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WO2011152485A1 - Nouveau dérivé de pyrimidine condensé en 4,5 - Google Patents

Nouveau dérivé de pyrimidine condensé en 4,5 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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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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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.

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Abstract

L'invention divulgue un dérivé de pyrimidine condensé en 4,5 qui est utile comme produit pharmaceutique. Elle divulgue spécifiquement un dérivé de pyrimidine qui est efficace dans la prophylaxie et/ou le traitement de maladies associées à une signalisation médiée par un récepteur de type Toll (TLR).
PCT/JP2011/062674 2010-06-02 2011-06-02 Nouveau dérivé de pyrimidine condensé en 4,5 Ceased WO2011152485A1 (fr)

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WO2014015291A1 (fr) 2012-07-20 2014-01-23 Han-Jie Zhou Pyrimidines fusionnées en tant qu'inhibiteurs du complexe p97
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WO2013108837A1 (fr) * 2012-01-18 2013-07-25 興和株式会社 Dérivé de pyrazole doté de propriétés inhibitrices de tlr
US10010554B2 (en) 2012-07-20 2018-07-03 Cleave Biosciences, Inc. Fused pyrimidines as inhibitors of P97 complex
WO2014015291A1 (fr) 2012-07-20 2014-01-23 Han-Jie Zhou Pyrimidines fusionnées en tant qu'inhibiteurs du complexe p97
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US9475824B2 (en) 2012-07-20 2016-10-25 Cleave Biosciences, Inc. Fused pyrimidines as inhibitors of p97 complex
EP3208270A1 (fr) 2012-07-20 2017-08-23 Cleave Biosciences, Inc. Pyrimidines fondues utilisées en tant qu'inhibiteurs du complexe p97
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
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