタノール溶液（５４.９ｍｌ、０.１４０ｍｏｌ）を加え、５０℃にて３０分攪拌した。室温に冷却後、４－ブロモ－１－ブテン（１３.５ｇ、０.１００ｍｏｌ）を加えた。終夜攪拌した後、反応溶液を減圧濃縮した。得られた残渣を水で希釈し、ジエチルエーテル／ヘキサン（２：１）混合溶媒で抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残渣を減圧蒸留（６０℃，１ｍｍＨｇ）することにより、表題化合物９Ａを無色オイルとして得た（１６.４ｇ、収率７６％）。
1H-NMR (CDCl3,δ ppm): 5.68-5.82 (1H, m), 4.97-5.06 (2H, m), 4.13-4.22 (4H, m), 3.31-3.35 (1H, m), 2.01-2.12 (2H, m), 1.94-1.99 (2H, m), 1.20-1.28 (6H, m). (A) Diethyl 2- (3-butenyl) malonate To a solution of diethyl malonate (22.4 g, 0.140 mol) in ethanol (100 ml) was added a 20% sodium ethoxide / ethanol solution (54.9 ml, 0.140 mol). And stirred at 50 ° C. for 30 minutes. After cooling to room temperature, 4-bromo-1-butene (13.5 g, 0.100 mol) was added. After stirring overnight, the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with water and extracted with a mixed solvent of diethyl ether / hexane (2: 1). The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure (60 ° C., 1 mmHg) to give the title compound 9A as a colorless oil (16.4 g, yield 76%).
1 H-NMR (CDCl 3 , δ ppm): 5.68-5.82 (1H, m), 4.97-5.06 (2H, m), 4.13-4.22 (4H, m), 3.31-3.35 (1H, m), 2.01- 2.12 (2H, m), 1.94-1.99 (2H, m), 1.20-1.28 (6H, m).
（ｂ）５－（３－ブテニル）ピリミジン－２，４，６（１Ｈ，３Ｈ，５Ｈ）－トリオン
　上記で得られた化合物９Ａ（１６.０ｇ、０.０７４７ｍｏｌ）のエタノール（６４ｍｌ）、アセトン（１６ｍｌ）の混合溶液に、尿素（４.４９ｇ、０.０７４７ｍｏｌ）、２０％ ナトリウムエトキシド／エタノール溶液（２９.３ｍｌ、０.０７４７ｍｏｌ）を加え、８０℃にて攪拌した。４時間後、室温に冷却し、析出している固体をろ取した。得られた固体を水（２００ｍｌ）に溶解し、濃塩酸でｐＨ＝１とした。析出した固体をろ過後、水およびジエチルエーテル／ヘキサンで洗浄することにより化合物９Ｂを得た（１２.１ｇ、収率８９％）。
1H-NMR (DMSO-d6,δ ppm): 11.19 (2H, s), 5.67-5.78 (1H, m), 4.92-5.01 (2H, m),3.56 (1H, m), 2.01 (4H, m). (B) 5- (3-butenyl) pyrimidine-2,4,6 (1H, 3H, 5H) -trione Compound 9A obtained above (16.0 g, 0.0747 mol) in ethanol (64 ml), acetone ( 16 ml) was added urea (4.49 g, 0.0747 mol) and 20% sodium ethoxide / ethanol solution (29.3 ml, 0.0747 mol), and the mixture was stirred at 80 ° C. After 4 hours, the mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was dissolved in water (200 ml) and adjusted to pH = 1 with concentrated hydrochloric acid. The precipitated solid was filtered and then washed with water and diethyl ether / hexane to obtain Compound 9B (12.1 g, yield 89%).
1 H-NMR (DMSO-d 6 , δ ppm): 11.19 (2H, s), 5.67-5.78 (1H, m), 4.92-5.01 (2H, m), 3.56 (1H, m), 2.01 (4H, m).
（ｃ）５－（３－ブテニル）－２，４，６－トリクロロピリミジン
　上記で得られた化合物９Ｂ（１２.０ｇ、０.０６５９ｍｏｌ）に、オキシ塩化リン（３０.１ｍｌ、０.３２９ｍｏｌ）、Ｎ，Ｎ－ジメチルアニリン（４.１７ｍｌ、０.０３２９ｍｏｌ）を加え、１２０℃で過熱攪拌した。５時間後、反応溶液を氷水に加え、酢酸エチルで分液抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより化合物９Ｃを得た（３.１５ｇ、収率２０％）。
1H-NMR (CDCl3,δ ppm): 5.78-5.91 (1H, m), 5.01-5.08 (2H, m), 2.92-2.97 (2H, m), 2.31-2.39 (2H, m). (C) 5- (3-Butenyl) -2,4,6-trichloropyrimidine Compound 9B (12.0 g, 0.0659 mol) obtained above was added phosphorus oxychloride (30.1 ml, 0.329 mol), N, N-dimethylaniline (4.17 ml, 0.0329 mol) was added, and the mixture was stirred with heating at 120 ° C. After 5 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to obtain Compound 9C (3.15 g, yield 20%).
1 H-NMR (CDCl 3 , δ ppm): 5.78-5.91 (1H, m), 5.01-5.08 (2H, m), 2.92-2.97 (2H, m), 2.31-2.39 (2H, m).
（ｄ）３－（２，４，６－トリクロロピリミジン－５－イル）プロパナール
　上記で得られた化合物９Ｃ（３.１０ｇ、０.０１３１ｍｏｌ）のアセトン（３０ｍｌ）、水（３０ｍｌ）の混合溶液に、カリウム オスメート（ＩＶ）２水和物（２４０ｍｇ、０.６５３ｍｍｏｌ）を加え、メタ過ヨウ素酸ナトリウム（８.３７ｇ、０.０３９２ｍｏｌ）を少量ずつ添加し、室温にて攪拌した。３.５時間後、セライトろ過し、アセトンを減圧留去後、酢酸エチルで分液抽出した。有機層を５％－チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物９Ｄを得た（１.３５ｇ、収率４３％）。
1H-NMR (CDCl3,δ ppm): 9.84 (1H, s), 3.14-3.19 (2H, m), 2.75-2.81 (2H, m). (D) 3- (2,4,6-trichloropyrimidin-5-yl) propanal A mixed solution of the compound 9C obtained above (3.10 g, 0.0131 mol) in acetone (30 ml) and water (30 ml) To the solution, potassium osmate (IV) dihydrate (240 mg, 0.653 mmol) was added, sodium metaperiodate (8.37 g, 0.0392 mol) was added little by little, and the mixture was stirred at room temperature. After 3.5 hours, the mixture was filtered through Celite, and acetone was distilled off under reduced pressure, followed by separation and extraction with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution and saturated brine, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 9D (1.35 g, yield 43%).
1 H-NMR (CDCl 3 , δ ppm): 9.84 (1H, s), 3.14-3.19 (2H, m), 2.75-2.81 (2H, m).
（ｅ）２，４－ジクロロ－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン
　上記で得られた化合物９Ｄ（４７９ｍｇ、２.００ｍｍｏｌ）のメタノール（９.０ｍｌ）溶液に、０℃にて酢酸（２２９μｌ、４.００ｍｍｏｌ）、３－（ピロリジン－１－イル）プロパン－１－アミン（２７８μｌ、２.２０ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１７６ｍｇ、２.８０ｍｍｏｌ）を加え、室温にて攪拌した。終夜攪拌した後、飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物９Ｅを白色固体として得た（４７８ｍｇ、収率７６％）。
1H-NMR (CDCl3,δ ppm): 3.62 (2H, t, J = 7.2 Hz), 3.36-3.42 (2H, m), 2.68 (2H, t, J = 6.5 Hz), 2.41-2.50 (6H, m), 1.85-1.95 (2H, m), 1.73-1.83 (6H, m). (E) 2,4-Dichloro-8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine Compound 9D obtained above (479 mg, 2.00 mmol) in methanol (9.0 ml) at 0 ° C. with acetic acid (229 μl, 4.00 mmol), 3- (pyrrolidin-1-yl) propan-1-amine (278 μl, 2.20 mmol) ), Sodium cyanoborohydride (176 mg, 2.80 mmol) was added and stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 9E as a white solid (478 mg, yield 76%).
1 H-NMR (CDCl 3 , δ ppm): 3.62 (2H, t, J = 7.2 Hz), 3.36-3.42 (2H, m), 2.68 (2H, t, J = 6.5 Hz), 2.41-2.50 (6H , m), 1.85-1.95 (2H, m), 1.73-1.83 (6H, m).
（参考例３９）
４－［３－（２，４－ジクロロ－６，７－ジヒドロピリド［２，３－ｄ］ピリミジン－８（５Ｈ）－イル）プロピル］モルホリン
Figure JPOXMLDOC01-appb-C000056
 　参考例３８で得られる化合物９Ｄを用い、参考例３８（ｅ）と同様の方法にて合成することにより、表題化合物１０Ａを白色固体として得た（５６７ｍｇ、収率８６％）。
1H-NMR (CDCl3,δ ppm): 3.68-3.71 (4H, m), 3.59-3.64 (2H, m), 3.37-3.40 (2H, m), 2.69 (2H, t, J = 6.4 Hz), 2.42 (4H, m), 2.34 (2H, t, J = 7.1 Hz), 1.88-1.96 (2H, m), 1.72-1.82 (2H, m). (Reference Example 39)
4- [3- (2,4-Dichloro-6,7-dihydropyrido [2,3-d] pyrimidin-8 (5H) -yl) propyl] morpholine
Figure JPOXMLDOC01-appb-C000056
 The title compound 10A was obtained as a white solid (567 mg, 86% yield) by synthesis using the compound 9D obtained in Reference Example 38 in the same manner as in Reference Example 38 (e).
1 H-NMR (CDCl 3 , δ ppm): 3.68-3.71 (4H, m), 3.59-3.64 (2H, m), 3.37-3.40 (2H, m), 2.69 (2H, t, J = 6.4 Hz) , 2.42 (4H, m), 2.34 (2H, t, J = 7.1 Hz), 1.88-1.96 (2H, m), 1.72-1.82 (2H, m).
（参考例４０）
４－［３－（２，４－ジクロロ－７，８－ジヒドロ－５Ｈ－ピリミド［４，５－ｂ］アゼピン－９（６Ｈ）－イル）プロピル］モルホリン
Figure JPOXMLDOC01-appb-C000057
 (Reference Example 40)
4- [3- (2,4-Dichloro-7,8-dihydro-5H-pyrimido [4,5-b] azepin-9 (6H) -yl) propyl] morpholine
Figure JPOXMLDOC01-appb-C000057
（ａ）ジエチル ２－（ペンテン－４－イル）マロネート
　エタノール溶液（６０.０ｍｌ）にナトリウム（６.６ｇ、６２.４ｍｍｏｌ）を加え、ナトリウムが完全に溶解するまで２０分撹拌し、その後ジエチルマロネート（１０.０ｇ、６２.４ｍｍｏｌ）を加え、５０℃で３０分撹拌した。室温に放熱した後、５－ブロモペンタ－１－エン（６.６ｇ、４４.６０ｍｍｏｌ）を滴下した。２２時間攪拌した後、反応溶液を減圧濃縮した。得られた残渣を水で希釈し、ジエチルエーテル／ヘキサン（２：１）混合溶媒で抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムにて乾燥し、ろ過後減圧濃縮した。得られた残渣を、シリカゲルクロマトグラフィー（溶出条件；ヘキサン：酢酸エチル）にて精製し、表題化合物１１Aを無色油状物として得た（５.１ｇ、収率４９％）。
1H-NMR (CDCl3,δ ppm): 5.69-5.83 (1H, m), 4.92-5.03 (2H, m), 4.12-4.22 (4H, m), 3.27-3.35 (1H, m), 2.03-2.15 (2H, m), 1.85-1.92 (2H, m), 1.35-1.45 (2H, m), 1.22-1.29 (6H, m). (A) Diethyl 2- (penten-4-yl) malonate Sodium (6.6 g, 62.4 mmol) was added to an ethanol solution (60.0 ml), and the mixture was stirred for 20 minutes until the sodium was completely dissolved. Nate (10.0 g, 62.4 mmol) was added and stirred at 50 ° C. for 30 minutes. After releasing heat to room temperature, 5-bromopent-1-ene (6.6 g, 44.60 mmol) was added dropwise. After stirring for 22 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with water and extracted with a mixed solvent of diethyl ether / hexane (2: 1). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution condition: hexane: ethyl acetate) to give the title compound 11A as a colorless oil (5.1 g, yield 49%).
1 H-NMR (CDCl 3 , δ ppm): 5.69-5.83 (1H, m), 4.92-5.03 (2H, m), 4.12-4.22 (4H, m), 3.27-3.35 (1H, m), 2.03- 2.15 (2H, m), 1.85-1.92 (2H, m), 1.35-1.45 (2H, m), 1.22-1.29 (6H, m).
（ｂ）５－（ペンテン－４－イル）ピリミジン－２，４，６（１Ｈ，３Ｈ，５Ｈ）－トリオン
　上記で得られた化合物１１Ａ（５.１ｇ、２２.３ｍｍｏｌ）のエタノール（２０ｍｌ）、アセトン（１０ｍｌ）の混合溶液に、尿素（１.３４ｇ、２２.３ｍｍｏｌ）、２８％ナトリウムエトキシド／エタノール溶液（４.３ｇ、２２.３ｍｍｏｌ）を加え、６０℃にて攪拌した。２時間後、室温に冷却し、析出している固体をろ取した。得られた固体を水（２００ｍｌ）に溶解し、濃塩酸でｐＨ＝１とした。析出した固体をろ過後、水で洗浄することにより白色固体として化合物１１Ｂを得た（１.５８ｇ、収率３６％）。
1H-NMR (DMSO, δ ppm): 11.2 (2H, s), 5.67-5.80 (1H, m), 4.91-5.01 (2H, m), 3.5-3.54 (1H, m), 1.94-2.01 (2H, m), 1.83-1.90 (2H, m), 1.26-1.36 (2H, m). (B) 5- (Penten-4-yl) pyrimidine-2,4,6 (1H, 3H, 5H) -trione Compound 11A obtained above (5.1 g, 22.3 mmol) in ethanol (20 ml), Urea (1.34 g, 22.3 mmol) and 28% sodium ethoxide / ethanol solution (4.3 g, 22.3 mmol) were added to a mixed solution of acetone (10 ml), and the mixture was stirred at 60 ° C. After 2 hours, the mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was dissolved in water (200 ml) and adjusted to pH = 1 with concentrated hydrochloric acid. The precipitated solid was filtered and then washed with water to obtain Compound 11B as a white solid (1.58 g, yield 36%).
1 H-NMR (DMSO, δ ppm): 11.2 (2H, s), 5.67-5.80 (1H, m), 4.91-5.01 (2H, m), 3.5-3.54 (1H, m), 1.94-2.01 (2H , m), 1.83-1.90 (2H, m), 1.26-1.36 (2H, m).
（ｃ）２，４，６－トリクロロ－５－（ペンテン－４－イル）ピリミジン
　上記で得られた化合物１１Ｂ（１.９７ｇ、２０.０ｍｍｏｌ）に、オキシ塩化リン（１０.０ｍｌ、０.１０９ｍｏｌ）、Ｎ，Ｎ－ジメチルアニリン（０.６４ｍｌ、５.０２ｍｍｏｌ）を加え、１２０℃で加熱攪拌した。５時間後、反応溶液を氷水に加え、酢酸エチルで分液抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより淡黄色油状物として化合物１１Ｃを得た（７７２ｍｇ、収率３０％）。
1H-NMR (CDCl3,δ ppm): 5.74-5.85 (1H, m), 5.00-5.10 (2H, m), 2.81-2.86 (2H, m), 2.14-2.22 (2H, m), 1.62-1.72 (2H, m). (C) 2,4,6-trichloro-5- (penten-4-yl) pyrimidine To the compound 11B obtained above (1.97 g, 20.0 mmol) was added phosphorus oxychloride (10.0 ml, 0.109 mol). ), N, N-dimethylaniline (0.64 ml, 5.02 mmol) was added, and the mixture was stirred with heating at 120 ° C. After 5 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give Compound 11C as a pale yellow oil (772 mg, yield 30%).
1 H-NMR (CDCl 3 , δ ppm): 5.74-5.85 (1H, m), 5.00-5.10 (2H, m), 2.81-2.86 (2H, m), 2.14-2.22 (2H, m), 1.62- 1.72 (2H, m).
（ｄ）４－（２，４，６－トリクロロピリミジン－５－イル）ブタナール
　上記で得られた化合物１１Ｃ（７７２ｍｇ、３.０７ｍｍｏｌ）のアセトン（６.０ｍｌ）、水（６.０ｍｌ）の混合溶液に、カリウム オスメート（ＩＶ）２水和物（５７ｍｇ、０.１５３ｍｍｏｌ）を加え、メタ過ヨウ素酸ナトリウム（２.０ｇ、９.２１ｍｍｏｌ）を少量ずつ添加し、室温にて攪拌した。３.５時間後、セライトろ過し、アセトンを減圧留去後、酢酸エチルで分液抽出した。有機層を５％－チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより淡黄色油状物として表題化合物１１Ｄを得た（４６２ｍｇ、収率５９％）。
1H-NMR (CDCl3,δ ppm): 9.81 (1H, s), 2.86-2.92 (2H, m), 2.57-2.61 (2H, m), 1.88-1.98 (2H, m). (D) 4- (2,4,6-trichloropyrimidin-5-yl) butanal Compound 11C (772 mg, 3.07 mmol) obtained above mixed with acetone (6.0 ml) and water (6.0 ml) To the solution was added potassium osmate (IV) dihydrate (57 mg, 0.153 mmol), sodium metaperiodate (2.0 g, 9.21 mmol) was added in portions, and the mixture was stirred at room temperature. After 3.5 hours, the mixture was filtered through Celite, and acetone was distilled off under reduced pressure, followed by separation and extraction with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution and saturated brine, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 11D as a pale yellow oil (462 mg, yield 59%).
1 H-NMR (CDCl 3 , δ ppm): 9.81 (1H, s), 2.86-2.92 (2H, m), 2.57-2.61 (2H, m), 1.88-1.98 (2H, m).
（ｅ）４－［３－（２，４－ジクロロ－７，８－ジヒドロ－５Ｈ－ピリミド［４，５－ｂ］アゼピン－９（６Ｈ）－イル）プロピル］モルホリン
　上記で得られた化合物１１Ｄ（１３９ｍｇ、０.５４９ｍｍｏｌ）のメタノール（４.０ｍｌ）溶液に、酢酸（６９.０μｌ、１.２１ｍｍｏｌ）、３－（ピロリジン－１－イル）プロパン－１－アミン（８８μｌ、０.６０４ｍｍｏｌ）、０℃にてシアノ水素化ホウ素ナトリウム（４８ｍｇ、０.７６９ｍｍｏｌ）を加え、室温にて攪拌した。３.５時間攪拌した後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１１Ｅを白色固体として得た（９１ｍｇ、収率４８％）。
1H-NMR (CDCl3,δ ppm): 3.69-3.72 (4H, m), 3.53-3.58 (4H, m), 2.82-2.86 (2H, m), 2.44 (4H, brs), 2.36 (2H, t, J = 6.5 Hz), 1.88-1.92 (4H, m), 1.73-1.83 (2H, m). (E) 4- [3- (2,4-Dichloro-7,8-dihydro-5H-pyrimido [4,5-b] azepin-9 (6H) -yl) propyl] morpholine Compound 11D obtained above To a solution of (139 mg, 0.549 mmol) in methanol (4.0 ml), acetic acid (69.0 μl, 1.21 mmol), 3- (pyrrolidin-1-yl) propan-1-amine (88 μl, 0.604 mmol), Sodium cyanoborohydride (48 mg, 0.769 mmol) was added at 0 ° C., and the mixture was stirred at room temperature. After stirring for 3.5 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 11E as a white solid (91 mg, yield 48%).
1 H-NMR (CDCl 3 , δ ppm): 3.69-3.72 (4H, m), 3.53-3.58 (4H, m), 2.82-2.86 (2H, m), 2.44 (4H, brs), 2.36 (2H, t, J = 6.5 Hz), 1.88-1.92 (4H, m), 1.73-1.83 (2H, m).
（参考例４１）
メチル ２－（２，４－ジクロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）アセテート
Figure JPOXMLDOC01-appb-C000058
 (Reference Example 41)
Methyl 2- (2,4-dichloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) acetate
Figure JPOXMLDOC01-appb-C000058
（ａ）（Ｅ）－メチル ４－（２，４，６－トリクロロピリミジン－５－イル）－２－ブタノエート
　メチル ２－（ジエトキシホスホリル）アセテートのテトラヒドロフラン溶液（４．５ｍｌ）に－７８℃にてナトリウムヘキサメチルジシラジド-テトラヒドロフラン溶液（１．０６Ｍ、０．４９ｍｌ）を加え、参考例１（ｃ）で得られた化合物（５００ｍｇ、２．２２ｍｍｏｌ）のテトラヒドロフラン（３．５ｍｌ）を滴下した。氷冷下で２時間撹拌後、飽和塩化アンモニウム水溶液で反応停止した。酢酸エチルで分液抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧除去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより淡黄色油状物として表題化合物１２Ａを得た（２８５ｍｇ、収率４５％）。
1H-NMR (CDCl3,δ ppm): 6.94-6.85 (1H, m,), 5.87-5.81 (1H, m), 3.77-3.71 (5H, m). (A) (E) -Methyl 4- (2,4,6-trichloropyrimidin-5-yl) -2-butanoate Methyl 2- (diethoxyphosphoryl) acetate in tetrahydrofuran (4.5 ml) at −78 ° C. Sodium hexamethyldisilazide-tetrahydrofuran solution (1.06M, 0.49 ml) was added, and tetrahydrofuran (3.5 ml) of the compound (500 mg, 2.22 mmol) obtained in Reference Example 1 (c) was added dropwise. . After stirring for 2 hours under ice cooling, the reaction was quenched with saturated aqueous ammonium chloride. After separation and extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 12A as a pale yellow oil (285 mg, yield 45%).
1 H-NMR (CDCl 3 , δ ppm): 6.94-6.85 (1H, m,), 5.87-5.81 (1H, m), 3.77-3.71 (5H, m).
（ｂ）メチル ２－（２，４－ジクロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）アセテート
　上記で得た化合物（２８５ｍｇ、１．０１ｍｍｏｌ）の１，４－ジオキサン溶液（４．０ｍｌ）に３－アミノプロピルモルホリン（０．１８ｍｌ、１．２１ｍｍｏｌ）とＮ，Ｎ－ジイソプロピルエチルアミン（０．３６ｍｌ、２．０２ｍｍｏｌ）を加え、室温にて撹拌した。１１時間後、反応液に飽和食塩水を加え反応停止し、酢酸エチルにて分液抽出した。有機層を硫酸マグネシウムで乾燥後、減圧乾燥した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製した。得られた油状物をテトラヒドロフラン（５．０ｍｌ）に溶解し、氷浴下で水素化ナトリウム（４６ｍｇ、１．０４ｍｍｏｌ）加え室温で１．５時間撹拌した。反応を水で停止後、酢酸エチルにて分液抽出した。有機層を硫酸マグネシウムで乾燥後、減圧乾燥した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより、表題化合物１２Ｂを無色油状物として得た（８０ｍｇ、収率１５％）。
1H-NMR (CDCl3,δ ppm): 4.41-4.31 (1H, m), 3.78-3.66 (8H, m), 3.34-3.24 (1H, m), 3.21-3.11 (1H, m), 2.90-2.72 (2H, m), 2.55-2.47 (1H, m), 2.40-2.31 (6H, m), 1.85-1.67 (2H, m). (B) Methyl 2- (2,4-dichloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) acetate Compound obtained above (285 mg, 1.01 mmol) in 1,4-dioxane solution (4.0 ml) and 3-aminopropylmorpholine (0.18 ml, 1.21 mmol) and N, N-diisopropylethylamine (0.36 ml, 2.02 mmol) And stirred at room temperature. After 11 hours, the reaction solution was quenched with saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate). The obtained oil was dissolved in tetrahydrofuran (5.0 ml), sodium hydride (46 mg, 1.04 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 1.5 hr. The reaction was stopped with water, followed by liquid separation extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 12B as a colorless oil (80 mg, yield 15%).
1 H-NMR (CDCl 3 , δ ppm): 4.41-4.31 (1H, m), 3.78-3.66 (8H, m), 3.34-3.24 (1H, m), 3.21-3.11 (1H, m), 2.90- 2.72 (2H, m), 2.55-2.47 (1H, m), 2.40-2.31 (6H, m), 1.85-1.67 (2H, m).
（参考例４２）
４－（３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）ブチル）モルホリン
Figure JPOXMLDOC01-appb-C000059
 　参考例１（ｃ）で得られた化合物１Ｃと対応する試薬を用い、参考例１（ｄ）に記載の方法と同様に反応・処理して表題の化合物を無色油状物として得た（３４５ｍｇ、収率７８％）。
1H-NMR (CDCl3,δ ppm): 4.37-4.30 (1H, m), 3.68-3.57 (6H, m), 3.00 (2H, t, J = 8.7 Hz), 2.42-2.26 (6H, m), 1.81-1.56 (5H, m). (Reference Example 42)
4- (3- (2,4-Dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) butyl) morpholine
Figure JPOXMLDOC01-appb-C000059
 The title compound was obtained as a colorless oil by reacting and treating in the same manner as described in Reference Example 1 (d) using the corresponding reagent of Compound 1C obtained in Reference Example 1 (c) (345 mg, Yield 78%).
1 H-NMR (CDCl 3 , δ ppm): 4.37-4.30 (1H, m), 3.68-3.57 (6H, m), 3.00 (2H, t, J = 8.7 Hz), 2.42-2.26 (6H, m) , 1.81-1.56 (5H, m).
（参考例４３）
２－（４，６－ジクロロピリミジン－５－イル）アセトアルデヒド
Figure JPOXMLDOC01-appb-C000060
 (Reference Example 43)
2- (4,6-Dichloropyrimidin-5-yl) acetaldehyde
Figure JPOXMLDOC01-appb-C000060
（ａ）５－アリルピリミジン－４，６－ジオール
　ホルムアミジン酢酸塩（５．２０ｇ、４９．９４ｍｍｏｌ）とアリルジエチルマロネート（１０．０ｇ、４９．９４ｍｍｏｌ）、２１％ナトリウムエトキシド／エタノール溶液（３２．４ｇ、９９．８８ｍｍｏｌ）を用いて参考例１（ａ）と同様の方法により表題化合物１３Ａを淡黄色固体として得た（１．２５ｇ、収率７２％）。
1H-NMR (DMSO-d6,δ ppm): 7.91 (1H, s), 5.82-5.70 (1H, m), 4.96-4.85 (2H, m), 2.98-2.96 (2H, m). (A) 5-allylpyrimidine-4,6-diol formamidine acetate (5.20 g, 49.94 mmol) and allyl diethyl malonate (10.0 g, 49.94 mmol), 21% sodium ethoxide / ethanol solution ( The title compound 13A was obtained as a pale yellow solid in the same manner as in Reference Example 1 (a) using 32.4 g (99.88 mmol) (1.25 g, yield 72%).
1 H-NMR (DMSO-d 6 , δ ppm): 7.91 (1H, s), 5.82-5.70 (1H, m), 4.96-4.85 (2H, m), 2.98-2.96 (2H, m).
（ｂ）５－アリル－４，６－ジクロロピリミジン
　上記で得た化合物（４．２０ｇ、２７．６ｍｍｏｌ）を用いて参考例１（ｂ）と同様の方法により表題化合物１３Ｂ淡黄色油状物として得た（４．７４ｇ、収率９０％）。
1H-NMR (CDCl3,δ ppm): 8.64 (1H, s), 5.90-5.79 (1H, m), 5.18-5.08 (1H, m), 3.66-3.63 (2H, m). (B) 5-allyl-4,6-dichloropyrimidine Using the compound obtained above (4.20 g, 27.6 mmol), the title compound 13B was obtained as a pale yellow oil by the same method as in Reference Example 1 (b). (4.74 g, yield 90%).
1 H-NMR (CDCl 3 , δ ppm): 8.64 (1H, s), 5.90-5.79 (1H, m), 5.18-5.08 (1H, m), 3.66-3.63 (2H, m).
（ｃ）２－（４，６－ジクロロピリミジン－５－イル）アセトアルデヒド
　上記で得た化合物（５００ｍｇ、２．６５ｍｍｏｌ）のジオキサン／水（３／１、２４．０ｍｌ）溶液に２，６－ルチジン（０．６２ｍｌ、５．３０ｍｍｏｌ）を加えたのち、氷浴下にてカリウム オスメート（ＩＶ）２水和物（１９．０ｍｇ、０．０５２９ｍｍｏｌ）を加え、メタ過ヨウ素酸ナトリウム（２．２７ｇ、１０．６ｍｍｏｌ）を少量ずつ添加し、室温で攪拌した。２４時間後セライトろ過し、酢酸エチルで分液抽出した。有機層を１０％－チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１Ｃを白色個体として得た（４１２ｍｇ、収率８１％）。
1H-NMR (CDCl3,δ ppm): 9.79 (1H, m), 8.72 (1H, s), 4.14 (2H, s). (C) 2- (4,6-Dichloropyrimidin-5-yl) acetaldehyde To a solution of the compound obtained above (500 mg, 2.65 mmol) in dioxane / water (3/1, 24.0 ml), 2,6-lutidine (0.62 ml, 5.30 mmol) followed by potassium osmate (IV) dihydrate (19.0 mg, 0.0529 mmol) in an ice bath and sodium metaperiodate (2.27 g, 10.6 mmol) was added in small portions and stirred at room temperature. After 24 hours, the mixture was filtered through Celite, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 1C as a white solid (412 mg, yield 81%).
1 H-NMR (CDCl 3 , δ ppm): 9.79 (1H, m), 8.72 (1H, s), 4.14 (2H, s).
（参考例４４）
２－（４，６－ジクロロ－２－メチルピリミジン－５－イル）アセトアルデヒド
Figure JPOXMLDOC01-appb-C000061
 (Reference Example 44)
2- (4,6-Dichloro-2-methylpyrimidin-5-yl) acetaldehyde
Figure JPOXMLDOC01-appb-C000061
（ａ）５－アリル－２－メチルピリミジン－４，６－ジオール
　アセトアミジン塩酸塩（４．７ｇ、４９．９ｍｍｏｌ）とアリルジエチルマロネート（１０．０ｇ、４９．９ｍｍｏｌ）を用いて参考例１（ａ）と同様の方法により表題化合物１４Ａを白色固体として得た（４．４ｇ、収率５３％）。
1H-NMR (DMSO-d6,δ ppm): 11.65 (1H, s), 5.82-5.69 (1H, m), 4.92-4.82 (2H, m), 2.94-2.92 (2H, m), 2.19 (3H, s). (A) Reference Example 1 using 5-allyl-2-methylpyrimidine-4,6-diol acetamidine hydrochloride (4.7 g, 49.9 mmol) and allyl diethyl malonate (10.0 g, 49.9 mmol) The title compound 14A was obtained as a white solid by the same method as (a) (4.4 g, yield 53%).
1 H-NMR (DMSO-d 6 , δ ppm): 11.65 (1H, s), 5.82-5.69 (1H, m), 4.92-4.82 (2H, m), 2.94-2.92 (2H, m), 2.19 ( 3H, s).
（ｂ）５－アリル－４，６－ジクロロ－２－メチルピリミジン
　上記で得た化合物（４．４０ｇ、２６．５ｍｍｏｌ）を用いて参考例１（ｂ）と同様の方法により表題化合物１４Ｂを淡黄色油状物として得た（４．７ｇ、収率８８％）。
1H-NMR (CDCl3,δ ppm): 5.91-5.77 (1H, m), 5.16-5.05 (2H, m), 3.61-3.58 (2H, m), 2.65 (3H, s). (B) 5-allyl-4,6-dichloro-2-methylpyrimidine Using the compound obtained above (4.40 g, 26.5 mmol), the title compound 14B was palely synthesized in the same manner as in Reference Example 1 (b). Obtained as a yellow oil (4.7 g, 88% yield).
1 H-NMR (CDCl 3 , δ ppm): 5.91-5.77 (1H, m), 5.16-5.05 (2H, m), 3.61-3.58 (2H, m), 2.65 (3H, s).
（ｃ）２－（４，６－ジクロロ－２－メチルピリミジン－５－イル）アセトアルデヒド
　上記で得た化合物（１．００ｇ、６．０２ｍｍｏｌ）を用いて参考例１（ｃ）と同様の方法により表題化合物１４Ｃを白色固体として得た（５３５ｍｇ、収率４３％）。
1H-NMR (CDCl3,δ ppm): 9.77 (1H, s), 4.08 (2H, s), 2.69 (3H, s). (C) 2- (4,6-Dichloro-2-methylpyrimidin-5-yl) acetaldehyde Using the compound obtained above (1.00 g, 6.02 mmol) in the same manner as in Reference Example 1 (c) The title compound 14C was obtained as a white solid (535 mg, 43% yield).
1 H-NMR (CDCl 3 , δ ppm): 9.77 (1H, s), 4.08 (2H, s), 2.69 (3H, s).
（参考例４５）
４－クロロ－７－（２－（ピロリジン－１－イル）エチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000062
 　参考例４３（ｃ）で得られた化合物１２Ｃ（１００ｍｇ、０.５２４ｍｍｏｌ）のメタノール（４.０ｍｌ）溶液に、０℃にて酢酸（５７.０μｌ、１.１５ｍｍｏｌ）、２－（ピロリジン－１－イル）エタンアミン（７３.０μｌ、０.５７６ｍｍｏｌ）、シアノ 水素化ホウ素ナトリウム（４６.０ｍｇ、０.７３４ｍｍｏｌ）を加え、室温にて攪拌した。１７時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を白色固体として得た（６１.０ｍｇ、収率４３％）。
1H-NMR (CDCl3,δ ppm): 8.15 (1H, s), 3.71 (2H, t, J = 8.7 Hz), 3.53 (2H, t, J = 6.7 Hz), 3.03 (2H, t, J = 8.7 Hz), 2.66 (2H, t, J = 6.7 Hz), 2.54-2.51 (4H, m), 1.77-1.73 (4H, m). (Reference Example 45)
4-Chloro-7- (2- (pyrrolidin-1-yl) ethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000062
 To a solution of compound 12C (100 mg, 0.524 mmol) obtained in Reference Example 43 (c) in methanol (4.0 ml) at 0 ° C., acetic acid (57.0 μl, 1.15 mmol), 2- (pyrrolidine-1 -Yl) ethanamine (73.0 μl, 0.576 mmol) and sodium cyanoborohydride (46.0 mg, 0.734 mmol) were added and stirred at room temperature. After 17 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off 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 a white solid (61.0 mg, yield 43%).
1 H-NMR (CDCl 3 , δ ppm): 8.15 (1H, s), 3.71 (2H, t, J = 8.7 Hz), 3.53 (2H, t, J = 6.7 Hz), 3.03 (2H, t, J = 8.7 Hz), 2.66 (2H, t, J = 6.7 Hz), 2.54-2.51 (4H, m), 1.77-1.73 (4H, m).
参考例４６－５１：
　対応する原料化合物と試薬を用い、参考例４５に記載の方法と同様に反応・処理して表４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000063
 Reference Example 46-51 :
Using the corresponding starting materials and reagents, the reaction and treatment were carried out in the same manner as in the method described in Reference Example 45 to obtain the compounds shown in Table 4.
Figure JPOXMLDOC01-appb-T000063
（参考例５２）
３－（４－クロロ－２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロパナール
Figure JPOXMLDOC01-appb-C000064
 (Reference Example 52)
3- (4-Chloro-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propanal
Figure JPOXMLDOC01-appb-C000064
（ａ）４－クロロ－７－（３，３－ジエトキシプロピル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　参考例１１（ａ）で得られた化合物２Ａ（５９０ｍｇ、１.８４ｍｍｏｌ）の１，４－ジオキサン溶液（７.３６ｍｌ）に１－メチル－４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン（５８４ｍｇ、１.９３ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（２１２ｍｇ、０.１８４ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（１.８４ｍｌ、５.５２ｍｍｏｌ）を加え、マイクロウエーブ照射下１１０℃にて攪拌した。３時間後、反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、溶媒を減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１４Ａを白色個体として得た（４０１ｍｇ、収率６７％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 4.57 (1H, t, J = 5.5 Hz), 3.68-3.45 (8H, m), 3.31-3.28 (4H, m), 3.02 (2H, t, J = 8.4 Hz), 2.57-2.54 (4H, m), 2.34 (3H, s), 1.98-1.91 (2H, m), 1.19 (6H, t, J = 7.1 Hz). (A) 4-chloro-7- (3,3-diethoxypropyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine 1-methyl-4- [4- (4,4,4) was added to a solution of compound 2A obtained in Reference Example 11 (a) (590 mg, 1.84 mmol) in 1,4-dioxane (7.36 ml). 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (584 mg, 1.93 mmol), tetrakistriphenylphosphine palladium (212 mg, 0.184 mmol), 3 mol / L aqueous sodium carbonate solution ( 1.84 ml, 5.52 mmol) was added, and the mixture was stirred at 110 ° C. under microwave irradiation. After 3 hours, water was added to the reaction solution to stop the reaction, followed by separation and extraction with ethyl acetate. The organic layer is washed with saturated brine, the solvent is evaporated under reduced pressure, and the resulting residue is purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 14A as a white solid. (401 mg, 67% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 4.57 (1H, t, J = 5.5 Hz), 3.68- 3.45 (8H, m), 3.31-3.28 (4H, m), 3.02 (2H, t, J = 8.4 Hz), 2.57-2.54 (4H, m), 2.34 (3H, s), 1.98-1.91 (2H, m), 1.19 (6H, t, J = 7.1 Hz).
（ｂ）３－（４－クロロ－２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロパナール
　上記で得た化合物１５Ａ（４００ｍｇ、０．８７０ｍｍｏｌ）を用いて参考例１１（ｂ）と同様の方法により表題化合物１５Ｂを淡黄色固体として得た（３４０ｍｇ、収率１００％）。
1H-NMR (CDCl3,δ ppm): 9.86 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.79 (2H, t, J = 6.6 Hz), 3.66 (2H, t, J = 8.5 Hz), 3.31-3.28 (4H, m), 3.02 (2H, t, J = 8.5 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.57-2.54 (4H, m), 2.34 (3H, s). (B) 3- (4-Chloro-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propanal The title compound 15B was obtained as a pale yellow solid in the same manner as in Reference Example 11 (b) using the compound 15A obtained in (400 mg, 0.870 mmol) (340 mg, yield 100%).
1 H-NMR (CDCl 3 , δ ppm): 9.86 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.79 (2H, t, J = 6.6 Hz), 3.66 (2H, t, J = 8.5 Hz), 3.31-3.28 (4H, m), 3.02 (2H, t, J = 8.5 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.57-2.54 (4H, m), 2.34 (3H, s).
（参考例５３）
３－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロパナール
Figure JPOXMLDOC01-appb-C000065
 (Reference Example 53)
3- (2- (4- (4-Methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propanal
Figure JPOXMLDOC01-appb-C000065
（ａ）７－（３，３－ジエトキシプロピル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　参考例５３（ａ）で得られた化合物１５Ａ（９６５ｍｇ、２．１０ｍｍｏｌ）を用いて参考例１３（ｂ）と同様の方法を用いて表題化合物１６Ａを淡黄色固体として得た（５０７ｍｇ、収率５７％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.2 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.2 Hz), 4.59 (1H, t, J = 5.6 Hz), 3.71-3.44 (8H, m), 3.30-3.27 (4H, m), 2.99 (2H, t, J = 8.1 Hz), 2.58-2.54 (4H, m), 2.34 (3H, s), 1.99-1.92 (2H, m), 1.19 (6H, t, J = 7.1 Hz). (A) 7- (3,3-diethoxypropyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine Using the compound 15A (965 mg, 2.10 mmol) obtained in Reference Example 53 (a) and the same method as in Reference Example 13 (b), the title compound 16A was obtained as a pale yellow solid (507 mg, yield). 57%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.2 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.2 Hz), 4.59 (1H, t, J = 5.6 Hz), 3.71-3.44 (8H, m), 3.30-3.27 (4H, m), 2.99 (2H, t, J = 8.1 Hz), 2.58-2.54 (4H, m), 2.34 (3H, s) , 1.99-1.92 (2H, m), 1.19 (6H, t, J = 7.1 Hz).
（ｂ）３－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロパナール
　上記で得た化合物１６Ａ（５００ｍｇ、１．１７ｍｍｏｌ）を用いて参考例１１（ｂ）と同様の方法により表題化合物１６Ｂを淡黄色アモルファスとして得た（４１１ｍｇ、収率１００％）。
1H-NMR (CDCl3,δ ppm): 9.87 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 7.94 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.80 (2H, t, J = 6.5 Hz), 3.61 (2H, t, J = 8.4 Hz), 3.30-3.27 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.86 (2H, t, J = 6.5 Hz), 2.58-2.54 (4H, m), 2.34 (3H, s). (B) 3- (2- (4- (4-Methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propanal Compound obtained above Using 16A (500 mg, 1.17 mmol), the title compound 16B was obtained as a pale yellow amorphous product in the same manner as in Reference Example 11 (b) (411 mg, yield 100%).
1 H-NMR (CDCl 3 , δ ppm): 9.87 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 7.94 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.80 (2H, t, J = 6.5 Hz), 3.61 (2H, t, J = 8.4 Hz), 3.30-3.27 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.86 (2H, t , J = 6.5 Hz), 2.58-2.54 (4H, m), 2.34 (3H, s).
（参考例５４）
（Ｓ）－ベンジル ３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－４－（ピロリジン－１－イル）ブタノエート
Figure JPOXMLDOC01-appb-C000066
 (Reference Example 54)
(S) -Benzyl 3- (2,4-dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -4- (pyrrolidin-1-yl) butanoate
Figure JPOXMLDOC01-appb-C000066
（ａ）（Ｓ）－ベンジル ３－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－（ピロリジン－１－イル）ブタノエート
　（Ｓ）－ベンジル ３－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－オキソ－４－（ピロリジン－１－イル）ブタノエート（２.００ｇ、５.３１ｍｍｏｌ）のテトラヒドロフラン溶液（１５ｍｌ）を氷浴下、１ｍｏｌ／Ｌボラン－テトラヒドロフラン（９.７５ｍｌ、１０.６３ｍｍｏｌ）溶液に滴下し、室温にて撹拌した。３０時間後、氷浴下にて飽和硫酸水素カリウム水溶液を加えて反応を停止した。溶液を２Ｎ水酸化ナトリウム水溶液でｐＨ＝９とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧除去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１７Ａを無色油状物として得た（８８３ｍｇ、収率４６％）。
1H-NMR (CDCl3,δ ppm): 7.34-7.26 (5H, m), 5.14-5.05 (2H, m), 3.99-3.97 (1H, m), 2.77-2.70 (1H, m), 2.60-2.46 (8H, m), 1.72-1.68 (4H, m), 1.41 (9H, s). (A) (S) -benzyl 3- (tert-butoxycarbonylamino) -4- (pyrrolidin-1-yl) butanoate (S) -benzyl 3- (tert-butoxycarbonylamino) -4-oxo-4- ( A solution of pyrrolidin-1-yl) butanoate (2.00 g, 5.31 mmol) in tetrahydrofuran (15 ml) was added dropwise to a 1 mol / L borane-tetrahydrofuran (9.75 ml, 10.63 mmol) solution in an ice bath at room temperature. Stir. After 30 hours, the reaction was stopped by adding a saturated aqueous potassium hydrogen sulfate solution in an ice bath. The solution was adjusted to pH = 9 with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 17A as a colorless oil. (883 mg, 46% yield).
1 H-NMR (CDCl 3 , δ ppm): 7.34-7.26 (5H, m), 5.14-5.05 (2H, m), 3.99-3.97 (1H, m), 2.77-2.70 (1H, m), 2.60- 2.46 (8H, m), 1.72-1.68 (4H, m), 1.41 (9H, s).
（ｂ）（Ｓ）－ベンジル ３－（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－４－（ピロリジン－１－イル）ブタノエート
　上記で得られた化合物１７Ａ（４００ｍｇ、１.１０ｍｍｏｌ）に４Ｍ 塩酸－ジオキサン溶液（４.０ｍｌ）を加え、１時間撹拌した。溶媒を減圧除去後、メタノール（１０ｍｌ）に溶解した。溶液に氷浴下、酢酸（０.１５ｍｌ、２.６８ｍｍｏｌ）、参考例１（ｃ）で得られた化合物１Ｃ（３０１ｍｇ、１.３４ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１１８ｍｇ、１.８８ｍｍｏｌ）を加え、室温にて撹拌した。２９時間後、飽和炭酸水素ナトリウム水溶液にて反応停止し、クロロホルムにて分液抽出した。有機層を硫酸ナトリウムにて乾燥後、溶媒を減圧除去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物１７Ｂを白色固体として得た（５４２ｍｇ、収率９３％）。
1H-NMR (CDCl3,δ ppm): 7.36-7.25 (5H, m), 5.08-5.00 (2H, m), 3.76-3.59 (1H, m), 3.62-3.59 (2H, m), 3.01-2.60 (4H, m), 2.53-2.03 (6H, m), 1.72-1.65 (4H, m). (B) (S) -Benzyl 3- (2,4-dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -4- (pyrrolidin-1-yl) butanoate obtained above To the obtained compound 17A (400 mg, 1.10 mmol) was added 4M hydrochloric acid-dioxane solution (4.0 ml), and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and then dissolved in methanol (10 ml). In an ice bath, acetic acid (0.15 ml, 2.68 mmol), compound 1C obtained in Reference Example 1 (c) (301 mg, 1.34 mmol), sodium cyanoborohydride (118 mg, 1.88 mmol) were added to the solution. The mixture was added and stirred at room temperature. After 29 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound 17B as a white solid. (542 mg, 93% yield).
1 H-NMR (CDCl 3 , δ ppm): 7.36-7.25 (5H, m), 5.08-5.00 (2H, m), 3.76-3.59 (1H, m), 3.62-3.59 (2H, m), 3.01- 2.60 (4H, m), 2.53-2.03 (6H, m), 1.72-1.65 (4H, m).
（参考例５５）
（Ｒ）－４－ベンジル－２－（（４－クロロ－２－（４－（ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
Figure JPOXMLDOC01-appb-C000067
 (Reference Example 55)
(R) -4-benzyl-2-((4-chloro-2- (4- (piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Methyl) morpholine
Figure JPOXMLDOC01-appb-C000067
（ａ）（Ｒ）－４－ベンジル－２－（（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
　参考例１（ｃ）で得られた化合物１Ｃ（６．１９ｇ、２７．４７ｍｍｏｌ）と対応する試薬を用い、参考例１（ｄ）に記載の方法と同様に反応・処理して表題の化合物18Aを白色固体として得た（７．６７ｇ、収率７４％）。
1H-NMR (CDCl3,δ ppm): 7.31-7.27 (5H, m), 3.90-3.72 (4H, m), 3.63-3.56 (1H, m), 3.47-3.32 (4H, m), 2.99 (2H, t, J = 8.7 Hz), 2.76-2.72 (1H, m), 2.65-2.62 (1H, m), 2.18-2.09 (1H, m), 1.90-1.83 (1H, m). (A) (R) -4-benzyl-2-((2,4-dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl) morpholine In Reference Example 1 (c) The obtained compound 1C (6.19 g, 27.47 mmol) and the corresponding reagent were used for reaction and treatment in the same manner as described in Reference Example 1 (d) to obtain the title compound 18A as a white solid ( 7.67 g, yield 74%).
1 H-NMR (CDCl 3 , δ ppm): 7.31-7.27 (5H, m), 3.90-3.72 (4H, m), 3.63-3.56 (1H, m), 3.47-3.32 (4H, m), 2.99 ( 2H, t, J = 8.7 Hz), 2.76-2.72 (1H, m), 2.65-2.62 (1H, m), 2.18-2.09 (1H, m), 1.90-1.83 (1H, m).
（ｂ）（Ｒ）－４－ベンジル－２－（（４－クロロ－２－（４－（ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
　上記で得られた化合物１８Ａ（９７７ｍｇ、２．５８ｍｍｏｌ）の１，４－ジオキサン（１０．３ｍｌ）溶液に、ｔ－ブチル ４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン－１－カルボキシレート（１．００ｇ、２．５８ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（２９８ｍｇ、０．２５８ｍｍｏｌ)、３ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（２．５８ｍｌ、７．７４ｍｍｏｌ）を加え、１２０℃にて攪拌した。３０分後、反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥しろ過後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製した。得られた油状物をメタノール（３．０ｍｌ）に溶解し、２ｍｏｌ／Ｌ塩酸／メタノール（１２ｍｌ）加え、室温にて１６時間撹拌した。水を加え、水層を酢酸エチルで洗浄し、水酸化ナトリウム水溶液によりｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥し、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、表題化合物を黄色アモルファスとして得た（６６３mg、収率５１％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 9.2 Hz), 7.26 (5H, m), 6.89 (2H, d, J = 9.2 Hz), 3.87-3.42 (10H, m), 3.26-2.23 (4H, m), 3.05-2.99 (6H, m), 2.84-2.80 (1H, m), 2.65-2.61 (1H, m), 2.19-2.11 (1H, m), 2.02-1.95 (1H, m). (B) (R) -4-benzyl-2-((4-chloro-2- (4- (piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Yl) methyl) morpholine To a solution of the compound 18A obtained above (977 mg, 2.58 mmol) in 1,4-dioxane (10.3 ml) was added t-butyl 4- [4- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate (1.00 g, 2.58 mmol), tetrakistriphenylphosphine palladium (298 mg, 0.258 mmol), 3 mol / L An aqueous sodium hydroxide solution (2.58 ml, 7.74 mmol) was added, and the mixture was stirred at 120 ° C. After 30 minutes, water was added to the reaction solution to stop the reaction, followed by separation and extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate). The obtained oil was dissolved in methanol (3.0 ml), 2 mol / L hydrochloric acid / methanol (12 ml) was added, and the mixture was stirred at room temperature for 16 hr. Water was added, the aqueous layer was washed with ethyl acetate, adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a yellow amorphous substance (663 mg, yield 51%).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 9.2 Hz), 7.26 (5H, m), 6.89 (2H, d, J = 9.2 Hz), 3.87-3.42 (10H, m ), 3.26-2.23 (4H, m), 3.05-2.99 (6H, m), 2.84-2.80 (1H, m), 2.65-2.61 (1H, m), 2.19-2.11 (1H, m), 2.02-1.95 (1H, m).
（参考例５６）
（Ｓ）－４－ベンジル－２－（（２，４－ジクロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
Figure JPOXMLDOC01-appb-C000068
 　対応する原料化合物と試薬を用い、参考例１（ｄ）に記載の方法と同様に反応・処理して表題の化合物を白色固体として得た（２.３６ｇ、 収率６９％）。
1H-NMR (CDCl3,δ ppm): 7.33-7.22 (5H, m), 3.90-3.72 (4H, m), 3.64-3.56 (1H, m), 3.49-3.32 (4H, m), 2.99 (2H, t, J = 8.7 Hz), 2.74 (1H, d, J = 11.4 Hz), 2.64 (1H, dd, J = 1.8, 11.4 Hz), 2.18-2.09 (1H, m), 1.91-1.84 (1H, m). (Reference Example 56)
(S) -4-Benzyl-2-((2,4-dichloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl) morpholine
Figure JPOXMLDOC01-appb-C000068
 The title compound was obtained as a white solid (2.36 g, yield 69%) by reacting and treating in the same manner as described in Reference Example 1 (d) using the corresponding starting compounds and reagents.
1 H-NMR (CDCl 3 , δ ppm): 7.33-7.22 (5H, m), 3.90-3.72 (4H, m), 3.64-3.56 (1H, m), 3.49-3.32 (4H, m), 2.99 ( 2H, t, J = 8.7 Hz), 2.74 (1H, d, J = 11.4 Hz), 2.64 (1H, dd, J = 1.8, 11.4 Hz), 2.18-2.09 (1H, m), 1.91-1.84 (1H , m).
（参考例５７）
４－（２－（４－クロロ－２－（４－（ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）エチル）モルホリン
Figure JPOXMLDOC01-appb-C000069
 　参考例４（７００ｍｇ、２.３１ｍｍｏｌ）を用いて、参考例５５（ｂ）と同様の方法を用いて表題化合物を薄黄色固体として得た（４０３ｍｇ、４１％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.72-3.60 (8H, m), 3.25-3.22 (4H, m), 3.06-3.00 (6H, m), 2.61-2.52 (6H, m). (Reference Example 57)
4- (2- (4-Chloro-2- (4- (piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) ethyl) morpholine
Figure JPOXMLDOC01-appb-C000069
 Using Reference Example 4 (700 mg, 2.31 mmol) and using a method similar to Reference Example 55 (b), the title compound was obtained as a pale yellow solid (403 mg, 41%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.72-3.60 (8H, m), 3.25-3.22 (4H , m), 3.06-3.00 (6H, m), 2.61-2.52 (6H, m).
（参考例５８）
４－｛３－［２－（ベンジルオキシ）－４－クロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル｝モルホリン
Figure JPOXMLDOC01-appb-C000070
 　ベンジルアルコール（１８０μｌ、１.７４ｍｍｏｌ）のＴＨＦ（１０ｍｌ）溶液に、０℃にて水素化ナトリウム（８２.９ｍｇ、１.９０ｍｍｏｌ）を加え、１時間撹拌した。反応液を－５℃に冷却し、参考例５で得られた化合物（５００ｍｇ、１.５８ｍｍｏｌ）のＴＨＦ（５ｍｌ）溶液を加え、室温へ昇温して終夜攪拌した。飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで分液抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を無色ガム状物質として得た（１９３ｍｇ、収率３１％）。
1H-NMR (CDCl3,δ ppm): 7.45-7.42 (2H, m), 7.35-7.24 (3H, m), 5.31 (2H, s), 3.71-3.61 (6H, m), 3.42 (2H, t, J = 7.2 Hz), 2.95 (2H, t, J = 8.1 Hz), 2.42-2.33 (6H, m), 1.79-1.74 (2H, m). (Reference Example 58)
4- {3- [2- (benzyloxy) -4-chloro-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl} morpholine
Figure JPOXMLDOC01-appb-C000070
 Sodium hydride (82.9 mg, 1.90 mmol) was added to a THF (10 ml) solution of benzyl alcohol (180 μl, 1.74 mmol) at 0 ° C., and the mixture was stirred for 1 hour. The reaction mixture was cooled to −5 ° C., a solution of the compound obtained in Reference Example 5 (500 mg, 1.58 mmol) in THF (5 ml) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction was stopped with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off 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 a colorless gum (193 mg, yield 31%).
1 H-NMR (CDCl 3 , δ ppm): 7.45-7.42 (2H, m), 7.35-7.24 (3H, m), 5.31 (2H, s), 3.71-3.61 (6H, m), 3.42 (2H, t, J = 7.2 Hz), 2.95 (2H, t, J = 8.1 Hz), 2.42-2.33 (6H, m), 1.79-1.74 (2H, m).
参考例５９－６０：
　対応する原料化合物と試薬を用い、参考例５８に記載の方法と同様に反応・処理して表５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000071
 Reference Example 59-60 :
The corresponding starting materials and reagents were used and reacted and treated in the same manner as in the method described in Reference Example 58 to obtain the compounds shown in Table 5.
Figure JPOXMLDOC01-appb-T000071
（実施例１）
３－｛４－クロロ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝－Ｎ，Ｎ－ジメチルプロパン－１－アミン
Figure JPOXMLDOC01-appb-C000072
 　参考例１で得た化合物１Ｄ（４００ｍｇ、１.５６ｍｍｏｌ）の１，４－ジオキサン（６.２ｍｌ）溶液に、１－メチル－４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン（４７０ｍｇ、１.５６ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１８０ｍｇ、０.１５６ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（１.５５ｍｌ、４.６７ｍｍｏｌ）を加え、マイクロウエーブ照射下１２０℃にて攪拌した。２時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１０とし、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→酢酸エチル：クロロホルム）で精製した。得られた固体をジエチルエーテル／ヘキサンでリパルプ洗浄することにより表題化合物を白色固体として得た（１６７ｍｇ、収率２６％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.63 (2H, t, J = 8.6 Hz), 3.51 (2H, t, J = 7.2 Hz), 3.28-3.31 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.54-2.57 (4H, m), 2.29-2.34 (2H, m), 2.33 (3H, s), 2.22 (6H, s), 1.74-1.84 (2H, m). Example 1
3- {4-Chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} -N, N-dimethyl Propan-1-amine
Figure JPOXMLDOC01-appb-C000072
 To a solution of compound 1D (400 mg, 1.56 mmol) obtained in Reference Example 1 in 1,4-dioxane (6.2 ml), 1-methyl-4- [4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] piperazine (470 mg, 1.56 mmol), tetrakistriphenylphosphine palladium (180 mg, 0.156 mmol), 3 mol / L aqueous sodium carbonate (1.55 ml, 4.67 mmol) And stirred at 120 ° C. under microwave irradiation. After 2 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → ethyl acetate: chloroform). The obtained solid was repulped with diethyl ether / hexane to give the title compound as a white solid (167 mg, yield 26%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.63 (2H, t, J = 8.6 Hz), 3.51 ( 2H, t, J = 7.2 Hz), 3.28-3.31 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.54-2.57 (4H, m), 2.29-2.34 (2H, m), 2.33 (3H, s), 2.22 (6H, s), 1.74-1.84 (2H, m).
　　実施例２－２０：
　対応する原料化合物と試薬を用いて実施例１と同様に反応・処理し、表６に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
 Example 2-20 :
The corresponding starting materials and reagents were used for the reaction and treatment in the same manner as in Example 1 to obtain the compounds shown in Table 6.
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
（実施例２１）
４－クロロ－２－［４－（ピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000077
 　参考例３で得た化合物（２００ｍｇ、０.６６４ｍｍｏｌ）の１，４－ジオキサン（２.６５ｍｌ）溶液に、ｔ－ブチル ４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン－１－カルボキシレート（２７０ｍｇ、０.６９７ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（７７.０ｍｇ、０.０６６４ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０.６６ｍｌ、１.９９ｍｍｏｌ）を加え、１２０℃にて攪拌した。５時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥しろ過後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製した。得られた油状物をメタノール（１.０ｍｌ）に溶解し、４Ｍ塩酸／１，４－ジオキサン（３.０ｍｌ）加え、室温にて２時間撹拌した。水を加え、水層を酢酸エチルで洗浄し、水酸化ナトリウム水溶液によりｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムにより乾燥し、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、表題化合物を黄色油状物として得た（１５４ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.65 (2H, t, J = 8.6 Hz), 3.55 (2H, t, J = 6.9 Hz), 3.30-3.34 (2H, m), 3.21-3.25 (4H, m), 3.00-3.06 (6H, m), 2.62 (5H, brs), 1.84-1.94 (6H, m). (Example 21)
4-Chloro-2- [4- (piperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] Pyrimidine
Figure JPOXMLDOC01-appb-C000077
 To a solution of the compound obtained in Reference Example 3 (200 mg, 0.664 mmol) in 1,4-dioxane (2.65 ml), t-butyl 4- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate (270 mg, 0.697 mmol), tetrakistriphenylphosphine palladium (77.0 mg, 0.0664 mmol), 3 mol / L aqueous sodium carbonate solution (0.0. 66 ml, 1.99 mmol) was added and stirred at 120 ° C. After 5 hours, aqueous hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol). The obtained oil was dissolved in methanol (1.0 ml), 4M hydrochloric acid / 1,4-dioxane (3.0 ml) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, the aqueous layer was washed with ethyl acetate, adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a yellow oil (154 mg, yield 56%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.65 (2H, t, J = 8.6 Hz), 3.55 ( 2H, t, J = 6.9 Hz), 3.30-3.34 (2H, m), 3.21-3.25 (4H, m), 3.00-3.06 (6H, m), 2.62 (5H, brs), 1.84-1.94 (6H, m).
　　実施例２２－３２：
　対応する原料化合物と試薬を用い、実施例２１に記載の方法と同様に反応・処理して表７に示す化合物を得た。 Examples 22-32 :
The corresponding starting materials and reagents were used and reacted and treated in the same manner as in Example 21 to give the compounds shown in Table 7.
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
（実施例３３）
４－（４－｛４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）－１－メチルピペリジン－４－オール
Figure JPOXMLDOC01-appb-C000080
 　実施例２２で得た化合物（６０.０ｍｇ、０.１３６ｍｍｏｌ）のメタノール溶液（１.５ｍｌ）に酢酸（１４μｌ、０.２４８ｍｍｏｌ）、３５％ ホルムアルデヒド水溶液（４５μｌ、１.２２ｍｍｏｌ）、水素化ホウ素ナトリウム（１５ｍｇ、０.２３８ｍｍｏｌ）を加え、室温にて攪拌した。１時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧蒸留した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：酢酸エチル）で精製し、得られた残渣をジエチルエーテルで洗浄することにより表題化合物を白色固体として得た（３８ｍｇ、収率６７％）。
1H-NMR (CDCl3,δ ppm): 8.30 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz), 3.70 (2H, t, J = 8.6Hz), 3.57 (2H, t, J = 7.0 Hz), 3.06 (2H, t, J = 8.6 Hz), 2.72-2.86 (8H, m), 2.44 (3H, s), 2.33 (1H, brs), 1.67-1.89 (12H, m). (Example 33)
4- (4- {4-Chloro-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl)- 1-methylpiperidin-4-ol
Figure JPOXMLDOC01-appb-C000080
 Acetic acid (14 μl, 0.248 mmol), 35% aqueous formaldehyde solution (45 μl, 1.22 mmol), sodium borohydride in a methanol solution (1.5 ml) of the compound obtained in Example 22 (60.0 mg, 0.136 mmol) (15 mg, 0.238 mmol) was added and stirred at room temperature. After 1 hour, the reaction was stopped with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate), and the obtained residue was washed with diethyl ether to give the title compound as a white solid (38 mg, yield 67). %).
1 H-NMR (CDCl 3 , δ ppm): 8.30 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz), 3.70 (2H, t, J = 8.6 Hz), 3.57 ( 2H, t, J = 7.0 Hz), 3.06 (2H, t, J = 8.6 Hz), 2.72-2.86 (8H, m), 2.44 (3H, s), 2.33 (1H, brs), 1.67-1.89 (12H , m).
　　実施例３４－３７：
　対応する原料化合物と試薬を用い、実施例３３に記載の方法と同様に反応・処理して表８に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000082
 Examples 34-37 :
The corresponding starting materials and reagents were used and reacted and treated in the same manner as in Example 33 to give the compounds shown in Table 8.
Figure JPOXMLDOC01-appb-T000082
（実施例３８）
４－クロロ－２－［４－（４－エチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000083
 　実施例２１で得た化合物（６４.０ｍｇ、０.１５０ｍｍｏｌ）のジクロロメタン／メタノール（２.０ｍｌ／０.５０ｍｌ）溶液に、アセトアルデヒド（１７.０μｌ、０.３００ｍｍｏｌ）とトリアセトキシボロヒドリド（６４.０ｍｇ、０.３００ｍｍｏｌ）を加えて、室温下２時間撹拌した。飽和炭酸水素ナトリウム水溶液で反応停止し、クロロホルムで分液抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥し、ろ過後減圧濃縮し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：酢酸エチル）で精製し、表題化合物を黄色油状物として得た（４０.０ｍｇ、収率５８％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.67 (2H, t, J = 8.6 Hz), 3.56 (2H, t, J = 6.2 Hz), 3.01-3.33 (4H, m), 3.04 (2H, t, J = 8.6 Hz), 2.58-2.75 (4H, m), 2.47 (2H, q, J = 7.0 Hz), 1.91-2.02 (6H, m), 1.56 (6H, brs), 1.12 (3H, t, J = 7.0 Hz). (Example 38)
4-Chloro-2- [4- (4-ethylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine
Figure JPOXMLDOC01-appb-C000083
 To a solution of the compound obtained in Example 21 (64.0 mg, 0.150 mmol) in dichloromethane / methanol (2.0 ml / 0.50 ml), acetaldehyde (17.0 μl, 0.300 mmol) and triacetoxyborohydride (64. 0 mg, 0.300 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying over magnesium sulfate, filtration and concentration under reduced pressure, the resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate) to obtain the title compound as a yellow oil (40.0 mg, yield). Rate 58%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.67 (2H, t, J = 8.6 Hz), 3.56 ( 2H, t, J = 6.2 Hz), 3.01-3.33 (4H, m), 3.04 (2H, t, J = 8.6 Hz), 2.58-2.75 (4H, m), 2.47 (2H, q, J = 7.0 Hz ), 1.91-2.02 (6H, m), 1.56 (6H, brs), 1.12 (3H, t, J = 7.0 Hz).
（実施例３９）
Ｎ，Ｎ－ジメチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン
Figure JPOXMLDOC01-appb-C000084
 　実施例１で得た化合物（１００ｍｇ、０.２４１ｍｍｏｌ）のメタノール（４.０ｍｌ）溶液に、１０％パラジウム炭素（５０％含水）（３０ｍｇ）、トリフルオロ酢酸（３滴）を加え、水素雰囲気下（０.４ＭＰａ）４０℃にて攪拌した。６時間後、反応溶液をセライトろ過し、減圧濃縮した。得られた残渣をメタノールに希釈し、トリエチルアミンを加え中和後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：酢酸エチル）で精製することにより表題化合物を白色固体として得た（５３.３ｍｇ、収率５８％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.58 (2H, t, J = 8.4 Hz), 3.50 (2H, t, J = 7.2 Hz), 3.26-3.29 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.54-2.57 (4H, m), 2.30-2.35 (2H, m), 2.33 (3H, s), 2.22 (6H, s), 1.75-1.84 (2H, m). (Example 39)
N, N-dimethyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propane-1- Amine
Figure JPOXMLDOC01-appb-C000084
 To a solution of the compound obtained in Example 1 (100 mg, 0.241 mmol) in methanol (4.0 ml), 10% palladium on carbon (containing 50% water) (30 mg) and trifluoroacetic acid (3 drops) were added. (0.4 MPa) The mixture was stirred at 40 ° C. After 6 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained residue was diluted with methanol, neutralized with triethylamine, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: ethyl acetate) to give the title compound as a white solid (53.3 mg, yield 58%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.58 (2H, t, J = 8.4 Hz), 3.50 (2H, t, J = 7.2 Hz), 3.26-3.29 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.54-2.57 (4H, m), 2.30-2.35 (2H, m), 2.33 (3H, s), 2.22 (6H, s), 1.75-1.84 (2H, m).
　　実施例４０－６８：
　対応する原料化合物と試薬を用いて実施例３９と同様に反応・処理し、表９に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
 Examples 40-68 :
Reaction and treatment were carried out in the same manner as in Example 39 using the corresponding starting materials and reagents, and the compounds shown in Table 9 were obtained.
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
（実施例６９）
４－（２－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エチル）モルホリン
Figure JPOXMLDOC01-appb-C000091
 　実施例３で得た化合物（１３１ｍｇ、０.２９６ｍｍｏｌ）の メタノール（５.０ｍｌ）溶液に、蟻酸アンモニウム（１８７ｍｇ、２.９６ｍｍｏｌ）、１０％パラジウム炭素（５０％含水）（１００ｍｇ）、トリフルオロ酢酸（３滴）を加え、５０℃にて攪拌した。２時間後、室温へ放冷した後、反応溶液をセライトろ過し、減圧濃縮した。得られた残渣を酢酸エチルに希釈し、飽和炭酸水素ナトリウム水溶液を加えて分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：メタノール）にて精製することにより表題化合物を白色固体として得た（６４.６ｍｇ、収率５３％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 8.7 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 8.7 Hz), 3.61-3.68 (8H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.4 Hz), 2.54-2.63 (10H, m), 2.34 (3H, s). (Example 69)
4- (2- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethyl) morpholine
Figure JPOXMLDOC01-appb-C000091
 To a solution of the compound obtained in Example 3 (131 mg, 0.296 mmol) in methanol (5.0 ml), ammonium formate (187 mg, 2.96 mmol), 10% palladium carbon (containing 50% water) (100 mg), trifluoroacetic acid (3 drops) was added and stirred at 50 ° C. After 2 hours, the reaction solution was allowed to cool to room temperature, filtered through Celite, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added for liquid separation extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: methanol) to give the title compound as a white solid (64.6 mg, yield 53%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 8.7 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 8.7 Hz), 3.61-3.68 (8H, m ), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.4 Hz), 2.54-2.63 (10H, m), 2.34 (3H, s).
　　実施例７０－７４：
　対応する原料化合物と試薬を用いて実施例６９と同様に反応・処理し、表１０に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
 Examples 70-74 :
Reaction and treatment were carried out in the same manner as in Example 69 using the corresponding starting materials and reagents, and the compounds shown in Table 10 were obtained.
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
（実施例７５）
４－（３－｛２－［２－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000094
 (Example 75)
4- (3- {2- [2- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000094
（ａ）ｔ－ブチル ４－（２－（４－クロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　参考例５で得た化合物（１００ｍｇ、０.３１５ｍｍｏｌ）の１，４－ジオキサン（１.２６ｍｌ）溶液に、ｔ－ブチル ４－［２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン－１－カルボキシレート（１２８ｍｇ、０.３３１ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（３６ｍｇ、０.０３２ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０.３２ｍｌ、０.９９３ｍｍｏｌ）を加え、マイクロウエーブ照射下１１０℃にて攪拌した。１時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝９とし、クロロホルムで分液抽出した。有機層を硫酸マグネシウムで乾燥後、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を白色アモルファスとして得た（１５５ｍｇ、収率９１％）。
1H-NMR (CDCl3,δ ppm): 7.54-7.59 (2H, m), 7.25-7.29 (1H, m), 6.96-7.04 (2H, m), 3.65-3.71 (6H, m), 3.48 (2H, t, J = 7.5 Hz), 3.41-3.44 (4H, m), 3.08 (2H, t, J = 8.5 Hz), 2.89-2.92 (4H, m), 2.34-2.40 (6H, m), 1.76-1.81 (2H, m), 1.43 (9H, s). (A) t-butyl 4- (2- (4-chloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine -1-Carboxylate To a solution of the compound obtained in Reference Example 5 (100 mg, 0.315 mmol) in 1,4-dioxane (1.26 ml) was added t-butyl 4- [2- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate (128 mg, 0.331 mmol), tetrakistriphenylphosphine palladium (36 mg, 0.032 mmol), 3 mol / L aqueous sodium carbonate solution (0.32 ml, 0.993 mmol) was added and stirred at 110 ° C. under microwave irradiation. After 1 hour, hydrochloric acid was added to the reaction solution to stop the reaction, and the reaction solution was washed with ethyl acetate. The aqueous layer was adjusted to pH = 9 with an aqueous sodium hydroxide solution and subjected to liquid separation extraction with chloroform. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a white amorphous substance (155 mg, Yield 91%).
1 H-NMR (CDCl 3 , δ ppm): 7.54-7.59 (2H, m), 7.25-7.29 (1H, m), 6.96-7.04 (2H, m), 3.65-3.71 (6H, m), 3.48 ( 2H, t, J = 7.5 Hz), 3.41-3.44 (4H, m), 3.08 (2H, t, J = 8.5 Hz), 2.89-2.92 (4H, m), 2.34-2.40 (6H, m), 1.76 -1.81 (2H, m), 1.43 (9H, s).
（ｂ）ｔ－ブチル ４－（２－（７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記（ａ）で得た化合物（１５０ｍｇ、０.２７６ｍｍｏｌ）のメタノール溶液に蟻酸アンモニウム（８７.０ｍｇ、１.３８ｍｍｏｌ）と１０％パラジウム炭素（５０％含水）（１２７ｍｇ）を加え、５０℃にて５時間撹拌した。反応溶液を室温に放冷後、セライトろ過し、ろ液を減圧濃縮した。残渣を酢酸エチルに溶解し、１ｍｏｌ／Ｌ塩酸水溶液で抽出し、水層を酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した後、硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を白色アモルファスとして得た（６５.０ｍｇ、収率４６％）。
1H-NMR (CDCl3,δ ppm): 7.97 (1H, s), 7.47-7.50 (1H, m), 7.30-7.25 (1H, m), 6.95-7.04 (2H, m), 3.61-3.69 (6H, m), 3.48 (2H, t, J = 7.2 Hz), 3.36-3.40 (4H, m), 3.04 (2H, t, J = 8.3 Hz), 2.87-2.90 (4H, m), 2.35-2.40 (6H, m), 1.77-1.82 (2H, m), 1.43 (9H, s). (B) t-butyl 4- (2- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine-1-carboxyl Rate Ammonium formate (87.0 mg, 1.38 mmol) and 10% palladium carbon (containing 50% water) (127 mg) were added to a methanol solution of the compound obtained in (a) (150 mg, 0.276 mmol), and the mixture was heated to 50 ° C. And stirred for 5 hours. The reaction solution was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, extracted with 1 mol / L aqueous hydrochloric acid solution, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, extracted with ethyl acetate, dried over magnesium 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 a white amorphous (65.0 mg, yield 46%).
1 H-NMR (CDCl 3 , δ ppm): 7.97 (1H, s), 7.47-7.50 (1H, m), 7.30-7.25 (1H, m), 6.95-7.04 (2H, m), 3.61-3.69 ( 6H, m), 3.48 (2H, t, J = 7.2 Hz), 3.36-3.40 (4H, m), 3.04 (2H, t, J = 8.3 Hz), 2.87-2.90 (4H, m), 2.35-2.40 (6H, m), 1.77-1.82 (2H, m), 1.43 (9H, s).
（ｃ）４－（３－｛２－［２－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
　上記（ｂ）で得た化合物（６５.０ｍｇ、０.１２８ｍｍｏｌ）をＴＨＦ（２.０ｍｌ）に溶解し、リチウムアルミニウムヒドリド（１４.０ｍｇ、０.３８３ｍｍｏｌ）を加え、８０℃加熱還流下で２.５時間撹拌した。反応溶液を室温に放冷し、水（１４μｌ）、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１４μｌ）、水（２８μｌ）を加えた。セライトろ過後、溶液を酢酸エチルで分液抽出した。硫酸マグネシウムで乾燥後、ろ過し減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム）で精製し、表題化合物を淡黄色アモルファスとして得た（２３.０ｍｇ、収率４３％）。
1H-NMR (CDCl3,δ ppm): 7.98 (1H, s), 7.47 (1H, dd, J = 7.9 Hz, 1.7 Hz), 7.28 (1H, m), 6.98 (2H, m), 3.60-3.69 (6H, m), 3.49 (2H, J = 7.2 Hz), 3.04 (2H, t, J = 8.3 Hz), 2.95-2.98 (4H, m), 2.36-2.41 (10H, m), 2.26 (3H, s), 1.79-1.86 (2H, m). (C) 4- (3- {2- [2- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine The compound obtained in (b) (65.0 mg, 0.128 mmol) was dissolved in THF (2.0 ml), lithium aluminum hydride (14.0 mg, 0.383 mmol) was added, and the mixture was heated under reflux at 80 ° C. for 2. Stir for 5 hours. The reaction solution was allowed to cool to room temperature, and water (14 μl), 2 mol / L aqueous sodium hydroxide solution (14 μl), and water (28 μl) were added. After filtration through celite, the solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by amino silica gel chromatography (elution solvent: chloroform) to obtain the title compound as a pale yellow amorphous (23.0 mg, 43% yield).
1 H-NMR (CDCl 3 , δ ppm): 7.98 (1H, s), 7.47 (1H, dd, J = 7.9 Hz, 1.7 Hz), 7.28 (1H, m), 6.98 (2H, m), 3.60- 3.69 (6H, m), 3.49 (2H, J = 7.2 Hz), 3.04 (2H, t, J = 8.3 Hz), 2.95-2.98 (4H, m), 2.36-2.41 (10H, m), 2.26 (3H , s), 1.79-1.86 (2H, m).
（実施例７６）
４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000095
 (Example 76)
4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000095
（ａ）１－（４－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノン
　実施例５９で得た化合物（７８.０ｍｇ、０.１９１ｍｍｏｌ）のジクロロメタン（２.０ｍｌ）に氷冷下でアセチルクロライド（１５μｌ、０.２１０ｍｍｏｌ）を加え、１時間撹拌した。氷冷下で飽和炭酸水素ナトリウム水溶液を加え、溶液をクロロホルムで分液抽出した。硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物を無色固体として得た（６３.０ｍｇ、収率７３％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.75-3.78 (2H, m),  3.70-3.73 (4H, m), 3.52-3.63 (6H, m), 3.22-3.29 (4H, m),  3.01 (2H, t, J = 8.1 Hz), 2.39-2.44 (6H, m), 2.13 (3H, s), 1.77-1.86 (2H, m). (A) 1- (4- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazin-1-yl ) Ethanone Acetyl chloride (15 μl, 0.210 mmol) was added to dichloromethane (2.0 ml) of the compound obtained in Example 59 (78.0 mg, 0.191 mmol) under ice-cooling and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, and the solution was subjected to liquid separation extraction with chloroform. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a colorless solid (63.0 mg, yield 73%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.75-3.78 (2H, m) , 3.70-3.73 (4H, m), 3.52-3.63 (6H, m), 3.22-3.29 (4H, m), 3.01 (2H, t, J = 8.1 Hz), 2.39-2.44 (6H, m), 2.13 (3H, s), 1.77-1.86 (2H, m).
（ｂ）４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
　上記（ａ）で得た化合物（４９.０ｍｇ、０.１０９ｍｍｏｌ）をＴＨＦ（２.０ｍｌ）に溶解し、リチウムアルミニウムヒドリド（１２.０ｍｇ、０.３２６ｍｍｏｌ）を加え、８０℃加熱還流下で２.５時間撹拌した。反応溶液を室温に放冷し、水（１２μｌ）、２Ｎ水酸化ナトリウム水溶液（１２μｌ）、水（２４μｌ）を加えた。セライトろ過後、溶液を酢酸エチルで分液抽出した。硫酸マグネシウムで乾燥後、ろ過し減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：メタノール）で精製し、表題化合物を無色油状物として得た（２６.０ｍｇ、収率５４％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.70-3.72 (4H, m),  3.51-3.59 (4H, m), 3.28-3.31 (4H, m), 3.00 (2H, t, J = 7.2 Hz), 2.58-2.61 (4H, m), 2.39-2.50 (8H, m), 1.79-1.83 (2H, m), 1.12 (3H, t, J = 7.2 Hz). (B) 4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine The compound obtained in (a) (49.0 mg, 0.109 mmol) was dissolved in THF (2.0 ml), lithium aluminum hydride (12.0 mg, 0.326 mmol) was added, and the mixture was heated under reflux at 80 ° C. for 2. Stir for 5 hours. The reaction solution was allowed to cool to room temperature, and water (12 μl), 2N aqueous sodium hydroxide solution (12 μl), and water (24 μl) were added. After filtration through celite, the solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: methanol) to obtain the title compound as a colorless oil (26.0 mg, yield 54%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.70-3.72 (4H, m) , 3.51-3.59 (4H, m), 3.28-3.31 (4H, m), 3.00 (2H, t, J = 7.2 Hz), 2.58-2.61 (4H, m), 2.39-2.50 (8H, m), 1.79 -1.83 (2H, m), 1.12 (3H, t, J = 7.2 Hz).
（実施例７７）
２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000096
 (Example 77)
2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000096
（ａ）２－メトキシ－１－［４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－イル］エタノン
　実施例５１の化合物と２－メトキシアセチルクロライド（１５.０μｌ、０.１６３ｍｍｏｌ）を用いて実施例７６（ａ）と同様の方法にて合成することにより、表題化合物を淡黄色油状物として得た（５３.０ｍｇ、収率７７％）。
1H-NMR (CDCl3,δ ppm): 8.27 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.75-3.78 (2H, m), 3.51-3.66 (6H, m), 3.43 (3H, s), 3.26-3.28 (4H, m), 3.00 (2H, t, J = 8.6 Hz), 2.50-2.54 (6H, m), 1.78-1.91 (6H, m). (A) 2-methoxy-1- [4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Yl} phenyl) piperazin-1-yl] ethanone Synthesis using the compound of Example 51 and 2-methoxyacetyl chloride (15.0 μl, 0.163 mmol) in the same manner as in Example 76 (a). Gave the title compound as a pale yellow oil (53.0 mg, 77% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.27 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.75-3.78 (2H, m), 3.51-3.66 (6H, m), 3.43 (3H, s), 3.26-3.28 (4H, m), 3.00 (2H, t, J = 8.6 Hz), 2.50-2.54 ( 6H, m), 1.78-1.91 (6H, m).
（ｂ）２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　上記（ａ）で得られた化合物（５３.０ｍｇ、０.１１５ｍｍｏｌ）を用いて実施例７６（ｂ）と同様の方法にて合成することにより、表題化合物を淡黄色固体として得た（２１.０ｍｇ、収率４０％）。
1H-NMR (CDCl3,δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.86 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 3.46-3.54 (6H, m),  3.31 (3H, s), 3.24-3.27 (4H, m), 2.94 (2H, t, J = 8.0 Hz), 2.56-2.62 (6H, m), 2.44-2.49 (4H, m), 1.70-1.85 (6H, m), 1.12-1.28 (2H, m). (B) 2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine Using the compound obtained in (a) above (53.0 mg, 0.115 mmol) and synthesizing in the same manner as in Example 76 (b), the title compound Obtained as a yellow solid (21.0 mg, 40% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.86 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 3.46-3.54 (6H, m ), 3.31 (3H, s), 3.24-3.27 (4H, m), 2.94 (2H, t, J = 8.0 Hz), 2.56-2.62 (6H, m), 2.44-2.49 (4H, m), 1.70- 1.85 (6H, m), 1.12-1.28 (2H, m).
（実施例７８）
４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
(Example 78)
4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
（ａ）１－（４－｛４－［４－クロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノン
　実施例３１で得た化合物（１２４ｍｇ、０.２８０ｍｍｏｌ）を用い、実施例７６（ａ）と同様の方法により、表題化合物を淡黄色アモルファスとして得た（１２３ｍｇ、収率９０％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.60-3.78 (10H, m), 3.54 (2H, t, J = 7.0 Hz), 3.23-3.30 (4H, m), 3.04 (2H, t, J = 8.5 Hz), 2.38-2.42 (6H, m), 2.13 (3H, s), 1.78-1.83 (2H, m). (A) 1- (4- {4- [4-Chloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazine -1-yl) ethanone Using the compound obtained in Example 31 (124 mg, 0.280 mmol), the title compound was obtained as a pale yellow amorphous substance in the same manner as in Example 76 (a) (123 mg, yield 90). %).
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.60-3.78 (10H, m), 3.54 (2H, t , J = 7.0 Hz), 3.23-3.30 (4H, m), 3.04 (2H, t, J = 8.5 Hz), 2.38-2.42 (6H, m), 2.13 (3H, s), 1.78-1.83 (2H, m).
（ｂ）１－（４－｛４－［４－メチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノン
　上記（ａ）で得た化合物（６０.０ｍｇ、０.１４１ｍｍｏｌ）のＴＨＦ（１.２ｍｌ）溶液に、ビス（トリ－ｔ－ブチルホスフィン）ジパラジウム（０）（１３.０ｍｇ、０.０２４７ｍｍｏｌ）、２Ｍ塩化メチル亜鉛－ＴＨＦ溶液（０.３１ｍｌ、０.６２０ｍｍｏｌ）を加え、室温にて攪拌した。３時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムで乾燥し、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物を淡黄色油状物として得た（５１.０ｍｇ、収率８９％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 3.75-3.78 (2H, m), 3.70-3.73 (4H, m), 3.49-3.63 (6H, m), 3.20-3.27 (4H, m), 2.95 (2H, t, J = 8.2 Hz), 2.38-2.43 (6H, m), 2.27 (3H, s), 2.13 (3H, s), 1.76-1.85 (2H, m). (B) 1- (4- {4- [4-Methyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazine -1-yl) ethanone To a solution of the compound obtained in (a) above (60.0 mg, 0.141 mmol) in THF (1.2 ml) was added bis (tri-t-butylphosphine) dipalladium (0) (13. (0 mg, 0.0247 mmol), 2M methylzinc chloride-THF solution (0.31 ml, 0.620 mmol) was added, and the mixture was stirred at room temperature. Three hours later, aqueous hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a pale yellow oil (51. 0 mg, 89% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 3.75-3.78 (2H, m), 3.70-3.73 (4H , m), 3.49-3.63 (6H, m), 3.20-3.27 (4H, m), 2.95 (2H, t, J = 8.2 Hz), 2.38-2.43 (6H, m), 2.27 (3H, s), 2.13 (3H, s), 1.76-1.85 (2H, m).
（ｃ）４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
　上記（ｂ）で得た化合物（４６.０ｍｇ、０.０９９０ｍｍｏｌ）を用い、実施例７６（ｂ）と同様の方法により、表題化合物を淡黄色アモルファスとして得た（１２.０ｍｇ、収率２８％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 3.70-3.72 (4H, m),  3.49-3.60 (4H, m), 3.27-3.30 (4H, m), 2.94 (2H, t, J = 8.3 Hz), 2.60-2.61 (4H, m), 2.38-2.50 (8H, m), 2.26 (3H, s), 1.78-1.82 (2H, m), 1.12 (3H, t, J = 7.2 Hz). (C) 4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Propyl) morpholine Using the compound obtained in (b) above (46.0 mg, 0.0990 mmol), the title compound was obtained as a pale yellow amorphous (12.0 mg, yield) by the same method as in Example 76 (b). Rate 28%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 3.70-3.72 (4H, m), 3.49-3.60 (4H , m), 3.27-3.30 (4H, m), 2.94 (2H, t, J = 8.3 Hz), 2.60-2.61 (4H, m), 2.38-2.50 (8H, m), 2.26 (3H, s), 1.78-1.82 (2H, m), 1.12 (3H, t, J = 7.2 Hz).
（実施例７９）
４－（３－｛４－エチル－２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000098
 (Example 79)
4- (3- {4-Ethyl-2- [4- (4-ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000098
（ａ）１－（４－｛４－［４－エチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノン
　実施例７８（ａ）で得た化合物（６０.０ｍｇ、０.１２４ｍｍｏｌ）のＴＨＦ（１.５ｍｌ）溶液に、ビス（トリ－ｔ－ブチルホスフィン）ジパラジウム（０）（１９.０ｍｇ、０.０３７２ｍｍｏｌ）、１ｍｏｌ／Ｌジエチル亜鉛－ヘキサン溶液（０.６２ｍｌ、０.６２０ｍｍｏｌ）を加え、マイクロウエーブ照射下、１持間攪拌した。反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。有機層を硫酸マグネシウムで乾燥し、ろ過後減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン→クロロホルム）で精製し、表題化合物を淡黄色油状物として得た（４５.０ｍｇ、収率７５％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 3.71-3.74 (2H, m), 3.65-3.68 (4H, m), 3.45-3.59 (6H, m), 3.15-3.22 (4H, m), 2.92 (2H, t, J =8.3 Hz), 2.50 (2H, q, J = 7.6 Hz), 2.34-2.39 (6H, m), 2.08 (3H, s), 1.71-1.81 (2H, m), 1.21 (3H, t, J = 7.6 Hz). (A) 1- (4- {4- [4-Ethyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazine -1-yl) ethanone To a solution of the compound obtained in Example 78 (a) (60.0 mg, 0.124 mmol) in THF (1.5 ml) was added bis (tri-t-butylphosphine) dipalladium (0) ( (19.0 mg, 0.0372 mmol), 1 mol / L diethyl zinc-hexane solution (0.62 ml, 0.620 mmol) was added, and the mixture was stirred for 1 hour under microwave irradiation. The reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: hexane → chloroform) to give the title compound as a pale yellow oil. Obtained (45.0 mg, 75% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 3.71-3.74 (2H, m), 3.65-3.68 (4H , m), 3.45-3.59 (6H, m), 3.15-3.22 (4H, m), 2.92 (2H, t, J = 8.3 Hz), 2.50 (2H, q, J = 7.6 Hz), 2.34-2.39 ( 6H, m), 2.08 (3H, s), 1.71-1.81 (2H, m), 1.21 (3H, t, J = 7.6 Hz).
（ｂ）４－（３－｛４－エチル－２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
　上記（ａ）で得た化合物（４５.０ｍｇ、０.０９９０ｍｍｏｌ）を用い、実施例７６（ｂ）と同様の方法により、表題化合物を淡黄色アモルファスとして得た（１６.０ｍｇ、収率３６％）。
1H-NMR (CDCl3,δ ppm): 8.27 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 3.70-3.73 (4H, m), 3.49-3.59 (4H, m), 3.26-3.30 (4H, m), 2.96 (2H, t, J =8.6 Hz), 2.39-2.62 (14H, m), 1.76-1.85 (2H, m), 1.25 (3H, t, J = 7.5 Hz), 1.12 (3H, t, J = 7.2 Hz). (B) 4- (3- {4-Ethyl-2- [4- (4-ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Propyl) morpholine Using the compound (45.0 mg, 0.0990 mmol) obtained in (a) above, the title compound was obtained as a pale yellow amorphous (16.0 mg, yield) by the same method as in Example 76 (b). Rate 36%).
1 H-NMR (CDCl 3 , δ ppm): 8.27 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 3.70-3.73 (4H, m), 3.49-3.59 (4H , m), 3.26-3.30 (4H, m), 2.96 (2H, t, J = 8.6 Hz), 2.39-2.62 (14H, m), 1.76-1.85 (2H, m), 1.25 (3H, t, J = 7.5 Hz), 1.12 (3H, t, J = 7.2 Hz).
（実施例８０）
４－（３－｛２－［３－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000099
 　参考例５で得た化合物（１２７ｍｇ、０.４００ｍｍｏｌ）の１，４－ジオキサン（１.６ｍｌ）溶液に、ｔ－ブチル ４－（３－（４、４、５、５－テトラメチル－１、３、２－ジオキサボロラン－２－イル）フェニル）ピペラジン－１－カルボキシレート（１２１ｍｇ、０.４００ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（４６.３ｍｇ、０.０４００ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（４００μｌ、１.２０ｍｍｏｌ）を加え、１１０℃にて攪拌した。１時間後、反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムにより乾燥し、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製し、Ｂｏｃ保護体を混合物として得た（１１５ｍｇ）。得られた混合物（１１５ｍｇ）のＴＨＦ（２.０ｍｌ）溶液に、水素化リチウムアルミニウム（１６.１ｍｇ、０.２１２ｍｍｏｌ）を加え、加熱還流した。２時間後、水素化リチウムアルミニウム（１６.１ｍｇ、０.２１２ｍｍｏｌ）を追加し、加熱還流した。３時間後、水酸化ナトリウム水溶液を加え反応を停止し、セライトろ過後、減圧濃縮した。得られた残渣をエタノール（３.０ｍｌ）に溶解し、１０％パラジウム炭素（５０％含水、４０ｍｇ）、蟻酸アンモニウム（２００ｍｇ）を加え、加熱還流した。１時間後、反応溶液をセライトろ過し、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：酢酸エチル）で精製することにより、表題化合物を淡黄色オイルとして得た（３５.９ｍｇ）。
1H-NMR (CDCl3,δ ppm): 7.90 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 7.25 (1H, dd, J = 8.0, 8.0 Hz), 6.93 (1H, dd, J = 8.0, 2.2 Hz), 3.63-3.66 (4H, m), 3.56 (2H, t, J = 8.5 Hz), 3.49 (2H, t, J = 7.1 Hz), 3.21-3.25 (4H, m), 2.96 (2H, t, J = 8.5 Hz), 2.51-2.55 (4H, m), 2.34-2.39 (6H, m), 2.29 (3H, s), 1.72-1.82 (2H, m). (Example 80)
4- (3- {2- [3- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000099
 To a solution of the compound obtained in Reference Example 5 (127 mg, 0.400 mmol) in 1,4-dioxane (1.6 ml), t-butyl 4- (3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (121 mg, 0.400 mmol), tetrakistriphenylphosphine palladium (46.3 mg, 0.0400 mmol), 3 mol / L aqueous sodium carbonate solution (400 μl, 1.20 mmol) was added and stirred at 110 ° C. After 1 hour, water was added to the reaction solution to stop the reaction, followed by separation and extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate) to obtain a Boc protected product as a mixture (115 mg). To a solution of the obtained mixture (115 mg) in THF (2.0 ml) was added lithium aluminum hydride (16.1 mg, 0.212 mmol), and the mixture was heated to reflux. After 2 hours, lithium aluminum hydride (16.1 mg, 0.212 mmol) was added and heated to reflux. After 3 hours, the reaction was stopped by adding an aqueous sodium hydroxide solution, filtered through Celite, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (3.0 ml), 10% palladium carbon (containing 50% water, 40 mg) and ammonium formate (200 mg) were added, and the mixture was heated to reflux. After 1 hour, the reaction solution was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: ethyl acetate) to give the title compound as a pale yellow oil (35.9 mg).
1 H-NMR (CDCl 3 , δ ppm): 7.90 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 7.25 (1H, dd, J = 8.0, 8.0 Hz), 6.93 (1H, dd , J = 8.0, 2.2 Hz), 3.63-3.66 (4H, m), 3.56 (2H, t, J = 8.5 Hz), 3.49 (2H, t, J = 7.1 Hz), 3.21-3.25 (4H, m) , 2.96 (2H, t, J = 8.5 Hz), 2.51-2.55 (4H, m), 2.34-2.39 (6H, m), 2.29 (3H, s), 1.72-1.82 (2H, m).
（実施例８１）
Ｎ，Ｎ－ジメチル－３－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン
Figure JPOXMLDOC01-appb-C000100
 　実施例１で得た化合物（１００ｍｇ、０.２４１ｍｍｏｌ）のＴＨＦ（２.０ｍｌ）溶液に、ビス（トリ－ｔ－ブチルホスフィン）ジパラジウム（０）（２４.６ｍｇ、０.０４８２ｍｍｏｌ）、１ｍｏｌ／Ｌジメチル亜鉛－ＴＨＦ溶液（１.２０ｍｌ、１.２０ｍｍｏｌ）を加え、室温にて攪拌した。８時間後、ビス（トリ－ｔ－ブチルホスフィン）ジパラジウム（０）（２４.６ｍｇ、０.０４８２ｍｍｏｌ）、１ｍｏｌ／Ｌジメチル亜鉛－ＴＨＦ溶液（０.６０２ｍｌ、０.６０２ｍｍｏｌ）を追加し、室温にて攪拌した。２日後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１０とし、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール）で精製した。得られた固体をジエチルエーテル／ヘキサンでリパルプ洗浄することにより表題化合物を白色固体として得た（４９.９ｍｇ、収率５２％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 9.0 Hz), 3.57 (2H, t, J = 8.4 Hz), 3.49 (2H, t, J = 7.2 Hz), 3.25-3.28 (4H, m), 2.94 (2H, t, J = 8.4 Hz), 2.54-2.57 (4H, m), 2.30-2.35 (2H, m), 2.33 (3H, s), 2.22 (3H, s), 2.18 (6H, s), 1.74-1.84 (2H, m). (Example 81)
N, N-dimethyl-3- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Propan-1-amine
Figure JPOXMLDOC01-appb-C000100
 To a solution of the compound obtained in Example 1 (100 mg, 0.241 mmol) in THF (2.0 ml), bis (tri-t-butylphosphine) dipalladium (0) (24.6 mg, 0.0482 mmol), 1 mol / L-dimethylzinc-THF solution (1.20 ml, 1.20 mmol) was added and stirred at room temperature. After 8 hours, bis (tri-t-butylphosphine) dipalladium (0) (24.6 mg, 0.0482 mmol), 1 mol / L dimethylzinc-THF solution (0.602 ml, 0.602 mmol) was added, and room temperature was added. Was stirred. Two days later, aqueous hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: methanol). The obtained solid was repulped with diethyl ether / hexane to give the title compound as a white solid (49.9 mg, 52% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 9.0 Hz), 3.57 (2H, t, J = 8.4 Hz), 3.49 ( 2H, t, J = 7.2 Hz), 3.25-3.28 (4H, m), 2.94 (2H, t, J = 8.4 Hz), 2.54-2.57 (4H, m), 2.30-2.35 (2H, m), 2.33 (3H, s), 2.22 (3H, s), 2.18 (6H, s), 1.74-1.84 (2H, m).
　　実施例８２－９５：
　対応する原料化合物と試薬を用いて実施例８１と同様に反応・処理し、表１１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
 Examples 82-95 :
Reaction and treatment were carried out in the same manner as in Example 81 using the corresponding starting materials and reagents, and the compounds shown in Table 11 were obtained.
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
（実施例９６）
２－［４－（ピペリジン－４－イルオキシ）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000104
 　参考例１３で得た化合物４Ｃ（５７.０ｍｇ、０.１１２ｍｍｏｌ）に４ｍｏｌ／Ｌ塩酸／１，４－ジオキサン溶液（２.０ｍｌ）加え、室温にて２.５時間撹拌した。水を加え、酢酸エチルで水層を洗浄した後、水酸化ナトリウム水溶液でｐＨ＝１１とし、酢酸エチルで分液抽出した。硫酸マグネシウムで乾燥後ろ過し、溶媒を減圧除去した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製し、表題化合物を無色油状物として得た（２３.０ｍｇ、収率５１％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.39－4.47 (1H, m), 3.61 (2H, t, J = 8.2 Hz), 3.54 (2H, t, J = 7.2 Hz), 3.10-3.17 (2H, m), 3.00 (2H, t, J = 8.2 Hz), 2.68-2.77 (2H, m), 2.52-2.57 (6H, m), 2.00-2.03 (2H, m), 1.65-1.93 (9H, m). (Example 96)
2- [4- (Piperidin-4-yloxy) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000104
 To the compound 4C obtained in Reference Example 13 (57.0 mg, 0.112 mmol) was added 4 mol / L hydrochloric acid / 1,4-dioxane solution (2.0 ml), and the mixture was stirred at room temperature for 2.5 hours. Water was added, the aqueous layer was washed with ethyl acetate, adjusted to pH = 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. After drying over magnesium sulfate and filtering, the solvent was removed under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a colorless oil (23.0 mg, yield 51%).
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.39-4.47 (1H, m ), 3.61 (2H, t, J = 8.2 Hz), 3.54 (2H, t, J = 7.2 Hz), 3.10-3.17 (2H, m), 3.00 (2H, t, J = 8.2 Hz), 2.68-2.77 (2H, m), 2.52-2.57 (6H, m), 2.00-2.03 (2H, m), 1.65-1.93 (9H, m).
　　実施例９７－１０２：
　対応する原料化合物と試薬を用いて実施例９６と同様に反応・処理し、表１２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
 Examples 97-102 :
Reaction and treatment were carried out in the same manner as in Example 96 using the corresponding starting materials and reagents, and the compounds shown in Table 12 were obtained.
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
（実施例１０３）
２－［４－（１－メチルピペリジン－４－イルオキシ）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000107
 　実施例９６で得た化合物（２３.０ｍｇ、０.０５７０ｍｍｏｌ）のメタノール／ジクロロメタン（２：５）溶液（１.０ｍｌ）に３５％ ホルムアルデヒド水溶液（２０.０ μl）、トリアセトキシボロヒドリド（２４.０ｍｇ、０.１１４ｍｍｏｌ）を加え、室温にて１時間撹拌した。飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し硫酸マグネシウムで乾燥後、ろ過、溶媒を減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製することにより表題化合物を無色油状物として得た（１７ｍｇ、収率７０％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 8.8 Hz), 4.39 (1H, brs), 3.62 (2H, t, J = 8.4 Hz), 3.55 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 8.4 Hz), 2.67 (8H, m), 2.30-2.32 (5H, m), 1.85-1.99 (10H, m). (Example 103)
2- [4- (1-Methylpiperidin-4-yloxy) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000107
 A 35% aqueous formaldehyde solution (20.0 μl) and triacetoxyborohydride (24.0 μl) were added to a methanol / dichloromethane (2: 5) solution (1.0 ml) of the compound obtained in Example 96 (23.0 mg, 0.0570 mmol). 0 mg, 0.114 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, followed by separation and extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to give the title compound as a colorless oil (17 mg, yield 70%).
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 8.8 Hz), 4.39 (1H, brs), 3.62 (2H, t, J = 8.4 Hz), 3.55 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 8.4 Hz), 2.67 (8H, m), 2.30-2.32 (5H, m ), 1.85-1.99 (10H, m).
　　実施例１０４－１０５：
　対応する原料化合物と試薬を用いて実施例１０３と同様に反応・処理し、表１３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000108
 Examples 104-105 :
Reaction and treatment were carried out in the same manner as in Example 103 using the corresponding starting materials and reagents, and the compounds shown in Table 13 were obtained.
Figure JPOXMLDOC01-appb-T000108
（実施例１０６）
２－［３－（１－メチルピペリジン－４－イルオキシ）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000109
 　実施例１００で得た化合物（３８.６ｍｇ、０.０９４７ｍｍｏｌ）のメタノール（１.０ｍｌ）溶液に、３５％ホルマリン水溶液（１５.０μｌ、０.１８９ｍｍｏｌ）、酢酸（１６.３μｌ、０.２８４ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１１.９ｍｇ、０.１８９ｍｍｏｌ）を加え、室温にて攪拌した。５時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄し、減圧留去後、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：メタノール）で精製した。得られた固体をジエチルエーテル／ヘキサンでリパルプ洗浄することにより表題化合物を白色固体として得た（１０.４ｍｇ、収率２６％）。
1H-NMR (CDCl3,δ ppm): 7.89-7.93 (3H, m), 7.29 (1H, dd, J = 8.2, 8.2 Hz), 6.92-6.95 (1H, m), 4.41 (1H, m), 3.60 (2H, t, J = 8.4 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 8.4 Hz), 2.67 (2H, m), 2.48-2.53 (6H, m), 2.27 (3H, s), 2.25 (2H, m), 1.99 (2H, m), 1.75-1.89 (8H, m). (Example 106)
2- [3- (1-Methylpiperidin-4-yloxy) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000109
 To a solution of the compound obtained in Example 100 (38.6 mg, 0.0947 mmol) in methanol (1.0 ml), a 35% formalin aqueous solution (15.0 μl, 0.189 mmol), acetic acid (16.3 μl, 0.284 mmol). , Sodium cyanoborohydride (11.9 mg, 0.189 mmol) was added and stirred at room temperature. After 5 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: methanol). The obtained solid was repulped with diethyl ether / hexane to give the title compound as a white solid (10.4 mg, yield 26%).
1 H-NMR (CDCl 3 , δ ppm): 7.89-7.93 (3H, m), 7.29 (1H, dd, J = 8.2, 8.2 Hz), 6.92-6.95 (1H, m), 4.41 (1H, m) , 3.60 (2H, t, J = 8.4 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.00 (2H, t, J = 8.4 Hz), 2.67 (2H, m), 2.48-2.53 (6H, m), 2.27 (3H, s), 2.25 (2H, m), 1.99 (2H, m), 1.75-1.89 (8H, m).
　　実施例１０７－１１７：
　対応する原料化合物と試薬を用いて実施例１０６と同様に反応・処理し、表１４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
 Examples 107-117 :
Reaction and treatment were carried out in the same manner as in Example 106 using the corresponding starting materials and reagents, and the compounds shown in Table 14 were obtained.
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
（実施例１１８）
４－メチル－２－（｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝メチル）モルホリン
Figure JPOXMLDOC01-appb-C000113
 　実施例７１で得た化合物（７９.１ｍｇ、０.２０１ｍｍｏｌ）のメタノール（２.０ｍｌ）溶液に、０℃にて酢酸（２３.０μｌ、０.４０２ｍｍｏｌ）、ホルムアルデヒド（３５％水溶液）（１６.６μｌ、０.２０１ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（２５.３ｍｇ、０.４０２ｍｍｏｌ）を加え、室温にて攪拌した。５時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製することにより表題化合物を淡黄色固体として得た（５８.１ｍｇ、収率７１％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 8.7 Hz), 7.94 (1H, s), 6.93 (2H, d, J= 8.7 Hz), 3.88-3.92 (1H, m), 3.62-3.74 (5H, m), 3.46-3.50 (1H, m), 3.30 (4H, m), 2.98-3.03 (2H, m), 2.79-2.82 (1H, m), 2.57-2.66 (5H, m), 2.34 (3H, s), 2.27 (3H, s). (Example 118)
4-methyl-2-({2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} methyl) morpholine
Figure JPOXMLDOC01-appb-C000113
 To a solution of the compound obtained in Example 71 (79.1 mg, 0.201 mmol) in methanol (2.0 ml) at 0 ° C., acetic acid (23.0 μl, 0.402 mmol), formaldehyde (35% aqueous solution) (16. 6 μl, 0.201 mmol) and sodium cyanoborohydride (25.3 mg, 0.402 mmol) were added and stirred at room temperature. After 5 hours, the reaction was stopped with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a pale yellow solid (58.1 mg, yield 71%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 8.7 Hz), 7.94 (1H, s), 6.93 (2H, d, J = 8.7 Hz), 3.88-3.92 (1H, m ), 3.62-3.74 (5H, m), 3.46-3.50 (1H, m), 3.30 (4H, m), 2.98-3.03 (2H, m), 2.79-2.82 (1H, m), 2.57-2.66 (5H m), 2.34 (3H, s), 2.27 (3H, s).
（実施例１１９）
２－（４－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノール
Figure JPOXMLDOC01-appb-C000114
 (Example 119)
2- (4- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazin-1-yl) ethanol
Figure JPOXMLDOC01-appb-C000114
（ａ）４－（３－（２－（４－｛４－［２－（ｔ－ブチルジメチルシリロキシ）エチル］ピペラジン－１－イル｝フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル｝モルホリン
　実施例５９で得た化合物（１８９ｍｇ、０.４６１ｍｍｏｌ）のメタノール（５.０ｍｌ）溶液に、酢酸（１０５μｌ、１，８４ｍｍｏｌ）、２－（ｔ－ブチルジメチルシリロキシ）アセトアルデヒド（２２０μｌ、１.１５ｍｍｏｌ）、０℃にてシアノ水素化ホウ素ナトリウム（６４.０ｍｇ、１.０１ｍｍｏｌ）を加え、室温にて攪拌した。１時間撹拌後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより淡黄色油状物として表題化合物を得た（１８４ｍｇ、収率７０％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 3.80 (2H, t, J = 6.2 Hz), 3.72-3.78 (4H, m), 3.51-3.64 (4H, m), 3.27-3.31 (4H, m), 3.02 (2H, t, J = 8.4 Hz), 2.68-2.71 (4H, m), 2.59 (2H, t, J = 6.4 Hz), 2.41-2.46 (6H, m), 1.78-1.88 (2H, m), 0.90 (9H, s), 0.07 (6H, s). (A) 4- (3- (2- (4- {4- [2- (t-butyldimethylsilyloxy) ethyl] piperazin-1-yl} phenyl) -5H-pyrrolo [2,3-d] pyrimidine -7 (6H) -yl] propyl} morpholine To a solution of the compound obtained in Example 59 (189 mg, 0.461 mmol) in methanol (5.0 ml), acetic acid (105 μl, 1,84 mmol), 2- (t-butyl) Dimethylsilyloxy) acetaldehyde (220 μl, 1.15 mmol) and sodium cyanoborohydride (64.0 mg, 1.01 mmol) were added at 0 ° C. and stirred at room temperature, and after stirring for 1 hour, saturated aqueous sodium bicarbonate solution The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a pale yellow oil by purification by romatography (elution solvent; hexane: ethyl acetate) (184 mg, yield 70%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 3.80 (2H, t, J = 6.2 Hz), 3.72-3.78 (4H, m), 3.51-3.64 (4H, m), 3.27-3.31 (4H, m), 3.02 (2H, t, J = 8.4 Hz), 2.68-2.71 (4H, m), 2.59 (2H, t, J = 6.4 Hz), 2.41-2.46 (6H, m), 1.78-1.88 (2H, m), 0.90 (9H, s), 0.07 (6H, s).
（ｂ）２－（４－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノール
　上記（ａ）で得られた化合物（１８４ｍｇ、０.３２５ｍｍｏｌ）のＴＨＦ（３.０ｍｌ）溶液に氷冷下１ｍｏｌ／Ｌテトラブチルアンモニウムフルオリド／ＴＨＦ溶液（０.７０ｍｌ、０.７００ｍｍｏｌ）加えた。室温で１時間撹拌後、水を加えて反応を停止した。クロロホルムにて分液抽出し、硫酸マグネシウムにて乾燥後ろ過し、溶媒を減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製した。得られた油状物にヘキサンを加えて固体化させ、ろ過することにより表題化合物を淡黄色固体として得た（８２ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.70-3.73 (4H, m), 3.51-3.67 (6H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.0 Hz), 2.65-2.68 (4H, m), 2.60 (2H, t, J = 5.3 Hz), 2.39-2.44 (6H, m), 1.77-1.86 (2H, m), 1.57 (1H, m). (B) 2- (4- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazin-1-yl ) Ethanol A solution of the compound obtained in (a) above (184 mg, 0.325 mmol) in a THF (3.0 ml) solution under ice-cooling with 1 mol / L tetrabutylammonium fluoride / THF (0.70 ml, 0.700 mmol) added. After stirring for 1 hour at room temperature, water was added to stop the reaction. Liquid separation extraction was carried out with chloroform, it filtered after drying with magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol). Hexane was added to the obtained oil to solidify it, followed by filtration to obtain the title compound as a pale yellow solid (82 mg, yield 56%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.70-3.73 (4H, m ), 3.51-3.67 (6H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.0 Hz), 2.65-2.68 (4H, m), 2.60 (2H, t, J = 5.3 Hz), 2.39-2.44 (6H, m), 1.77-1.86 (2H, m), 1.57 (1H, m).
（実施例１２０）
４－（３－｛２－［４－（１－メチルピペリジン－４－イルオキシ）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000115
 　参考例１７で得た化合物（２２９ｍｇ、０.４３７ｍｍｏｌ）のＴＨＦ（５.０ｍｌ）溶液に、水素化リチウムアルミニウム（４９.８ｍｇ、１.３１ｍｍｏｌ）を加え、加熱還流した。２時間後、水酸化ナトリウム水溶液を加え反応を停止し、セライトろ過した。ろ液を減圧濃縮後、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：酢酸エチル）で精製することにより表題化合物を淡黄色固体として得た（９０.１ｍｇ、収率４７％）。
1H-NMR (CDCl3,δ ppm): 8.23-8.28 (2H, m), 7.92 (1H, ｓ), 6.89-6.94 (2H, m), 4.38 (1H, m), 3.69-3.72 (4H, m), 3.60 (2H, t, J = 8.4 Hz), 3.54 (2H, m, J = 7.2 Hz), 3.01 (2H, t, J = 8.4 Hz), 2.68 (1H, m), 2.41-2.44 (6H, m), 2.29 (3H, s), 2.25 (2H, m), 1.97-2.04 (2H, m), 1.77-1.90 (4H, m). (Example 120)
4- (3- {2- [4- (1-Methylpiperidin-4-yloxy) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000115
 To a solution of the compound obtained in Reference Example 17 (229 mg, 0.437 mmol) in THF (5.0 ml) was added lithium aluminum hydride (49.8 mg, 1.31 mmol), and the mixture was heated to reflux. Two hours later, an aqueous sodium hydroxide solution was added to stop the reaction, and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: ethyl acetate) to give the title compound as a pale yellow solid (90.1 mg). Yield 47%).
1 H-NMR (CDCl 3 , δ ppm): 8.23-8.28 (2H, m), 7.92 (1H, s), 6.89-6.94 (2H, m), 4.38 (1H, m), 3.69-3.72 (4H, m), 3.60 (2H, t, J = 8.4 Hz), 3.54 (2H, m, J = 7.2 Hz), 3.01 (2H, t, J = 8.4 Hz), 2.68 (1H, m), 2.41-2.44 ( 6H, m), 2.29 (3H, s), 2.25 (2H, m), 1.97-2.04 (2H, m), 1.77-1.90 (4H, m).
　　実施例１２１－１２２：
　対応する原料化合物と試薬を用いて実施例１２０と同様に反応・処理し、表１５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000116
 Examples 121-122 :
Reaction and treatment were carried out in the same manner as in Example 120 using the corresponding starting compounds and reagents, and the compounds shown in Table 15 were obtained.
Figure JPOXMLDOC01-appb-T000116
（実施例１２３）
４－メトキシ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000117
 　実施例４で得た化合物（５０.０ｍｇ、０.１１３ｍｍｏｌ）をメタノール（２.０ｍｌ）に溶解し、２８％ナトリウムメトキシド／メタノール溶液（１０９ｍｇ、０.５６５ｍｍｏｌ）を加えマイクロウェーブ照射下１２０℃で５時間撹拌した。反応溶液に酢酸エチル、続いて水を加えた後に酢酸エチルで分液抽出した。有機層を水、飽和食塩水で洗浄、硫酸マグネシウムで乾燥し、ろ過後減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物を薄黄色ガム状として得た（３０.０ｍｇ、収率６１％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 3.96 (3H, s), 3.46-3.55 (4H, m), 3.23-3.26 (4H, m), 2.88 (2H, t, J = 8.2 Hz), 2.51-2.56 (4H, m), 2.30 (3H, s), 1.98 (2H, m), 1.51 (10H, m). (Example 123)
4-Methoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine
Figure JPOXMLDOC01-appb-C000117
 The compound obtained in Example 4 (50.0 mg, 0.113 mmol) was dissolved in methanol (2.0 ml), 28% sodium methoxide / methanol solution (109 mg, 0.565 mmol) was added, and 120 ° C. under microwave irradiation. For 5 hours. Ethyl acetate and then water were added to the reaction solution, followed by separation and extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a pale yellow gum (30.0 mg, 61% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 3.96 (3H, s), 3.46-3.55 (4H, m ), 3.23-3.26 (4H, m), 2.88 (2H, t, J = 8.2 Hz), 2.51-2.56 (4H, m), 2.30 (3H, s), 1.98 (2H, m), 1.51 (10H, m).
（実施例１２４）
Ｎ，Ｎ－ジメチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－アミン
Figure JPOXMLDOC01-appb-C000118
 　実施例４で得た化合物（６０.０ｍｇ、０.１３６ｍｍｏｌ）をＮ－メチルピロリジノン（１.５ｍｌ）に溶解し、２ｍｏｌ／Ｌジメチルアミン／ＴＨＦ溶液（１.５ｍｌ、３.００ｍｍｏｌ）を加え、マイクロウェーブ照射下１８０℃で２時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで分液抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。ろ過後、減圧濃縮し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物を黄色アモルファスとして得た（４３.０ｍｇ、収率７０％）。
1H-NMR (CDCl3,δ ppm): 8.27 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 3.46 (2H, t, J = 7.2 Hz), 3.42 (2H, t, J = 8.6 Hz), 3.24-3.28 (4H, m), 3.15-3.21 (8H, m), 2.54-2.58 (4H, m), 2.49-2.51 (6H, m), 2.33 (3H, s), 1.75-1.87 (6H, m). (Example 124)
N, N-dimethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2 , 3-d] pyrimidin-4-amine
Figure JPOXMLDOC01-appb-C000118
 The compound obtained in Example 4 (60.0 mg, 0.136 mmol) was dissolved in N-methylpyrrolidinone (1.5 ml), 2 mol / L dimethylamine / THF solution (1.5 ml, 3.00 mmol) was added, The mixture was stirred at 180 ° C. for 2 hours under microwave irradiation. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a yellow amorphous (43.0 mg, yield 70%).
1 H-NMR (CDCl 3 , δ ppm): 8.27 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 3.46 (2H, t, J = 7.2 Hz), 3.42 ( 2H, t, J = 8.6 Hz), 3.24-3.28 (4H, m), 3.15-3.21 (8H, m), 2.54-2.58 (4H, m), 2.49-2.51 (6H, m), 2.33 (3H, s), 1.75-1.87 (6H, m).
（実施例１２５）
２－［４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－イル］エタノール
Figure JPOXMLDOC01-appb-C000119
 (Example 125)
2- [4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl) piperazine- 1-yl] ethanol
Figure JPOXMLDOC01-appb-C000119
（ａ）２－（４－｛４－［２－（ベンジルオキシ）エチル］ピペラジン－１－イル｝フェニル）－４－クロロ－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　実施例５１で得た化合物（９０.０ｍｇ、０.２１１ｍｍｏｌ）と２－（ベンジルオキシ）アセトアルデヒド（６３.０ｍｇ、０.４２２ｍｍｏｌ）を用い、実施例３８と同様の方法により表題化合物を淡黄色油状物として得た（６５.０ｍｇ、収率５５％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 8.8 Hz), 7.27-7.36 (5H, m), 6.89 (2H, d, J = 8.8 Hz), 4.54 (2H, s), 3.54-3.69 (6H, m), 3.28-3.32 (4H, m), 3.04 (2H, t, J = 8.3 Hz), 2.63-2.68 (10H, m), 1.89-1.99 (6H, m), 1.56 (2H, m). (A) 2- (4- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} phenyl) -4-chloro-7- [3- (pyrrolidin-1-yl) propyl] -6, 7-Dihydro-5H-pyrrolo [2,3-d] pyrimidine Using the compound obtained in Example 51 (90.0 mg, 0.211 mmol) and 2- (benzyloxy) acetaldehyde (63.0 mg, 0.422 mmol) The title compound was obtained as a pale-yellow oil by a method similar to that in Example 38 (65.0 mg, yield 55%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 8.8 Hz), 7.27-7.36 (5H, m), 6.89 (2H, d, J = 8.8 Hz), 4.54 (2H, s ), 3.54-3.69 (6H, m), 3.28-3.32 (4H, m), 3.04 (2H, t, J = 8.3 Hz), 2.63-2.68 (10H, m), 1.89-1.99 (6H, m), 1.56 (2H, m).
（ｂ）２－（４－｛４－［２－（ベンジルオキシ）エチル］ピペラジン－１－イル｝フェニル）－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　上記（ａ）で得た化合物（６５.０ｍｇ、０.１１６ｍｍｏｌ）を用い、実施例３９と同様の方法にて表題化合物を白色固体として得た（２３.０ｍｇ、収率３７％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.94 (1H, s), 7.27-7.34 (5H, m), 6.89 (2H, d, J = 9.0 Hz), 4.55 (2H, s), 3.54-3.65 (6H, m), 3.28-3.31 (4H, m), 3.01 (2H, t, J = 8.1 Hz), 2.63-2.69 (10H, m), 1.92-2.06 (6H, m), 1.57 (2H, m). (B) 2- (4- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} phenyl) -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro- 5H-pyrrolo [2,3-d] pyrimidine Using the compound obtained in (a) above (65.0 mg, 0.116 mmol), the title compound was obtained as a white solid in the same manner as in Example 39 (23 0.0 mg, 37% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.94 (1H, s), 7.27-7.34 (5H, m), 6.89 (2H, d, J = 9.0 Hz) ), 4.55 (2H, s), 3.54-3.65 (6H, m), 3.28-3.31 (4H, m), 3.01 (2H, t, J = 8.1 Hz), 2.63-2.69 (10H, m), 1.92- 2.06 (6H, m), 1.57 (2H, m).
（ｃ）２－［４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－イル］エタノール
　上記（ｂ）で得た化合物（２３ｍｇ、０.０４３ｍｍｏｌ）のジクロロメタン溶液（０.９０ｍｌ）に、氷冷下で１ｍｏｌ／Ｌトリブロモボラン／ジクロロメタン溶液（０.２７ｍｌ、０.２７ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応溶液を氷水に入れて反応停止し、酢酸エチルで分液抽出した。硫酸マグネシウムで乾燥後ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製し、表題化合物を白色固体として得た（８.０ｍｇ、収率４２％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.30-3.66 (8H, m), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.1 Hz), 2.51-2.68 (9H, m), 1.78-1.86 (6H, m), 1.17-1.23 (2H, m). (C) 2- [4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl ) Piperazin-1-yl] ethanol To a dichloromethane solution (0.90 ml) of the compound obtained in the above (b) (23 mg, 0.043 mmol) was added 1 mol / L tribromoborane / dichloromethane solution (0.27 ml) under ice-cooling. 0.27 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was put into ice water to stop the reaction, and the solution was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid (8.0 mg, yield 42%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.30-3.66 (8H, m ), 3.27-3.30 (4H, m), 3.00 (2H, t, J = 8.1 Hz), 2.51-2.68 (9H, m), 1.78-1.86 (6H, m), 1.17-1.23 (2H, m).
（実施例１２６）
２－｛エチル［２－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノキシ）エチル］アミノ｝エタノール
Figure JPOXMLDOC01-appb-C000120
 (Example 126)
2- {ethyl [2- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenoxy) Ethyl] amino} ethanol
Figure JPOXMLDOC01-appb-C000120
（ａ）２－（ｔ－ブチルジメチルシリロキシ）－Ｎ－エチル－Ｎ－（２－（４－（７－（３－（ピロリジン－１－イル）プロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェノキシ）エチル）エタンアミン
　実施例９９で得た化合物（５０ｍｇ、０.１２７ｍｍｏｌ）と２－（ｔ－ブチルジメチルシリロキシ）アセトアルデヒド（４８μｌ、０.２５４ｍｍｏｌ）を用いて実施例１１９（ａ）と同様の方法により表題化合物を無色油状物として得た（７０ｍｇ、収率１００％）。
1H-NMR (CDCl3,δ ppm): 8.29(2H, d, J = 8.8 Hz), 7.94 (1H, s), 6.93 (2H, d, J = 8.8 Hz), 4.08 (2H, t, J = 6.3 Hz), 3.72 (2H, t, J = 6.6 Hz), 3.62 (2H, t, J = 8.4 Hz), 3.56 (2H, t, J = 7,1 Hz), 3.02 (2H, t, J = 8.4 Hz), 2.96 (2H, t, J = 6.3 Hz), 2.66-2.74 (4H, m), 2.52-2.54 (6H, m), 1.80-1.93 (6H, m), 1.07 (3H, t, J = 7.2 Hz), 0.90 (9H, s), 0.06 (6H, s). (A) 2- (t-butyldimethylsilyloxy) -N-ethyl-N- (2- (4- (7- (3- (pyrrolidin-1-yl) propyl) -6,7-dihydro-5H- Pyrrolo [2,3-d] pyrimidin-2-yl) phenoxy) ethyl) ethanamine The compound obtained in Example 99 (50 mg, 0.127 mmol) and 2- (t-butyldimethylsilyloxy) acetaldehyde (48 μl, 0. In the same manner as in Example 119 (a), the title compound was obtained as a colorless oil (70 mg, 100% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.29 (2H, d, J = 8.8 Hz), 7.94 (1H, s), 6.93 (2H, d, J = 8.8 Hz), 4.08 (2H, t, J = 6.3 Hz), 3.72 (2H, t, J = 6.6 Hz), 3.62 (2H, t, J = 8.4 Hz), 3.56 (2H, t, J = 7,1 Hz), 3.02 (2H, t, J = 8.4 Hz), 2.96 (2H, t, J = 6.3 Hz), 2.66-2.74 (4H, m), 2.52-2.54 (6H, m), 1.80-1.93 (6H, m), 1.07 (3H, t, J = 7.2 Hz), 0.90 (9H, s), 0.06 (6H, s).
（ｂ）２－｛エチル［２－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノキシ）エチル］アミノ｝エタノール
　上記（ａ）で得られた化合物（７０ｍｇ、０.１２６ｍｍｏｌ）のＴＨＦ（１.５ｍｌ）溶液に氷冷下１ｍｏｌ／Ｌテトラブチルアンモニウムフルオリド／ＴＨＦ溶液（０.３０ｍｌ、０.３００ｍｍｏｌ）加えた。室温で２時間撹拌後、水を加えて反応を停止した。クロロホルムにて分液抽出し、硫酸マグネシウムにて乾燥後ろ過し、溶媒を減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製し表題化合物を淡黄色固体として得た（３１ｍｇ、収率５５％）。
1H-NMR (CDCl3,δ ppm): 8.28 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.04-4.08 (2H, m), 3.51-3.63 (7H, m), 3.00 (2H, t, J = 8.3 Hz), 2.92 (2H, t, J = 5.8 Hz), 2.66-2.72 (4H, m), 2.48-2.52 (6H, m), 1.78-1.89 (6H, m), 1.06 (3H, t, J = 7.1 Hz). (B) 2- {Ethyl [2- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl } Phenoxy) ethyl] amino} ethanol A solution of the compound obtained in (a) above (70 mg, 0.126 mmol) in a THF (1.5 ml) solution under ice cooling with a 1 mol / L tetrabutylammonium fluoride / THF solution (0.0. 30 ml, 0.300 mmol). After stirring at room temperature for 2 hours, water was added to stop the reaction. Liquid separation extraction was carried out with chloroform, it filtered after drying with magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a pale yellow solid (31 mg, yield 55%).
1 H-NMR (CDCl 3 , δ ppm): 8.28 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.04-4.08 (2H, m ), 3.51-3.63 (7H, m), 3.00 (2H, t, J = 8.3 Hz), 2.92 (2H, t, J = 5.8 Hz), 2.66-2.72 (4H, m), 2.48-2.52 (6H, m), 1.78-1.89 (6H, m), 1.06 (3H, t, J = 7.1 Hz).
（実施例１２７）
２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－｛２－［２－（ピロリジン－１－イル）エトキシ］エチル｝－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000121
 　参考例３７で得た化合物（１３１ｍｇ、０.２７ｍｍｏｌ）のＴＨＦ－ジエチルエーテル（１.０ｍｌ－１.０ｍｌ）溶液に水素化リチウムアルミニウム（２０.４ｍｇ、０.５４ｍｍｏｌ）を加え、室温にて攪拌した。３時間後、クロロホルム－水酸化ナトリウム水溶液で分液抽出し、有機層を飽和食塩水で洗浄後、減圧留去した。得られた残査をメタノール（２.０ｍｌ）に溶かし、ギ酸アンモニウム（２３９ｍｇ、３.７９ｍｍｏｌ）、１０％パラジウム炭素（５８ｍｇ）を加え、６０℃にて攪拌した。７時間後、パラジウム炭素をろ過して、ろ液をクロロホルム－水で分液抽出し、有機層を飽和食塩水で洗浄後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：クロロホルム）で精製することにより表題化合物を淡黄色固体として得た（４０.２ｍｇ、収率４５％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.92 (1H, m), 6.92 (2H, d, J = 9.0 Hz), 3.66-3.73 (6H, m), 3.61 (2H, t, J = 6.0 Hz), 3.25-3.31 (4H, m), 2.99 (2H, t, J = 7.8 Hz), 2.64 (2H, t, J = 6.0 Hz), 2.53-2.58 (4H, m), 2.46-2.52 (4H, m), 2.33 (3H, s), 1.68-1.77 (4H, m). (Example 127)
2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- {2- [2- (pyrrolidin-1-yl) ethoxy] ethyl} -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000121
 To a solution of the compound obtained in Reference Example 37 (131 mg, 0.27 mmol) in THF-diethyl ether (1.0 ml-1.0 ml) was added lithium aluminum hydride (20.4 mg, 0.54 mmol), and the mixture was stirred at room temperature. did. After 3 hours, the mixture was subjected to separation / extraction with chloroform-aqueous sodium hydroxide solution, and the organic layer was washed with saturated brine and evaporated under reduced pressure. The obtained residue was dissolved in methanol (2.0 ml), ammonium formate (239 mg, 3.79 mmol), 10% palladium carbon (58 mg) was added, and the mixture was stirred at 60 ° C. After 7 hours, palladium on carbon was filtered, and the filtrate was subjected to liquid separation extraction with chloroform-water. The organic layer was washed with saturated brine, and then distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: chloroform) to give the title compound as a pale yellow solid (40.2 mg, yield 45%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.92 (1H, m), 6.92 (2H, d, J = 9.0 Hz), 3.66-3.73 (6H, m ), 3.61 (2H, t, J = 6.0 Hz), 3.25-3.31 (4H, m), 2.99 (2H, t, J = 7.8 Hz), 2.64 (2H, t, J = 6.0 Hz), 2.53-2.58 (4H, m), 2.46-2.52 (4H, m), 2.33 (3H, s), 1.68-1.77 (4H, m).
（実施例１２８）
（Ｓ）－メチル １－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）ピロリジン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000122
 (Example 128)
(S) -methyl 1- (3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) Pyrrolidine-2-carboxylate
Figure JPOXMLDOC01-appb-C000122
（ａ）（Ｓ）－メチル １－（３－｛４－クロロ－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）ピロリジン－２－カルボキシレート
　参考例１１で得られる化合物２Ａ（５００ｍｇ、１.５６ｍｍｏｌ）の１，４－ジオキサン（８.２ｍｌ）溶液に、１－メチル－４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン（２９６ｍｇ、０.９８ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１０８ｍｇ、０.０９３ｍｍｏｌ）、３ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０.９３ｍｌ、２.７９ｍｍｏｌ）、水（０.５ｍｌ）を加え、マイクロウエーブ照射下１２０℃にて攪拌した。２.５時間後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１０とし、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残査のメタノール（１４ｍｌ）溶液に酢酸（８２μｌ、１.４３ｍｍｏｌ）、プロリン塩酸塩（２６０ｍｇ、１.５７ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１２５ｍｇ、２.００ｍｍｏｌ）を加え、室温にて攪拌した。１.５時間撹拌後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより黄色油状物として表題化合物を得た（１３０ｍｇ、収率１７％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.68 (3H, s), 3.63 (2H, t, J = 8.5 Hz), 3.45-3.57 (2H, m), 3.28-3.31 (4H, m), 3.13-3.22 (2H, m), 3.02 (2H, t, J = 8.4 Hz), 2.69-2.78 (1H, m), 2.54-2.59 (4H, m), 2.42-2.51 (1H, m), 2.30-2.38 (4H, m), 2.07-2.15 (1H, m), 1.81-1.97 (5H, m). (A) (S) -Methyl 1- (3- {4-chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 ( 6H) -yl} propyl) pyrrolidine-2-carboxylate To a solution of compound 2A obtained in Reference Example 11 (500 mg, 1.56 mmol) in 1,4-dioxane (8.2 ml), 1-methyl-4- [4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (296 mg, 0.98 mmol), tetrakistriphenylphosphine palladium (108 mg, 0.093 mmol), 3 mol / L Aqueous sodium carbonate (0.93 ml, 2.79 mmol) and water (0.5 ml) were added, and the mixture was stirred at 120 ° C. under microwave irradiation. After 2.5 hours, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. Acetic acid (82 μl, 1.43 mmol), proline hydrochloride (260 mg, 1.57 mmol), sodium cyanoborohydride (125 mg, 2.00 mmol) were added to a methanol (14 ml) solution of the obtained residue, and at room temperature. Stir. After stirring for 1.5 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous 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 a yellow oil (130 mg, 17% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 3.68 (3H, s), 3.63 (2H, t, J = 8.5 Hz), 3.45-3.57 (2H, m), 3.28-3.31 (4H, m), 3.13-3.22 (2H, m), 3.02 (2H, t, J = 8.4 Hz), 2.69-2.78 (1H, m), 2.54-2.59 (4H, m), 2.42-2.51 (1H, m), 2.30-2.38 (4H, m), 2.07-2.15 (1H, m), 1.81-1.97 (5H, m).
（ｂ）（Ｓ）－メチル １－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）ピロリジン－２－カルボキシレート
　上記（ａ）で得られた化合物（６７.０ｍｇ、０.２４６ｍｍｏｌ）のメタノール（４.５ｍｌ）溶液に、１０％パラジウム炭素（５０％含水）（１５０ｍｇ）を加え、水素雰囲気下（０.４ＭＰａ）室温にて攪拌した。５.５時間後、反応溶液をセライトろ過し、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→クロロホルム：酢酸エチル）で精製することにより表題化合物を橙色油状物として得た（７８.０ｍｇ、収率６８％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.68 (3H, s), 3.58 (2H, t, J = 8.4 Hz), 3.48-3.54 (2H, m), 3.27-3.30 (4H, m), 3.13-3.23 (2H, m), 2.99 (2H, t, J = 8.1 Hz), 2.70-2.80 (1H, m), 2.55-2.58 (4H, m), 2.44-2.50 (1H, m), 2.31-2.39 (4H, m), 2.06-2.15 (1H, m), 1.79-1.98 (5H, m). (B) (S) -methyl 1- (3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl } Propyl) pyrrolidine-2-carboxylate To a solution of the compound (67.0 mg, 0.246 mmol) obtained in (a) above in methanol (4.5 ml) was added 10% palladium carbon (containing 50% water) (150 mg). In addition, the mixture was stirred at room temperature under a hydrogen atmosphere (0.4 MPa). After 5.5 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → chloroform: ethyl acetate) to give the title compound as an orange oil (78.0 mg, yield 68%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.68 (3H, s), 3.58 (2H, t, J = 8.4 Hz), 3.48-3.54 (2H, m), 3.27-3.30 (4H, m), 3.13-3.23 (2H, m), 2.99 (2H, t, J = 8.1 Hz) , 2.70-2.80 (1H, m), 2.55-2.58 (4H, m), 2.44-2.50 (1H, m), 2.31-2.39 (4H, m), 2.06-2.15 (1H, m), 1.79-1.98 ( 5H, m).
（実施例１２９）
（Ｓ）－１－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）ピロリジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000123
 　実施例１２８で得た化合物（６５.０ｍｇ、０.１４０ｍｍｏｌ）のメタノール（２.０ｍｌ）溶液に２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１.８ｍｌ）加えた。終夜撹拌後、１Ｍ塩酸水溶液でｐＨ＝８とし、クロロホルム／エタノール（３／１）で分液抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮し、橙色アモルファスとして表題化合物を得た（５４ｍｇ、収率８５％）。
1H-NMR (DMSO3,δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 3.53-3.67 (4H, m), 3.36-3.46 (4H, m), 3.19-3.22 (4H, m), 2.88-3.00 (3H, m), 2.72-2.82 (1H, m), 2.42-2.45 (4H, m), 2.18-2.25 (3H, s), 2.08-2.18 (1H, m), 1.79-1.93 (4H, m), 1.56-1.69 (1H, m). (Example 129)
(S) -1- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) pyrrolidine -2-carboxylic acid
Figure JPOXMLDOC01-appb-C000123
 To a solution of the compound obtained in Example 128 (65.0 mg, 0.140 mmol) in methanol (2.0 ml) was added 2 mol / L aqueous sodium hydroxide solution (1.8 ml). After stirring overnight, the pH was adjusted to 8 with a 1M aqueous hydrochloric acid solution, followed by separation / extraction with chloroform / ethanol (3/1). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as an orange amorphous (54 mg, 85% yield).
1 H-NMR (DMSO 3 , δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 3.53-3.67 (4H, m ), 3.36-3.46 (4H, m), 3.19-3.22 (4H, m), 2.88-3.00 (3H, m), 2.72-2.82 (1H, m), 2.42-2.45 (4H, m), 2.18-2.25 (3H, s), 2.08-2.18 (1H, m), 1.79-1.93 (4H, m), 1.56-1.69 (1H, m).
（実施例１３０）
４－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－６，７－ジヒドロピリド［２，３－ｄ］ピリミジン－８（５Ｈ）－イル｝プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000124
 　参考例３９で得た化合物１０Ａ（１００ｍｇ、０.３０２ｍｍｏｌ）を用いて、実施例１と同様の方法でカップリング体を混合物として得た（７７.１ｍｇ）。この混合物を実施例６９と同様の方法で反応を行うことにより表題化合物を淡黄色オイルとして得た（５６.１ｍｇ、収率４３％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.87 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.68-3.76 (6H, m), 3.40 (2H, t, J = 5.5 Hz), 3.26-3.29 (4H, m), 2.64 (2H, t, J = 6.1 Hz), 2.54-2.57 (4H, m), 2.38-2.42 (6H, m), 2.33 (3H, s), 1.79-1.93 (4H, m). (Example 130)
4- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -6,7-dihydropyrido [2,3-d] pyrimidin-8 (5H) -yl} propyl) morpholine
Figure JPOXMLDOC01-appb-C000124
 Using compound 10A (100 mg, 0.302 mmol) obtained in Reference Example 39, a coupled product was obtained as a mixture (77.1 mg) in the same manner as in Example 1. The mixture was reacted in the same manner as in Example 69 to give the title compound as a pale yellow oil (56.1 mg, 43% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.87 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.68-3.76 (6H, m ), 3.40 (2H, t, J = 5.5 Hz), 3.26-3.29 (4H, m), 2.64 (2H, t, J = 6.1 Hz), 2.54-2.57 (4H, m), 2.38-2.42 (6H, m), 2.33 (3H, s), 1.79-1.93 (4H, m).
（実施例１３１）
Ｎ，Ｎ－ジエチル－２－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェノキシ）エタンアミン
Figure JPOXMLDOC01-appb-C000125
 　参考例１３で得られる化合物４Ｂ（５０.０ｍｇ、０.１５４ｍｍｏｌ）のＤＭＦ（２.０ｍｌ）溶液に２－クロロ－Ｎ，Ｎ－ジエチルエタンアミン塩酸塩（２８ｍｇ、０.１６２ｍｍｏｌ）、炭酸カリウム（４５.０ｍｇ、０.３２３ｍｍｏｌ）を加えた。室温で７時間撹拌後、酢酸エチルと７％アンモニア水溶液を加えた。酢酸エチルで分液抽出し、有機層を硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、白色固体として表題化合物を得た（１４.０ｍｇ、収率２２％）。
1H-NMR (CDCl3,δ ppm): 8.27 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.09 (2H, t, J = 6.4 Hz), 3.61 (2H, t, J = 8.3 Hz), 3.55 (2H, t, J = 6.9 Hz), 3.01 (2H, t, J = 8.3 Hz), 2.88 (2H, t, J = 6.3 Hz), 2.60-2.67 (10H, m), 1.83-1.94 (6H, m), 1.06 (6H, t, J = 7.2 Hz ). (Example 131)
N, N-diethyl-2- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenoxy ) Ethanamine
Figure JPOXMLDOC01-appb-C000125
 To a solution of compound 4B obtained in Reference Example 13 (50.0 mg, 0.154 mmol) in DMF (2.0 ml) was added 2-chloro-N, N-diethylethanamine hydrochloride (28 mg, 0.162 mmol), potassium carbonate ( 45.0 mg, 0.323 mmol) was added. After stirring at room temperature for 7 hours, ethyl acetate and 7% aqueous ammonia solution were added. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to give the title compound as a white solid (14.0 mg, yield 22%).
1 H-NMR (CDCl 3 , δ ppm): 8.27 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.09 (2H, t, J = 6.4 Hz), 3.61 (2H, t, J = 8.3 Hz), 3.55 (2H, t, J = 6.9 Hz), 3.01 (2H, t, J = 8.3 Hz), 2.88 (2H, t, J = 6.3 Hz), 2.60-2.67 (10H, m), 1.83-1.94 (6H, m), 1.06 (6H, t, J = 7.2 Hz).
（実施例１３２）
（Ｓ）－イソプロピル １－（３－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）ピロリジン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000126
 　実施例１２９で得られた化合物（５０.０ｍｇ、０.１５４ｍｍｏｌ）のイソプロパノール（２.０ｍｌ）溶液に４ｍｏｌ／Ｌ塩酸／１，４－ジオキサン溶液（０.５０ｍｌ）を加えて室温に７時間撹拌後、６０度にて８時間撹拌した。飽和炭酸水素ナトリウム水溶液にて反応停止後、エタノール／クロロホルム（１／３）で分液抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧除去し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製することにより、淡黄色油状物として表題化合物を得た（９.８５ｍｇ、収率２３％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 5.08-4.99 (1H, m), 3.64-3.47 (4H, m), 3.32-3.29 (4H, m), 3.23-3.19 (1H, m), 3.14-3.10 (1H, m), 3.00 (2H, t, J = 8.3 Hz), 2.80-2.73 (1H, m), 2.60-2.56 (4H, m), 2.53-2.47 (1H, m), 2.38-2.36 (4H, m), 2.14-2.09 (1H, m), 1.93-1.80 (5H, m), 1.22 (6H, d, J = 6.4 Hz). (Example 132)
(S) -Isopropyl 1- (3- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) Pyrrolidine-2-carboxylate
Figure JPOXMLDOC01-appb-C000126
 To a solution of the compound obtained in Example 129 (50.0 mg, 0.154 mmol) in isopropanol (2.0 ml) was added 4 mol / L hydrochloric acid / 1,4-dioxane solution (0.50 ml), and the mixture was stirred at room temperature for 7 hours. Then, it stirred at 60 degree | times for 8 hours. The reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation extraction with ethanol / chloroform (1/3). The organic layer is dried over sodium sulfate and removed under reduced pressure. The resulting residue is purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate → ethyl acetate: methanol) to give the title compound as a pale yellow oil. (9.85 mg, 23% yield) was obtained.
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.94 (2H, d, J = 9.0 Hz), 5.08-4.99 (1H, m ), 3.64-3.47 (4H, m), 3.32-3.29 (4H, m), 3.23-3.19 (1H, m), 3.14-3.10 (1H, m), 3.00 (2H, t, J = 8.3 Hz), 2.80-2.73 (1H, m), 2.60-2.56 (4H, m), 2.53-2.47 (1H, m), 2.38-2.36 (4H, m), 2.14-2.09 (1H, m), 1.93-1.80 (5H , m), 1.22 (6H, d, J = 6.4 Hz).
（実施例１３３）
（２Ｓ，４Ｒ）－メチル ４－ヒドロキシ－１－（３－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）ピロリジン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000127
 　参考例５３で得られた化合物１５Ｂ（５０.０ｍｇ、０.１４２ｍｍｏｌ）のメタノール溶液（１.５ｍｌ）に氷冷下、酢酸（１９.０μｌ、０.３１２ｍｍｏｌ）、（２Ｓ，４Ｒ）－メチル ４－ヒドロキシピロリジン－２－カルボキシレート（２８.０ｍｇ、０.１５６ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１２.０ｍｇ、０.１９９ｍｍｏｌ）を加えた。室温で１６時間撹拌後、飽和炭酸水素ナトリウム水溶液を加えて反応停止した。クロロホルムで分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧除去した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、無色アモルファスとして表題化合物を得た（３４.０ｍｇ、収率５０％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.46 (1H, m), 3.65 (3H, s), 3.61-3.47 (5H, m), 3.44-3.39 (1H, m), 3.30-2.67 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.80-2.76 (1H, m), 2.62-2.48 (7H, m), 2.34 (3H, s), 2.23-2.16 (1H, m), 2.09-2.06 (1H, m), 1.85-1.80 (2H, m). (Example 133)
(2S, 4R) -Methyl 4-hydroxy-1- (3- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H ) -Yl) propyl) pyrrolidine-2-carboxylate
Figure JPOXMLDOC01-appb-C000127
 Acetic acid (19.0 μl, 0.312 mmol), (2S, 4R) -methyl 4 was added to a methanol solution (1.5 ml) of compound 15B (50.0 mg, 0.142 mmol) obtained in Reference Example 53 under ice-cooling. -Hydroxypyrrolidine-2-carboxylate (28.0 mg, 0.156 mmol) and sodium cyanoborohydride (12.0 mg, 0.199 mmol) were added. After stirring at room temperature for 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate and then removed under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) to give the title compound as a colorless amorphous (34.0 mg, yield 50%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 4.46 (1H, m), 3.65 (3H, s), 3.61-3.47 (5H, m), 3.44-3.39 (1H, m), 3.30-2.67 (4H, m), 2.99 (2H, t, J = 8.4 Hz), 2.80-2.76 ( 1H, m), 2.62-2.48 (7H, m), 2.34 (3H, s), 2.23-2.16 (1H, m), 2.09-2.06 (1H, m), 1.85-1.80 (2H, m).
（実施例１３４）
２－（４－（４－（４－メチル－７－（３－（ピロリジン－１－イル）プロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノール
Figure JPOXMLDOC01-appb-C000128
 (Example 134)
2- (4- (4- (4-Methyl-7- (3- (pyrrolidin-1-yl) propyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) Phenyl) piperazin-1-yl) ethanol
Figure JPOXMLDOC01-appb-C000128
（ａ）２－（４－（４－（２－（ｔｅｒｔ－ブチルジメチルシリロキシ）エチル）ピペラジン－１－イル）フェニル）－４－クロロ－７－（３－（ピロリジン－１－イル）プロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
　実施例２１で得られた化合物（１００ｍｇ、０.２３４ｍｍｏｌ）のメタノール溶液（３.０ｍｌ）に氷冷下、酢酸（５４.０μｌ、０.９３６ｍｍｏｌ）、２－（ｔｅｒｔ－ブチルジメチルシリロキシ）アセトアルデヒド（１１１μｌ、０.５８５ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（３２.０ｍｇ、０.５１５ｍｍｏｌ）を加えた。室温で４時間撹拌後、飽和炭酸水素ナトリウム水溶液を加えて反応停止した。クロロホルムで分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧除去した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより、無色油状物として表題化合物を得た（１２０ｍｇ、収率８８％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 8.6 Hz), 6.89 (2H, d, J = 8.6 Hz), 3.78 (2H, t, J = 6.2 Hz), 3.63 (2H, t, J = 8.6 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.29-3.26 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.68-2.65 (4H, m), 2.57 (2H, t, J = 6.2 Hz), 2.51-2.47 (6H, m), 1.88-1.77 (6H, m), 0.88 (9H, m), 0.05 (6H, m). (A) 2- (4- (4- (2- (tert-butyldimethylsilyloxy) ethyl) piperazin-1-yl) phenyl) -4-chloro-7- (3- (pyrrolidin-1-yl) propyl ) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine To a solution of the compound obtained in Example 21 (100 mg, 0.234 mmol) in methanol (3.0 ml) under acetic acid (54 0.0 μl, 0.936 mmol), 2- (tert-butyldimethylsilyloxy) acetaldehyde (111 μl, 0.585 mmol), sodium cyanoborohydride (32.0 mg, 0.515 mmol) were added. After stirring at room temperature for 4 hours, the reaction was stopped by adding a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate and then removed under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a colorless oil (120 mg, yield 88%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 8.6 Hz), 6.89 (2H, d, J = 8.6 Hz), 3.78 (2H, t, J = 6.2 Hz), 3.63 ( 2H, t, J = 8.6 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.29-3.26 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.68-2.65 (4H, m ), 2.57 (2H, t, J = 6.2 Hz), 2.51-2.47 (6H, m), 1.88-1.77 (6H, m), 0.88 (9H, m), 0.05 (6H, m).
（ｂ）２－（４－（４－（４－メチル－７－（３－（ピロリジン－１－イル）プロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノール
　上記で得られた化合物（１２０ｍｇ、０.２０５ｍｍｏｌ）のテトラヒドロフラン溶液（２.０ｍｌ）にビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム（２１.０ｍｇ、０.０４１０ｍｍｏｌ）、２ｍｏｌ／Ｌメチルジンククロライド－テトラヒドロフラン溶液（０.５０ｍｌ、１.０３ｍｍｏｌ）を加え、室温にて撹拌した。７時間後、１Ｍ塩酸水溶液を加え、１時間撹拌した。溶液を酢酸エチルで洗浄後、５Ｍ水酸化ナトリウム水溶液でｐＨ＝１０とし、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧除去した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製後、ジエチルエーテルでリパルプすることにより、淡黄色固体として表題化合物を得た（３６.０ｍｇ、収率３９％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 3.65-3.49 (6H, m), 3.28-3.25 (4H, m), 2.94 (2H, t, J = 8.3 Hz), 2.77 (1H, brs), 2.68-2.65 (4H, m), 2.59 (2H, t, J = 5.2 Hz), 2.53-2.48 (6H, m), 2.26 (3H, s), 1.87-1.77 (6H, m). (B) 2- (4- (4- (4-Methyl-7- (3- (pyrrolidin-1-yl) propyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2) -Yl) phenyl) piperazin-1-yl) ethanol To a tetrahydrofuran solution (2.0 ml) of the compound (120 mg, 0.205 mmol) obtained above was added bis (tri-tert-butylphosphine) palladium (21.0 mg, 0 (0.0410 mmol) and 2 mol / L methyl zinc chloride-tetrahydrofuran solution (0.50 ml, 1.03 mmol) were added, and the mixture was stirred at room temperature. After 7 hours, 1M aqueous hydrochloric acid solution was added and stirred for 1 hour. The solution was washed with ethyl acetate, adjusted to pH = 10 with 5M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; chloroform: methanol) and repulped with diethyl ether to give the title compound as a pale yellow solid (36.0 mg, yield 39%).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.6 Hz), 3.65-3.49 (6H, m), 3.28-3.25 (4H , m), 2.94 (2H, t, J = 8.3 Hz), 2.77 (1H, brs), 2.68-2.65 (4H, m), 2.59 (2H, t, J = 5.2 Hz), 2.53-2.48 (6H, m), 2.26 (3H, s), 1.87-1.77 (6H, m).
（実施例１３５）
（Ｒ）－２－（４－（４－（７－（モルホリン－２－イルメチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノール
Figure JPOXMLDOC01-appb-C000129
 (Example 135)
(R) -2- (4- (4- (7- (morpholin-2-ylmethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine-1 -Il) Ethanol
Figure JPOXMLDOC01-appb-C000129
（ａ）（Ｒ）－４－ベンジル－２－（（２－（４－（４－（２－（tert－ブチルジメチルシリロキシ）エチル）ピペラジン－１－イル）フェニル）－４－クロロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
　参考例５５（ｂ）で得られた化合物１７Ｂ（１．４６ｇ、２．８９ｍｍｏｌ）を用いて、実施例１３４（ａ）と同様の方法を用いることによって、表題化合物を無色アモルファスとして得た（１．４６ｇ、収率７６％）。
1H-NMR (CDCl3,δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.27-7.22 (5H, m), 6.88 (2H, d, J = 9.0 Hz), 3.87-3.41 (11H, m), 3.30-3.26 (4H, m), 3.01 (2H, t, J = 8.6 Hz), 2.83-2.79 (1H, m), 2.69-2.66 (4H, m), 2.61-2.55 (3H, m), 2.18-2.10 (1H, m), 2.02-1.94 (1H, m), 0.88 (9H, m), 0.05 (6H, m). (A) (R) -4-Benzyl-2-((2- (4- (4- (2- (tert-butyldimethylsilyloxy) ethyl) piperazin-1-yl) phenyl) -4-chloro-5H -Pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) methyl) morpholine Example 134 (1.46 g, 2.89 mmol) was used for Compound 134 (1.46 g, 2.89 mmol) obtained in Reference Example 55 (b). The title compound was obtained as a colorless amorphous by using the same method as in a) (1.46 g, yield 76%).
1 H-NMR (CDCl 3 , δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.27-7.22 (5H, m), 6.88 (2H, d, J = 9.0 Hz), 3.87-3.41 (11H , m), 3.30-3.26 (4H, m), 3.01 (2H, t, J = 8.6 Hz), 2.83-2.79 (1H, m), 2.69-2.66 (4H, m), 2.61-2.55 (3H, m ), 2.18-2.10 (1H, m), 2.02-1.94 (1H, m), 0.88 (9H, m), 0.05 (6H, m).
（ｂ）（Ｒ）－２－（（２－（４－（４－（２－（ｔｅｒｔ－ブチルジメチルシリロキシ）エチル）ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
　上記で得られた化合物（１．４６ｇ、２．２０ｍｍｏｌ）を用いて、実施例６９と同様の方法を用いることにより、表題化合物を淡黄色ガム状物として得た。（１．０４g、収率８８％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.82 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 3.89-3.86 (1H, m), 3.80-3.55 (8H, m), 3.45-3.38 (1H, m), 3.28-3.25 (4H, m) 3.02 (3H, m), 2.91-2.76 (2H, m), 2.69-2.65 (4H, m), 2.61-2.54 (2H, m), 0.88 (9H, m), 0.05 (6H, m). (B) (R) -2-((2- (4- (4- (2- (tert-Butyldimethylsilyloxy) ethyl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d ] Pyrimidin-7 (6H) -yl) methyl) morpholine Using the compound obtained above (1.46 g, 2.20 mmol) and using a method similar to Example 69, the title compound was obtained as a pale yellow gum. Obtained as a product. (1.04 g, 88% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.82 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 3.89-3.86 (1H, m ), 3.80-3.55 (8H, m), 3.45-3.38 (1H, m), 3.28-3.25 (4H, m) 3.02 (3H, m), 2.91-2.76 (2H, m), 2.69-2.65 (4H, m), 2.61-2.54 (2H, m), 0.88 (9H, m), 0.05 (6H, m).
（ｃ）（Ｒ）－２－（４－（４－（７－（モルホリン－２－イルメチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノール
　上記で得られた化合物（８２０ｍｇ、１．５２ｍｍｏｌ）を用いて、実施例１２６（ｂ）と同様の方法を用いることにより、表題化合物を淡黄色固体として得た。（５２０ｍｇ、収率８０％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.90-3.86 (1H, m), 3.75-3.55 (8H, m), 3.47-3.39 (1H, m), 3.36-3.27 (4H, m), 3.03-2.97 (3H, t, J = 8.5 Hz), 2.91-2.77 (2H, m), 2.69-2.65 (4H, m), 2.61-2.57 (2H, m). (C) (R) -2- (4- (4- (7- (morpholin-2-ylmethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) Piperazin-1-yl) ethanol Using the compound obtained above (820 mg, 1.52 mmol) and using a method similar to Example 126 (b), the title compound was obtained as a pale yellow solid. (520 mg, 80% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.90-3.86 (1H, m ), 3.75-3.55 (8H, m), 3.47-3.39 (1H, m), 3.36-3.27 (4H, m), 3.03-2.97 (3H, t, J = 8.5 Hz), 2.91-2.77 (2H, m ), 2.69-2.65 (4H, m), 2.61-2.57 (2H, m).
（実施例１３６）
（Ｒ）－２－（（２－（４－（４－（２－メトキシエチル）ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
Figure JPOXMLDOC01-appb-C000130
 (Example 136)
(R) -2-((2- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Methyl) morpholine
Figure JPOXMLDOC01-appb-C000130
（ａ）（Ｒ）－１－（４－（４－（７－（（４－ベンジルモルホリン－２－イル）メチル）－４－クロロ－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）－２－メトキシエタノン
　参考例５５（ｂ）で得られた化合物１８Ｂ（１．６０ｇ, ３．１６ｍｍｏｌ）を用いて、実施例７７（ａ）と同様の方法を用いることによって、表題化合物を無色アモルファスとして得た（１．５０ｇ、収率８２％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 7.3 Hz), 7.27-7.23 (5H, m), 6.89 (2H, d, J = 7.3 Hz), 4.14 (2H, m), 3.87-3.46 (13H, m), 3.43-3.42 (3H, m), 3.29-3.26 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.83-2.79 (1H, m), 2.65-2.61 (1H, m), 2.20-2.11 (1H, m), 2.03-1.95 (1H, m). (A) (R) -1- (4- (4- (7-((4-Benzylmorpholin-2-yl) methyl) -4-chloro-6,7-dihydro-5H-pyrrolo [2,3- d] Pyrimidin-2-yl) phenyl) piperazin-1-yl) -2-methoxyethanone Example 77 using compound 18B (1.60 g, 3.16 mmol) obtained in Reference Example 55 (b) The title compound was obtained as a colorless amorphous by using the same method as in (a) (1.50 g, yield 82%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 7.3 Hz), 7.27-7.23 (5H, m), 6.89 (2H, d, J = 7.3 Hz), 4.14 (2H, m ), 3.87-3.46 (13H, m), 3.43-3.42 (3H, m), 3.29-3.26 (4H, m), 3.02 (2H, t, J = 8.6 Hz), 2.83-2.79 (1H, m), 2.65-2.61 (1H, m), 2.20-2.11 (1H, m), 2.03-1.95 (1H, m).
（ｂ）（Ｒ）－２－メトキシ－１－（４－（４－（７－（モルホリン－２－イルメチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノン
　上記で得られた化合物（１．５０ｇ、２．６０ｍｍｏｌ）を用いて、実施例６９と同様の方法を用いることにより、表題化合物を無色固体として得た（９１１ｍｇ、収率７７％）。
1H-NMR (CDCl3,δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.93 (１H, s), 6.92 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.96-3.86 (1H, m), 3.79-3.55 (10H, m), 3.46-3.39 (4H, m), 3.27-3.24 (4H, m), 3.03-2.96 (3H, m), 2.91-2.78 (2H, m), 2.69-2.62 (1H, m). (B) (R) -2-Methoxy-1- (4- (4- (7- (morpholin-2-ylmethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2- Yl) phenyl) piperazin-1-yl) ethanone Using the compound obtained above (1.50 g, 2.60 mmol) and using a method similar to Example 69, the title compound was obtained as a colorless solid. (911 mg, 77% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.25 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.96-3.86 (1H, m), 3.79-3.55 (10H, m), 3.46-3.39 (4H, m), 3.27-3.24 (4H, m), 3.03-2.96 (3H, m), 2.91-2.78 (2H , m), 2.69-2.62 (1H, m).
（ｃ）（Ｒ）－２－（（２－（４－（４－（２－メトキシエチル）ピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）モルホリン
　上記で得られた化合物（４３５ｍｇ, ０．９６１ｍｍｏｌ）を用いて、実施例７７（ｂ）と同様の方法を用いることにより、表題化合物を黄色固体として得た（１６９ｍｇ、収率４０％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.89-3.86 (1H, m), 3.75-3.52 (8H, m), 3.45-3.36 (4H, m), 3.32-3.28 (4H, m), 3.02-2.96 (3H, m), 2.91-2.77 (2H, m), 2.69-2.61 (7H, m). (C) (R) -2-((2- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il) methyl) morpholine Using the compound obtained above (435 mg, 0.961 mmol) and using a method similar to Example 77 (b), the title compound was obtained as a yellow solid (169 mg, yield). 40%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.89-3.86 (1H, m ), 3.75-3.52 (8H, m), 3.45-3.36 (4H, m), 3.32-3.28 (4H, m), 3.02-2.96 (3H, m), 2.91-2.77 (2H, m), 2.69-2.61 (7H, m).
（実施例１３７）
(Ｒ)－Ｎ－メチル－１－(４－(７－(３－モルホリノプロピル)－６，７－ジヒドロ－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－２－イル)フェニル)ピペリジン－３－アミン
Figure JPOXMLDOC01-appb-C000131
 　参考例５で得られた化合物（２７３ｍｇ、０．８６１ｍｍｏｌ）を用いて、実施例７５と同様にして表題化合物を淡黄色油状物として得た（７０．０ｍｇ、収率１８％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.73-3.70 (5H, t, J = 4.7 Hz), 3.62-3.51 (5H, m), 2.99 (2H, t, J = 8.4 Hz), 2.96-2.84 (1H, m), 2.76-2.63 (2H, m), 2.49 (3H, s), 2.44-2.35 (6H, m), 1.96-1.93 (1H, m), 1.86-1.77 (3H, m), 1.71-1.59 (1H, m), 1.38-1.26 (1H, m). (Example 137)
(R) -N-methyl-1- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperidine-3 -Amine
Figure JPOXMLDOC01-appb-C000131
 Using the compound (273 mg, 0.861 mmol) obtained in Reference Example 5, the title compound was obtained as a pale yellow oil in the same manner as in Example 75 (70.0 mg, 18% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.93 (2H, d, J = 9.0 Hz), 3.73-3.70 (5H, t , J = 4.7 Hz), 3.62-3.51 (5H, m), 2.99 (2H, t, J = 8.4 Hz), 2.96-2.84 (1H, m), 2.76-2.63 (2H, m), 2.49 (3H, s), 2.44-2.35 (6H, m), 1.96-1.93 (1H, m), 1.86-1.77 (3H, m), 1.71-1.59 (1H, m), 1.38-1.26 (1H, m).
（実施例１３８）
４－ベンジル－２－（４－（４－クロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）モルホリン
Figure JPOXMLDOC01-appb-C000132
 (Example 138)
4-Benzyl-2- (4- (4-chloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) morpholine
Figure JPOXMLDOC01-appb-C000132
（ａ）２－（ベンジルアミノ）－１－（４－ブロモフェニル）エタノール
　水素化ナトリウム（５５％含量、８７２ｍｇ、２０．８ｍｍｏｌ）のＴＨＦ（４０ｍｌ）懸濁液に、ヨウ化 トリメチルスルホニウム（４．１６ｇ、２０．０ｍｍｏｌ）のＤＭＳＯ（４０ｍｌ）溶液を０℃にて滴下した。１０分後、４－ブロモベンズアルデヒド（３．７０ｇ、２０．０ｍｍｏｌ）のＴＨＦ（１０ｍｌ）溶液を滴下した。３０分後、室温に昇温した。１時間後、氷水に注ぎ反応を停止し、ヘキサンで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮し混合物（４．７８ｇ）を得た。得られた混合物（２．０ｇ、１０．０ｍｍｏｌ）にベンジルアミン（１．３２ｍｌ、１２．１ｍｍｏｌ）、リチウム パークロレート（２１４ｍｇ、２．０ｍｍｏｌ）を加え、室温にて終夜攪拌した。反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製することにより、白色固体として表題化合物を得た（１．４８ｇ、収率３３％）。
1H-NMR (CDCl3,δ ppm): 7.45 (2H, m), 7.20-7.35 (7H, m), 4.65 (1H, dd, J = 8.9, 3.7 Hz), 3.84 (1H, d, J = 13.2 Hz), 3.78 (1H, d, J = 13.2 Hz), 2.90 (1H, dd, J = 12.3, 3.7 Hz), 2.66 (1H, dd, J = 12.3, 8.9 Hz). (A) 2- (Benzylamino) -1- (4-bromophenyl) ethanol To a suspension of sodium hydride (55% content, 872 mg, 20.8 mmol) in THF (40 ml), trimethylsulfonium iodide (4. 16 g, 20.0 mmol) in DMSO (40 ml) was added dropwise at 0 ° C. After 10 minutes, a solution of 4-bromobenzaldehyde (3.70 g, 20.0 mmol) in THF (10 ml) was added dropwise. After 30 minutes, the temperature was raised to room temperature. After 1 hour, the reaction was stopped by pouring into ice water, followed by liquid separation extraction with hexane. The organic layer was washed with saturated brine, and concentrated under reduced pressure to obtain a mixture (4.78 g). Benzylamine (1.32 ml, 12.1 mmol) and lithium perchlorate (214 mg, 2.0 mmol) were added to the obtained mixture (2.0 g, 10.0 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a white solid (1.48 g, yield 33%).
1 H-NMR (CDCl 3 , δ ppm): 7.45 (2H, m), 7.20-7.35 (7H, m), 4.65 (1H, dd, J = 8.9, 3.7 Hz), 3.84 (1H, d, J = 13.2 Hz), 3.78 (1H, d, J = 13.2 Hz), 2.90 (1H, dd, J = 12.3, 3.7 Hz), 2.66 (1H, dd, J = 12.3, 8.9 Hz).
（ｂ）４－ベンジル－６－（４－ブロモフェニル）モルホリン－３－オン
　上記で得た化合物（１．４８ｇ、４．８３ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液に、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（６．２８ｍｌ、６．２８ｍｍｏｌ）、塩化クロロアセチル（５００μｌ、６．２８ｍｍｏｌ）を加えた。反応溶液をｐＨ＝８となるまで水酸化ナトリウム水溶液を滴下した。２時間後、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮し混合物を得た。得られた混合物のイソプロパノール（１０ｍｌ）溶液に、水酸化カリウム（５４２ｍｇ、９．６７ｍｍｏｌ）を加え、室温にて終夜攪拌した。反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより、白色固体として表題化合物を得た（１．７１ｇ、収率１００％）。
1H-NMR (CDCl3,δ ppm): 7.45 (2H, m), 7.24-7.35 (5H, m), 7.18 (2H, m), 4.72 (1H, dd, J = 10.3, 3.7 Hz), 4.70 (1H, d, J = 14.3 Hz), 4.57 (1H, d, J = 14.3 Hz), 4.46 (1H, d, J = 16.7 Hz), 4.36 (1H, d, J = 16.7 Hz), 3.34 (1H, dd, J = 12.3, 10.3 Hz), 3.24 (1H, dd, J = 12.3, 3.7 Hz). (B) 4-Benzyl-6- (4-bromophenyl) morpholin-3-one To a solution of the compound obtained above (1.48 g, 4.83 mmol) in dichloromethane (20 ml) was added 1 mol / L aqueous sodium hydroxide solution ( 6.28 ml, 6.28 mmol) and chloroacetyl chloride (500 μl, 6.28 mmol) were added. A sodium hydroxide aqueous solution was added dropwise until the reaction solution reached pH = 8. After 2 hours, liquid separation extraction was performed with chloroform. The organic layer was washed with saturated brine and then concentrated under reduced pressure to obtain a mixture. To a solution of the obtained mixture in isopropanol (10 ml) was added potassium hydroxide (542 mg, 9.67 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a white solid (1.71 g, yield 100%).
1 H-NMR (CDCl 3 , δ ppm): 7.45 (2H, m), 7.24-7.35 (5H, m), 7.18 (2H, m), 4.72 (1H, dd, J = 10.3, 3.7 Hz), 4.70 (1H, d, J = 14.3 Hz), 4.57 (1H, d, J = 14.3 Hz), 4.46 (1H, d, J = 16.7 Hz), 4.36 (1H, d, J = 16.7 Hz), 3.34 (1H , dd, J = 12.3, 10.3 Hz), 3.24 (1H, dd, J = 12.3, 3.7 Hz).
（ｃ）４－ベンジル－６－（４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）モルホリン－３－オン
　上記で得た化合物（１．７０ｇ、４．９１ｍｍｏｌ）の１，４－ジオキサン（３０ｍｌ）溶液に、[１，１’－ビス（ジフェニルホスフィノ）フェロセン]パラジウム（ＩＩ）ジクロリド ジクロロメタン錯体（４００ｍｇ、０．４９１ｍｍｏｌ）、ビス（ピナコラート）ジボロン（２．４９ｇ、９．８２ｍｍｏｌ）、酢酸カリウム（１．９３ｇ、１９．６ｍｍｏｌ）を加え、９０℃にて攪拌した。２時間後、反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより、淡黄色固体として表題化合物を得た（２．０８ｇ、収率１００％）。
1H-NMR (CDCl3,δ ppm): 7.76 (2H, d, J = 7.9 Hz), 7.24-7.35 (7H, m), 4.76 (1H, dd, J = 10.5, 3.5 Hz), 4.69 (1H, d, J = 14.5 Hz), 4.35-4.58 (3H, m), 3.36 (1H, dd, J = 12.3, 10.5 Hz), 3.26 (1H, dd, J = 12.3, 3.5 Hz). (C) 4-Benzyl-6- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholin-3-one Compound (1) obtained above To a solution of 1.70 g, 4.91 mmol) in 1,4-dioxane (30 ml), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (400 mg, 0.491 mmol), bis ( Pinacolato) diboron (2.49 g, 9.82 mmol) and potassium acetate (1.93 g, 19.6 mmol) were added, and the mixture was stirred at 90 ° C. After 2 hours, water was added to the reaction solution to stop the reaction, followed by separation and extraction with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a pale yellow solid (2.08 g, yield 100%).
1 H-NMR (CDCl 3 , δ ppm): 7.76 (2H, d, J = 7.9 Hz), 7.24-7.35 (7H, m), 4.76 (1H, dd, J = 10.5, 3.5 Hz), 4.69 (1H , d, J = 14.5 Hz), 4.35-4.58 (3H, m), 3.36 (1H, dd, J = 12.3, 10.5 Hz), 3.26 (1H, dd, J = 12.3, 3.5 Hz).
（ｄ）４－ベンジル－６－（４－（４－クロロ－１－（３－モルホリノプロピル）インドリン－６－イル）フェニル）モルホリン－３－オン
　上記で得た化合物（１．０ｇ、２．５４ｍｍｏｌ）の１，４－ジオキサン（２０ｍｌ）溶液に、参考例５で得た化合物（８０７ｍｇ, ２．５４ｍｍｏｌ)、テトラキストリフェニルホスフィンパラジウム(２９４ｍｇ、０．２５４ｍｍｏｌ)、２Ｍ 水酸化リチウム水溶液（５．１ｍｌ, １０．２ｍｍｏｌ）を加え、１２０℃にて攪拌した。２時間後、反応溶液に水を加え反応を停止し、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより、白色固体として表題化合物を得た（６５２ｍｇ、収率４７％）。
1H-NMR (CDCl3,δ ppm): 8.30 (2H, d, J = 8.3 Hz), 7.24-7.35 (7H, m), 4.80 (1H, dd, J = 10.4, 3.5 Hz), 4.72 (1H, d, J = 14.7 Hz), 4.55 (1H, d, J = 14.7 Hz), 4.52 (1H, d, J = 16.7 Hz), 4.39 (1H, d, J = 16.7 Hz), 3.66-3.71 (6H, m), 3.53 (2H, t, J = 7.1 Hz), 3.40 (1H, dd, J = 12.3, 10.3 Hz), 3.28 (1H, dd, J = 12.3, 3.5 Hz), 3.05 (2H, m), 2.36-2.41 (6H, m), 1.80 (2H, m). (D) 4-Benzyl-6- (4- (4-chloro-1- (3-morpholinopropyl) indoline-6-yl) phenyl) morpholin-3-one The compound obtained above (1.0 g, 2. 54 mmol) in 1,4-dioxane (20 ml), the compound obtained in Reference Example 5 (807 mg, 2.54 mmol), tetrakistriphenylphosphine palladium (294 mg, 0.254 mmol), 2M aqueous lithium hydroxide solution (5. 1 ml, 10.2 mmol) was added, and the mixture was stirred at 120 ° C. After 2 hours, water was added to the reaction solution to stop the reaction, followed by separation and extraction with ethyl acetate. The organic layer was washed with saturated brine 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 a white solid (652 mg, yield 47%).
1 H-NMR (CDCl 3 , δ ppm): 8.30 (2H, d, J = 8.3 Hz), 7.24-7.35 (7H, m), 4.80 (1H, dd, J = 10.4, 3.5 Hz), 4.72 (1H , d, J = 14.7 Hz), 4.55 (1H, d, J = 14.7 Hz), 4.52 (1H, d, J = 16.7 Hz), 4.39 (1H, d, J = 16.7 Hz), 3.66-3.71 (6H , m), 3.53 (2H, t, J = 7.1 Hz), 3.40 (1H, dd, J = 12.3, 10.3 Hz), 3.28 (1H, dd, J = 12.3, 3.5 Hz), 3.05 (2H, m) , 2.36-2.41 (6H, m), 1.80 (2H, m).
（ｅ）４－ベンジル－２－（４－（４－クロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）モルホリン
　上記で得た化合物（５３４ｍｇ、０．９７ｍｍｏｌ）のＴＨＦ(１０ｍｌ)溶液に、水素化アルミニウムリチウム（７７．９ｍｇ, ２．１１ｍｍｏｌ)を加え、加熱還流にて攪拌した。２時間後、反応溶液に水、２Ｍ 水酸化ナトリウム水溶液を加え反応を停止した。反応溶液をセライトでろ過を行い、濃縮することで、黄色油状物として表題化合物を得た（５０３ｍｇ、収率９７％）。
1H-NMR (CDCl3,δ ppm): 8.28 (2H, d, J = 8.4 Hz), 7.21-7.39 (7H, m), 4.61 (1H, dd, J = 10.2, 2.1 Hz), 3.96-4.04 (1H, m), 3.77-3.87 (1H, m), 3.60-3.73 (6H, m), 3.44-3.58 (4H, m), 3.04 (2H, t, J = 8.5 Hz), 2.87-2.94 (1H, m), 2.69-2.76 (1H, m), 2.36-2.45 (6H, m), 2.21-2.31 (1H, m), 2.05-2.13 (1H, m), 1.76-1.83 (2H, m). (E) 4-Benzyl-2- (4- (4-chloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) Morpholine Lithium aluminum hydride (77.9 mg, 2.11 mmol) was added to a THF (10 ml) solution of the compound obtained above (534 mg, 0.97 mmol), and the mixture was stirred with heating under reflux. After 2 hours, water and 2M aqueous sodium hydroxide solution were added to the reaction solution to stop the reaction. The reaction solution was filtered through celite and concentrated to give the title compound as a yellow oil (503 mg, yield 97%).
1 H-NMR (CDCl 3 , δ ppm): 8.28 (2H, d, J = 8.4 Hz), 7.21-7.39 (7H, m), 4.61 (1H, dd, J = 10.2, 2.1 Hz), 3.96-4.04 (1H, m), 3.77-3.87 (1H, m), 3.60-3.73 (6H, m), 3.44-3.58 (4H, m), 3.04 (2H, t, J = 8.5 Hz), 2.87-2.94 (1H , m), 2.69-2.76 (1H, m), 2.36-2.45 (6H, m), 2.21-2.31 (1H, m), 2.05-2.13 (1H, m), 1.76-1.83 (2H, m).
（実施例１３９）
４－（３－（２－（４－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000133
 (Example 139)
4- (3- (2- (4-((3S, 5R) -3,5-dimethylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl ) Propyl) morpholine
Figure JPOXMLDOC01-appb-C000133
（ａ）４－（３－（４－クロロ－２－（４－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
　参考例５で得られた化合物（２７４ｍｇ、０.８６４ｍｍｏｌ）の１，４－ジオキサン（３.５ｍｌ）溶液に、（２Ｓ，６Ｒ）－ｔｅｒｔ－ブチル ２，６－ジメチル－４－（４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）ピペラジン－１－カルボキシラート（３７７ｍｇ、０.９１ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１００ｍｇ、０.０８６ｍｍｏｌ）、３ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０.８６ｍｌ、２.５９ｍｍｏｌ）を加え、マイクロウエーブ照射下１２０℃にて攪拌した。３０分後、反応溶液を酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製後、得られた油状物をメタノール（３.０ｍｌ）溶液に４ｍｏｌ／Ｌ 塩酸／１，４－ジオキサン（６.０ｍｌ）を加えて室温にて攪拌した。１７時間撹拌後、溶媒を減圧除去した。残渣に水を加え、酢酸エチルで洗浄後、５ｍｏｌ／Ｌ 水酸化ナトリウム水溶液でｐＨ＝１０とし、酢酸エチルで分液抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）にて精製することにより黄色油状物として表題化合物を得た（１３６ｍｇ、収率３３％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 3.72-3.70 (4H, m), 3.66-3.60 (4H, m), 3.53 (2H, t, J = 7.1 Hz), 3.05-2.98 (4H, m), 2.43-2.30 (8H, m), 1.85-1.75 (2H, m), 1.15 (3H, s), 1.13 (3H, s). (A) 4- (3- (4-Chloro-2- (4-((3S, 5R) -3,5-dimethylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine -7 (6H) -yl) propyl) morpholine To a solution of the compound obtained in Reference Example 5 (274 mg, 0.864 mmol) in 1,4-dioxane (3.5 ml), (2S, 6R) -tert-butyl 2 , 6-Dimethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (377 mg, 0.91 mmol), Tetrakistriphenylphosphinepalladium (100 mg, 0.086 mmol), 3 mol / L aqueous sodium hydroxide solution (0.86 ml, 2.59 mmol) were added, and under microwave irradiation, 12 ℃ and the mixture was stirred at. After 30 minutes, the reaction solution was subjected to liquid separation extraction with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate), and the obtained oil was added to a methanol (3.0 ml) solution with 4 mol / L hydrochloric acid / 1,4-dioxane ( 6.0 ml) was added and stirred at room temperature. After stirring for 17 hours, the solvent was removed under reduced pressure. Water was added to the residue, washed with ethyl acetate, adjusted to pH = 10 with a 5 mol / L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous 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 a yellow oil (136 mg, yield 33%).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 3.72-3.70 (4H, m), 3.66-3.60 (4H , m), 3.53 (2H, t, J = 7.1 Hz), 3.05-2.98 (4H, m), 2.43-2.30 (8H, m), 1.85-1.75 (2H, m), 1.15 (3H, s), 1.13 (3H, s).
（ｂ）４－（３－（２－（４－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
　上記で得られた化合物（１３６ｍｇ, ０．２８９ｍｍｏｌ）を用いて、実施例６９と同様の方法を用いることにより、表題化合物を白色固体として得た（７１．０ｍｇ, 収率５６％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 8.8 Hz), 7.91 (1H, s), 6.91 (2H, d, J = 8.8 Hz), 4.11-4.09 (4H, m), 3.73-3.51 (6H, m), 3.06-2.97 (4H, m), 2.44-2.30 (8H, m), 1.86-1.76 (2H, m), 1.15 (3H, s), 1.13 (3H, s). (B) 4- (3- (2- (4-((3S, 5R) -3,5-dimethylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H ) -Yl) propyl) morpholine Using the compound obtained above (136 mg, 0.289 mmol) and using a method similar to Example 69, the title compound was obtained as a white solid (71.0 mg, yield). Rate 56%).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 8.8 Hz), 7.91 (1H, s), 6.91 (2H, d, J = 8.8 Hz), 4.11-4.09 (4H, m ), 3.73-3.51 (6H, m), 3.06-2.97 (4H, m), 2.44-2.30 (8H, m), 1.86-1.76 (2H, m), 1.15 (3H, s), 1.13 (3H, s ).
（実施例１４０）
４－（３－（２－（２－（４－メチルピペラジン－１－イル）ピリミジン－５－イル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000134
 　参考例５で得られた化合物（１００ｍｇ、０.３１５ｍｍｏｌ）と対応する試薬を用いて実施例１と実施例３９と同様に操作することにより、表題化合物を薄黄色油状物として得た（１６.０ｍｇ、収率１３％）。
1H-NMR (CDCl3,δ ppm): 9.18 (2H, s), 7.88 (1H, s), 3.93-3.91 (4H, m), 3.71-3.68 (4H, m), 3.61 (2H, t, J = 8.6 Hz), 3.49 (2H, t, J = 7.1 Hz), 3.01 (2H, t, J = 8.6 Hz), 2.48-2.36 (10H, m), 2.33 (3H, s), 1.85-1.75 (2H, m). (Example 140)
4- (3- (2- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) morpholine
Figure JPOXMLDOC01-appb-C000134
 The title compound was obtained as a pale yellow oil by operating in the same manner as in Example 1 and Example 39 using the compound obtained in Reference Example 5 (100 mg, 0.315 mmol) and the corresponding reagent (16. 0 mg, 13% yield).
1 H-NMR (CDCl 3 , δ ppm): 9.18 (2H, s), 7.88 (1H, s), 3.93-3.91 (4H, m), 3.71-3.68 (4H, m), 3.61 (2H, t, J = 8.6 Hz), 3.49 (2H, t, J = 7.1 Hz), 3.01 (2H, t, J = 8.6 Hz), 2.48-2.36 (10H, m), 2.33 (3H, s), 1.85-1.75 ( 2H, m).
（実施例１４１）
４－（２－（２－（４－（４－エチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）エチル）モルホリン
Figure JPOXMLDOC01-appb-C000135
 　参考例５７（８０.０ｍｇ、０.１９２ｍｍｏｌ）を用いて、実施例７６（ａ）と実施例６９と実施例７６（ｂ）と同様の方法を用いることにより、表題化合物を薄黄色固体として得た。（３３.０ｍｇ、収率３１％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.2 Hz), 3.68-3.61 (8H, m), 3.31-3.28 (4H, m), 3.00 (2H, t, J = 8.0 Hz), 2.63-2.58 (5H, m), 2.55-2.54 (3H, m), 2.46 (2H, q, J = 7.2 Hz), 1.62-1.60 (2H, m), 1.12 (3H, t, J = 7.2 Hz). (Example 141)
4- (2- (2- (4- (4-Ethylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) ethyl) morpholine
Figure JPOXMLDOC01-appb-C000135
 Using Reference Example 57 (80.0 mg, 0.192 mmol) and using the same methods as in Example 76 (a), Example 69, and Example 76 (b), the title compound was obtained as a pale yellow solid. It was. (33.0 mg, 31% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 6.93 (2H, d, J = 9.2 Hz), 3.68-3.61 (8H, m ), 3.31-3.28 (4H, m), 3.00 (2H, t, J = 8.0 Hz), 2.63-2.58 (5H, m), 2.55-2.54 (3H, m), 2.46 (2H, q, J = 7.2 Hz), 1.62-1.60 (2H, m), 1.12 (3H, t, J = 7.2 Hz).
（実施例１４２）
（Ｓ）－メチル ３－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）－４－（ピロリジン－１－イル）ブタノエート
Figure JPOXMLDOC01-appb-C000136
 　参考例５４で得られた化合物１６Ｂ（２４０ｍｇ、０.５５１ｍｍｏｌ）を用いて、実施例１と実施例３９と同様の方法により得られた残渣をメタノール（２.０ｍｌ）に溶解し、氷冷下、４ｍｏｌ／Ｌ塩酸／１，４－ジオキサン（１.０ｍｌ）を加え、室温で撹拌した。４時間後、減圧濃縮し、飽和炭酸水素ナトリウム水溶液を加えて、エタノール／クロロホルム（３／１）で分液抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧除去し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより、無色油状物として表題化合物を得た（４０.０ｍｇ、収率９１％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.89 (2H, d, J = 9.0 Hz), 4.68-4.61 (1H, m), 3.60 (2H, t, J = 8.5 Hz), 3.49 (3H, s), 3.26-3.23 (4H, m), 2.93 (2H, t, J = 8.5 Hz), 2.73-2.65 (3H, m), 2.53-2.50 (8H, m), 2.29 (4H, s), 1.65 (4H, m). (Example 142)
(S) -methyl 3- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) -4- (pyrrolidine -1-yl) butanoate
Figure JPOXMLDOC01-appb-C000136
 Using the compound 16B obtained in Reference Example 54 (240 mg, 0.551 mmol), the residue obtained in the same manner as in Example 1 and Example 39 was dissolved in methanol (2.0 ml), and the mixture was cooled with ice. 4 mol / L hydrochloric acid / 1,4-dioxane (1.0 ml) was added, and the mixture was stirred at room temperature. After 4 hours, the solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethanol / chloroform (3/1). The organic layer was dried over sodium sulfate and then removed under reduced pressure. The resulting residue was purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a colorless oil (40. 0 mg, 91% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.89 (2H, d, J = 9.0 Hz), 4.68-4.61 (1H, m ), 3.60 (2H, t, J = 8.5 Hz), 3.49 (3H, s), 3.26-3.23 (4H, m), 2.93 (2H, t, J = 8.5 Hz), 2.73-2.65 (3H, m) , 2.53-2.50 (8H, m), 2.29 (4H, s), 1.65 (4H, m).
　　実施例１４３－２４８：
　対応する原料化合物と試薬を用いて反応・処理し、表１６に示す化合物を得た。なお合成方法としては、実施例１と同様の場合をＡ、実施例３９をＢ、実施例６９をＣ、実施例７６をＤ、実施例７８をＥ、実施例８１をＦ、実施例１０６をＧ、実施例１１９をＨ、実施例１２９をＩ、実施例１３３をＪ、実施例１３４をＫ、実施例１３９（ａ）をＬとし、これらを組みあわせて行った。
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
 Examples 143-248 :
Reaction and treatment were carried out using the corresponding starting compounds and reagents, and the compounds shown in Table 16 were obtained. As the synthesis method, A is the same as in Example 1, B is Example 39, C is Example 69, D is Example 76, E is Example 78, F is Example 81, and 106 is Example 106. G, Example 119 was H, Example 129 was I, Example 133 was J, Example 134 was K, Example 139 (a) was L, and these were combined.
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
（実施例２４９）
４－（３－（２－（ベンジルオキシ）－４－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000155
 　参考例５８で得た化合物（１９１ｍｇ、０.４９１ｍｍｏｌ）の１，４－ジオキサン（２ｍｌ）溶液に、１－メチル－４－［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］ピペラジン（１７８ｍｇ、０.５８９ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（５６.８ｍｇ、０.０４９ｍｍｏｌ）、３ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５００μｌ、１.５０ｍｍｏｌ）を加え、マイクロウエーブ照射下１５０℃にて攪拌した。３０分後、反応溶液に塩酸水を加え反応を停止し、酢酸エチルで洗浄した。水層を水酸化ナトリウム水溶液でｐＨ＝１０とし、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄後、減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製することにより表題化合物を白色固体として得た（２３６ｍｇ、収率９１％）。
1H-NMR (CDCl3,δ ppm): 7.83 (2H, d, J = 9.0 Hz), 7.49-7.47 (2H, m), 7.34-7.22 (3H, m), 6.94 (2H, d, J = 9.0 Hz), 5.43 (2H, s), 3.70-3.67 (4H, m), 3.61 (2H, t, J = 8.1 Hz), 3.46 (2H, t, J = 7.2 Hz), 3.31-3.28 (4H, m), 3.20 (2H, t, J = 8.1 Hz), 2.60-2.57 (4H, m), 2.42-2.35 (9H, m), 1.83-1.74 (2H, m). (Example 249)
4- (3- (2- (benzyloxy) -4- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Propyl) morpholine
Figure JPOXMLDOC01-appb-C000155
 To a solution of the compound obtained in Reference Example 58 (191 mg, 0.491 mmol) in 1,4-dioxane (2 ml) was added 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3). , 2-Dioxaborolan-2-yl) phenyl] piperazine (178 mg, 0.589 mmol), tetrakistriphenylphosphine palladium (56.8 mg, 0.049 mmol), 3 mol / L aqueous sodium hydroxide solution (500 μl, 1.50 mmol). In addition, the mixture was stirred at 150 ° C. under microwave irradiation. After 30 minutes, the reaction solution was quenched with aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH = 10 with an aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed with saturated brine and evaporated under reduced pressure. The resulting residue is purified by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate → ethyl acetate: methanol) to give the title compound as a white solid. (236 mg, 91% yield).
1 H-NMR (CDCl 3 , δ ppm): 7.83 (2H, d, J = 9.0 Hz), 7.49-7.47 (2H, m), 7.34-7.22 (3H, m), 6.94 (2H, d, J = 9.0 Hz), 5.43 (2H, s), 3.70-3.67 (4H, m), 3.61 (2H, t, J = 8.1 Hz), 3.46 (2H, t, J = 7.2 Hz), 3.31-3.28 (4H, m), 3.20 (2H, t, J = 8.1 Hz), 2.60-2.57 (4H, m), 2.42-2.35 (9H, m), 1.83-1.74 (2H, m).
　　実施例２５０－２６４：
　対応する原料化合物と試薬を用いて反応・処理し、表１７に示す化合物を得た。なお合成方法としては、実施例１と同様の場合をＡ、実施例７６をＤ、実施例１１９をＨ、実施例１３９（ａ）をＬ、実施例２４９をＭとし、これらを組みあわせて行った。
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
 Examples 250-264 :
Reaction and treatment were carried out using the corresponding starting compounds and reagents, and the compounds shown in Table 17 were obtained. As the synthesis method, A is the same as in Example 1, D is Example 76, H is Example 119, L is Example 139 (a), and M is Example 249. It was.
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
（実施例２６５）
メチル ２－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）アセテート
Figure JPOXMLDOC01-appb-C000160
 　参考例４１で得られた化合物１１Ｃ（７５.０ｍｇ、０.１９３ｍｍｏｌ）を用いて、実施例１と実施例３９と同様の操作により、表題化合物を淡黄色油状物として得た（６.０ｍｇ、収率６％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.27-4.21 (1H, m), 3.89-3.79 (1H, m), 3.71-3.70 (8H, m), 3.30-3.16 (6H, m), 2.89-2.84 (1H, m), 2.77-2.72 (1H, m), 2.58-2.34 (13H, m), 1.88-1.75 (2H, m). (Example 265)
Methyl 2- (2- (4- (4-methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-6 -Il) Acetate
Figure JPOXMLDOC01-appb-C000160
 Using the compound 11C obtained in Reference Example 41 (75.0 mg, 0.193 mmol), the title compound was obtained as a pale yellow oil by the same procedure as in Example 1 and Example 39 (6.0 mg, Yield 6%).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 4.27-4.21 (1H, m ), 3.89-3.79 (1H, m), 3.71-3.70 (8H, m), 3.30-3.16 (6H, m), 2.89-2.84 (1H, m), 2.77-2.72 (1H, m), 2.58-2.34 (13H, m), 1.88-1.75 (2H, m).
（実施例２６６）
２－（４－（４－（７－（２－モルホリノエチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－イル）エタノール
Figure JPOXMLDOC01-appb-C000161
 　参考例５７で得られた化合物（１００ｍｇ、０.２３３ｍｍｏｌ）を用いて、実施例１３４（ａ）と実施例６９と実施例１２６（ｂ）と同様の方法により、表題化合物を白色固体として得た（５６.０ｍｇ、収率５５％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.2 Hz), 3.68-3.61 (10H, m), 3.29-3.28 (4H, m), 3.01 (2H, t, J = 8.3 Hz), 2.74 (1H, brs), 2.65-2.57 (12H, m). (Example 266)
2- (4- (4- (7- (2-morpholinoethyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazin-1-yl) ethanol
Figure JPOXMLDOC01-appb-C000161
 Using the compound obtained in Reference Example 57 (100 mg, 0.233 mmol), the title compound was obtained as a white solid in the same manner as in Example 134 (a), Example 69, and Example 126 (b). (56.0 mg, 55% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 6.92 (2H, d, J = 9.2 Hz), 3.68-3.61 (10H, m ), 3.29-3.28 (4H, m), 3.01 (2H, t, J = 8.3 Hz), 2.74 (1H, brs), 2.65-2.57 (12H, m).
（実施例２６７）
２－（１－（１－メチルピペリジン－４－イル）－１Ｈ－インドール－５－イル）－７－（３－（ピロリジン－１－イル）プロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン
Figure JPOXMLDOC01-appb-C000162
 　参考例３で得られた化合物（１４１ｍｇ、０.４６９ｍｍｏｌ）を用いて、実施例１３９（ａ）、６９、１０６と同様にして表題化合物を白色固体として得た（２８.０ｍｇ、収率２０％）。
1H-NMR (CDCl3,δ ppm): 8.66 (1H, s), 8.24 (1H, d, J = 9.0 Hz), 7.96 (1H, s), 7.36 (1H, d, J = 9.0 Hz), 6.57 (1H, d, J = 3.1 Hz), 4.22 (1H, brs), 3.62-3.57 (4H, m), 3.04-3.01 (4H, m), 2.56-2.53 (6H, m), 2.35 (3H, s), 2.20-2.17 (2H, m), 2.10-2.06 (4H, m), 1.88 (2H, t, J = 7.2 Hz), 1.80-1.77 (4H, m). (Example 267)
2- (1- (1-Methylpiperidin-4-yl) -1H-indol-5-yl) -7- (3- (pyrrolidin-1-yl) propyl) -6,7-dihydro-5H-pyrrolo [ 2,3-d] pyrimidine
Figure JPOXMLDOC01-appb-C000162
 Using the compound (141 mg, 0.469 mmol) obtained in Reference Example 3, the title compound was obtained as a white solid (28.0 mg, 20% yield) in the same manner as in Examples 139 (a), 69 and 106. ).
1 H-NMR (CDCl 3 , δ ppm): 8.66 (1H, s), 8.24 (1H, d, J = 9.0 Hz), 7.96 (1H, s), 7.36 (1H, d, J = 9.0 Hz), 6.57 (1H, d, J = 3.1 Hz), 4.22 (1H, brs), 3.62-3.57 (4H, m), 3.04-3.01 (4H, m), 2.56-2.53 (6H, m), 2.35 (3H, s), 2.20-2.17 (2H, m), 2.10-2.06 (4H, m), 1.88 (2H, t, J = 7.2 Hz), 1.80-1.77 (4H, m).
（実施例２６８）
４－（３－（２－（２－（４－シクロプロピルピペラジン－１－イル）ピリミジン－５－イル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000163
 　参考例５９で得た化合物（４０.０ｍｇ、０.０９８ｍｍｏｌ）とケトン等価体として（１－エトキシシクロプロポキシ）トリメチルシランを用い、実施例１０６と同様の操作を５０度で行い、精製し、表題化合物を黄色固体として得た（２７.０ｍｇ、収率６１％）。
1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.72-3.70 (4H, m), 3.62-3.51 (4H, m), 3.25-3.23 (4H, m), 3.00 (2H, t, J = 8.3 Hz), 2.77-2.75 (4H, m), 2.42-2.40 (6H, m), 1.82-1.80 (2H, m), 1.65-1.60 (1H, m), 0.48-0.45 (4H, m). (Example 268)
4- (3- (2- (2- (4-Cyclopropylpiperazin-1-yl) pyrimidin-5-yl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) Morpholine
Figure JPOXMLDOC01-appb-C000163
 Using the compound obtained in Reference Example 59 (40.0 mg, 0.098 mmol) and (1-ethoxycyclopropoxy) trimethylsilane as a ketone equivalent, the same operation as in Example 106 was performed at 50 ° C., and the title was purified. The compound was obtained as a yellow solid (27.0 mg, 61% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.72-3.70 (4H, m ), 3.62-3.51 (4H, m), 3.25-3.23 (4H, m), 3.00 (2H, t, J = 8.3 Hz), 2.77-2.75 (4H, m), 2.42-2.40 (6H, m), 1.82-1.80 (2H, m), 1.65-1.60 (1H, m), 0.48-0.45 (4H, m).
（実施例２６９）
実施例６２で合成した４－（３－（２－（４－（４－メチルピペラジン－イル－）フェニル）－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－７（６Ｈ）－イル）プロピル）モルホリンは、以下の方法によっても合成できる。
Figure JPOXMLDOC01-appb-C000164
 (Example 269)
4- (3- (2- (4- (4-Methylpiperazin-yl-) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl synthesized in Example 62) Morpholine can also be synthesized by the following method.
Figure JPOXMLDOC01-appb-C000164
（ａ）エチル ４－（４－シアノフェニル）ピペラジン－1－カルボキシレート
　４－フルオロベンゾニトリル（１２１ｇ、１．０ｍｏｌ）のＤＭＦ（１０００ｍｌ）溶液に、エチル ピペリジン－１－カルボキシレート（１７６ｍｌ、１．２ｍｏｌ）、炭酸セシウム（４５６ｇ、１．４ｍｏｌ）を加え、９０℃にて攪拌した。２１時間後、反応溶液をセライトろ過し、ろ液を減圧濃縮した。得られた残渣を酢酸エチルで希釈し、５％－クエン酸水溶液で洗浄した。有機層を飽和食塩水で洗浄後、減圧留去し、得られた残査をジイソプロピルエーテルで再結晶することにより表題化合物を淡黄色固体として得た（１７１ｇ、収率６６％）。
1H-NMR (CDCl3,δ ppm):7.49 (2H, d, J = 9.0 Hz), 6.84 (2H, d, J -= 9.0 Hz), 4.15 (2H, q, J = 7.2 Hz), 3.61 (4H, m), 3.29 (4H, m), 1.26 (3H, t, J = 7.2 Hz). (A) Ethyl 4- (4-cyanophenyl) piperazine-1-carboxylate To a solution of 4-fluorobenzonitrile (121 g, 1.0 mol) in DMF (1000 ml), ethyl piperidine-1-carboxylate (176 ml, 1. 2 mol) and cesium carbonate (456 g, 1.4 mol) were added and stirred at 90 ° C. After 21 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with 5% -citric acid aqueous solution. The organic layer was washed with saturated brine, evaporated under reduced pressure, and the obtained residue was recrystallized from diisopropyl ether to give the title compound as a pale yellow solid (171 g, yield 66%).
1 H-NMR (CDCl 3 , δ ppm): 7.49 (2H, d, J = 9.0 Hz), 6.84 (2H, d, J-= 9.0 Hz), 4.15 (2H, q, J = 7.2 Hz), 3.61 (4H, m), 3.29 (4H, m), 1.26 (3H, t, J = 7.2 Hz).
（ｂ）エチル （４－（４－（５－アリル－４，６－ジヒドロキシピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　リチウムヘキサメチルジシラジド（７４．０ｇ、０．４０ｍｏｌ）のジエチルエーテル溶液（５００ｍｌ）に上記で得られた化合物（５２．０ｇ、０．２０ｍｏｌ）を室温で加え、５５℃にて６時間攪拌した。反応溶液を０℃に冷却した後、メタノール（５００ｍｌ）とアリルマロン酸ジエチル（７２．９ｍｌ、０．４０ｍｏｌ）を順に加えた、６５℃にて３時間攪拌した。反応溶液を減圧濃縮し、得られた黄色個体をアセトニトリルから晶析させた。得られた個体を塩酸水溶液によりｐＨ＝３とすることにより、淡黄色固体の表題化合物を得た（６３．０ｇ, 収率８２％）。
1H-NMR (DMSO-d6,δ ppm): 8.00 (2H, d, J = 9.0 Hz), 7.01 (2H, d, J = 9.0 Hz), 5.86-5.75 (1H, m), 4.99-4.87 (2H, m), 4.09-4.02 (2H, m), 3.51-3.47 (4H, m), 3.36-3.28 (4H, m), 3.05-3.01 (2H, m), 1.21-1.17 (7H, m). (B) ethyl (4- (4- (5-allyl-4,6-dihydroxypyrimidin-2-yl) phenyl) piperazine-1-carboxylate lithium hexamethyldisilazide (74.0 g, 0.40 mol) To the diethyl ether solution (500 ml) was added the compound obtained above (52.0 g, 0.20 mol) at room temperature and stirred for 6 hours at 55 ° C. After cooling the reaction solution to 0 ° C., methanol (500 ml) And diethyl allylmalonate (72.9 ml, 0.40 mol) were sequentially added and stirred for 3 hours at 65 ° C. The reaction solution was concentrated under reduced pressure, and the resulting yellow solid was crystallized from acetonitrile. The solid was adjusted to pH = 3 with aqueous hydrochloric acid to obtain the title compound as a pale yellow solid (63.0 g, yield 82%).
1 H-NMR (DMSO-d 6 , δ ppm): 8.00 (2H, d, J = 9.0 Hz), 7.01 (2H, d, J = 9.0 Hz), 5.86-5.75 (1H, m), 4.99-4.87 (2H, m), 4.09-4.02 (2H, m), 3.51-3.47 (4H, m), 3.36-3.28 (4H, m), 3.05-3.01 (2H, m), 1.21-1.17 (7H, m) .
（ｃ）エチル （４－（４－（５－アリル－４，６－ジクロロピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　塩化ホスホリル（２９８ｍｌ, ３．２ｍｏｌ）に４－ジメチルアミノピリジン（１９．５ｇ、１５９ｍｏｌ）と上記で得た化合物（６１．４ｇ, １５９ｍｏｌ）とを０℃にて加えた。反応溶液を９０℃昇温して３時間攪拌した後、反応溶液を減圧濃縮した。残渣に氷を加えて反応を停止させた後に、溶液を酢酸エチルで分液抽出した。その後、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。得られた残渣はシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製し、ヘキサンとジイソプロピルエーテルの混合溶媒から再結晶することにより表題化合物を淡黄色固体として得た（４８．５ｇ、収率７１％）。
1H-NMR (CDCl3,δ ppm): 8.28 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 9.0 Hz), 5.92-5.81 (1H, m), 5.15-5.09 (2H, m), 4.20-4.12 (2H, m), 3.65-3.61 (6H, m), 3.33-3.29 (4H, m), 1.29-1.25 (3H, m). (C) Ethyl (4- (4- (5-allyl-4,6-dichloropyrimidin-2-yl) phenyl) piperazine-1-carboxylate phosphoryl chloride (298 ml, 3.2 mol) in 4-dimethylaminopyridine ( 19.5 g, 159 mol) and the compound obtained above (61.4 g, 159 mol) were added at 0 ° C. The reaction solution was heated to 90 ° C. and stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. Ice was added to the residue to stop the reaction, and the solution was separated and extracted with ethyl acetate, and then the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) and recrystallized from a mixed solvent of hexane and diisopropyl ether to give the title compound. As a pale yellow solid (48.5 g, 71% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.28 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 9.0 Hz), 5.92-5.81 (1H, m), 5.15-5.09 (2H , m), 4.20-4.12 (2H, m), 3.65-3.61 (6H, m), 3.33-3.29 (4H, m), 1.29-1.25 (3H, m).
（ｄ）エチル （４－（４－（４－クロロ－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得た化合物（７０．０ｇ, １６６ｍｍｏｌ）の１，４－ジオキサン（１．５ｌ）と水（５００ｍｌ）との混合溶液に０℃にてカリウムオスミウムテトラオキシド（１．２２ｇ、３．３ｍｍｏｌ）、過ヨウ素酸ナトリウム（１４２ｇ、６６４ｍｍｏｌ）、２，６－ルチジン（３８．５ｍｌ、３３２ｍｍｏｌ）を加えた。室温にて１２時間攪拌した後、セライトろ過により固体を除去し、反応溶液を減圧濃縮した。残渣に酢酸エチルと１０％チオ硫酸ナトリウムとを加え１時間攪拌した後、分液抽出した。その後、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。次に、得られた残渣のメタノール（７００ｍｌ）とテトラヒドロフラン（７００ｍｌ）との混合溶媒に３－（ピロリジン－１－イル）プロパン－１－アミン（４９ｍｌ、３３２ｍｍｏｌ）と酢酸（５７ｍｌ、１．０ｍｏｌ）とを加え、室温にて１２時間攪拌した。反応溶液を減圧濃縮し、残渣に酢酸エチルと飽和炭酸水素ナトリウムとを加え１時間攪拌した後、分液抽出した。その後、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）による精製と、メタノールから再結晶を行うことにより表題化合物を白色固体として得た(３５．９ｇ、収率４２％)。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 4.19-4.12 (2H, m), 3.72-3.61 (10H, m), 3.56-3.51 (2H, m), 3.26-3.22 (4H, m), 3.06-3.01 (2H, m), 2.42-2.37 (6H, m), 1.83-1.80 (2H, m),1.29-1.24 (3H, m). (D) Ethyl (4- (4- (4-Chloro-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine- 1-carboxylate To a mixed solution of the compound obtained above (70.0 g, 166 mmol) in 1,4-dioxane (1.5 l) and water (500 ml) at 0 ° C., potassium osmium tetraoxide (1.22 g, 3.3 mmol), sodium periodate (142 g, 664 mmol), and 2,6-lutidine (38.5 ml, 332 mmol) were added, and the mixture was stirred at room temperature for 12 hours, and then the solid was removed by Celite filtration. The residue was added with ethyl acetate and 10% sodium thiosulfate and stirred for 1 hour, followed by separation and extraction, and then the organic layer was washed with saturated brine. After drying with magnesium sulfate, the solvent was concentrated under reduced pressure, and then 3- (pyrrolidin-1-yl) propan-1-amine (49 ml) was added to a mixed solvent of methanol (700 ml) and tetrahydrofuran (700 ml) of the obtained residue. 332 mmol) and acetic acid (57 ml, 1.0 mol) were added, and the mixture was stirred for 12 hours at room temperature, and the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate were added to the residue, and the mixture was stirred for 1 hour. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure, purified by silica gel column chromatography (elution solvent: chloroform: methanol), and recrystallized from methanol. This gave the title compound as a white solid (35.9 g, 42% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 4.19-4.12 (2H, m), 3.72-3.61 (10H , m), 3.56-3.51 (2H, m), 3.26-3.22 (4H, m), 3.06-3.01 (2H, m), 2.42-2.37 (6H, m), 1.83-1.80 (2H, m), 1.29 -1.24 (3H, m).
（ｅ）４－（３－（２－（４－（４－メチルピペラジン）フェニル）－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
　上記で得た化合物（２２．０ｇ、３８．８ｍｍｏｌ）のメタノール（２５０ｍｌ）とテトラヒドロフラン（１２５ｍｌ）との混合溶媒に室温でギ酸アンモニウム（１７．０ｇ, ２７２ｍｏｌ）とパラジウム炭素（５０％ 含水）（４．０ｇ）を加え、７０℃にて５時間攪拌した。室温へと氷冷した後、セライトを用いてろ過を行った後に減圧濃縮した。酢酸エチルと飽和炭酸水素ナトリウム水溶液とを加えて分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し混合物を得た。
　続いて、水素化リチウムアルミニウム（４．４ｇ、１１６ｍｍｏｌ）のテトラヒドロフラン（２７０ｍｌ）溶液に０℃にて、上記で得た混合物のテトラヒドロフラン（２００ｍｌ）溶液を加えた。７０℃にて２時間攪拌した後、氷冷下で水酸化ナトリウム水溶液を加えてｐＨ＝１０とした後に酢酸エチルで分液抽出した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール）で精製した後、水とイソプロピルアルコールとの混合溶媒から再結晶することにより表題化合物を白色固体として得た（１７．１ｇ、収率９６％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.90 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.72-3.69 (4H, m), 3.60-3.50 (4H, m), 3.29-3.24 (4H, m), 3.01-2.96 (2H, m), 2.58-2.52 (4H, m), 2.44-2.37 (6H, m), 2.33 (3H, s), 1.82-1.77 (2H, m). (E) 4- (3- (2- (4- (4-methylpiperazine) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl) morpholine Compound obtained above To a mixed solvent of methanol (250 ml) and tetrahydrofuran (125 ml) (22.0 g, 38.8 mmol), ammonium formate (17.0 g, 272 mol) and palladium carbon (containing 50% water) (4.0 g) were added at room temperature. , And stirred at 70 ° C. for 5 hours. After cooling to room temperature with ice, the mixture was filtered through celite and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to perform liquid separation extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a mixture.
Subsequently, a solution of the mixture obtained above in tetrahydrofuran (200 ml) was added to a solution of lithium aluminum hydride (4.4 g, 116 mmol) in tetrahydrofuran (270 ml) at 0 ° C. After stirring at 70 ° C. for 2 hours, an aqueous sodium hydroxide solution was added under ice cooling to adjust the pH to 10, followed by liquid separation extraction with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: methanol) and then recrystallized from a mixed solvent of water and isopropyl alcohol to obtain the title compound as a white solid (17. 1 g, yield 96%).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.90 (1H, s), 6.92 (2H, d, J = 9.0 Hz), 3.72-3.69 (4H, m ), 3.60-3.50 (4H, m), 3.29-3.24 (4H, m), 3.01-2.96 (2H, m), 2.58-2.52 (4H, m), 2.44-2.37 (6H, m), 2.33 (3H , s), 1.82-1.77 (2H, m).
（実施例２７０）
４－（３－［６－メチル－２－｛４－（４－メチルピペラジン－１－イル）フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル）モルホリン、および
（実施例２７１）
４－（３－［６－メチル－２－｛４－（ピペラジン－１－イル）フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000165
 (Example 270)
4- (3- [6-Methyl-2- {4- (4-methylpiperazin-1-yl) phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl) morpholine And (Example 271)
4- (3- [6-Methyl-2- {4- (piperazin-1-yl) phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl) morpholine
Figure JPOXMLDOC01-appb-C000165
（ａ）エチル 4-(4-(4,6-ジクロロ-5-(2-オキソプロピル)ピリミジン-2-イル)フェニル)ピペラジン-1-カルボキシレート 
　実施例２６９（ｃ）で得られた化合物（１３６ｍｇ、０．３２３ｍｍｏｌ）のＤＭＦ（６ｍｌ）溶液に、水（１ｍｌ）、塩化パラジウム（II）(５．７ｍｇ、０．０３２０ｍｍｏｌ)、塩化銅（Ｉ）（５２．２ｍｇ、０．３８８ｍｍｏｌ）を加えて、室温にて撹拌した。終夜撹拌後、反応液に１ｍｏｌ／Ｌ塩酸を加えて、酢酸エチルで分液抽出した。有機層を水および飽和食塩水で順次洗浄し、硫酸ナトリウムにより乾燥後ろ過し、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を白色固体として得た（７８．５ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 8.26 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.03 (2H, s), 3.65-3.61 (4H, m), 3.33-3.30 (4H, m), 2.31 (3H, s), 1.27 (3H, t, J = 7.2 Hz). (A) Ethyl 4- (4- (4,6-dichloro-5- (2-oxopropyl) pyrimidin-2-yl) phenyl) piperazine-1-carboxylate
To a solution of the compound obtained in Example 269 (c) (136 mg, 0.323 mmol) in DMF (6 ml), water (1 ml), palladium (II) chloride (5.7 mg, 0.0320 mmol), copper chloride (I ) (52.2 mg, 0.388 mmol) was added and stirred at room temperature. After stirring overnight, 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a white solid (78.5 mg, yield 56%).
1 H-NMR (CDCl 3 , δ ppm): 8.26 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.03 ( 2H, s), 3.65-3.61 (4H, m), 3.33-3.30 (4H, m), 2.31 (3H, s), 1.27 (3H, t, J = 7.2 Hz).
（ｂ）エチル ４－（４－（４－クロロ－６－メチル－７－（３－オキソプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得られた化合物（４５．５ｍｇ、０．１０４ｍｍｏｌ）のＴＨＦ（１ｍｌ）－メタノール (１ｍｌ)溶液に、０℃にて酢酸（１３．１μｌ、０．２２９ｍｍｏｌ）、３，３－ジエトキシ－１－プロピルアミン（２５．２μｌ、０．１５６ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（１３．１ｍｇ、０．２０８ｍｍｏｌ）を加え、室温にて攪拌した。終夜撹拌後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にてろ過することにより粗生成物を得た。得られた粗生成物のアセトン（１．０ｍｌ）－水（０．２５ｍｌ）溶液に、ｐ－トルエンスルホン酸・１水和物（２２．４ｍｇ、０．１１８ｍｍｏｌ）を加え、室温にて３時間攪拌した後、５５℃にて１時間加熱撹拌した。室温へ放冷後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）にて精製することにより表題化合物を淡黄色ガム状物質として得た（２０．３ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 9.81 (1H, s), 8.19 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 6.9 Hz), 3.99-3.80 (2H, m), 3.63-3.54 (5H, m), 3.22-3.08 (5H, m), 2.93-2.73 (2H, m), 2.60-2.52 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 6.9 Hz). (B) Ethyl 4- (4- (4-chloro-6-methyl-7- (3-oxopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl ) Piperazine-1-carboxylate To a THF (1 ml) -methanol (1 ml) solution of the compound obtained above (45.5 mg, 0.104 mmol), acetic acid (13.1 μl, 0.229 mmol) at 0 ° C., 3,3-Diethoxy-1-propylamine (25.2 μl, 0.156 mmol) and sodium cyanoborohydride (13.1 mg, 0.208 mmol) were added, and the mixture was stirred at room temperature. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was filtered through silica gel column chromatography (elution solvent; chloroform: methanol) to obtain a crude product. P-Toluenesulfonic acid monohydrate (22.4 mg, 0.118 mmol) was added to a solution of the obtained crude product in acetone (1.0 ml) -water (0.25 ml), and the mixture was stirred at room temperature for 3 hours. After stirring, the mixture was heated and stirred at 55 ° C. for 1 hour. After cooling to room temperature, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, followed by separation and extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a pale yellow gum (20.3 mg, yield 56%).
1 H-NMR (CDCl 3 , δ ppm): 9.81 (1H, s), 8.19 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 6.9 Hz), 3.99-3.80 (2H, m), 3.63-3.54 (5H, m), 3.22-3.08 (5H, m), 2.93-2.73 (2H, m), 2.60-2.52 (1H, m), 1.30 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 6.9 Hz).
（ｃ）エチル ４－（４－（４－クロロ－６－メチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得られた化合物（２０．３ｍｇ、０．０４４ｍｍｏｌ）のメタノール（１ｍｌ）溶液に、０℃にて酢酸（５．１μｌ、０．０８９ｍｍｏｌ）、モルホリン（５．７μｌ、０．０６７ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（５．６ｍｇ、０．０８９ｍｍｏｌ）を加え、室温にて攪拌した。３時間後、飽和炭酸水素ナトリウム水溶液で反応を停止し、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、表題化合物を淡黄色ガム状物質として得た（２２．６ｍｇ、収率９６％）。
1H-NMR (CDCl3,δ ppm): 8.19 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 6.9 Hz), 4.02-3.90 (1H, m), 3.76-3.65 (5H, m), 3.59-3.56 (4H, m), 3.30-3.12 (6H, m), 2.59-2.51 (1H, m), 2.42-2.33 (6H, m), 1.85-1.70 (2H, m), 1.28 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 6.9 Hz). (C) Ethyl 4- (4- (4-chloro-6-methyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl ) Piperazine-1-carboxylate A solution of the compound obtained above (20.3 mg, 0.044 mmol) in methanol (1 ml) at 0 ° C. with acetic acid (5.1 μl, 0.089 mmol), morpholine (5.7 μl). 0.067 mmol) and sodium cyanoborohydride (5.6 mg, 0.089 mmol) were added and stirred at room temperature. After 3 hours, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a pale yellow gum (22.6 mg, yield 96%).
1 H-NMR (CDCl 3 , δ ppm): 8.19 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 6.9 Hz), 4.02- 3.90 (1H, m), 3.76-3.65 (5H, m), 3.59-3.56 (4H, m), 3.30-3.12 (6H, m), 2.59-2.51 (1H, m), 2.42-2.33 (6H, m ), 1.85-1.70 (2H, m), 1.28 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 6.9 Hz).
（ｄ）エチル ４－｛４－［６－メチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－カルボキシレート
　上記で得た化合物（１９．８ｍｇ、０．０３７ｍｍｏｌ）のメタノール（１．０ｍｌ）溶液に、ギ酸アンモニウム（２４ｍｇ、０．３７ｍｍｏｌ）、１０％パラジウム炭素（５０％ 含水）（１０ｍｇ）を加え、５０℃にて攪拌した。２．５時間後、室温へ放冷した後、反応溶液をセライトろ過し、減圧濃縮した。得られた残渣に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮することにより表題化合物を淡黄色ガム状物質として得た(１５．３ｍｇ、収率８３％)。
1H-NMR (CDCl3,δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 7.2 Hz), 3.95-3.88 (1H, m), 3.76-3.65 (5H, m), 3.60-3.56 (4H, m), 3.30-3.08 (6H, m), 2.56-2.48 (1H, m), 2.39-2.34 (6H, m), 1.84-1.71 (2H, m), 1.26 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 7.2 Hz). (D) Ethyl 4- {4- [6-methyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazine-1 -Carboxylate To a solution of the compound obtained above (19.8 mg, 0.037 mmol) in methanol (1.0 ml), ammonium formate (24 mg, 0.37 mmol), 10% palladium carbon (containing 50% water) (10 mg) was added. In addition, the mixture was stirred at 50 ° C. After 2.5 hours, the reaction solution was allowed to cool to room temperature, filtered through Celite, and concentrated under reduced pressure. To the obtained residue, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow gum (15.3 mg, yield 83%).
1 H-NMR (CDCl 3 , δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 4.11 (2H, q, J = 7.2 Hz), 3.95-3.88 (1H, m), 3.76-3.65 (5H, m), 3.60-3.56 (4H, m), 3.30-3.08 (6H, m), 2.56-2.48 (1H, m), 2.39-2.34 (6H, m), 1.84-1.71 (2H, m), 1.26 (3H, d, J = 6.3 Hz), 1.22 (3H, t, J = 7.2 Hz).
（ｅ）４－（３－［６－メチル－２－｛４－（４－メチルピペラジン－１－イル）フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル）モルホリン、および
４－（３－［６－メチル－２－｛４－（ピペラジン－１－イル）フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル］プロピル）モルホリン
　上記で得た化合物（１５．３ｍｇ、０．０３１ｍｍｏｌ）をＴＨＦ（２．０ｍｌ）に溶解し、０℃にてリチウムアルミニウムヒドリド（３．５ｍｇ、０．０９３ｍｍｏｌ）を加えた後、６０℃にて１時間撹拌した。反応溶液を０℃に冷却し、水（３．５μｌ）、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（３．５μｌ）、水（７．０μｌ）を加え、室温にて１時間撹拌した。セライトろ過後、ろ液を減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製し、表題化合物を得た（実施例２７０：無色ガム状物質、３．６ｍｇ、収率２７％、実施例２７１：淡黄色ガム状物質、５．８ｍｇ、収率４４％）。
実施例２７０：1H-NMR (CDCl3,δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.84 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.94-3.87 (1H, m), 3.75-3.65 (5H, m), 3.30-3.07 (6H, m), 2.55-2.48 (5H, m), 2.39-2.34 (6H, m), 2.29 (3H, s), 1.83-1.71 (2H, m), 1.26 (3H, d, J = 6.0 Hz).
実施例２７１：1H-NMR (CDCl3,δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.84 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 3.95-3.87 (1H, m), 3.76-3.65 (5H, m), 3.30-3.13 (6H, m), 3.10-2.96 (4H, m), 2.55-2.47 (1H, m), 2.41-2.11 (6H, m), 1.83-1.71 (2H, m), 1.26 (3H, d, J = 6.0 Hz). (E) 4- (3- [6-Methyl-2- {4- (4-methylpiperazin-1-yl) phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] Propyl) morpholine, and 4- (3- [6-methyl-2- {4- (piperazin-1-yl) phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl] propyl ) Morpholine The compound obtained above (15.3 mg, 0.031 mmol) was dissolved in THF (2.0 ml), lithium aluminum hydride (3.5 mg, 0.093 mmol) was added at 0 ° C, and then 60 ° C. For 1 hour. The reaction solution was cooled to 0 ° C., water (3.5 μl), 2 mol / L aqueous sodium hydroxide solution (3.5 μl) and water (7.0 μl) were added, and the mixture was stirred at room temperature for 1 hour. After filtration through celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound (Example 270: colorless gum, 3.6 mg, 27% yield, Example 271). Pale yellow gum, 5.8 mg, 44% yield).
Example 270: 1 H-NMR (CDCl 3 , δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.84 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.94-3.87 (1H, m), 3.75-3.65 (5H, m), 3.30-3.07 (6H, m), 2.55-2.48 (5H, m), 2.39-2.34 (6H, m), 2.29 (3H, s), 1.83 -1.71 (2H, m), 1.26 (3H, d, J = 6.0 Hz).
Example 271: 1 H-NMR (CDCl 3 , δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.84 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 3.95-3.87 (1H, m), 3.76-3.65 (5H, m), 3.30-3.13 (6H, m), 3.10-2.96 (4H, m), 2.55-2.47 (1H, m), 2.41-2.11 (6H, m) , 1.83-1.71 (2H, m), 1.26 (3H, d, J = 6.0 Hz).
（実施例２７２）
２－(２－(４－(４－メチルピペラジン－１－イル)フェニル)－７－(３－モルホリノプロピル)－６，７－ジヒドロ－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－６－イル)エタノール
Figure JPOXMLDOC01-appb-C000166
 (Example 272)
2- (2- (4- (4-Methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-6- Yl) ethanol
Figure JPOXMLDOC01-appb-C000166
（ａ）エチル ４－（４－（４，６－ジクロロ－５－（２－オキソエチル）ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　実施例２６９（ｃ）で得た化合物（１．０ｇ、２．２１ｍｍｏｌ）の１,４-ジオキサン(２４ｍｌ)と水(８ｍｌ)との混合溶液に０℃にてカリウムオスミウムテトラオキシド（１６ｍｇ、０．０４ｍｍｏｌ）、過ヨウ素酸ナトリウム（１．８９ｇ、８．８５ｍｍｏｌ）、２,６－ルチジン（０．５４ｍｌ、４．４３ｍｍｏｌ）を加えた。室温にて１２時間攪拌した後、セライトろ過により固体を除去し、反応溶液を減圧濃縮した。残渣に酢酸エチルと１０％チオ硫酸ナトリウムとを加え１時間攪拌した後、分液抽出した。その後、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。得られた残渣はシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物Ｄを黄色油状物として得た(０．９１ｇ、収率９１％)。
1H-NMR (CDCl3,δ ppm): 9.71 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.14-4.07 (2H, m), 4.01 (2H, s), 3.59-3.56 (4H, m), 3.29-3.25 (4H, m), 1.24-1.19 (3H, m). (A) Ethyl 4- (4- (4,6-dichloro-5- (2-oxoethyl) pyrimidin-2-yl) phenyl) piperazine-1-carboxylate The compound obtained in Example 269 (c) (1. 0 g, 2.21 mmol) in a mixed solution of 1,4-dioxane (24 ml) and water (8 ml) at 0 ° C. with potassium osmium tetraoxide (16 mg, 0.04 mmol), sodium periodate (1.89 g, (8.85 mmol), 2,6-lutidine (0.54 ml, 4.43 mmol) was added. After stirring at room temperature for 12 hours, the solid was removed by Celite filtration, and the reaction solution was concentrated under reduced pressure. Ethyl acetate and 10% sodium thiosulfate were added to the residue, and the mixture was stirred for 1 hour, followed by liquid separation extraction. Thereafter, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound D as a yellow oil (0.91 g, yield 91%).
1 H-NMR (CDCl 3 , δ ppm): 9.71 (1H, s), 8.23 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 4.14-4.07 (2H, m ), 4.01 (2H, s), 3.59-3.56 (4H, m), 3.29-3.25 (4H, m), 1.24-1.19 (3H, m).
（ｂ）エチル ４－（４－（４－クロロ－６－（２－メトキシ－２－オキソエチル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ[２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得た化合物（１．０ｇ、２．３７ｍｍｏｌ）のトルエン（１０ｍｌ）溶液に室温でカルボメトキシメチレントリフェニルホスホラン（１．０３ｇ、３．０８ｍｍｏｌ）を加え、１１０℃にて１時間攪拌した。氷冷下で飽和食塩水を加え、溶液をクロロホルムで分液抽出した。その後、硫酸マグネシウムで乾燥し、減圧濃縮した。次に得られた残渣の１，４－ジオキサン溶液に３－（ピロリジン－１－イル）プロパン－１－アミン（３５２μｌ、２．３９ｍｍｏｌ）と炭酸カリウム（０．９ｇ、６．５１ｍｍｏｌ）を加え、１１０℃にて１時間攪拌した。その後、氷冷下で水素化ナトリウム（１０４ｍｇ、４．３５ｍｍｏｌ）を加えて室温で攪拌した。１時間攪拌した後、飽和塩化アンモニウム水溶液で反応を停止し、飽和炭酸水素ナトリウム水溶液を加えてｐＨ＝８とした後にクロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を黄色油状物として得た（６５１ｍｇ、収率４７％）。
1H-NMR (CDCl3,δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 4.32-4.29 (1H, m), 4.19-4.12 (2H, m), 3.86-3.81 (1H, m), 3.71-3.60 (11H, m), 3.36-3.19 (6H, m), 2.91-2.73 (2H, m), 2.55-2.35 (7H, m), 1.83-1.78 (2H, m), 1.27-1.24 (3H, m). (B) Ethyl 4- (4- (4-chloro-6- (2-methoxy-2-oxoethyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d ] Pyrimidin-2-yl) phenyl) piperazine-1-carboxylate A solution of the compound obtained above (1.0 g, 2.37 mmol) in a toluene (10 ml) solution at room temperature with carbomethoxymethylenetriphenylphosphorane (1.03 g, 3.08 mmol) was added, and the mixture was stirred at 110 ° C. for 1 hour. Saturated saline was added under ice cooling, and the solution was subjected to liquid separation extraction with chloroform. Then, it dried with magnesium sulfate and concentrated under reduced pressure. Next, 3- (pyrrolidin-1-yl) propan-1-amine (352 μl, 2.39 mmol) and potassium carbonate (0.9 g, 6.51 mmol) were added to a 1,4-dioxane solution of the obtained residue. Stir at 110 ° C. for 1 hour. Thereafter, sodium hydride (104 mg, 4.35 mmol) was added under ice cooling, and the mixture was stirred at room temperature. After stirring for 1 hour, the reaction was stopped with a saturated aqueous ammonium chloride solution, and a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, followed by separation and extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off 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 a yellow oil (651 mg, yield 47%).
1 H-NMR (CDCl 3 , δ ppm): 8.24 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 4.32-4.29 (1H, m), 4.19-4.12 (2H , m), 3.86-3.81 (1H, m), 3.71-3.60 (11H, m), 3.36-3.19 (6H, m), 2.91-2.73 (2H, m), 2.55-2.35 (7H, m), 1.83 -1.78 (2H, m), 1.27-1.24 (3H, m).
（ｃ）エチル ４－（４－（６－（２－メトキシ－２－オキソエチル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ[２，３－ｄ]ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得た化合物（６５０ｍｇ、１．１０ｍｍｏｌ）のメタノール（１０ｍｌ）溶液に室温でギ酸アンモニウム（１．５ｇ、２３．８ｍｍｏｌ）とパラジウム炭素（５０％含水）（３００ｍｇ）を加え、７０℃にて５時間攪拌した。室温へと氷冷した後、セライトを用いてろ過を行った後に減圧濃縮した。飽和炭酸水素ナトリウム水溶液を加えてｐＨ＝８とした後にクロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を黄色油状物として得た（５５０ｍｇ、収率９０％）。
1H-NMR (CDCl3,δ ppm): 1H-NMR (CDCl3,δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.88 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 4.22-4.06 (3H, m), 3.84-3.74 (1H, m), 3.66-3.55 (11H, m), 3.27-3.11 (6H, m), 2.84-2.66 (2H, m), 2.47-2.31 (7H, m), 1.81-1.74 (2H, m), 1.24-1.19 (3H, m). (C) Ethyl 4- (4- (6- (2-methoxy-2-oxoethyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Yl) phenyl) piperazine-1-carboxylate A solution of the compound obtained above (650 mg, 1.10 mmol) in methanol (10 ml) at room temperature with ammonium formate (1.5 g, 23.8 mmol) and palladium on carbon (containing 50% water) ) (300 mg) was added and stirred at 70 ° C. for 5 hours. After cooling to room temperature with ice, the mixture was filtered through celite and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, followed by separation and extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off 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 a yellow oil (550 mg, yield 90%).
1 H-NMR (CDCl 3 , δ ppm): 1 H-NMR (CDCl 3 , δ ppm): 8.18 (2H, d, J = 9.0 Hz), 7.88 (1H, s), 6.87 (2H, d, J = 9.0 Hz), 4.22-4.06 (3H, m), 3.84-3.74 (1H, m), 3.66-3.55 (11H, m), 3.27-3.11 (6H, m), 2.84-2.66 (2H, m), 2.47-2.31 (7H, m), 1.81-1.74 (2H, m), 1.24-1.19 (3H, m).
（ｄ）２－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈピロロ［２，３－ｄ］ピリミジン－６－イル）エタノール
　上記で得た化合物（５５０ｍｇ、１．００ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液に０℃で水素化リチウムアルミニウム（１８９ｍｇ、４．９８ｍｍｏｌ）を加え、７０℃にて２時間攪拌した。氷冷下で水酸化ナトリウム水溶液を加えてｐＨ＝１０とした後にクロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール）で精製することにより表題化合物を黄色油状物として得た（１８０ｍｇ、収率３９％）。
1H-NMR (CDCl3,δ ppm): 1H-NMR (CDCl3,δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.90 (2H, d, J = 9.0 Hz), 3.99-3.96 (1H, m), 3.80-3.67 (6H, m), 3.28-3.25 (4H, m), 3.14-3.05 (1H, m), 2.80-2.64 (2H, m), 2.56-2.52 (4H, m), 2.41-2.31 (8H, m), 2.10-2.05 (1H, m), 1.83-1.67 (3H, m). (D) 2- (2- (4- (4-Methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5Hpyrrolo [2,3-d] pyrimidine- 6-yl) ethanol To a solution of the compound obtained above (550 mg, 1.00 mmol) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (189 mg, 4.98 mmol) at 0 ° C., and the mixture was stirred at 70 ° C. for 2 hours. Under ice cooling, an aqueous sodium hydroxide solution was added to adjust to pH = 10, followed by separation and extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: methanol) to give the title compound as a yellow oil (180 mg, yield 39%).
1 H-NMR (CDCl 3 , δ ppm): 1 H-NMR (CDCl 3 , δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.90 (2H, d, J = 9.0 Hz), 3.99-3.96 (1H, m), 3.80-3.67 (6H, m), 3.28-3.25 (4H, m), 3.14-3.05 (1H, m), 2.80-2.64 (2H, m), 2.56-2.52 (4H, m), 2.41-2.31 (8H, m), 2.10-2.05 (1H, m), 1.83-1.67 (3H, m).
（実施例２７３）
２－（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）エタノール
Figure JPOXMLDOC01-appb-C000167
 (Example 273)
2- (7-(((R) -4-methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) ethanol
Figure JPOXMLDOC01-appb-C000167
（ａ）エチル ４－（４－（７－（（（Ｒ）－４－ベンジルモルホリン－２－イル）メチル）－４－クロロ－６－（２－メトキシ－２－オキソエチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　実施例２７２（ａ）で得られた化合物（１．０ｇ、２．３７ｍｍｏｌ）を用いて、実施例２７２（ｂ）と同様の方法により、表題化合物を黄色油状物として得た（９００ｍｇ、収率５９％）。
1H-NMR (CDCl3,δ ppm): 8.22-8.18 (2H, m), 7.29-7.24 (5H, m), 6.90-6.86 (2H, m), 4.45-4.35 (1H, m), 4.19-4.12 (2H, m), 3.80-3.23 (19H, m), 3.00-2.92 (1H, m), 2.82-2.73 (2H, m), 2.64-2.48 (2H, m), 2.16-2.08 (1H, m), 1.97-1.94 (1H, m), 1.29-1.25 (3H, m). (A) Ethyl 4- (4- (7-(((R) -4-benzylmorpholin-2-yl) methyl) -4-chloro-6- (2-methoxy-2-oxoethyl) -6,7- Dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine-1-carboxylate Using the compound (1.0 g, 2.37 mmol) obtained in Example 272 (a), The title compound was obtained as a yellow oil (900 mg, yield 59%) by a method similar to that in Example 272 (b).
1 H-NMR (CDCl 3 , δ ppm): 8.22-8.18 (2H, m), 7.29-7.24 (5H, m), 6.90-6.86 (2H, m), 4.45-4.35 (1H, m), 4.19- 4.12 (2H, m), 3.80-3.23 (19H, m), 3.00-2.92 (1H, m), 2.82-2.73 (2H, m), 2.64-2.48 (2H, m), 2.16-2.08 (1H, m ), 1.97-1.94 (1H, m), 1.29-1.25 (3H, m).
（ｂ）エチル ４－（４－（７－（（（Ｒ）－４－ベンジルモルホリン－２－イル）メチル）－６－（２－メトキシ－２－オキソエチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　上記で得た化合物（９００ｍｇ, １．３９ｍｍｏｌ）のメタノール（１５ｍｌ）溶液に室温でギ酸アンモニウム（３．０ｇ, ４６．９ｍｍｏｌ）とパラジウム炭素（５０％含水）（４５０ｍｇ）を加え、８０℃にて５時間攪拌した。室温へと氷冷した後、セライトを用いてろ過を行った後に溶媒を減圧濃縮した。次に得られた残渣のメタノール（１０ｍｌ）と酢酸（５００μｌ）の混合溶液に、ホルムアルデヒド（１２０μｌ、４．１７ｍｍｏｌ）、シアノ水素化ホウ素ナトリウム（２６２ｍｇ、４．１７ｍｍｏｌ）を加えた。室温で５時間撹拌後、飽和炭酸水素ナトリウム水溶液を加えて反応停止した。クロロホルムで分液抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより、黄色アモルファスとしてジアステレオマー混合物の表題化合物を得た（３４０ｍｇ、収率４５％）。
1H-NMR (CDCl3,δ ppm): 8.20-8.17 (2H, m), 7.90-7.88 (1H, m), 6.88-6.85 (2H, m), 4.40-4.30 (1H, m), 4.16-4.06 (2H, m), 3.80-3.77 (2H, m), 3.61-3.57 (9H, m), 3.43-3.18 (6H, m), 2.93-2.87 (1H, m), 2.79-2.69 (2H, m), 2.60-2.56 (1H, m), 2.48-2.41 (1H, m), 2.21 (3H, s), 2.08-2.01 (1H, m), 1.87-1.80 (1H, m), 1.23-1.19 (3H, m). (B) Ethyl 4- (4- (7-(((R) -4-benzylmorpholin-2-yl) methyl) -6- (2-methoxy-2-oxoethyl) -6,7-dihydro-5H- Pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) piperazine-1-carboxylate A solution of the compound obtained above (900 mg, 1.39 mmol) in methanol (15 ml) at room temperature with ammonium formate (3.0 g, 46.9 mmol) and palladium on carbon (containing 50% water) (450 mg) were added, and the mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature with ice, the mixture was filtered using Celite, and then the solvent was concentrated under reduced pressure. Next, formaldehyde (120 μl, 4.17 mmol) and sodium cyanoborohydride (262 mg, 4.17 mmol) were added to a mixed solution of the resulting residue in methanol (10 ml) and acetic acid (500 μl). After stirring at room temperature for 5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. Liquid separation extraction was carried out with chloroform, the organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel chromatography (elution solvent; hexane: ethyl acetate) to give the title compound of a diastereomeric mixture as a yellow amorphous (340 mg, yield 45%).
1 H-NMR (CDCl 3 , δ ppm): 8.20-8.17 (2H, m), 7.90-7.88 (1H, m), 6.88-6.85 (2H, m), 4.40-4.30 (1H, m), 4.16- 4.06 (2H, m), 3.80-3.77 (2H, m), 3.61-3.57 (9H, m), 3.43-3.18 (6H, m), 2.93-2.87 (1H, m), 2.79-2.69 (2H, m ), 2.60-2.56 (1H, m), 2.48-2.41 (1H, m), 2.21 (3H, s), 2.08-2.01 (1H, m), 1.87-1.80 (1H, m), 1.23-1.19 (3H , m).
（ｃ）２－（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）エタノール
　上記で得た化合物（３４０ｍｇ、０．６３ｍｍｏｌ）を用いて、実施例２７２（ｄ）と同様の方法により、ジアステレオマー混合物の表題化合物を黄色油状物として得た（１４０ｍｇ、収率４９％）。
1H-NMR (CDCl3,δ ppm): 8.25-8.21 (2H, m), 7.90-7.89 (1H, m), 6.93-6.90 (2H, m), 4.17-4.08 (1H, m), 3.90-3.58 (7H, m), 3.48-3.11 (6H, m), 2.84-2.59 (7H, m), 2.35-2.34 (3H, m), 2.25-2.24 (3H, m), 2.11-2.02 (2H, m), 1.96-1.86 (1H, m), 1.78-1.76 (1H, m). (C) 2- (7-(((R) -4-methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro- 5H-pyrrolo [2,3-d] pyrimidin-6-yl) ethanol By using the compound obtained above (340 mg, 0.63 mmol) in the same manner as in Example 272 (d), diastereomer mixture The title compound was obtained as a yellow oil (140 mg, 49% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.25-8.21 (2H, m), 7.90-7.89 (1H, m), 6.93-6.90 (2H, m), 4.17-4.08 (1H, m), 3.90- 3.58 (7H, m), 3.48-3.11 (6H, m), 2.84-2.59 (7H, m), 2.35-2.34 (3H, m), 2.25-2.24 (3H, m), 2.11-2.02 (2H, m ), 1.96-1.86 (1H, m), 1.78-1.76 (1H, m).
（実施例２７４）
Ｎ，Ｎ－ジメチル－２－（２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈピロロ［２，３－ｄ］ピリミジン－６－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000168
 (Example 274)
N, N-dimethyl-2- (2- (4- (4-methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5Hpyrrolo [2,3-d ] Pyrimidin-6-yl) acetamide
Figure JPOXMLDOC01-appb-C000168
（ａ）２－（４－クロロ－２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリンプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）－Ｎ，Ｎ－ジメチルアセトアミド
　参考例４１で得た化合物１２Ｂ（３３０ｍｇ, ０．８５ｍｍｏｌ）の１，４－ジオキサン（１６ｍｌ）と水との（４．０ｍｌ）混合溶液に、１－メチル－４－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）ピペラジン（２５６ｍｇ, ０．８５ｍｍｏｌ)、テトラキストリフェニルホスフィンパラジウム（９８ｍｇ、０．０９０ｍｍｏｌ）、水酸化リチウム（８１ｍｇ、３．４０ｍｍｏｌ）を加え、１２０℃にて攪拌した。１時間後、反応溶液を室温へと冷却し溶媒を減圧留去した。得られた油状物をクロロホルム（３，０ｍｌ）に溶解させ、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（３２５ｍｇ、１．７０ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（２２９ｍｇ、１．７０ｍｍｏｌ）、２ｍｏｌ／Ｌジメチルアミンテトラヒドロフラン溶液（２．１ｍｌ）を加え、室温にて８時間攪拌し、反応溶液を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、表題化合物を黄色アモルファスとして得た（２００ｍｇ、収率４５％）。
1H-NMR (CDCl3,δ ppm): 8.17 (2H, d, J = 9.0 Hz), 6.84 (2H, d, J = 9.0 Hz), 4.40-4.37 (1H, m), 3.93-3.80 (1H, m), 3.66-3.62 (4H, m), 3.39-3.09 (6H, m), 2.94-2.91 (6H, m), 2.81-2.74 (1H, m), 2.63-2.49 (5H, m), 2.44-2.29 (12H, m), 1.77-1.72 (2H, m). (A) 2- (4-Chloro-2- (4- (4-methylpiperazin-1-yl) phenyl) -7- (3-morpholinepropyl) -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidin-6-yl) -N, N-dimethylacetamide Compound 12B (330 mg, 0.85 mmol) obtained in Reference Example 41 mixed with 1,4-dioxane (16 ml) and water (4.0 ml) To the solution was added 1-methyl-4--4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (256 mg, 0.85 mmol), tetrakistriphenylphosphine. Palladium (98 mg, 0.090 mmol) and lithium hydroxide (81 mg, 3.40 mmol) were added, and the mixture was stirred at 120 ° C. After 1 hour, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained oil was dissolved in chloroform (3,0 ml) to give 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (325 mg, 1.70 mmol), 1-hydroxybenzotriazole (229 mg, 1.70 mmol). 2 mol / L dimethylamine tetrahydrofuran solution (2.1 ml) was added and stirred at room temperature for 8 hours, and the reaction solution was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a yellow amorphous (200 mg, yield 45%).
1 H-NMR (CDCl 3 , δ ppm): 8.17 (2H, d, J = 9.0 Hz), 6.84 (2H, d, J = 9.0 Hz), 4.40-4.37 (1H, m), 3.93-3.80 (1H , m), 3.66-3.62 (4H, m), 3.39-3.09 (6H, m), 2.94-2.91 (6H, m), 2.81-2.74 (1H, m), 2.63-2.49 (5H, m), 2.44 -2.29 (12H, m), 1.77-1.72 (2H, m).
（ｂ）Ｎ，Ｎ－ジメチル－２－（２－（４－(４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈピロロ［２，３－ｄ］ピリミジン－６－イル）アセトアミド
　上記で得た化合物（２００ｍｇ、０．３７ｍｍｏｌ）を用いて、実施例２７１（ｃ）と同様の方法により、白色固体としての表題化合物を得た（７４ｍｇ、収率３９％）。
1H-NMR (CDCl3,δ ppm): 8.33 (2H, m), 7.91 (1H, m), 6.92 (2H, m), 4.55-4.50 (1H, m), 3.90-3.80 (6H, m), 3.58-3.37 (7H, m), 3.03-2.87 (8H, m), 2.79-2.51 (12H, m), 2.11-1.96 (2H, m). (B) N, N-dimethyl-2- (2- (4- (4-methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H pyrrolo [2, 3-d] pyrimidin-6-yl) acetamide The title compound as a white solid was obtained in the same manner as in Example 271 (c) using the compound obtained above (200 mg, 0.37 mmol) (74 mg Yield 39%).
1 H-NMR (CDCl 3 , δ ppm): 8.33 (2H, m), 7.91 (1H, m), 6.92 (2H, m), 4.55-4.50 (1H, m), 3.90-3.80 (6H, m) , 3.58-3.37 (7H, m), 3.03-2.87 (8H, m), 2.79-2.51 (12H, m), 2.11-1.96 (2H, m).
（実施例２７５）
Ｎ．Ｎ－ジメチル－２－（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロー５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000169
 (Example 275)
N. N-dimethyl-2- (7-(((R) -4-methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro- 5H-pyrrolo [2,3-d] pyrimidin-6-yl) acetamide
Figure JPOXMLDOC01-appb-C000169
（ａ）２－（７－（（（Ｒ）－４－ベンジルモルホリノ－２－）メチル）－４－クロロ－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）－Ｎ，Ｎ－ジメチルアセトアミド
　参考例４１で得た化合物１２Ａ（１．５ｇ、５．３５ｍｍｏｌ）の１，４－ジオキサン溶液に（Ｓ）－（４－ベンジルモルホリン－２－イル）メタンアミン（１．１ｇ、５．３５ｍｍｏｌ）と炭酸カリウム（１．５ｇ、１０．７ｍｍｏｌ）加え、２時間攪拌した。その後、氷冷下で水素化ナトリウム（１０４ｍｇ、４．３５ｍｍｏｌ）を加えて室温で攪拌した。１時間攪拌した後、飽和塩化アンモニウム水溶液で反応を停止し、飽和炭酸水素ナトリウム水溶液を加えてｐＨ＝８とした後にクロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で簡易精製した。得られた残査を１，４－ジオキサン（１６ｍｌ）と水との（４ｍｌ）混合溶液に溶解させ、１－メチル－４－（４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）ピペラジン（３９０ｍｇ、１．２９ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１２３ｍｇ、０．１１ｍｍｏｌ）、水酸化リチウム（１０２ｍｇ、４．３０ｍｍｏｌ）を加え、１２０℃にて攪拌した。１時間後、反応溶液を室温へと冷却し溶媒を減圧留去した。得られた油状物をクロロホルム（５．０ｍｌ）に溶解させ、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（４１０ｍｇ、２．１４ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（２８９ｍｇ、２．１４ｍｍｏｌ）、２ｍｏｌ／Ｌジメチルアミンテトラヒドロフラン溶液（２．７ｍｌ）を加え、室温にて８時間攪拌し、反応溶液を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール）で精製することにより、ジアステレオマーの表題化合物を黄色アモルファスとして得た（２９４ｍｇ、収率９％）
1H-NMR (CDCl3,δ ppm): 8.22-8.19 (2H, m), 7.31-2.70 (5H, m), 6.90-6.86 (2H, m), 4.50-4.44 (1H, m), 3.81-3.68 (4H, m), 3.49-3.34 (9H, m), 3.07-2.95 (8H, m), 2.87-2.65 (5H, m), 2.49-2.33 (4H, m), 2.12-1.97 (2H, m). (A) 2- (7-(((R) -4-benzylmorpholin-2-) methyl) -4-chloro-2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7 -Dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) -N, N-dimethylacetamide 1,4-dioxane solution of compound 12A obtained in Reference Example 41 (1.5 g, 5.35 mmol) To (S)-(4-benzylmorpholin-2-yl) methanamine (1.1 g, 5.35 mmol) and potassium carbonate (1.5 g, 10.7 mmol) were added and stirred for 2 hours. Thereafter, sodium hydride (104 mg, 4.35 mmol) was added under ice cooling, and the mixture was stirred at room temperature. After stirring for 1 hour, the reaction was stopped with a saturated aqueous ammonium chloride solution, and a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, followed by separation and extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was simply purified by amino silica gel column chromatography (elution solvent; chloroform: methanol). The obtained residue was dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) piperazine (390 mg, 1.29 mmol), tetrakistriphenylphosphine palladium (123 mg, 0.11 mmol), lithium hydroxide (102 mg, 4.30 mmol) were added, and the mixture was heated to 120 ° C. And stirred. After 1 hour, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained oil was dissolved in chloroform (5.0 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (410 mg, 2.14 mmol), 1-hydroxybenzotriazole (289 mg, 2.14 mmol) 2 mol / L dimethylamine tetrahydrofuran solution (2.7 ml) was added and stirred at room temperature for 8 hours, and the reaction solution was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the diastereomeric title compound as a yellow amorphous substance (294 mg, yield 9%).
1 H-NMR (CDCl 3 , δ ppm): 8.22-8.19 (2H, m), 7.31-2.70 (5H, m), 6.90-6.86 (2H, m), 4.50-4.44 (1H, m), 3.81- 3.68 (4H, m), 3.49-3.34 (9H, m), 3.07-2.95 (8H, m), 2.87-2.65 (5H, m), 2.49-2.33 (4H, m), 2.12-1.97 (2H, m ).
（ｂ）Ｎ，Ｎ－ジメチル－２－（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル）アセトアミド
　上記で得た化合物（２９４ｍｇ、０．４９ｍｍｏｌ）を用いて、実施例２７２（ｂ）と同様の方法により、白色固体としての表題化合物を得た（７１ｍｇ、収率３０％）。
1H-NMR (CDCl3,δ ppm): 8.33-8.28 (2H, m), 7.95-7.94 (1H, m), 6.94-6.92 (2H, m), 4.50-4.41 (1H, m), 3.89-3.74 (4H, m), 3.56-3.35 (7H, m), 3.05-2.95 (10H, m), 2.85-2.64 (5H, m), 2.54-2.36 (5H, m), 2.27-2.10 (2H, m). (B) N, N-dimethyl-2- (7-(((R) -4-methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl)- 6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) acetamide Using the compound obtained above (294 mg, 0.49 mmol), in the same manner as in Example 272 (b) To give the title compound as a white solid (71 mg, 30% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.33-8.28 (2H, m), 7.95-7.94 (1H, m), 6.94-6.92 (2H, m), 4.50-4.41 (1H, m), 3.89- 3.74 (4H, m), 3.56-3.35 (7H, m), 3.05-2.95 (10H, m), 2.85-2.64 (5H, m), 2.54-2.36 (5H, m), 2.27-2.10 (2H, m ).
（実施例２７６）
（２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）メタノール
Figure JPOXMLDOC01-appb-C000170
 (Example 276)
(2- (4- (4-Methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) methanol
Figure JPOXMLDOC01-appb-C000170
（ａ）エチル ４－（４－（４，６－ジクロロ－５－（２－メトキシ－２－オキソエチル）ピリミジン－２－イル）フェニル）ピペラジン－１－カルボキシレート
　実施例２７２（ａ）で得た化合物（２．０ｇ、４．７３ｍｍｏｌ）のｔ－ブタノール（１５ｍｌ）と水（１５ｍｌ）との混合溶液に０℃で、亜塩素酸ナトリウム（１．２８ｇ、１４．２ｍｍｏｌ）、リン酸ナトリウム（３．２ｇ、２３．６ｍｍｏｌ）、２－メチル－２－ブテン（５．０ｍｌ、４７．３ｍｍｏｌ）を加え、室温で３時間攪拌した。氷冷下で飽和食塩水を加え、溶液をクロロホルムで分液抽出した。硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。次に得られた残渣のメタノール溶液に０℃で、２ｍｏｌ／Ｌトリメチルシリルジアゾメタンヘキサン溶液（９．４７ｍｌ）加え、０℃で１０時間攪拌した。その後、氷冷下で酢酸（５．０ｍｌ）を加えて反応を停止した。飽和炭酸水素ナトリウム水溶液をｐＨ＝８となるまで加えた後、酢酸エチルにより分液抽出した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を黄色アモルファスとして得た（１．７ｇ、収率８０％）。
1H-NMR (CDCl3,δ ppm): 8.29 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 4.19-4.13 (2H, m), 3.94 (2H, s), 3.74 (3H, s), 3.65-3.59 (4H, m), 3.34-3.30 (4H, m), 1.30-1.25 (3H, m). (A) Ethyl 4- (4- (4,6-dichloro-5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) phenyl) piperazine-1-carboxylate obtained in Example 272 (a) To a mixed solution of compound (2.0 g, 4.73 mmol) in t-butanol (15 ml) and water (15 ml) at 0 ° C., sodium chlorite (1.28 g, 14.2 mmol), sodium phosphate (3 0.2 g, 23.6 mmol) and 2-methyl-2-butene (5.0 ml, 47.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated saline was added under ice cooling, and the solution was subjected to liquid separation extraction with chloroform. It dried with magnesium sulfate and concentrated the solvent under reduced pressure. Next, 2 mol / L trimethylsilyldiazomethanehexane solution (9.47 ml) was added to the methanol solution of the obtained residue at 0 ° C., and the mixture was stirred at 0 ° C. for 10 hours. Thereafter, acetic acid (5.0 ml) was added under ice cooling to stop the reaction. A saturated aqueous sodium hydrogen carbonate solution was added until pH = 8, followed by separation and extraction with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a yellow amorphous (1.7 g, yield 80%).
1 H-NMR (CDCl 3 , δ ppm): 8.29 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 4.19-4.13 (2H, m), 3.94 (2H, s ), 3.74 (3H, s), 3.65-3.59 (4H, m), 3.34-3.30 (4H, m), 1.30-1.25 (3H, m).
（ｂ）メチル ４－クロロ－２－（４－（４－（エトキシカルボニル）ピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－カルボキシレート
　上記で得た化合物（１．２５ｇ、２．７６ｍｍｏｌ)のトルエン（２０ｍｌ）溶液にホルムアルデヒド（２２３μｌ、７．７０ｍｍｏｌ)、テトラブチルアンモニウムヨージド（４０ｍｇ、０．１１ｍｍｏｌ)、炭酸カリウム（１．１４ｇ、８．２８ｍｍｏｌ）を加え６０℃にて２日間攪拌した。その後、セライトろ過により沈殿物を除去たのち、溶媒を減圧留去した。得られた残査の１，４－ジオキサン溶液に３－（ピロリジン－１－イル）プロパン－１－アミン（３７８μｌ、２．７６ｍｍｏｌ）と炭酸カリウム（０．９０ｇ、６．５１ｍｍｏｌ）を加え、１１０℃にて２日間攪拌した。その後、セライトろ過により沈殿物を除去した後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル）で精製することにより表題化合物を黄色油状物として得た（７５３ｍｇ、収率４８％）。
1H-NMR (CDCl3,δ ppm): 8.21 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 4.15-4.06 (3H, m), 3.80-3.76 (2H, m), 3.71-3.57 (12H, m), 3.46-3.41 (1H, m), 3.23-3.17 (4H, m), 2.37-2.32 (6H, m), 1.78-1.74 (2H, m), 1.25-1.20 (3H, m). (B) Methyl 4-chloro-2- (4- (4- (ethoxycarbonyl) piperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine-5-carboxylate To a solution of the compound obtained above (1.25 g, 2.76 mmol) in toluene (20 ml) was added formaldehyde (223 μl, 7.70 mmol), tetrabutylammonium iodide (40 mg, 0.47 mmol). 11 mmol) and potassium carbonate (1.14 g, 8.28 mmol) were added, and the mixture was stirred at 60 ° C. for 2 days. Thereafter, the precipitate was removed by Celite filtration, and then the solvent was distilled off under reduced pressure. To the resulting 1,4-dioxane solution, 3- (pyrrolidin-1-yl) propan-1-amine (378 μl, 2.76 mmol) and potassium carbonate (0.90 g, 6.51 mmol) were added. Stir at C for 2 days. Thereafter, the precipitate was removed by Celite filtration, and then the solvent was distilled off 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 a yellow oil (753 mg, yield 48%).
1 H-NMR (CDCl 3 , δ ppm): 8.21 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 4.15-4.06 (3H, m), 3.80-3.76 (2H , m), 3.71-3.57 (12H, m), 3.46-3.41 (1H, m), 3.23-3.17 (4H, m), 2.37-2.32 (6H, m), 1.78-1.74 (2H, m), 1.25 -1.20 (3H, m).
（ｃ）（２－（４－（４－メチルピペラジン－１－イル）フェニル）－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）メタノール
　上記で得た化合物（７５３ｍｇ、１．３２ｍｍｏｌ）のメタノール（１０ｍｌ）溶液に室温でギ酸アンモニウム（３．０ｇ、４６．９ｍｍｏｌ）とパラジウム炭素（５０％含水）（３５０ｍｇ）を加え、８０℃にて５時間攪拌した。室温へと氷冷した後、セライトを用いてろ過を行い減圧濃縮することにより混合物を得た。得られた混合物のテトラヒドロフラン（１０ｍｌ）溶液に０℃で水素化リチウムアルミニウム（１７６ｍｇ、４．６４ｍｍｏｌ）を加え、７０℃にて２時間攪拌した。氷冷下で水酸化ナトリウム水溶液を加えてｐＨ＝１０とした後にクロロホルムで分液抽出した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール）で精製することにより表題化合物を黄色油状物として得た（２３０ｍｇ、収率３９％）。
1H-NMR (CDCl3,δ ppm): 1H-NMR (CDCl3,δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 3.77-3.65 (7H, m), 3.59-3.41 (4H, m), 3.35-3.25 (4H, m), 2.60-2.55 (4H, m), 2.48-2.30 (10H, m), 1.85-1.78 (2H, m). (C) (2- (4- (4-Methylpiperazin-1-yl) phenyl) -7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-5 -Yl) methanol Ammonium formate (3.0 g, 46.9 mmol) and palladium on carbon (containing 50% water) (350 mg) were added to a methanol (10 ml) solution of the compound obtained above (753 mg, 1.32 mmol) at room temperature, Stir at 80 ° C. for 5 hours. After cooling to room temperature with ice, the mixture was filtered using Celite and concentrated under reduced pressure to obtain a mixture. Lithium aluminum hydride (176 mg, 4.64 mmol) was added to a tetrahydrofuran (10 ml) solution of the obtained mixture at 0 ° C., and the mixture was stirred at 70 ° C. for 2 hours. Under ice cooling, an aqueous sodium hydroxide solution was added to adjust to pH = 10, followed by separation and extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; ethyl acetate: methanol) to give the title compound as a yellow oil (230 mg, yield 39%).
1 H-NMR (CDCl 3 , δ ppm): 1 H-NMR (CDCl 3 , δ ppm): 8.22 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 3.77-3.65 (7H, m), 3.59-3.41 (4H, m), 3.35-3.25 (4H, m), 2.60-2.55 (4H, m), 2.48-2.30 (10H, m), 1.85-1.78 (2H, m).
（実施例２７７）
（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）メタノール
Figure JPOXMLDOC01-appb-C000171
 (Example 277)
(7-(((R) -4-Methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-5H-pyrrolo [2 , 3-d] pyrimidin-5-yl) methanol
Figure JPOXMLDOC01-appb-C000171
（ａ）メチル （７－（（（Ｒ）－４－ベンジルモルホリン－２－イル）メチル）－４－クロロ－２－（４－（４－（エトキシカルボニル）ピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－カルボキシレート
　実施例２７６（ａ）で得た化合物（１．２５ｇ、２．７６ｍｍｏｌ）を用いて、実施例２７６（ｂ）と同様の方法により、黄色油状物としての表題化合物を得た（７２０ｍｇ、収率４１％）。
1H-NMR (CDCl3,δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.28-7.23 (5H, m), 6.88 (2H, d, J = 9.0 Hz), 4.19-4.10 (3H, m), 4.06-3.82 (4H, m), 3.74-3.48 (12H, m), 3.28-3.24 (4H, m), 2.83-2.80 (1H, m), 2.67-2.65 (1H, m), 2.16-2.12 (1H, m), 2.00-1.96 (1H, m), 1.29-1.24 (3H, m). (A) Methyl (7-((((R) -4-benzylmorpholin-2-yl) methyl) -4-chloro-2- (4- (4- (ethoxycarbonyl) piperazin-1-yl) phenyl)- 6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-carboxylate Example 276 (b ) To give the title compound as a yellow oil (720 mg, 41% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.23 (2H, d, J = 9.0 Hz), 7.28-7.23 (5H, m), 6.88 (2H, d, J = 9.0 Hz), 4.19-4.10 (3H , m), 4.06-3.82 (4H, m), 3.74-3.48 (12H, m), 3.28-3.24 (4H, m), 2.83-2.80 (1H, m), 2.67-2.65 (1H, m), 2.16 -2.12 (1H, m), 2.00-1.96 (1H, m), 1.29-1.24 (3H, m).
（ｂ）メチル ２－（４－（４－（エトキシカルボニル）ピペラジン－１－イル）フェニル）－７－（（（Ｒ）－４－メチルモルホリン－２－イル)メチル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－カルボキシレート
　上記で得た化合物（７２０ｍｇ、１．１３ｍｍｏｌ）を用いて、実施例２７３（ｂ）と同様の方法により、黄色油状物としてジアステレオマー混合物の表題化合物を得た（２８１ｍｇ、収率４７％）。
1H-NMR (CDCl3,δ ppm): 8.27-8.24 (2H, m), 8.16-8.15 (1H, m), 6.93-6.90 (2H, m), 4.18-4.04 (4H, m), 3.92-3.84 (3H, m), 3.77-3.52 (10H, m), 3.30-3.23 (4H, m), 2.87-2.83 (1H, m), 2.73-2.69 (1H, m), 2.34-2.30 (3H, m), 2.18-2.14 (1H, m), 2.02-1.97 (1H, m), 1.28-1.24 (2H, m). (B) Methyl 2- (4- (4- (ethoxycarbonyl) piperazin-1-yl) phenyl) -7-(((R) -4-methylmorpholin-2-yl) methyl) -6,7-dihydro -5H-pyrrolo [2,3-d] pyrimidine-5-carboxylate Using the compound obtained above (720 mg, 1.13 mmol) in the same manner as in Example 273 (b), dia The title compound was obtained as a stereomeric mixture (281 mg, 47% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.27-8.24 (2H, m), 8.16-8.15 (1H, m), 6.93-6.90 (2H, m), 4.18-4.04 (4H, m), 3.92- 3.84 (3H, m), 3.77-3.52 (10H, m), 3.30-3.23 (4H, m), 2.87-2.83 (1H, m), 2.73-2.69 (1H, m), 2.34-2.30 (3H, m ), 2.18-2.14 (1H, m), 2.02-1.97 (1H, m), 1.28-1.24 (2H, m).
（ｃ）（７－（（（Ｒ）－４－メチルモルホリン－２－イル）メチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）メタノール
　上記で得た化合物（２８１ｍｇ、０．５４ｍｍｏｌ）を用いて、実施例２７１（ｄ）と同様の方法により、黄色油状物としてジアステレオマー混合物の表題化合物を得た（１３２ｍｇ、収率５６％）。
1H-NMR (CDCl3,δ ppm): 8.26-8.22 (2H, m), 7.98-7.96 (1H, m), 6.93-6.90 (2H, m), 3.86-3.50 (11H, m), 3.35-3.32 (4H, m), 2.83-2.79 (1H, m), 2.62-2.59 (5H, m), 2.39-2.36 (3H, m), 2.28-2.26 (3H, m), 2.19-2.15 (1H, m), 1.98-1.91 (1H, m). (C) (7-(((R) -4-Methylmorpholin-2-yl) methyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -6,7-dihydro-5H- Pyrrolo [2,3-d] pyrimidin-5-yl) methanol Using the compound obtained above (281 mg, 0.54 mmol) and a diastereomer as a yellow oil by the same method as in Example 271 (d) The title compound of the mixture was obtained (132 mg, 56% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.26-8.22 (2H, m), 7.98-7.96 (1H, m), 6.93-6.90 (2H, m), 3.86-3.50 (11H, m), 3.35- 3.32 (4H, m), 2.83-2.79 (1H, m), 2.62-2.59 (5H, m), 2.39-2.36 (3H, m), 2.28-2.26 (3H, m), 2.19-2.15 (1H, m ), 1.98-1.91 (1H, m).
（実施例２７８）
４－（３－（６－（２－メトキシエチル)－２－（４－（４－メトキシピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000172
 　実施例２７２で得た化合物（５９．０ｍｇ、０．１３ｍｍｏｌ）の塩化メチレン(５ｍｌ)溶液に０℃にてテトラフルオロホウ酸（５３ｍｇ、０．２５ｍｍｏｌ）、２ｍｏｌ／Ｌトリメチルシリルジアゾメタンヘキサン溶液（０．２５ｍｌ、０．５０ｍｍｏｌ）を順に加えた。０℃にて１時間攪拌した後、クロロホルムと水とを加え１時間攪拌した後、分液抽出した。その後、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。得られた残渣はアミンシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール）で精製することにより表題化合物を黄色油状物として得た（９．０ｍｇ、収率１５％）。
1H-NMR (CDCl3,δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.95-3.92 (1H, m), 3.81-3.65 (5H, m), 3.42-3.38 (2H, m), 3.26-3.17 (8H, m), 3.13-3.04 (1H, m), 2.72-2.64 (1H, m), 2.53-2.50 (4H, m), 2.39-2.29 (9H, m), 2.12-2.06 (1H, m), 1.81-1.63 (3H, m). (Example 278)
4- (3- (6- (2-methoxyethyl) -2- (4- (4-methoxypiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H)- Yl) propyl) morpholine
Figure JPOXMLDOC01-appb-C000172
 A solution of the compound obtained in Example 272 (59.0 mg, 0.13 mmol) in methylene chloride (5 ml) at 0 ° C. with tetrafluoroboric acid (53 mg, 0.25 mmol), 2 mol / L trimethylsilyldiazomethanehexane solution (0. 25 ml, 0.50 mmol) was added in order. After stirring at 0 ° C. for 1 hour, chloroform and water were added and stirred for 1 hour, followed by liquid separation extraction. Thereafter, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by amine silica gel column chromatography (elution solvent; ethyl acetate: methanol) to give the title compound as a yellow oil (9.0 mg, yield 15%).
1 H-NMR (CDCl 3 , δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.85 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.95-3.92 (1H, m ), 3.81-3.65 (5H, m), 3.42-3.38 (2H, m), 3.26-3.17 (8H, m), 3.13-3.04 (1H, m), 2.72-2.64 (1H, m), 2.53-2.50 (4H, m), 2.39-2.29 (9H, m), 2.12-2.06 (1H, m), 1.81-1.63 (3H, m).
（実施例２７９）
（２Ｒ）－２－（（６－（２－メトキシエチル）－２－（４－（４－メトキシピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）－４－メチルモルホリン
Figure JPOXMLDOC01-appb-C000173
 　実施例２７３で得た化合物（７９ｍｇ、０．１８ｍｍｏｌ）を用いて、実施例２７８と同様の方法により、黄色油状物としての表題化合物を得た（１１ｍｇ、収率１４％）。
1H-NMR (CDCl3,δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.87(1H, s), 6.88 (2H, d, J = 9.0 Hz), 4.09-3.96 (1H, m), 3.84-3.80 (2H, m), 3.66-3.54 (2H, m), 3.42-3.38 (3H, m), 3.36-3.23 (7H, m), 3.18-3.05 (1H, m), 2.78-2.66 (2H, m), 2.58-2.50 (5H, m), 2.29 (3H, s), 2.20-2.01 (5H, m), 1.91-1.80 (1H, m), 1.73-1.65 (1H, m). (Example 279)
(2R) -2-((6- (2-methoxyethyl) -2- (4- (4-methoxypiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H ) -Yl) methyl) -4-methylmorpholine
Figure JPOXMLDOC01-appb-C000173
 Using the compound obtained in Example 273 (79 mg, 0.18 mmol), the title compound as a yellow oil was obtained in the same manner as in Example 278 (11 mg, 14% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.87 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 4.09-3.96 (1H, m ), 3.84-3.80 (2H, m), 3.66-3.54 (2H, m), 3.42-3.38 (3H, m), 3.36-3.23 (7H, m), 3.18-3.05 (1H, m), 2.78-2.66 (2H, m), 2.58-2.50 (5H, m), 2.29 (3H, s), 2.20-2.01 (5H, m), 1.91-1.80 (1H, m), 1.73-1.65 (1H, m).
（実施例２８０）
４－（３－（５－（メトキシメチル）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル）モルホリン
Figure JPOXMLDOC01-appb-C000174
 　実施例２７６で得た化合物（９５ｍｇ、０．２０ｍｍｏｌ）を用いて、実施例２７８と同様の方法により、黄色油状物としての表題化合物を得た（８ｍｇ、収率８％）。
1H-NMR (CDCl3,δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.90(1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.68-3.60 (5H, m), 3.52-3.42 (4H, m), 3.39-3.32 (5H, m), 3.26-3.23 (4H, m), 2.53-2.50 (4H, m), 2.37-2.33 (6H, m), 2.29 (3H, m), 1.78-1.74 (2H, m). (Example 280)
4- (3- (5- (methoxymethyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) Propyl) morpholine
Figure JPOXMLDOC01-appb-C000174
 Using the compound obtained in Example 276 (95 mg, 0.20 mmol), the title compound was obtained as a yellow oil (8 mg, 8% yield) in the same manner as in Example 278.
1 H-NMR (CDCl 3 , δ ppm): 8.19 (2H, d, J = 9.0 Hz), 7.90 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 3.68-3.60 (5H, m ), 3.52-3.42 (4H, m), 3.39-3.32 (5H, m), 3.26-3.23 (4H, m), 2.53-2.50 (4H, m), 2.37-2.33 (6H, m), 2.29 (3H , m), 1.78-1.74 (2H, m).
（実施例２８１）
（２Ｒ）－２－（（５－（メトキシメチル）－２－（４－（４－メトキシピペラジン－１－イル）フェニル）－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）メチル）－４－メチルモルホリン
Figure JPOXMLDOC01-appb-C000175
 　実施例２７７で得た化合物（４６ｍｇ、０．１０ｍｍｏｌ）を用いて、実施例２７８と同様の方法により、黄色油状物としての表題化合物を得た（３ｍｇ、収率６％）。
1H-NMR (CDCl3,δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.94-7.93 (1H, m), 6.88 (2H, d, J = 9.0 Hz), 3.86-3.70 (3H, m), 3.63-3.35 (7H, m), 3.32 (3H, s), 3.27-3.23 (4H, m), 2.75-2.72 (1H, m), 2.60-2.50 (5H, m), 2.29 (3H, s), 2.21 (3H, s), 2.10-1.98 (1H, m), 1.90-1.74 (1H, m). (Example 281)
(2R) -2-((5- (methoxymethyl) -2- (4- (4-methoxypiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-d] pyrimidine-7 (6H)- Yl) methyl) -4-methylmorpholine
Figure JPOXMLDOC01-appb-C000175
 The title compound as a yellow oil was obtained in the same manner as in Example 278 using the compound obtained in Example 277 (46 mg, 0.10 mmol) (3 mg, 6% yield).
1 H-NMR (CDCl 3 , δ ppm): 8.20 (2H, d, J = 9.0 Hz), 7.94-7.93 (1H, m), 6.88 (2H, d, J = 9.0 Hz), 3.86-3.70 (3H , m), 3.63-3.35 (7H, m), 3.32 (3H, s), 3.27-3.23 (4H, m), 2.75-2.72 (1H, m), 2.60-2.50 (5H, m), 2.29 (3H , s), 2.21 (3H, s), 2.10-1.98 (1H, m), 1.90-1.74 (1H, m).
（実施例２８２）
２－（２－（４－（７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）モルホリノ）エタノール
Figure JPOXMLDOC01-appb-C000176
 　実施例１５０で得られた化合物（６２．０ｍｇ、０．１５１ｍｍｏｌ）を用いて、実施例１１９と同様の方法により、表題化合物を無色アモルファスとして得た（４９．０ｍｇ、収率７２％）。
1H-NMR (CDCl3,δ ppm): 8.30 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 7.40 (2H, d, J = 8.4 Hz), 4.59 (1H, dd, J = 10.5, 2.2 Hz), 4.06 (1H, dd, J = 11.6, 5.8 Hz), 3.86-3.79 (1H, m), 3.72-3.70 (4H, m), 3.63-3.61 (4H, m), 3.55 (2H, t, J = 7.2 Hz), 3.03 (2H, t, J = 8.6 Hz), 2.93 (1H, d, J = 11.6 Hz), 2.80 (1H, d, J = 10.5 Hz), 2.71 (1H, brs), 2.58-2.57 (2H, m), 2.44-2.33 (7H, m), 2.19 (1H, t, J = 10.6 Hz), 1.83-1.81 (2H, m). (Example 282)
2- (2- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) morpholino) ethanol
Figure JPOXMLDOC01-appb-C000176
 Using the compound (62.0 mg, 0.151 mmol) obtained in Example 150, the title compound was obtained as a colorless amorphous by the same method as in Example 119 (49.0 mg, yield 72%).
1 H-NMR (CDCl 3 , δ ppm): 8.30 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 7.40 (2H, d, J = 8.4 Hz), 4.59 (1H, dd, J = 10.5, 2.2 Hz), 4.06 (1H, dd, J = 11.6, 5.8 Hz), 3.86-3.79 (1H, m), 3.72-3.70 (4H, m), 3.63-3.61 (4H, m), 3.55 ( 2H, t, J = 7.2 Hz), 3.03 (2H, t, J = 8.6 Hz), 2.93 (1H, d, J = 11.6 Hz), 2.80 (1H, d, J = 10.5 Hz), 2.71 (1H, brs), 2.58-2.57 (2H, m), 2.44-2.33 (7H, m), 2.19 (1H, t, J = 10.6 Hz), 1.83-1.81 (2H, m).
（実施例２８３）
４－（２－メトキシエチル）－２－（４－（７－(３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル）フェニル）モルホリン
Figure JPOXMLDOC01-appb-C000177
 　実施例１５０で得られた化合物（１０６ｍｇ、０．２５９ｍｍｏｌ）と対応する試薬を用いて、実施例７６と同様の方法により、表題化合物を黄色油状物として得た（６９．０ｍｇ、収率５７％）。
1H-NMR (CDCl3,δ ppm): 8.29 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 7.39 (2H, d, J = 8.4 Hz), 4.65 (1H, dd, J = 10.4, 2.5 Hz), 4 (1H, dd, J = 11.6, 2.1 Hz), 3.90-3.86 (1H, m), 3.72-3.70 (4H, m), 3.61-3.53 (6H, m), 3.35 (3H, s), 3.03-2.97 (3H, m), 2.85 (1H, d, J = 11.6 Hz), 2.60 (2H, t, J = 5.5 Hz), 2.43-2.40 (6H, m), 2.31-2.27 (1H, m), 2.09 (1H, t, J = 10.8 Hz), 1.87-1.77 (2H, m). (Example 283)
4- (2-methoxyethyl) -2- (4- (7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) phenyl) morpholine
Figure JPOXMLDOC01-appb-C000177
 The title compound was obtained as a yellow oil (69.0 mg, yield 57%) by the same method as in Example 76 using the compound (106 mg, 0.259 mmol) obtained in Example 150 and the corresponding reagent. ).
1 H-NMR (CDCl 3 , δ ppm): 8.29 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 7.39 (2H, d, J = 8.4 Hz), 4.65 (1H, dd, J = 10.4, 2.5 Hz), 4 (1H, dd, J = 11.6, 2.1 Hz), 3.90-3.86 (1H, m), 3.72-3.70 (4H, m), 3.61-3.53 (6H, m), 3.35 ( 3H, s), 3.03-2.97 (3H, m), 2.85 (1H, d, J = 11.6 Hz), 2.60 (2H, t, J = 5.5 Hz), 2.43-2.40 (6H, m), 2.31-2.27 (1H, m), 2.09 (1H, t, J = 10.8 Hz), 1.87-1.77 (2H, m).
　次に、代表的な本発明の化合物の薬理作用について試験例により具体的に説明する。
試験例１：ヒトＴＬＲ９レポータージーン試験
　ＨＥＫ２９３細胞安定ヒトＴＬＲ９発現株（ヒトＴＬＲ９－２９３細胞）を起眠し、細胞の状態が安定するまで継代を繰り返した。細胞の培養は、ＣＯ２インキュベーター内（３７℃、５％ ＣＯ２）に放置した。細胞の回収はトリプシン－ＥＤＴＡを用いて細胞を剥離し、遠心後の細胞ペレットを増殖培地に懸濁した。３×１０５ cells／ｍＬに調製したヒトＴＬＲ９－２９３細胞を６穴コラーゲンプレートに播種し、一晩培養した。ＮＦ－κＢ－ルシフェラーゼ遺伝子を細胞に導入し、一晩培養した。ＮＦ－κＢ－ルシフェラーゼ遺伝子導入細胞を６.２５×１０５ cells／ｍＬに調製し、９６穴ブラックプレートに８０ μＬ／ウェルで播種した（５×１０４ cells／ウェル）。被験物質（最終濃度：１，３，１０，３０，１００，３００，１０００ｎＭ）及び、ＣｐＧ２００６（5'- TCG TCG TTT TGT GGT TTT GTC GTT -3'）（最終濃度３００ｎＭ）を各々１０μＬずつ添加後、６時間培養した。Bright－Glo調製液を１００μＬ／ウェル添加し、遮光下で２分間放置した。ルミノメーターを用いて発光を測定し、各被験物質の５０％阻害率（ＩＣ５０値）を算出し、表１８に示した。 Next, the pharmacological action of a representative compound of the present invention will be specifically described with reference to test examples.
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 TLR9-293 cells prepared to 3 × 10 5 cells / mL were seeded on a 6-well collagen plate and cultured overnight. The NF-κB-luciferase gene was introduced into the cells and cultured overnight. NF-κB-luciferase gene-introduced cells were prepared at 6.25 × 10 5 cells / mL, and seeded at 80 μL / well in a 96-well black plate (5 × 10 4 cells / well). After adding 10 μL each of the test substance (final concentration: 1, 3, 10, 30, 100, 300, 1000 nM) and CpG2006 (5′-TCG TCG TTT TGT GGT TTT GTC GTT-3 ′) (final concentration 300 nM) And cultured for 6 hours. Bright-Glo preparation solution was added at 100 μL / well and allowed to stand for 2 minutes in the dark. 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.
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
　表１８に示すように、本発明の化合物はＮＦ－ｋＢ阻害試験において強い阻害作用を示した。実施例３９、４０、４１、４２、４４、４５、４６、５０、５１、５９、６３、６４、６６、７６、７７、７８、７９、８１、８２、８６、９０、９１、９２、９３、９４、９５、１０３、１０４、１０５、１０７、１１２、１１７、１３４、１３７、１４３、１４６、１４８、１５１、１５６、１５８、１５９、１６１、１６２、１６５、１６７、１７４、１７５、１７９、１８３、２０７、２０８、２１０、２１２～２１９、２２１、２２３～２２６、２２８、２２９、２３５、２３７、２３８、２４０、２４２、２４３、２４５、２５０、２５１、２５３～２５７、２６７および２７４の化合物は、特に強い阻害作用を示した。 As shown in Table 18, the compound of the present invention showed a strong inhibitory action in the NF-kB inhibition test. Examples 39, 40, 41, 42, 44, 45, 46, 50, 51, 59, 63, 64, 66, 76, 77, 78, 79, 81, 82, 86, 90, 91, 92, 93, 94, 95, 103, 104, 105, 107, 112, 117, 134, 137, 143, 146, 148, 151, 156, 158, 159, 161, 162, 165, 167, 174, 175, 179, 183, 207, 208, 210, 212-219, 221, 223-226, 228, 229, 235, 237, 238, 240, 242, 243, 245, 250, 251, 253-257, 267 and 274 are Strong inhibitory action was shown.
試験例２：マウス脾臓細胞を用いたＣｐＧ誘発ＩＬ－６産生阻害試験
　マウス脾臓細胞を以下の通り調製した。Ｃ５７ＢＬ／６マウス（♀）から摘出した脾臓を外科用はさみで分割し、スライドガラスのすり部分ですりつぶした。遠心後、ＡＣＫを用いて溶血処理を行った。培地を加えてＡＣＫの反応を止め、遠心を行った。細胞を５×１０６ cells／ｍＬに調製し、９６穴プレートに１００ μＬ／wellで播種した（５×１０５ cells／ウェル）。被験物質（最終濃度：１，３，１０，３０，１００，３００，１０００ ｎＭ）を各々２０μＬ及びＣｐＧ１８２６（5'- TCC ATG ACG TTC CTG ACG TT -3'）（（最終濃度１００ｎＭ）を各々８０μＬずつ添加し、ＣＯ２インキュベーター（３７℃、５％ ＣＯ２）内で２４時間培養した。ＥＬＩＳＡ ｋｉｔを用いて培養上清中のＩＬ－６産生量を測定し、各被験物質の５０％阻害率（ＩＣ５０値）を算出し、表１９に示した。 Test Example 2 : CpG-induced IL-6 production inhibition test using mouse spleen cells Mouse spleen cells were prepared as follows. The spleen removed from C57BL / 6 mice (♀) was divided with surgical scissors and ground with a slide of a slide glass. After centrifugation, hemolysis was performed using ACK. Medium was added to stop the ACK reaction, and centrifugation was performed. The cells were prepared to 5 × 10 6 cells / mL, and seeded at 100 μL / well in a 96-well plate (5 × 10 5 cells / well). 20 μL each of test substances (final concentrations: 1, 3, 10, 30, 100, 300, 1000 nM) and 80 μL each of CpG1826 (5′-TCC ATG ACG TTC CTG ACG TT -3 ′) (final concentration 100 nM) Each was added and cultured for 24 hours in a CO 2 incubator (37 ° C., 5% CO 2 ) The amount of IL-6 produced in the culture supernatant was measured using an ELISA kit, and the 50% inhibition rate of each test substance (IC 50 value) was calculated and shown in Table 19.
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
　表１９に示すように、本発明の化合物はＩＬ－６産生阻害試験において強い阻害作用を示した。実施例４６、７８、８６、８７、９１、９５、１１０、１１７、１３９、１４８、１６１、１６５、１６７、１８３、１８９、１９３、２００、２０１、２０４、２０６、２４０、２４２～２４５、２５６、２５７および２６７の化合物は、特に強いＩＬ－６産生阻害作用を示した。 As shown in Table 19, the compound of the present invention exhibited a strong inhibitory action in the IL-6 production inhibition test. Examples 46, 78, 86, 87, 91, 95, 110, 117, 139, 148, 161, 165, 167, 183, 189, 193, 200, 201, 204, 206, 240, 242-245, 256, Compounds 257 and 267 showed particularly strong IL-6 production inhibitory action.
試験例３：ＣｐＧ１８２６投与モデル（腹腔投与）を用いた薬効評価試験
　エーテル麻酔下において、マウス腹腔内にＣｐＧ１８２６溶液を投与した。ＣｐＧ１８２６投与の１～６時間後にエーテル麻酔下で採血および腹腔洗浄液の回収を行った。採血は心臓より行いヘパリンが入ったチューブに回収し、腹腔洗浄はＰＢＳ（phosphate buffered saline）を腹腔内に注入し腹部を揉みほぐした後に回収した。化合物はＣｐＧ１８２６投与前にマウス尾静脈より投与した。血液は遠心分離により血漿とし、市販のＥＬＩＳＡキットによりサイトカインを測定した。ＩＬ－６産生量を測定し、各被験物質の溶媒対照との比較により阻害率（％）を算出し、表２０および表２１に示した。
　表２０および表２１に示すように、実施例４１、４５、４８、６２、７７、８４、８６、１０９、１１１、１１７、１１８、１１９、２５０および２５５はＣｐＧ１８２６投与２時間後の投与で、溶媒対照群と比較して顕著な炎症性サイトカイン産生抑制が確認でき、本発明の化合物がＴＬＲ９依存的な炎症性サイトカイン産生を抑制することが示された。
Figure JPOXMLDOC01-appb-T000182
 Test Example 3 : Drug efficacy evaluation test using CpG1826 administration model (peritoneal administration) A CpG1826 solution was administered intraperitoneally to mice under ether anesthesia. One to six hours after administration of CpG1826, blood was collected under ether anesthesia and 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. The blood was made into plasma by centrifugation, and cytokine was measured by a commercially available ELISA kit. IL-6 production was measured, and the inhibition rate (%) was calculated by comparison with the solvent control of each test substance. The results are shown in Table 20 and Table 21.
As shown in Table 20 and Table 21, Examples 41, 45, 48, 62, 77, 84, 86, 109, 111, 117, 118, 119, 250 and 255 are administered 2 hours after the administration of CpG1826. compared with the control group confirmed pronounced inflammatory cytokine production inhibitory compounds of the present invention have been shown to inhibit TLR 9 dependent inflammatory cytokine production.
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
試験例４：盲腸結紮穿刺（ＣＬＰ）モデルを用いた薬効評価試験
　盲腸結紮穿刺モデルは、セプシス研究において最も汎用されている動物モデルであり、現在のところヒトセプシス病態を最も反映しているモデルであると考えられている（Buras, J.A., et al., Nat. Rev. Drug Discov. 4, 854-865(2005), Rittirsch,D., et al. J. Leukoc. Biol. 81, 137-143(2007)）。Daniel Rittirschらの報告（Daniel Rittirsch,et al., Nature Protocols 4, 31-36 (2009)）を参考にＣ５７ＢＬ／６マウスに対してＣＬＰ処置を実施した。エーテルもしくはイソフルラン吸入麻酔下、腹中線をはさみで数センチ開き、盲腸と近辺臓器を露出させた。盲腸下部を結紮後、１８－２３Ｇ針を用いて盲腸壁を穿刺、穿孔させた（ＣＬＰ処置）。露出臓器を元の場所に戻した後、開腹創はシアノアクリレート系外科用接着剤にて閉鎖し、術野をイソジン綿で消毒した。手術後覚醒飼育を行い、少なくとも一日二回以上生存確認を実施した。一部は、手術数時間後に全採血による安楽死を行った後、腹腔洗浄液や臓器を採取し、サイトカインや臓器障害マーカー、生菌数の測定などに使用した。化合物はＣＬＰ処置前もしくは処置後に静脈内投与を行った。一部は３７℃に暖めた生理食塩水の皮下投与、抗菌剤の腹腔内投与と併用して実施した。図１および図２に示すように、実施例６２および８６は、ＣＬＰ処置６時間後の１０ｍｇ／ｋｇ投与で、溶媒対照群と比較して顕著な生存率を示した。また炎症性サイトカインおよび臓器障害マーカーなども有意に改善していることも確認し、本発明の化合物が臨床においても有用であることが示された。 Test Example 4 : Drug efficacy evaluation test using cecal ligation and puncture (CLP) model 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. (Buras, JA, et al., Nat. Rev. Drug Discov. 4, 854-865 (2005), Rittirsch, D., et al. J. Leukoc. Biol. 81, 137-143 ( 2007)). C57BL / 6 mice were treated with CLP with reference to Daniel Rittirsch et al. (Daniel Rittirsch, et al., Nature Protocols 4, 31-36 (2009)). Under ether or isoflurane inhalation anesthesia, the midline of the abdomen was opened several centimeters with scissors to expose the cecum and nearby organs. After ligating the lower cecum, the cecal wall was punctured and perforated using an 18-23G needle (CLP treatment). After returning the exposed organ to its original location, the laparotomy was closed with a cyanoacrylate surgical adhesive, and the surgical field was disinfected with isodine cotton. Awakening was carried out after surgery, and survival was confirmed 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. As shown in FIGS. 1 and 2, Examples 62 and 86 showed significant survival rates compared to the solvent control group at 10 mg / kg dose 6 hours after CLP treatment. It was also confirmed that inflammatory cytokines and organ damage markers were significantly improved, and the compounds of the present invention were shown to be useful in clinical practice.
試験例５：癌細胞増殖抑制試験
　ヒトミエローマ細胞株Ｒａｍｏｓは、ＴＬＲ９発現が確認されており、ＴＬＲ９リガンドによる増殖促進の報告がある（Cellular Immunology 259（2009）p90-99）。
　Ｒａｍｏｓ細胞株を６．２５×１０４ cells／ｍＬになるよう調製し、９６穴プレートに８０μＬ／ウェルで播腫した（５×１０３ cells／ウェル）。翌日、被験物質（最終濃度：０．０１、０．１、１、１０μＭ）及び、ＣｐＧ２００６（最終濃度：３μｇ／ｍＬ）を各々１０μＬずつ添加後、ＣＯ２インキュベーター内（３７℃、５％ ＣＯ２濃度）で１日間培養した。陽性対照として、ヒトＴＬＲ９特異的阻害剤であるinhibitory oligonucleotides （ｉＣｐＧ：5'- TTT AGG GTT AGG GTT AGG GTT AGG G -3'）を設定した。5-bromo-2'-deoxy-uridine （ＢｒｄＵ）溶液を各ウェルに１０μＬずつ添加し、さらに１６時間培養を行った。ＢｒｄＵの細胞への取り込みをルミノメーターにて測定した。ＣｐＧ２００６による癌細胞増殖促進に対する各被験物質の増殖阻害率を表２２および表２３に示した。表２２および表２３に示すように本発明の化合物は、ＴＬＲ９リガンド刺激による癌細胞増殖に対し、用量依存的に強い抑制効果を示した。
Figure JPOXMLDOC01-appb-T000184
 Test Example 5 : Cancer Cell Growth Inhibition Test TLR 9 expression has been confirmed in the human myeloma cell line Ramos, and there has been a report of growth promotion by TLR 9 ligand (Cellular Immunology 259 (2009) p90-99).
A Ramos cell line was prepared to be 6.25 × 10 4 cells / mL, and seeded in a 96-well plate at 80 μL / well (5 × 10 3 cells / well). The next day, 10 μL each of the test substance (final concentration: 0.01, 0.1, 1, 10 μM) and CpG2006 (final concentration: 3 μg / mL) were added, and then in a CO 2 incubator (37 ° C., 5% CO 2 1 day). As a positive control, inhibitory oligonucleotides (iCpG: 5′-TTT AGG GTT AGG GTT AGG GTT AGG G-3 ′), which is a human TLR 9- specific inhibitor, were set. 10 μL 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 Table 22 and Table 23, the compounds of the present invention showed a strong inhibitory effect on cancer cell proliferation by TLR 9 ligand stimulation in a dose-dependent manner.
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
　以上で説明したように、式（Ｉ）で表される誘導体、またはその製薬学上許容される塩は、自己免疫疾患の予防および／または治療、具体的には自己免疫疾患が関与する患（炎症、アレルギー、喘息、移植片拒絶、移植片対宿主病、感染症、癌）、免疫不全症または神経変性疾患（アルツハイマー、パーキンソン病など）の予防薬および／または治療薬として利用しうる。また、選択的にＴＬＲを阻害するようなＴＬＲ阻害剤を見出すことで、セプシス、特に重症セプシスの予防および／または治療にも有効な医薬品として利用しうる。特に、ＴＬＲ９阻害剤は、単独、ＴＬＲ２阻害剤と併用、ＴＬＲ４阻害剤との併用またはＴＬＲ２阻害剤およびＴＬＲ４との併用でのさらなる効果も期待でき、新しいセプシス治療として根本治療が期待できる。 As described above, the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, prevents and / or treats an autoimmune disease, specifically, a disease involving an autoimmune disease ( It can be used as a prophylactic and / or therapeutic agent for inflammation, allergy, asthma, graft rejection, graft-versus-host disease, infection, cancer), immunodeficiency or neurodegenerative diseases (Alzheimer, Parkinson's disease, etc.). In addition, 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. In particular, 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.

Claims (33)

  1. 下記式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ａ１およびＡ２は、下記式（Ａ）
    Figure JPOXMLDOC01-appb-C000002
     またはＺを表し、但し、
    　Ａ１が式（Ａ）のとき、Ａ２はＺを表し、
    　Ａ１がＺのとき、Ａ２は式（Ａ）を表し、
    　Ｑ１およびＱ２は、それぞれ独立して、水素原子；置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－８シクロアルキル；シアノ；置換されていてもよいＣ１－５アルキルカルボニル；置換されていてもよいＣ１－５アルコキシカルボニル；カルボキシル；置換されていてもよいアリール；置換されていてもよいヘテロアリール；または－ＣＯＮＲ５Ｒ６を表し、
    　Ａｌｋは、置換されていてもよいＣ１－５アルキレンを表し、
    　Ｚは、水素原子；置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－８シクロアルキル；シアノ；置換されていてもよいＣ１－５アルキルカルボニル；置換されていてもよいＣ１－５アルコキシカルボニル；置換されていてもよいアリール；置換されていてもよいヘテロアリール；ハロゲン；置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６を表し、
    　Ｘは、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－を表し、
    　Ｘ１は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は置換されていてもよいＣ２－８アルキレンであり、
    　Ｘ２は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｘが、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ２は置換されていてもよいＣ２－８アルキレンであり、
    　Ｗは、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－を表し、
    　Ｗ１は、置換されていてもよいＣ１－８アルキレンを表し、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のとき、Ｗ１は置換されていてもよいＣ２－８アルキレンであり、
    　Ｙは、置換されていてもよいアリーレンまたは置換されていてもよいヘテロアリーレンを表し、
    　Ｒ１、Ｒ２、Ｒ３およびＲ４は、それぞれ独立して、水素原子、置換されていてもよいＣ１－１０アルキル、置換されていてもよいＣ３－８シクロアルキルまたは置換されていてもよい４～１０員の飽和複素環を表し、
    　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９は、それぞれ独立して、水素原子または置換されていてもよいＣ１－１０アルキルを表し、
    　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせは、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）］
    で表される化合物またはその製薬学的に許容される塩。     Following formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, A 1 and A 2 represent the following formula (A)
    Figure JPOXMLDOC01-appb-C000002
     Or Z, provided that
    When A 1 is the formula (A), A 2 represents Z,
    When A 1 is Z, A 2 represents formula (A);
    Q 1 and Q 2 are each independently a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1 -5 alkylcarbonyl; optionally substituted C 1-5 alkoxycarbonyl; carboxyl; optionally substituted aryl; optionally substituted heteroaryl; or -CONR 5 R 6
    Alk represents an optionally substituted C 1-5 alkylene;
    Z is a hydrogen atom; an optionally substituted C 1-10 alkyl; an optionally substituted C 3-8 cycloalkyl; a cyano; an optionally substituted C 1-5 alkylcarbonyl; Optionally substituted C 1-5 alkoxycarbonyl; optionally substituted aryl; optionally substituted heteroaryl; halogen; optionally substituted C 1-5 alkoxy; —NR 5 R 6 ; or —CONR 5 R 6 represents
    X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 7 CONR 8 - X 2- , -X 1 -NR 7 -X 2 -or -X 1 -O-X 2-
    X 1 represents an optionally substituted C 1-8 alkylene, wherein X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X When 1 —NR 7 —X 2 — or —X 1 —O—X 2 —, X 1 is an optionally substituted C 2-8 alkylene;
    X 2 represents an optionally substituted C 1-8 alkylene, wherein X is —X 1 —CONR 7 —X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X When 1 —NR 7 —X 2 — or —X 1 —O—X 2 —, X 2 is an optionally substituted C 2-8 alkylene;
    W represents —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
    W 1 represents an optionally substituted C 1-8 alkylene, and when W is —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, W 1 Is an optionally substituted C 2-8 alkylene;
    Y represents an optionally substituted arylene or an optionally substituted heteroarylene;
    R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, an optionally substituted C 1-10 alkyl, an optionally substituted C 3-8 cycloalkyl or a substituted Represents a 4-10 membered saturated heterocycle,
    R 5 , R 6 , R 7 , R 8 and R 9 each independently represents a hydrogen atom or an optionally substituted C 1-10 alkyl;
    R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1, and each combination of R 5 and R 6 may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring by combining the carbon atoms of the respective groups (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring)]
    Or a pharmaceutically acceptable salt thereof.
  2. 　＜ｉ＞請求項１における置換されていてもよいアルキル、置換されていてもよいアルコキシおよび置換されていてもよいアルコキシカルボニル－のそれぞれの基のアルキル部分が、それぞれ独立して、
    　（１）ハロゲン原子、
    　（２）水酸基、
    　（３）シアノ、
    　（４）カルボキシル、
    　（５）置換されていてもよいＣ３－８シクロアルキル、
    　（６）置換されていてもよいアリール、
    　（７）置換されていてもよいヘテロアリール、
    　（８）置換されていてもよいＣ１－５アルコキシ、
    　（９）置換されていてもよいＣ３－８シクロアルコキシ、
    　（１０）置換されていてもよいＣ１－５アルコキシカルボニル－、
    　（１１）置換されていてもよいＣ１－５アルキルカルボニル－、
    　（１２）置換されていてもよい４～１０員の飽和複素環、
    　（１３）－ＮＲ１０Ｒ１１、
    　（１４）－ＣＯＮＲ１０Ｒ１１
    　（１５）－Ｎ（Ｒ１０）ＣＯＲ１１
    　（１６）－ＳＯ２Ｒ１０、および
    　（１７）－ＳＯ２ＮＲ１０Ｒ１１
    からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよく、
    　置換されていてもよいアルキレンが、前記（１）～（１７）、および
    　（１８）水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル
    からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよく
    （ここにおいて、前記（６）および（７）における置換基は、
    　（ａ）水酸基、
    　（ｂ）ハロゲン、
    　（ｃ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－１０アルキル、
    　（ｄ）１～５個のフッ素原子、水酸基またはＣ１－５アルコキシで置換されていてもよいＣ１－５アルコキシ、
    　（ｅ）シアノ、
    　（ｆ）カルボキシル、
    　（ｇ）Ｃ１－５アルコキシカルボニル－、
    　（ｈ）Ｃ１－５アルキルカルボニル－、
    　（ｉ）－ＮＲ１０Ｒ１１、
    　（ｊ）－ＣＯＮＲ１０Ｒ１１
    　（ｋ）－ＳＯ２Ｒ１０、および
    　（ｌ）－ＳＯ２ＮＲ１０Ｒ１１
    からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味し、
    　前記（５）、（８）、（９）、（１０）、（１１）および（１２）に示す基は、前記（ａ）～（ｄ）、（ｇ）～（ｊ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基を意味する）；
    　＜ｉｉ＞請求項１における置換されていてもよいシクロアルキルおよび置換されていてもよい飽和複素環が、それぞれ独立して、前記（ａ）～（ｄ）、（ｇ）～（ｊ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基であり；
    　＜ｉｉｉ＞請求項１における置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいアリーレンおよび置換されていてもよいヘテロアリーレンが、それぞれ独立して、前記（ａ）～（ｌ）からなる群から選択される同一または異なる１～５個の置換基で置換されていてもよい基であり；
    　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよい、
    請求項１に記載の化合物またはその製薬学的に許容される塩。     <I> The alkyl part of each group of the optionally substituted alkyl, the optionally substituted alkoxy and the optionally substituted alkoxycarbonyl- in claim 1 is independently
    (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) optionally substituted C 1-5 alkoxy,
    (9) optionally substituted C 3-8 cycloalkoxy,
    (10) optionally substituted C 1-5 alkoxycarbonyl-,
    (11) optionally substituted C 1-5 alkylcarbonyl-,
    (12) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
    (13) -NR 10 R 11 ,
    (14) -CONR 10 R 11
    (15) -N (R 10 ) COR 11
    (16) -SO 2 R 10 , and (17) -SO 2 NR 10 R 11
    May be substituted with the same or different 1 to 5 substituents selected from the group consisting of
    The optionally substituted alkylene is selected from the group consisting of the above (1) to (17), and (18) hydroxyl group, fluorine atom, C 1-5 alkoxy (this group is C 1-5 alkoxy and fluorine atom). Substituted with the same or different 1 to 3 substituents selected from the group consisting of 4 to 10-membered nitrogen-containing saturated heterocycle Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of optionally substituted C 1-10 alkyl (wherein the substituents in the above (6) and (7) are ,
    (A) a hydroxyl group,
    (B) halogen,
    (C) C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
    (D) C 1-5 alkoxy optionally substituted with 1 to 5 fluorine atoms, hydroxyl group or C 1-5 alkoxy,
    (E) cyano,
    (F) carboxyl,
    (G) C 1-5 alkoxycarbonyl-,
    (H) C 1-5 alkylcarbonyl-,
    (I) -NR 10 R 11 ,
    (J) -CONR 10 R 11
    (K) —SO 2 R 10 , and (l) —SO 2 NR 10 R 11
    Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of
    The groups shown in (5), (8), (9), (10), (11) and (12) are selected from the group consisting of the above (a) to (d) and (g) to (j) Meaning a group which may be substituted with the same or different 1 to 5 substituents)
    <Ii> The optionally substituted cycloalkyl and the optionally substituted saturated heterocycle in claim 1 are each independently composed of (a) to (d) and (g) to (j). A group optionally substituted by 1 to 5 identical or different substituents selected from the group;
    <Iii> The aryl which may be substituted, the heteroaryl which may be substituted, the arylene which may be substituted and the heteroarylene which may be substituted in claim 1 are each independently selected from the group (a ) To (l) are groups that may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
    R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. 　Ａ１が式（Ａ）のとき、Ａ２はＺであり、
    　Ａ１がＺのとき、Ａ２は式（Ａ）であり、
    　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールもしくはヘテロアリール；または－ＣＯＮＲ５Ｒ６であり、
    　Ａｌｋが、水酸基；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールおよびヘテロアリール；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ１０Ｒ１１；並びに－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキレンであり、
    　Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該アルキルおよび該アルコキシは、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；ハロゲン、Ｃ１－５アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいアリールもしくはヘテロアリール；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６であり、
    　Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
    　Ｘ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－、カルボキシルおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｘ２が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－であり、
    　Ｗ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｙが、同一または異なる１～３個の置換基で置換されていてもよいフェニレンまたは１～２個の窒素原子を含む単環もしくは縮環のヘテロアリーレンであり、当該置換基がハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択され、
    　Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－、Ｃ１－５アルキルカルボニル－、アリール、－ＳＯ２ＮＲ１０Ｒ１１、－ＮＲ１０Ｒ１１、１～３個のＣ１－１０アルキルで置換されていてもよいヘテロアリールおよび－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルもしくはＣ３－８シクロアルキル；－ＮＲ１０ＣＯＲ１１；または水酸基、フッ素原子、Ｃ１－６アルキル、Ｃ１－５アルコキシカルボニル－およびＣ１－５アルキルカルボニル－からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
    　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
    　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
    　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせが、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
    請求項１または２に記載の化合物またはその製薬学的に許容される塩。     When A 1 is formula (A), A 2 is Z;
    When A 1 is Z, A 2 is the formula (A),
    Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; Hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) C 3-8 cycloalkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of (optionally substituted with 1 substituent); cyano; hydroxyl group, C 1- C 1-5 alkylcarbonyl- or C 1-5 alkoxycarbonyl-, which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 5 alkoxy and fluorine atoms; carboxyl; halogen, C 1 to 3 substituents selected from the group consisting of 1-6 alkyl and C 1-5 alkoxy (wherein the alkyl portion may be substituted with 1 to 3 fluorine atoms) Aryl or heteroaryl optionally substituted by: or —CONR 5 R 6 ,
    Alk is a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) And a C 1-10 alkyl which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 4- to 10-membered nitrogen-containing saturated heterocycles; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) ) identical or different one to three optionally substituted with a substituent C 3-8 cycloalkyl is selected from the group consisting of cyano, hydroxyl, C 1-5 alkoxy and fluorine atom The same or different one to three optionally substituted with a substituent C 1-5 alkylcarbonyl is selected from the group consisting of - and C 1-5 alkoxycarbonyl -; carboxyl; halogen, C 1-6 alkyl and Substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy (the alkyl portion of the group may be optionally substituted with 1 to 3 fluorine atoms) Optionally aryl and heteroaryl; halogen; C 1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; and —NR 10 R 11 ; the same or different 1-3 substituents optionally C 1-5 alkylene optionally substituted with a group selected from the group consisting of -CONR 10 R 11 Ri,
    Z is a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) may be), C 1-5 alkoxycarbonyl - and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring to 10-membered or different one to three optionally substituted with a substituent C 1- 10 alkyl; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (wherein the alkyl and the alkoxy are the same or different 1 to 3 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) the same or different one to three which may be C 3-8 cycloalkyl substituted with a substituent selected from the group consisting of may also be) substituted with a substituent; cyano; Group, C 1-5 alkoxy and the same or different one to three are C 1-5 optionally alkylcarbonyl substituted with a substituent selected from the group consisting of fluorine atom - or C 1-5 alkoxycarbonyl - Identical or different 1 to 3 selected from the group consisting of halogen, C 1-5 alkyl and C 1-5 alkoxy (wherein the alkyl portion may be substituted with 1 to 3 fluorine atoms); Aryl or heteroaryl optionally substituted by 1 substituent; halogen; C 1-5 optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of a hydroxyl group and a fluorine atom Alkoxy; —NR 5 R 6 ; or —CONR 5 R 6 ,
    X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -CO-X 2 -, - X 1 -NR 7 CONR 8 - X 2 —, —X 1 —NR 7 —X 2 — or —X 1 —O—X 2 —,
    X 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group is the same or different 1 selected from the group consisting of hydroxyl group, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, carboxyl and fluorine atom) C 1-8 alkylene optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of (optionally substituted with ˜3 substituents), wherein X X is —X 1 —NR 7 CO—X 2 —, —X 1 —NR 7 CONR 8 —X 2 —, —X 1 —NR 7 —X 2 —, or —X 1 —O—X 2 — 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom; Good) It is the same or different one to three good C 2-8 alkylene optionally substituted with a substituent selected from the group consisting of,
    X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl;
    W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
    W 1 is a hydroxyl group, a fluorine atom and a C 1-6 alkyl (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a hydroxyl group, a C 1-5 alkoxy and a fluorine atom. C 1-8 alkylene optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of: and wherein W is —NR 9 —W 1 —, — In the case of CONR 9 —W 1 — or —O—W 1 —, W 1 is a hydroxyl group, a fluorine atom and C 1-6 alkyl (the group is selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom) C 2-8 alkylene optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of (optionally substituted with the same or different 1 to 3 substituents),
    Y is phenylene which may be substituted with the same or different 1 to 3 substituents, or monocyclic or condensed heteroarylene containing 1 to 2 nitrogen atoms, and the substituent is halogen, Selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms;
    R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl-, C 1-5 alkylcarbonyl-, aryl, -SO 2 NR 10 R 11 , -NR 10 R 11 , heteroaryl optionally substituted with 1 to 3 C 1-10 alkyls, and the same or different 1 selected from the group consisting of -CONR 10 R 11 C 1-10 alkyl or C 3-8 cycloalkyl optionally substituted with 3 substituents; —NR 10 COR 11 ; or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 alkoxycarbonyl - and C 1-5 alkylcarbonyl - same is selected from the group consisting of or different one to three 4 may be substituted with a substituent ~ 1 It is a member of the saturated heterocyclic ring,
    R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of fluorine, hydroxyl and C 1-5 alkoxy C 1-10 alkyl optionally substituted with
    R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
    R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring),
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. 　Ａ１が式（Ａ）のとき、Ａ２はＺであり、
    　Ａ１がＺのとき、Ａ２は式（Ａ）であり、
    　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－もしくはＣ１－５アルコキシカルボニル－；または－ＣＯＮＲ５Ｒ６であり、
    　Ａｌｋが、水酸基；水酸基、フッ素原子、Ｃ１－５アルコキシおよび４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキルカルボニル－およびＣ１－５アルコキシカルボニル－；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ１０Ｒ１１；並びに－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルキレンであり、
    　Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－５アルキルおよびＣ１－５アルコキシ（該アルキルおよび該アルコキシは、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６であり、
    　Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
    　Ｘ１が、水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｘが－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＮＲ７ＣＯＮＲ８－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－のとき、Ｘ１は水酸基、フッ素原子およびＣ１－６アルキル（該基は、水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｘ２が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－であり、
    　Ｗ１が、水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－８アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－、－ＣＯＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１は水酸基、フッ素原子およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ２－８アルキレンであり、
    　Ｙが、同一または異なる１～３個の置換基で置換されていてもよいフェニレンまたは１～２個の窒素原子を含む単環もしくは縮環のヘテロアリーレンであり、当該置換基がハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択され、
    　Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキルもしくはＣ３－８シクロアルキル；または水酸基、フッ素原子、Ｃ１－６アルキル、Ｃ１－５アルコキシカルボニル－およびＣ１－５アルキルカルボニル－からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
    　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
    　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
    　Ｒ１とＲ２、Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７、Ｒ７とＸ２、Ｒ３とＲ４、Ｒ３とＷ１、Ｒ３とＲ９、Ｒ９とＷ１およびＲ５とＲ６の各組み合わせが、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい（ただし、形成される含窒素飽和複素環の数は、－Ｘ－ＮＲ１Ｒ２および式（Ａ）において、それぞれ独立して０～２個である。また、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
    請求項１～３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     When A 1 is formula (A), A 2 is Z;
    When A 1 is Z, A 2 is the formula (A),
    Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) Optionally substituted with 3 substituents), C 1-5 alkoxycarbonyl-, which is the same or different 1 to 3 substituents selected from the group consisting of C 1-5 alkoxy and fluorine atoms the same or different one to three is C 1-10 optionally substituted with substituents selected from the group consisting of nitrogen-containing saturated heterocyclic ring which may be optionally) and 4-10 membered optionally substituted with a group; C 1-5 alkylcarbonyl- or C 1-5 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl group, C 1-5 alkoxy and fluorine atom Alkoxycarbonyl-; or -CONR 5 R 6 ,
    Alk may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group; a hydroxyl group, a fluorine atom, C 1-5 alkoxy and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. C 1-10 alkyl; C 1-5 alkylcarbonyl- and C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and a fluorine atom -5 alkoxycarbonyl-; halogen; C 1-5 alkoxy optionally substituted by the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and a fluorine atom; -NR 10 R 11 ; C 1-5 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of CONR 10 R 11 ;
    Z is a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) may be), C 1-5 alkoxycarbonyl - and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring to 10-membered or different one to three optionally substituted with a substituent C 1- 10 alkyl; hydroxyl group, fluorine atom, C 1-5 alkyl and C 1-5 alkoxy (wherein the alkyl and alkoxy are the same or different 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) the same or different one to three which may be C 3-8 cycloalkyl substituted with a substituent selected from the group consisting of may also be) substituted with a substituent; cyano; Androgenic; hydroxyl groups and the same is selected from the group consisting of fluorine atom, or a different one to three optionally substituted with a substituent C 1-5 alkoxy; -NR 5 R 6; or -CONR 5 be R 6 ,
    X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -NR 7 CONR 8 -X 2 -, - X 1 -NR 7 —X 2 — or —X 1 —O—X 2 —,
    X 1 is a hydroxyl group, a fluorine atom and a C 1-6 alkyl (the group is substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a hydroxyl group, a C 1-5 alkoxy and a fluorine atom. C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of: and wherein X is —X 1 —NR 7 CO—X In the case of 2- , -X 1 -NR 7 CONR 8 -X 2- , -X 1 -NR 7 -X 2 -or -X 1 -O-X 2- , X 1 represents a hydroxyl group, a fluorine atom and C 1- The same selected from the group consisting of 6 alkyls (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of hydroxyl, C 1-5 alkoxy and fluorine atoms) Or 1 to 3 different C 2-8 alkylene optionally substituted with a substituent,
    X 2 is C 2-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl;
    W is —W 1 —, —NR 9 —W 1 —, —NR 9 CO—W 1 —, —CONR 9 —W 1 — or —O—W 1 —,
    W 1 is C 1-8 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl, wherein W 1 Is —NR 9 —W 1 —, —CONR 9 —W 1 — or —O—W 1 —, W 1 is the same or different selected from the group consisting of a hydroxyl group, a fluorine atom and C 1-6 alkyl C 2-8 alkylene optionally substituted with 3 substituents,
    Y is phenylene which may be substituted with the same or different 1 to 3 substituents, or monocyclic or condensed heteroarylene containing 1 to 2 nitrogen atoms, and the substituent is halogen, Selected from the group consisting of C 1-6 alkyl optionally substituted with 3 fluorine atoms and C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms;
    R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl- and —CONR 10 R 11 C 1-10 alkyl or C 3-8 cycloalkyl which may be substituted with the same or different 1 to 3 substituents as described above; or hydroxyl group, fluorine atom, C 1-6 alkyl, C 1-5 alkoxycarbonyl A 4- to 10-membered saturated heterocyclic ring which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of-and C 1-5 alkylcarbonyl-;
    R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of fluorine, hydroxyl and C 1-5 alkoxy C 1-10 alkyl optionally substituted with
    R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
    R 1 and R 2 , R 1 and X 1 , R 1 and X 2 , R 1 and R 7 , R 7 and X 2 , R 3 and R 4 , R 3 and W 1 , R 3 and R 9 , R 9 And W 1 and each combination of R 5 and R 6 may be bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (however, the nitrogen-containing formed) The number of saturated heterocycles is independently 0 to 2 in —X—NR 1 R 2 and formula (A), and a nitrogen-containing saturated heterocycle formed by a combination of R 5 and R 6 As a morpholine ring),
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  5. 　Ｑ１およびＱ２が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；シアノ；水酸基、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシカルボニル－；カルボキシル；ハロゲン、Ｃ１－６アルキルおよびＣ１－５アルコキシ（該基のアルキル部分は、１～３個のフッ素原子で置換されていてもよい）からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいフェニルおよび５または６員の含窒素ヘテロアリール；または－ＣＯＮＲ５Ｒ６である、
    請求項１～３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Q 1 and Q 2 are each independently a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is the same or different from 1 to 5 selected from the group consisting of C 1-5 alkoxy and a fluorine atom) 3 may be substituted with a substituent) and 4-10 membered nitrogen-containing saturated same or different 1 to 3 of which may be substituted with a substituent C 1 is selected from the group consisting of heterocyclic -10 alkyl; hydroxyl group, fluorine atom, C 1-6 alkyl and C 1-5 alkoxy (the alkyl part of the group is the same or different from 1 to 3 selected from the group consisting of C 1-5 alkoxy and fluorine atom) the same or different one to three optionally substituted with a substituent C 3-8 cycloalkyl is selected from the group consisting of may also be) substituted with a substituent, cyano, hydroxyl, C 1 C 1-5 alkoxycarbonyl- which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of -5 alkoxy and fluorine atoms; carboxyl; halogen, C 1-6 alkyl and C 1 -5 alkoxy (the alkyl part of the group may be substituted with 1 to 3 fluorine atoms) may be substituted with the same or different 1 to 3 substituents selected from the group consisting of Phenyl and 5- or 6-membered nitrogen-containing heteroaryl; or -CONR 5 R 6
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  6. 　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－または－Ｏ－Ｗ１－であり、
    　Ｒ３とＲ９、Ｒ３とＷ１およびＲ９とＷ１の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい、
    請求項１～５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     W is -W 1- , -NR 9 -W 1- , -NR 9 CO-W 1 -or -O-W 1- ;
    Any one of the combinations of R 3 and R 9 , R 3 and W 1 and R 9 and W 1 is bonded to the carbon atom of each group to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. May be,
    The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
  7. 　Ｑ１およびＱ２が、それぞれ独立して、水素原子；または、水酸基、フッ素原子、Ｃ１－５アルコキシ、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルである、
    請求項１～６のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Q 1 and Q 2 are each independently a hydrogen atom; or a group consisting of a hydroxyl group, a fluorine atom, C 1-5 alkoxy, C 1-5 alkoxycarbonyl- and a 4- to 10-membered nitrogen-containing saturated heterocyclic ring C 1-6 alkyl optionally substituted with 1 to 3 identical or different selected substituents,
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  8. 　Ｚが、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシ（該基は、Ｃ１－５アルコキシおよびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい）、Ｃ１－５アルコキシカルボニル－および４～１０員の含窒素飽和複素環からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－１０アルキル；水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ３－８シクロアルキル；ハロゲン；水酸基およびフッ素原子からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－５アルコキシ；－ＮＲ５Ｒ６；または－ＣＯＮＲ５Ｒ６である、
    請求項１～７のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Z is a hydrogen atom; a hydroxyl group, a fluorine atom, a C 1-5 alkoxy (the group is substituted with 1 to 3 identical or different substituents selected from the group consisting of C 1-5 alkoxy and a fluorine atom) may be), C 1-5 alkoxycarbonyl - and 4 the same is selected from the group consisting of nitrogen-containing saturated heterocyclic ring to 10-membered or different one to three optionally substituted with a substituent C 1- 10 alkyl; C 3-8 cycloalkyl optionally 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 C 1-5 alkoxy; halogen; hydroxyl groups and the same is selected from the group consisting of fluorine atom, or a different one to three optionally substituted with a substituent C 1-5 alkoxy; -NR 5 R 6; or -C Is an NR 5 R 6,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
  9. 　Ｒ１、Ｒ２、Ｒ３およびＲ４が、それぞれ独立して、水素原子；水酸基、フッ素原子、Ｃ１－５アルコキシおよび－ＣＯＮＲ１０Ｒ１１からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルもしくはＣ３－８シクロアルキル；または水酸基、フッ素原子、およびＣ１－６アルキルからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよい４～１０員の飽和複素環であり、
    　Ｒ１０およびＲ１１が、それぞれ独立して、水素原子または１～５個のフッ素原子で置換されていてもよいＣ１－１０アルキルであるか、あるいは、Ｒ１０とＲ１１は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
    　Ｒ１とＲ２およびＲ３とＲ４の各組み合わせが、それぞれの基の炭素原子が結合して、４～７員の含窒素飽和複素環を形成していてもよい、
    請求項１～８のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     R 1 , R 2 , R 3 and R 4 are each independently the same or different 1 to 3 selected from the group consisting of a hydrogen atom; a hydroxyl group, a fluorine atom, C 1-5 alkoxy and —CONR 10 R 11 C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted with 1 substituent, or the same or different 1 to 3 selected from the group consisting of a hydroxyl group, a fluorine atom, and C 1-6 alkyl A 4- to 10-membered saturated heterocyclic ring which may be substituted with
    R 10 and R 11 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorine atoms, or R 10 and R 11 are taken together. A 4- to 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
    Each combination of R 1 and R 2 and R 3 and R 4 may be bonded to the carbon atom of each group to form a 4- to 7-membered nitrogen-containing saturated heterocyclic ring,
    The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　Ｒ５、Ｒ６、Ｒ７、Ｒ８およびＲ９が、それぞれ独立して、水素原子；またはフッ素、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３の置換基で置換されていてもよいＣ１－１０アルキルであり、
    　Ｒ５とＲ６の組み合わせが、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい（ただし、Ｒ５とＲ６の組み合わせで形成される含窒素飽和複素環としてモルホリン環は除く）、
    請求項１～９のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of fluorine, hydroxyl and C 1-5 alkoxy C 1-10 alkyl optionally substituted with
    A combination of R 5 and R 6 may form a 4- to 8-membered nitrogen-containing saturated heterocycle by combining the carbon atoms of the respective groups (provided that the combination of R 5 and R 6 is formed). A morpholine ring as a nitrogen-containing saturated heterocyclic ring),
    The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
  11. 　式（Ａ）が、下記式（Ａ’）、（Ａ’’）または（Ａ’’’）
    Figure JPOXMLDOC01-appb-C000003
     で表される基であり、
    　Ｙ１が、＝（－）Ｃ－Ｚ４または窒素原子であり、
    　Ｚ１、Ｚ２、Ｚ３およびＺ４が、それぞれ独立して、水素原子、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキル、または１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシである、
    請求項１～１０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Formula (A) is represented by the following formula (A ′), (A ″) or (A ′ ″)
    Figure JPOXMLDOC01-appb-C000003
     A group represented by
    Y 1 is = (−) CZ 4 or a nitrogen atom,
    Z 1 , Z 2 , Z 3 and Z 4 are each independently a hydrogen atom, halogen, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms, or 1 to 3 fluorines C 1-5 alkoxy optionally substituted with atoms,
    The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 　式（Ａ）が、下記式
    Figure JPOXMLDOC01-appb-C000004
     で表される基であり、Ｚ１、Ｚ２、Ｚ４およびＺ５が、それぞれ独立して、水素原子、ハロゲン、１～３個のフッ素原子で置換されていてもよいＣ１－６アルキルおよび１～３個のフッ素原子で置換されていてもよいＣ１－５アルコキシからなる群から選択される同一または異なる置換基であり、Ｈｅｔが、５～６員の含窒素部分飽和複素環または５～６員の含窒素不飽和複素環である、
    請求項１～１０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Formula (A) is
    Figure JPOXMLDOC01-appb-C000004
     A group represented by the formula: wherein Z 1 , Z 2 , Z 4 and Z 5 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl optionally substituted by 1 to 3 fluorine atoms And the same or different substituents selected from the group consisting of C 1-5 alkoxy optionally substituted with 1 to 3 fluorine atoms, wherein Het is a 5- to 6-membered nitrogen-containing partially saturated heterocyclic ring or A 5- to 6-membered nitrogen-containing unsaturated heterocycle,
    The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  13. 　Ａｌｋが、水酸基、フッ素原子、Ｃ１－６アルキルおよびＣ１－５アルコキシからなる群から選択される同一または異なる１～２個の置換基で置換されていてもよいＣ１－３アルキレンである、
    請求項１～１２のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Alk is C 1-3 alkylene which may be substituted with one or two same or different substituents selected from the group consisting of a hydroxyl group, a fluorine atom, C 1-6 alkyl and C 1-5 alkoxy ,
    The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  14. 　Ｑ１およびＱ２が、それぞれ水素原子である、
    請求項１～１３のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Q 1 and Q 2 are each a hydrogen atom,
    The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.
  15. 　Ｘが、－Ｘ１－、－Ｘ１－ＮＲ７ＣＯ－Ｘ２－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、－Ｘ１－ＮＲ７－Ｘ２－または－Ｘ１－Ｏ－Ｘ２－であり、
    　Ｒ１とＸ１、Ｒ１とＸ２、Ｒ１とＲ７およびＲ７とＸ２の各組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～１０員の含窒素飽和複素環を形成していてもよい、
    請求項１～１４のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     X is, -X 1 -, - X 1 -NR 7 CO-X 2 -, - X 1 -CONR 7 -X 2 -, - X 1 -NR 7 -X 2 - or -X 1 -O-X 2 -And
    Any one of the combinations of R 1 and X 1 , R 1 and X 2 , R 1 and R 7 and R 7 and X 2 is bonded to the carbon atom of each group to contain a 4- to 10-membered group. A nitrogen-saturated heterocyclic ring may be formed,
    The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.
  16. 　Ｘ１が、Ｃ１－４アルキレンであり、Ｘ２が、Ｃ２－４アルキレンである、
    請求項１～１５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     X 1 is C 1-4 alkylene, and X 2 is C 2-4 alkylene.
    The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
  17. 　Ａ１がＺであり、Ａ２が式（Ａ）である、
    請求項１～１６のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     A 1 is Z and A 2 is the formula (A).
    The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
  18. 　Ｘが、－Ｘ１－、－Ｘ１－ＣＯＮＲ７－Ｘ２－、または－Ｘ１－Ｏ－Ｘ２－であり、
    　Ｒ１およびＲ２が、それぞれ独立して、水素原子；または、水酸基、Ｃ１－５アルコキシおよび－ＣＯＮＨ２からなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルであり、
    　Ｒ１とＸ１、Ｒ１とＲ２およびＲ１とＲ７の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい、
    請求項１～１７のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     X is, -X 1 -, - X 1 -CONR 7 -X 2 -, or -X 1 -O-X 2 - is and,
    R 1 and R 2 are each independently substituted with a hydrogen atom; or 1-3 identical or different substituents selected from the group consisting of a hydroxyl group, C 1-5 alkoxy and —CONH 2 Is a good C 1-6 alkyl,
    Any one combination of R 1 and X 1 , R 1 and R 2 and R 1 and R 7 is bonded to the carbon atom of each group to form a 4- to 8-membered nitrogen-containing saturated heterocyclic ring. May be,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.
  19. 　Ｙが、同一または異なる１～２個の置換基で置換されていてもよいフェニレン、ピリジレンまたはチアゾリレンであり、当該置換基が、ハロゲンおよびＣ１－６アルキルからなる群から選択され、
    　Ｗが、－Ｗ１－、－ＮＲ９－Ｗ１－、－ＮＲ９ＣＯ－Ｗ１－または－Ｏ－Ｗ１－であり、
    　Ｗ１が、１個の水酸基で置換されていてもよいＣ１－４アルキレンであり、ここにおいて、Ｗが－ＮＲ９－Ｗ１－または－Ｏ－Ｗ１－のときＷ１はＣ２－４アルキレンであり、
    　Ｒ３およびＲ４が、それぞれ独立して、水素原子；または、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルであり、
    　Ｒ３とＲ９、Ｒ３とＷ１、Ｒ９とＷ１およびＲ３とＲ４の組み合わせのいずれか１組が、それぞれの基の炭素原子が結合して、４～８員の含窒素飽和複素環を形成していてもよい、
    請求項１～１１または１３～１８のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Y is phenylene, pyridylene, or thiazolylene optionally substituted with the same or different 1 to 2 substituents, and the substituents are selected from the group consisting of halogen and C 1-6 alkyl;
    W is -W 1- , -NR 9 -W 1- , -NR 9 CO-W 1 -or -O-W 1- ;
    W 1 is C 1-4 alkylene which may be substituted with one hydroxyl group, and here, when W is —NR 9 —W 1 — or —O—W 1 —, W 1 is C 2- 4 alkylene,
    R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl,
    Any one of the combinations of R 3 and R 9 , R 3 and W 1 , R 9 and W 1, and R 3 and R 4 is bonded to the carbon atom of each group to form a 4- to 8-membered nitrogen-containing May form a saturated heterocyclic ring,
    The compound according to any one of claims 1 to 11 or 13 to 18, or a pharmaceutically acceptable salt thereof.
  20. 　Ｚが、水素原子、Ｃ１－６アルキル、ハロゲン、Ｃ１－３アルコキシまたは－ＮＲ５Ｒ６であり、
    　Ｒ５およびＲ６が、それぞれ独立して、水素原子またはＣ１－６アルキルである、
    請求項１～１９のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Z is a hydrogen atom, C 1-6 alkyl, halogen, C 1-3 alkoxy or —NR 5 R 6 ;
    R 5 and R 6 are each independently a hydrogen atom or C 1-6 alkyl.
    The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.
  21. 　Ｚが、水素原子またはＣ１－３アルキルである、
    請求項１～２０のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Z is a hydrogen atom or C 1-3 alkyl,
    The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.
  22. 　Ａｌｋが、Ｃ１－３アルキレンである、
    請求項１～２１のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Alk is C 1-3 alkylene,
    The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.
  23. 　Ｙが、フェニレンまたはピリジレンであり、
    　式（Ａ）の－Ｗ－ＮＲ３Ｒ４が、
    Figure JPOXMLDOC01-appb-C000005
     で表される基であり、
    　Ｒ３およびＲ４が、それぞれ独立して、水素原子；または、水酸基およびＣ１－５アルコキシからなる群から選択される同一または異なる１～３個の置換基で置換されていてもよいＣ１－６アルキルである、
    請求項１～１１または１３～２２のいずれか一項に記載の化合物またはその製薬学的に許容される塩。     Y is phenylene or pyridylene;
    —W—NR 3 R 4 in formula (A) is
    Figure JPOXMLDOC01-appb-C000005
     A group represented by
    R 3 and R 4 are each independently a hydrogen atom; or C 1 which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a hydroxyl group and C 1-5 alkoxy -6 alkyl,
    The compound according to any one of claims 1 to 11 or 13 to 22, or a pharmaceutically acceptable salt thereof.
  24. 　式（Ｉ）で表される化合物が、
    ２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４１）
    ２－［４－（４－エチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４５）
    ２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４６）
    ２－［３－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４８）
    ４－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例６２）
    ４－（３－｛２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例６４）
    ４－（２－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エチル）モルホリン　（実施例６９）
    Ｎ，Ｎ－ジエチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例７０）
    Ｎ－（２－メトキシエチル）－Ｎ－メチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例７２）
    ２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例７７）
    ４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例７８）
    ４－（３－｛４－エチル－２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン （実施例７９）
    ４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８３）
    ４－（２－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エチル）モルホリン　（実施例８４）
    ４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８６）
    ４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８７）
    ４－（３－｛４－エチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９１）
    Ｎ，Ｎ－ジメチル－１－｛４－［４－メチル－７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペリジン－４－アミン　（実施例９５）
    ２－［４－（１－メチルピペリジン－４－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例１０９）
    （R）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－３－アミン　（実施例１１０）
    （S）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－３－アミン　（実施例１１１）
    Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－４－アミン　（実施例１１２）
    ４－［３－（２－｛４－［４－（２－メトキシエチル）ピペラジン－１－イル］フェニル｝－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル）プロピル］モルホリン　（実施例１１４）
    Ｎ，Ｎ－ジメチル－１－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペリジン－４－アミン　（実施例１１７）、
    ２－（４－｛４－［７－（３－モルホリノプロピル）－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル］フェニル｝ピペラジン－１－イル）エタノール　（実施例１１９）、
    からなる群から選択される請求項１記載の化合物又はそれらの製薬学的に許容される塩。     The compound represented by formula (I) is:
    2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 41)
    2- [4- (4-Ethylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 45)
    2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 46)
    2- [3- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 48)
    4- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 62) )
    4- (3- {2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 64) )
    4- (2- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethyl) morpholine (Example 69) )
    N, N-diethyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propane-1- Amine (Example 70)
    N- (2-methoxyethyl) -N-methyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il} propan-1-amine (Example 72)
    2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine (Example 77)
    4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 78)
    4- (3- {4-Ethyl-2- [4- (4-ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 79)
    4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 83)
    4- (2- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} ethyl) morpholine (Example 84)
    4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 86)
    4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 87)
    4- (3- {4-Ethyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 91)
    N, N-dimethyl-1- {4- [4-methyl-7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperidine -4-amine (Example 95)
    2- [4- (1-Methylpiperidin-4-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 109)
    (R) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) piperidin-3-amine (Example 110)
    (S) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) piperidin-3-amine (Example 111)
    N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl ) Piperidin-4-amine (Example 112)
    4- [3- (2- {4- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl) propyl] Morpholine (Example 114)
    N, N-dimethyl-1- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperidin-4-amine (Example 117),
    2- (4- {4- [7- (3-morpholinopropyl) -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl] phenyl} piperazin-1-yl) ethanol ( Example 119),
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  25. 　式（Ｉ）で表される化合物が、
    Ｎ，Ｎ－ジメチル－３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例３９）
    ２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４０）
    ４－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例４２）
    （Ｒ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピロリジン－３－アミン　（実施例４９）
    （Ｓ）－Ｎ，Ｎ－ジメチル－１－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピロリジン－３－アミン　（実施例５０）
    １－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペリジン－４－アミン　（実施例５４）
    ４－（４－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝ブチル）モルホリン　（実施例６３）
    ２－［４－（４－メチルピペラジン－１－イル）フェニル］－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン　（実施例６６）
    ２－［６－（４－メチルピペラジン－１－イル）ピリジン－３－イル］－８－［３－（ピロリジン－１－イル）プロピル］－５，６，７，８－テトラヒドロピリド［２，３－ｄ］ピリミジン　（実施例６７）
    ２－［メチル（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）アミノ］アセトアミド　（実施例７３）
    １－（４－メチルピペラジン－１－イル）－２－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝エタノン　（実施例７４）
    ４－（３－｛２－［４－（４－エチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例７６）
    Ｎ，Ｎ－ジメチル－３－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロパン－１－アミン　（実施例８１）
    ４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－［２－（ピロリジン－１－イル）エチル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８２）
    ２－［４－（４－メチルピペラジン－１－イル）フェニル］－４－プロピル－７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例８８）
    ４－（３－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９０）
    ４－（３－｛２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－４－メチル－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９２）
    ４－（３－｛４－エチル－２－［４－（４－イソプロピルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝プロピル）モルホリン　（実施例９３）
    ４－（４－｛４－メチル－２－［４－（４－メチルピペラジン－１－イル）フェニル］－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－７（６Ｈ）－イル｝ブチル）モルホリン　（実施例９４）
    ２－［４－（４－｛７－［３－（ピロリジン－１－イル）プロピル］－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン－２－イル｝フェニル）ピペラジン－１－イル］エタノール　（実施例１２５）、
    ２－［４－（４－メチルピペラジン－１－イル）フェニル］－７－｛２－［２－（ピロリジン－１－イル）エトキシ］エチル｝－６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｄ］ピリミジン　（実施例１２７）、および
    ４－（３－｛２－［４－（４－メチルピペラジン－１－イル）フェニル］－６，７－ジヒドロピリド［２，３－ｄ］ピリミジン－８（５Ｈ）－イル｝プロピル）モルホリン　（実施例１３０）
    からなる群から選択される請求項１記載の化合物又はそれらの製薬学的に許容される塩。     The compound represented by formula (I) is:
    N, N-dimethyl-3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propane-1- Amine (Example 39)
    2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 40)
    4- [4- (4-Methylpiperazin-1-yl) phenyl] -7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine (Example 42)
    (R) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Yl} phenyl) pyrrolidin-3-amine (Example 49)
    (S) -N, N-dimethyl-1- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-2 -Il} phenyl) pyrrolidin-3-amine (Example 50)
    1- (4- {7- [3- (Pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl) piperidin-4-amine (Example 54)
    4- (4- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} butyl) morpholine (Example 63) )
    2- [4- (4-Methylpiperazin-1-yl) phenyl] -8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2,3-d Pyrimidine (Example 66)
    2- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] -8- [3- (pyrrolidin-1-yl) propyl] -5,6,7,8-tetrahydropyrido [2 , 3-d] pyrimidine (Example 67)
    2- [Methyl (3- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) amino] acetamide (Example 73)
    1- (4-Methylpiperazin-1-yl) -2- {2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidine-7 (6H) -Il} ethanone (Example 74)
    4- (3- {2- [4- (4-Ethylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 76) )
    N, N-dimethyl-3- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} Propan-1-amine (Example 81)
    4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -7- [2- (pyrrolidin-1-yl) ethyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 82)
    2- [4- (4-Methylpiperazin-1-yl) phenyl] -4-propyl-7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3 -D] pyrimidine (Example 88)
    4- (3- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 90)
    4- (3- {2- [4- (4-Isopropylpiperazin-1-yl) phenyl] -4-methyl-5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 92)
    4- (3- {4-Ethyl-2- [4- (4-isopropylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} propyl) morpholine (Example 93)
    4- (4- {4-Methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] -5H-pyrrolo [2,3-d] pyrimidin-7 (6H) -yl} butyl) morpholine (Example 94)
    2- [4- (4- {7- [3- (pyrrolidin-1-yl) propyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl} phenyl) piperazine- 1-yl] ethanol (Example 125),
    2- [4- (4-Methylpiperazin-1-yl) phenyl] -7- {2- [2- (pyrrolidin-1-yl) ethoxy] ethyl} -6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidine (Example 127) and 4- (3- {2- [4- (4-Methylpiperazin-1-yl) phenyl] -6,7-dihydropyrido [2,3-d] pyrimidine- 8 (5H) -yl} propyl) morpholine (Example 130)
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  26. 　請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.
  27. 　請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を有効成分とするトール様受容体が関連する疾患の治療剤および／または予防剤。 A therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor comprising the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient.
  28. 　請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩を有効成分とするトール様受容体７および／または９が関連する疾患の治療剤および／または予防剤。 A therapeutic and / or prophylactic agent for a disease associated with toll-like receptor 7 and / or 9 comprising the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient .
  29. 　トール様受容体が関連する疾患がセプシス、自己免疫疾患または神経変性疾患である請求項２７に記載の治療剤および／または予防剤。 The therapeutic and / or prophylactic agent according to claim 27, wherein the disease associated with a toll-like receptor is sepsis, autoimmune disease or neurodegenerative disease.
  30. 　トール様受容体７および／または９が関連する疾患がセプシス、自己免疫疾患または神経変性疾患である請求項２８に記載の治療剤および／または予防剤。 The therapeutic agent and / or prophylactic agent according to claim 28, wherein the disease associated with Toll-like receptor 7 and / or 9 is sepsis, autoimmune disease or neurodegenerative disease.
  31. 　請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩の治療上の有効量を治療が必要な哺乳動物に投与することからなる、トール様受容体が関連する疾患の治療および／または予防方法。 A toll-like receptor comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof. To treat and / or prevent diseases.
  32. 　トール様受容体が関連する疾患の治療剤および／または予防剤を製造するための、請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩の使用。 Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease associated with a toll-like receptor.
  33. 　トール様受容体が関連する疾患の治療および／または予防に使用するための、請求項１～２５のいずれか一項に記載の化合物またはその製薬学的に許容される塩。 The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with a toll-like receptor.
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