WO2006038734A1 - Pyridazinone derivatives cytokines inhibitors - Google Patents

Pyridazinone derivatives cytokines inhibitors Download PDF

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Publication number
WO2006038734A1
WO2006038734A1 PCT/JP2005/018901 JP2005018901W WO2006038734A1 WO 2006038734 A1 WO2006038734 A1 WO 2006038734A1 JP 2005018901 W JP2005018901 W JP 2005018901W WO 2006038734 A1 WO2006038734 A1 WO 2006038734A1
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Prior art keywords
alkyl
pyridazinone
nmr
substituted
dmso
Prior art date
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PCT/JP2005/018901
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French (fr)
Inventor
Hitoshi Yamazaki
Chiyoshi Kasahara
Shinji Shigenaga
Koichi Higuchi
Hidekazu Mizuhara
Minoru Yasuda
Masaharu Yokomoto
Keiji Misumi
Tomohiko Kinoshita
Kimiko Katayama
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Astellas Pharma Inc.
Wakunaga Pharmaceutical Co., Ltd.
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Priority claimed from AU2004905844A external-priority patent/AU2004905844A0/en
Application filed by Astellas Pharma Inc., Wakunaga Pharmaceutical Co., Ltd. filed Critical Astellas Pharma Inc.
Publication of WO2006038734A1 publication Critical patent/WO2006038734A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a pyridazinone derivative and a salt thereof, which are useful as medicaments.
  • Rheumatoid arthritis is a systemic inflammatory disease which causes mainly in the arthrosynovia.
  • Methotrexate MTX
  • DMARD disease-modified anti-rheumatic drugs
  • the anti-RA drugs in the next generation are expected to overcome these problems, that is to be an orally small-molecule drug, which blocks or modulates selectively the function of these cytokines.
  • p38 ⁇ mitogen activated protein kinase belongs to intracellular phosphorylation kinase participating in production and/or functional expression of the cytokine (TNF, IL-I, IL-6), and it is reported that
  • p38 ⁇ MAPK is activated in the arthrosynovia of RA patients thereby cytokines are produced excessively, so that p38oc MAPK has been attracted as a target of anti-RA drug.
  • the present invention relates to a pyridazinone derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; a pharmaceutical composition comprising, as an active ingredient, said pyridazinone derivative or a pharmaceutically acceptable salt thereof; a use of said pyridazinone derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyridazinone derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyridazinone derivative or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the pyridazinone derivatives and a salt thereof are inhibitors of cytokines' production or their transduction,
  • analgesic in particular anti-RA agent, drug for pain and other conditions t associated with inflammation, drug for Crohn's disease, drug for inflammatory bowel disease, drug for psoriasis, or the like.
  • the pyridazinone derivative or a salt thereof of the present invention can be shown by the following formula (I) :
  • R 1 is lower alkyl substituted with hydroxy, hydroxycyclo(lower)alkyl or cyclo(lower)alkyl; or • aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy;
  • R 2 is aryl or thienyl, each of which may be sutstituted with substitutent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower, alkyl and lower alkoxy;
  • R 3 is hydrogen or lower alkyl;
  • A is O or S;
  • R 4 is halogen; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula: wherein
  • R 7 is hydrogen, hydroxy, halogen, lower alkyl, lower alkylamino, di(lower)alkylamino, N-lower alkanoyl-N-lower alkylamino,
  • R 7 and R 8 are taken together to form lower alkylene
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1; and
  • R 5 is hydrogen, lower alkyl or hydroxyl(lower)alkyl
  • R 6 is hydrogen; amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino- (lower) alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl(lower)alkyl or hydroxy(lower)alkyl; piperazinyl or N-lower alkoxycarbonylpiperazinyl; or R 5 andR 6 are taken together to form a group of the formula:
  • R 1 is lower alkyl substituted with hydroxycyclo(lower)alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
  • R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy) ; or
  • R 1 is lower alkyl substituted with hydroxycyclo(lower)- alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
  • R 2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy, and R 4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl
  • R 4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl
  • R 1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (C1-C4)alkyl or (Cl-C4)alkoxy;
  • R 2 is phenyl optionally substituted with substituent(s) selected from the group consisting of (C1-C4)alkyl and halogen;
  • R 3 is hydrogen or (Cl-C4)alkyl;
  • R 5 is hydrogen, (Cl-C4)alkyl or hydroxy(Cl-C4)alkyl;
  • R 6 is amino substituted with (Cl-C4)alkyl which may be substituted with (Cl-C4)alkoxy; morpholino; phenyl; cyclo(C5-C8)alkyl or hydroxy(C1-C4)alky1; or a salt thereof.
  • R 1 is phenyl substituted with (Cl-C4)alkyl or (C1-C4) alkoxy;
  • R 2 is phenyl substituted with halogen; and R 3 is hydrogen or (Cl-C4)alkyl; R 6 is amino substituted with (Cl-C4)alkyl; or a salt thereof.
  • R 3 is hydrogen or (Cl-C4)alkyl; R 6 is amino substituted with (Cl-C4)alkyl; or a salt thereof.
  • R 1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (Cl-C4)alkyl;
  • R 2 is phenyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl and halogen;
  • R 3 is hydrogen or (C1-C4)alkyl;
  • A is O or S; and
  • R 4 is halogen; amino optionally substituted with hydroxy(C1-C4)alkyl, hydroxycyclo(Cl-C4)alkyl, piperidyl, (Cl-C4)alkoxycarbonylpiperidyl or
  • R 7 is hydrogen, hydroxy, (Cl-C4)alkyl
  • R 1 is phenyl substituted with (Cl-C4)alkyl
  • R 2 is phenyl substituted with (C1-C4)alkyl or ⁇ halogen
  • R 3 is hydrogen or (Cl-C4)alkyl; and R 4 is a group of the formula:
  • R 7 is hydrogen, hydroxy, methyl, methylamino or dimethylamino; and R 8 is hydrogen; or R 7 and R 8 are taken together to form methylene or ethylene;
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1; or a salt thereof.
  • the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • Process 1
  • R 1 , R 2 , R 3 , R 7 , R 8 , A, X and n are defined above;
  • Hal is a halogen atom
  • R 4 a is amino optionally substituted with lower alkyl, hydroxyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula:
  • R 7 is hydrogen, hydroxy, halogen, lower alkyl, ' . lower alkylamino, di(lower)alkylamino,
  • N-lower alkanoyl-N-lower alkylamino N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloxy or -N + (CH 3 J 2 O " and R 8 is hydrogen; or
  • R 7 and R 8 are taken together to form lower alkylene;
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1;
  • R 6 a is amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino(lower)alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl- (lower)alkyl, piperazinyl or N-lower alkoxycarbonylpiperazinyl;
  • m is an integer of 1 to 4; and
  • R X a is aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alky1, lower alkanoyl, halogen and lower alkoxy.
  • the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in amanner similar thereto.
  • the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in amanner similar thereto.
  • the object compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.
  • solvating form of the compound (I) e.g. hydrate, ethanolate, etc.
  • any form of the crystal of the compound (I) are included within the scope of the present invention.
  • the compound (I) and other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
  • radiolabelled derivatives of compound (I) which are suitable for biological studies, are included within the scope of the present invention.
  • Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzy
  • All starting materials and product compounds may be salts.
  • the compounds of above processes can be converted to salts according to a conventional method.
  • lower alkyl and lower alkyl moiety in the terms "halo(lower)alkyl", “N-lower alkanoyl-N-lower alkylamino", “N-lower alkoxycarbonyl-N-lower alkylamino", “lower alkoxycarbonyl(lower)alkyl” , “hydroxy(lower)alkyl”, “lower alkylamino”,
  • di(lower)alkylamino may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be (C1-C4) alkyl and the more preferred one may be methyl, ethyl, isopropyl or isobutyl.
  • Suitable "cyclo(lower)alkyl” and cyclo(lower)alkyl moiety in the term “hydroxycyclo(lower)alkyl” may be cyclo(C3-C8)alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclo(C5-C8)alkyl and themore preferred onemaybe cyclohexyl or cycloheptyl.
  • Sutible "lower alkylene” maybe (Cl-C ⁇ )alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene or the like, in which the preferred one is methylene or ethylene.
  • Suitable "aryl” and aryl moiety in the term “aryloxy” may be phenyl, naphthyl, indenyl, anthryl, or the like, in which the preferred one may be (C6-C10) aryl, and the more preferred one may be phenyl or tolyl.
  • lower alkoxy and lower alkoxy moiety in the terms “lower alkoxycarbonyl(lower)alkyl", “N-lower alkoxycarbonyl-N-lower alkylamino", “N-lower alkoxycarbonylpiperazinyl” , “lower alkoxycarbonyl", “lower alkoxy(lower)alkyl” may include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferred one may be (Cl-C4)alkoxy and the more preferred one may be methoxy or ethoxy.
  • Suitable "lower alkanoyl” and lower alkanoyl moiety in the term "N-lower alkanoyl-N-lower alkylamino" may be formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, hexanoyl and the like, in which the preferred one is formyl or acetyl.
  • Suitable "lower alkoxycarbonyl” and lower alkoxycarbonyl moiety in the terms “lower alkoxycarbonyl- (lower)alky” , “N-lower alkoxycarbonyl-N-lower alkylamino” and “N-lower alkoxycarbonylpiperazinyl” may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like, in which the preferred one is ethoxycarbonyl or tert-butoxycarbonyl.
  • Suitable “lower alkylamino(lower)alkyl” maybe lower alkyl substituted with lower alkylamino.
  • Suitable “di(lower)alkylamino(lower)alkyl” may be lower alkyl substituted with di(lower)alkylamino, the "di(lower)alkyl” in which may be the same or different.
  • Suitable examples of the "lower alkylamino" are methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, and the like, in which the preferred one may be methylamino.
  • di(lower)alkylamino Suitable examples of the "di(lower)alkylamino" are dimethylamino, methyl(ethyl)amino, diethylamino, ethyl(propyl)amino and dipropylamino, or the like, inwhich the preferred one may be dimethylamino.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "halo(lower)alkyl” may be lower alkyl substitutedwith one or more halogens such as chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or the like, inwhich the preferred one may be trifluoromethyl.
  • the substitute(s) on aryl for R 1 and R 2 may be plural and in such case the substitute(s) may be the same or different.
  • the object compound (I) of the present invention is inhibitors of cytokines' production or their transduction andpossesses thevarious pharmacological actions as stated before.
  • Test method Inhibition of TNF-a production in THP-I cells [I] Test method
  • THP-I cells a human monocytic cell line, were maintained in RPMI 1640 (Sigma R8758) supplemented with
  • LPS LPS
  • lO ⁇ g/mL final Sigma L-4005, from E.coli serotype 055:B5
  • test compound 0.1% DMSO vehicle
  • the cell mixture was incubated for 20 hours in a humidified incubator at 37°C, 5% CO 2 .
  • the culture supernatants were harvested and TNF-a levels, from LPS stimulated cells in the presence of 100 nM test compound was calculated compared with control cells stimulated in the presence of 0.1% DMSO.
  • the pyridazinone compound (I) and a salt thereof of this invention are useful as inhibitors of cytokines' production or their transduction, and through inhibiting
  • the p38 ⁇ MAPK they possess pharmacological actions such as analgesic action, anti-inflammatory, anti arthritis mutilans action, or the like, and for the prevention and/or the treatment of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, drug for psoriasis, or the like.
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • a pharmaceutical preparation for example, in a solid, semisolid or liquid form, which contains the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use.
  • auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary.
  • the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce.the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
  • the composition For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the pyridazinone compound (I) varies depending on .the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, and in case of oral administration, a daily dose of 0.5 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.
  • Example 1 A mixture of 1- (2-phenylpyrazolo[1,5-a]pyridin-3 ⁇ yl)ethanone (1.0Og) and glyoxylic acid monohydrate (l:56g)in 1,2-dimethoxyethane (3ml) was refluxed for 15h. The mixture was concentrated in vacuo and taken up EtOAc (5ml) and water (4ml) . The aqueous layer was extracted with EtOAc (3ml) . The combined organic layer were washed with water (3ml) and concentrated in vacuo to give an oil.
  • Example 25 To a solution of 6- [2-amino ⁇ 4 ⁇ (4-fluorophenyl) ⁇ 1,3- thiazol-5-yl] -2-[ (1-hydroxycyclohexyl)methyl] -3(2H) - pyridazinone (200mg) in pyridine (1.58g) was added ethyl chloroformate (190mg) at room temperature. After 12h, the mixture was concentrated and triturated with water to give a crude solid (170mg) . The solid was dissolved in EtOAc and washed with IN HCl, sat. NaHCO 3 and brine, dried and evaporated in vacuo.
  • Example 52 A mixture of 2- [ (1-hydroxycyclohexyl)methyl] -6-(2- phenylpyrazolo[1,5-a]pyridin-3-yl) -3(2H)-pyridazinone (200mg) and palladium hydroxide (lOOmg, 20% wt. on carbon) in EtOH (20ml) was stirred for lday under the pressure of 3atm of hydrogen. After filtration of catalyst through the celite pad, the filtrate was concentrated in vacuo and crystallized from EtOH (2ml) and hexane (ImI) .
  • Example 79 To a suspension of 2- [3-[2- [3-(dimethylamino)-1- pyrrolidinyl] -4-(4-fluorophenyl) -1,3-thiazol-5-yl] -6- oxo-l(6H)-pyridazinyl]benzaldehyde (41mg) in THF (2ml) was added a solution of NaBH 4 (6.3mg) in H 2 O (0.3ml) at room temperature. After stirring for 2h, the mixture became clear solution and was quenched with cone. HCl (pH 3) . After Ih with stirring, the mixture was made alkaline with sat. NaHCO 3 and extracted with EtOAc.
  • Example 80 tert-Butyl 4- ⁇ 3- (4-fluorophenyl)-4- [1-(2-methylphenyl) - 6-oxo-l,6-dihydro-3-pyridazinyl] -lH-pyrazol-5-yl ⁇ -l- piperazinecarboxylate (48mg) was dissolved in 4N hydrogen chloride in dioxane (ImI) and methanol (0.5ml), and stirred for 2h at room temperature.
  • Example 86 A mixture of 6- [l-bromo-2-(2,4-difluorophenyl)-2- oxoethyl]-2-(2-methylphenyl)-3(2H)-pyridazinone (3.7g) and tert-butyl [1-(aminocarbonyl)-3-pyrrolidinyl] - methylcarbamate (3.8g) in xylene (21 ml) was stirred at 140 °C for 5h. After cooling to room temperature, the reaction mixture was diluted with H 2 O (50ml) and extracted with EtOAc (50ml) two times. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO 2 (eluent: CH 2 Cl2/Me0H 100:1-100:2-10:1) to give tert-butyl
  • Example 91 6- ⁇ 3-(2,4-Difluorophenyl)-5- [ (3-hydroxypropyl)amino] - lH-pyrazol-4-yl ⁇ -2-(2-methylphenyl) -3(2H) -pyridazinone was obtained in a similar manner to that of the above Preparations or Examples from 6- [l-bromo-2-(2,4- difluorophenyl)-2-oxoethyl]-2-(2-methylphenyl) -3(2H) - pyridazinone.
  • Example 94 To a solution of 6- ⁇ 2- [3-(dimethylamino) -1-pyrrolidinyl]- 4-(4-fluorophenyl) -1,3-thiazol-5-yl ⁇ -2-(2-methylphenyl) -3(2H)-pyridazinone (80mg) in CH2C12 (ImI) was added mCPBA (37.7mg) and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was washed with a mixture of sat.MaHCO3 and brine, 5% Na2S2O3, water and brine, successively.
  • 6- ⁇ 4-(2,4-Difluorophenyl)-2-[4-(dimethylamino)-1- piperidinyl] -1,3-oxazol-5-yl ⁇ -2-(2-methylphenyl) -3(2H) - pyridazinone was obtained in a conventional manner from 6- ⁇ 4-(2,4-Difluorophenyl) -2-[4- (methylamino) -1- piperidinyl] -1,3-oxazol-5-yl ⁇ -2-(2-methylphenyl)-3(2H)- pyridazinone

Abstract

A pyridazinone derivative shown by the following formula (I): wherein; which is useful as a medicament for cytokines mediated diseases.

Description

DESCRIPTION PYRIDAZINONE DERIVATIVES
TECHNICAL FIELD
The present invention relates to a pyridazinone derivative and a salt thereof, which are useful as medicaments.
BACKGROUND ART
Rheumatoid arthritis (RA) is a systemic inflammatory disease which causes mainly in the arthrosynovia. Today Methotrexate (MTX) is used generally as a disease-modified anti-rheumatic drugs (DMARD), but the efficacy for inflammatory responses or arthritis mutilans is not enough.
On the other hand, the biologies, which targeted cytokines
(TNF, IL-I, IL-6) , has been revealed recently its efficacy for RA, and it has been proved the importance of these cytokines in the manifestation of RA. In particular, the monoclonal TNF antibody Remicade and soluble TNF receptor fusion protein Enbrel, which inhibit the TNF function, are
'worthy of note because of the unprecedented efficacy not only for inflammatory response but for arthritis mutilans.
Though the fact above suggests that the importance of the treatment for RA in future, these biologies have fundamental drawbacks related to patient cost, efficacy of production, limitation of administration to hypodermal or intravenous injection, and so on. So, the anti-RA drugs in the next generation are expected to overcome these problems, that is to be an orally small-molecule drug, which blocks or modulates selectively the function of these cytokines.
In particular p38α mitogen activated protein kinase (p38α MAPK) belongs to intracellular phosphorylation kinase participating in production and/or functional expression of the cytokine (TNF, IL-I, IL-6), and it is reported that
p38α MAPK is activated in the arthrosynovia of RA patients thereby cytokines are produced excessively, so that p38oc MAPK has been attracted as a target of anti-RA drug.
These anti-inflammatory agents or compounds having cytokine inhibitory activity have been described (WO98/22457, WO00/41698, WO00/43384, WO01/22965, WO 02/07772, WO02/58695, WO03/041644, etc.) but a pyridazinone derivative having these activity is novel as far as we know.
DISCLOSURE OF INVENTION
The present invention relates to a pyridazinone derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; a pharmaceutical composition comprising, as an active ingredient, said pyridazinone derivative or a pharmaceutically acceptable salt thereof; a use of said pyridazinone derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyridazinone derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyridazinone derivative or a pharmaceutically acceptable salt thereof to a human being or an animal. The pyridazinone derivatives and a salt thereof are inhibitors of cytokines' production or their transduction,
and through inhibiting the p38α MAPK they possess pharmacological actions such as analgesic action, anti-inflammatory, anti arthritis mutilans action, or the like.
They are useful as an analgesic, in particular anti-RA agent, drug for pain and other conditions t associated with inflammation, drug for Crohn's disease, drug for inflammatory bowel disease, drug for psoriasis, or the like.
The pyridazinone derivative or a salt thereof of the present invention can be shown by the following formula (I) :
Figure imgf000005_0001
wherein
Figure imgf000006_0001
R1 is lower alkyl substituted with hydroxy, hydroxycyclo(lower)alkyl or cyclo(lower)alkyl; or • aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy;
R2 is aryl or thienyl, each of which may be sutstituted with substitutent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower, alkyl and lower alkoxy; R3 is hydrogen or lower alkyl; A is O or S;
R4 is halogen; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula:
Figure imgf000007_0001
wherein
R7 is hydrogen, hydroxy, halogen, lower alkyl, lower alkylamino, di(lower)alkylamino, N-lower alkanoyl-N-lower alkylamino,
N-lower alkoxycarbonyl-N-lower alkylamino, lower alkanoyloxy or -N+(CH3J2O"; and R8 is hydrogen; or
R7 and R8 are taken together to form lower alkylene;
X is CH2, NH, N(CH3) or O; and n is 0 or 1; and
R5 is hydrogen, lower alkyl or hydroxyl(lower)alkyl; R6 is hydrogen; amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino- (lower) alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl(lower)alkyl or hydroxy(lower)alkyl; piperazinyl or N-lower alkoxycarbonylpiperazinyl; or R5 andR6 are taken together to form a group of the formula:
(wherein Y is CH or N) , or
Figure imgf000007_0002
(wherein Z is CH2 or NH);
Figure imgf000008_0001
provided that R1 is lower alkyl substituted with hydroxycyclo(lower)alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
Figure imgf000008_0002
(wherein R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy) ; or
R1 is lower alkyl substituted with hydroxycyclo(lower)- alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
Figure imgf000008_0003
(wherein R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy, and R4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl) ; or a salt thereof.
The preferred embodiments of the pyridazinone compound of the present invention represented by the general formula (I) are as follows.
(1) The pyridazinone compound of the general formula (I) wherein
Figure imgf000009_0001
R1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (C1-C4)alkyl or (Cl-C4)alkoxy;
R2 is phenyl optionally substituted with substituent(s) selected from the group consisting of (C1-C4)alkyl and halogen; R3 is hydrogen or (Cl-C4)alkyl; R5 is hydrogen, (Cl-C4)alkyl or hydroxy(Cl-C4)alkyl; and
R6 is amino substituted with (Cl-C4)alkyl which may be substituted with (Cl-C4)alkoxy; morpholino; phenyl; cyclo(C5-C8)alkyl or hydroxy(C1-C4)alky1; or a salt thereof.
(2) The pyridazinone compound of (1) above wherein
R1 is phenyl substituted with (Cl-C4)alkyl or (C1-C4) alkoxy;
R2 is phenyl substituted with halogen; and R3 is hydrogen or (Cl-C4)alkyl; R6 is amino substituted with (Cl-C4)alkyl; or a salt thereof. (3) The pyridazinone compound of the general formula (I) wherein
Figure imgf000010_0001
R1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (Cl-C4)alkyl; R2 is phenyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl and halogen; R3 is hydrogen or (C1-C4)alkyl; A is O or S; and
R4 is halogen; amino optionally substituted with hydroxy(C1-C4)alkyl, hydroxycyclo(Cl-C4)alkyl, piperidyl, (Cl-C4)alkoxycarbonylpiperidyl or
(Cl-C4)alkylsulfonylpiperidyl;or a group of the formula:
Figure imgf000011_0001
wherein R7 is hydrogen, hydroxy, (Cl-C4)alkyl,
(Gl-C4)alkylamino, di(Cl-C4)alkylamino, (Cl-C4)alkanoyloxy or -N+(CH3)2O'; and R8 is hydrogen; or R7 and R8 are taken together to form
(Cl-C4)alkylene; X is CH2, NH, N(CH3) or O; and n is 0 or 1; or a salt thereof. (4) The pyridazinone compound of (3) above wherein
R1 is phenyl substituted with (Cl-C4)alkyl; R2 is phenyl substituted with (C1-C4)alkyl or ■ halogen;
R3 is hydrogen or (Cl-C4)alkyl; and R4 is a group of the formula:
Figure imgf000012_0001
wherein
R7 is hydrogen, hydroxy, methyl, methylamino or dimethylamino; and R8 is hydrogen; or R7 and R8 are taken together to form methylene or ethylene;
X is CH2, NH, N(CH3) or O; and n is 0 or 1; or a salt thereof.
The term "optionally substituted" refers to "unsubstituted or substituted with one or more suitable substituent(s) " .
The object compound (I) and a salt thereof of the present invention can be prepared by the following processes. Process 1
Figure imgf000013_0001
(II) (Ilia) (Ia) or a salt or a salt or a salt thereof thereof thereof
Process 2
Figure imgf000013_0002
(ID (IHb) (Ib) or a salt or a salt or a salt thereof thereof thereof
Process 3
Figure imgf000013_0003
(IV) (V) (Ic) or a salt or a salt or a salt thereof thereof thereof Process 4
Figure imgf000014_0001
(Id) (Ie) or a salt thereof or a salt thereof
Process 5
Figure imgf000014_0002
(Ie) (VI) (If) or a salt or a salt or a salt thereof thereof thereof
Process 6
Figure imgf000014_0003
(IV) (VIl) (ig) or a salt or a salt or a salt thereof thereof thereof [wherein
R1, R2, R3, R7, R8, A, X and n are defined above;
Figure imgf000015_0001
Hal is a halogen atom; R4 a is amino optionally substituted with lower alkyl, hydroxyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula:
Figure imgf000015_0002
wherein
R7 is hydrogen, hydroxy, halogen, lower alkyl, ' . lower alkylamino, di(lower)alkylamino,
N-lower alkanoyl-N-lower alkylamino, N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloxy or -N+(CH3J2O" and R8 is hydrogen; or
R7 and R8 are taken together to form lower alkylene; X is CH2, NH, N(CH3) or O; and n is 0 or 1; R6 a is amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino(lower)alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl- (lower)alkyl, piperazinyl or N-lower alkoxycarbonylpiperazinyl; m is an integer of 1 to 4; and
RX a is aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alky1, lower alkanoyl, halogen and lower alkoxy.]
In addition to the processes as mentioned above, the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in amanner similar thereto.
The starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in amanner similar thereto. . The object compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, ethanolate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
It is to be noted that the compound (I) and other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
It is also to be noted that radiolabelled derivatives of compound (I) , which are suitable for biological studies, are included within the scope of the present invention.
Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc. ) , a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like. All starting materials and product compounds may be salts. The compounds of above processes can be converted to salts according to a conventional method.
The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
Suitable "lower alkyl" and lower alkyl moiety in the terms "halo(lower)alkyl", "N-lower alkanoyl-N-lower alkylamino", "N-lower alkoxycarbonyl-N-lower alkylamino", "lower alkoxycarbonyl(lower)alkyl" , "hydroxy(lower)alkyl", "lower alkylamino",
"di(lower)alkylamino" , "lower alkylamino(lower)alkyl" , "di(lower)alkylamino(lower)alkyl" , "lower alkoxy(lower)alkyl" and "morpholino(lower)alkyl" may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be (C1-C4) alkyl and the more preferred one may be methyl, ethyl, isopropyl or isobutyl.
Suitable "cyclo(lower)alkyl" and cyclo(lower)alkyl moiety in the term "hydroxycyclo(lower)alkyl" may be cyclo(C3-C8)alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclo(C5-C8)alkyl and themore preferred onemaybe cyclohexyl or cycloheptyl. Sutible "lower alkylene" maybe (Cl-Cβ)alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene or the like, in which the preferred one is methylene or ethylene. Suitable "aryl" and aryl moiety in the term "aryloxy" may be phenyl, naphthyl, indenyl, anthryl, or the like, in which the preferred one may be (C6-C10) aryl, and the more preferred one may be phenyl or tolyl.
Suitable "lower alkoxy" and lower alkoxy moiety in the terms "lower alkoxycarbonyl(lower)alkyl", "N-lower alkoxycarbonyl-N-lower alkylamino", "N-lower alkoxycarbonylpiperazinyl" , "lower alkoxycarbonyl", "lower alkoxy(lower)alkyl" may include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferred one may be (Cl-C4)alkoxy and the more preferred one may be methoxy or ethoxy.
Suitable "lower alkanoyl" and lower alkanoyl moiety in the term "N-lower alkanoyl-N-lower alkylamino" may be formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, hexanoyl and the like, in which the preferred one is formyl or acetyl.
Suitable "lower alkoxycarbonyl" and lower alkoxycarbonyl moiety in the terms "lower alkoxycarbonyl- (lower)alky" , "N-lower alkoxycarbonyl-N-lower alkylamino" and "N-lower alkoxycarbonylpiperazinyl" may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like, in which the preferred one is ethoxycarbonyl or tert-butoxycarbonyl.
Suitable "lower alkylamino(lower)alkyl" maybe lower alkyl substituted with lower alkylamino. Suitable "di(lower)alkylamino(lower)alkyl" may be lower alkyl substituted with di(lower)alkylamino, the "di(lower)alkyl" in which may be the same or different.
Suitable examples of the "lower alkylamino" are methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, and the like, in which the preferred one may be methylamino.
Suitable examples of the "di(lower)alkylamino" are dimethylamino, methyl(ethyl)amino, diethylamino, ethyl(propyl)amino and dipropylamino, or the like, inwhich the preferred one may be dimethylamino.
Suitable "halogen" may be fluoro, chloro, bromo and iodo.
Suitable "halo(lower)alkyl" may be lower alkyl substitutedwith one or more halogens such as chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or the like, inwhich the preferred one may be trifluoromethyl.
The substitute(s) on aryl for R1 and R2 may be plural and in such case the substitute(s) may be the same or different.
The object compound (I) of the present invention is inhibitors of cytokines' production or their transduction andpossesses thevarious pharmacological actions as stated before.
In order to show the usefulness of the compound (I) of the present invention, the pharmacological test result of the representative compound of the present invention is shown in the following.
Test: Inhibition of TNF-a production in THP-I cells [I] Test method
THP-I cells, a human monocytic cell line, were maintained in RPMI 1640 (Sigma R8758) supplemented with
penicillin (50U/ml), streptomycin (50μg/ml) and 10% fetal bovine serum (Moregate BioTech. ) at 37°C, 5% CO2 in a humidified incubator. Initial stock solutions of test compounds were made in DMSO. All cells, reagents and test compounds were diluted into culture media. THP-I cells (IxIO5 cells/well final) and lipopolysaccharide
(LPS; lOμg/mL final; Sigma L-4005, from E.coli serotype 055:B5) were added to 96 well polypropylene culture plates (Sumilon, MS-8196F5; sterile) containing test compound or 0.1% DMSO vehicle. The cell mixture was incubated for 20 hours in a humidified incubator at 37°C, 5% CO2. The culture supernatants were harvested and TNF-a levels, from LPS stimulated cells in the presence of 100 nM test compound was calculated compared with control cells stimulated in the presence of 0.1% DMSO.
[II] Test compound
6-[2~amino-4-(4-fluorophenyl)-thiazol-5-yl] - 2-[ (1-hydroxycyclohexyl)methyl]-3(2H) -pyridazinone (Example 6)
6- [5-(ethylamino) -3-phenyl-,lH-pyrazol-4-yl] - 2-t (1-hydroxycyclohexyl)methyl]-3(2H) -pyridazinone (Example 54)
[III] Test result
Table 1 : Inhibition of TNF-a production in THP-I cells at 10OnM
Test compound % inhibition
(Example No.) of control
6 81.6 54 79 . 3
The pyridazinone compound (I) and a salt thereof of this invention are useful as inhibitors of cytokines' production or their transduction, and through inhibiting
the p38α MAPK they possess pharmacological actions such as analgesic action, anti-inflammatory, anti arthritis mutilans action, or the like, and for the prevention and/or the treatment of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, drug for psoriasis, or the like.
The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. In addition, auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary. The pyridazinone compound (I) or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce.the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the pyridazinone compound (I) varies depending on .the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, and in case of oral administration, a daily dose of 0.5 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.
The following preparations and examples are given for the purpose of illustrating the present invention in more detail.
The abbreviations, symbols and terms used in the preparations and examples have the following meanings. AcOH acetic acid
CDCl3 chloroform-d
CHCl3 chloroform
CH2Cl2 dichloromethane
CH3CN acetonitrile
EtOAc or AcOEt ethyl acetate
MeOH methanol
EtOH ethanol
PrOH propanol i-PrOH or IPA isopropyl alcohol
BuOH butanol t-(or tert-)BuOH t-(or tert-)butyl alcohol
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Et3N triethylamine
IPE diisopropyl ether
TFA trifluoroacetic acid THF tetrahydrofuran
HOBt or HOBT 1-hyroxybenzotriazole ~
EDCI or WSCD 1-ethyl-3- [3' -(dimethylamino)- propyl]carbodiimide
Pd/C palladium on carbon
MCPBA or mCPBA 3-chloroperoxybenzoic acid min minute(s) hr or h hour(s) cone. concentrated aq aqueous (ex. aq NaHCO3 solution]
HCl hydrochloric acid
CuBr2 copper(II) bromide
Na2CO3 sodium carbonate
NaOH sodium hydroxide
Na2SO4 sodium sulfate
(continued to the next page)
Preparation 1
To a solution of 3-chloro-6-methylpyridazine (5Ig) and. ethyl 4-fluorobenzoate (66.7g) in THF was added dropwise lithium bis(trimethylsilyl)amide (793ml, l.OMinTHF) over the period of 30min maintained below 150C. After stirring for 30min at room temperature, the mixture was recooled on an ice bath and to this was added cold water (250ml) and 6N HCl (175ml) to neutralize. A solid separated from the mixture was collected to give 2-(6-chloro-3-pyridazinyl) - 1-(4-fluorophenyl)ethanone (36.6g) as first crop. The organic layer separated from the mother liquor was washed with brine (150ml, twice), dried and concentrated to form a suspension. This was dissolved under reflux and to this was added hexane (600ml) and the suspension was aged for Ih with stirring at room temperature, collected and washed with hexane (200ml) to afford 2-(6-chloro-3-pyridazinyl)- 1-(4-fluorophenyl)ethanone (51.3g) as second crop. Mass ESI(+) 251(M+l) 1H NMR(300MHz, DMSO-d6)d 4.85 (2H, s) , 7.42 (2H, t, J= 9Hz) , 7.78 (IH, d, J=8.7Hz), 7.93 (IH, d, J=8.7Hz), 8.13-8.22 (2H, m) .
The following compounds were obtained in a similar manner to that of Preparation 1. Preparation 2
2-(6-Chloro-3-pyridazinyl) -1-(2-thienyl)ethanone 1HNMR (200MHz, DMSO-d6) d 4.79(2H, s), 7.32(1H, dd, J=4.0, 4.9 Hz), 7.8O(1H, d, J=8.9 Hz), 7.93(1H, d, J=8.9 Hz), 8.09(1H, dd, J=O.9, 4.9 Hz), 8.18(1H, dd, J=O.8, 4.0 Hz).
Preparation 3
2- (6-Chloro-3-pyridazinyl) -1-(4-fluoro-3-methylphenyl) - ethanone ESI(+) 265 (M+l)
1HNMR (200MHz, DMSO-d6) d2.33(3H, d) , 4.83(2H, s) , 7.34(1H, t, J=9.2 Hz), 7.77(IH, d, J=8.7 Hz), 7.93(IH, d, J=8.7 Hz), 7.96-8.10(2H, m) .
Preparation 4 l-(2-Chloro-4-fluorophenyl)-2- (6-chloro-3-pyridazinyl)- ethanone
1H NMR (200MHz, DMSO-d6) d 4.78(1.3H, s), 5.94(0.7H, s),
7.28-7.48(1H, m) , 7.52-7.74(1.3H, m) , 7.75-7.85(1.3H, m) , 7.95(0.7H, d, J=8.9 Hz), 8.01-8.11(0.7H, m) , 14.06(0.7H, brs) .
Preparation 5
2-(6-Chloro-3-pyridazinyl)-1-phenylethanone Mass ESI(+) 233(M+1) 1HNMR(SOOMHZ, DMSO-d6)d 4.86 (2H, s) , 7.59 (2H, t, J=7.8Hz) , 7.71 (IH, t, J=7.8Hz), 7.79 (IH, d, J=9Hz), 7.93 (IH, d, J=9Hz), 8.09 (2H, d, J=8.1Hz)
Preparation 6
2 - ( 6 -Chloro - 3 -pyridazinyl ) - 1 - ( 3 -methylphenyl ) ethanone
Mass ESI(+) 247 (M+l)
1H NMR(300MHz, DMSO-d6)d 2.41 (3H, s), 4.83 (2H, s),
7.42-7.55 (2H, m) , 7.75-7.82 (IH, m) , 7.85-7.96 (3H, m) .
Preparation 7
A mixture of 2-(6-chloro-3-pyridazinyl)-1-(4- fluorophenyl)ethanone (30.Og) and sodium acetate (19.6g) in AcOH (240ml) was stirred for 3h at 1350C. After cooling to room temperature, to this was added cold water (400ml) .
A solid separated from the mixture was collected, washed with water and dried in vacuo to give
6- [2-(4-fluorophenyl)-2-oxoethyl] -3(2H)-pyridazinone
(17g) as a gray solid. Mass ESI(+) 233(M+l)
1HNMROOOMHZ, DMSO-d6)d 4.43 (2H, s), 6.87 (IH, d, J=IOHz),
7.36-7.43 (3H, m) , 8.09-8.14 (2H, m) .
The following compounds were obtained in a similar manner to that of Preparation 7. Preparation 8
6-[2-Oxo-2-(2-thienyl)ethyl]-3(2H) -pyridazinone 1H NMR (200MHz, DMSO-d5) d 4.36(2H, s), 6.86(1H, d, J=9.7 Hz) , 7.25-7.32(IH, m), 7.39(IH, d, J=9.7 Hz), 8.01-8.10(2H, m) , 12.93(1H, s) .
Preparation 9
6-{2-OXO-2-[3-(trifluoromethyl)phenyl]ethyl}-3(2H)- pyridazinone
1H NMR (200MHz, DMSO-d6) d 4.52(2H, s), 6.88(1H, d, J=9.7 Hz), 7.39(1H, d, J=9.7Hz), 7.82(1H, t, J=7.7 Hz), 8.06(1H, d, J=7.7 Hz), 8.25-8.38(2H, m), 12.93(1H, brs).
1 Preparation 10
6- [2-(2-Fluorophenyl)-2-oxoethyl] -3(2H)-pyridazinone 1H NMR (200MHz, DMSO-d6) d 4.34(2H, d, 3=2.5 Hz) ,.6.87(IH, d, J=9.7 Hz), 7.30-7.48(2H, m) , 7.64-7.79(IH, m) , 7.91(1H, dt, J=I.8, 7.5 Hz), 12.91(1H, brs).
Preparation 11
6- [2- (4-Fluoro-3-methylphenyl) -2-oxoethyl]-3(2H)- pyridazinone
1H NMR (200MHz, DMSO-d6) d 2.31(3H, d, J=I.7 Hz), 4.40(2H, s) , 6.86(1H, d, J=9.7 Hz) , 7.26-7.40(2H, m) , 7.88-8.03(2H, m) , 12 . 91 ( 1H , brs ) .
Preparation 12
6-[2-(2-Chloro-4-fluorophenyl) -2-oxoethyl] -3(2H) - pyridazinone
1H NMR (200MHz, DMSO-d6) d 4.35(2H, s), 6.88(1H, d, J=9.7 Hz) , 7.32-7.48(2H, m) , 7.60(IH, dd, J=2.5; 9.0 Hz) , 7.97(IH, dd, J=6.1, 8.7 Hz), 12.96(1H, brs).
Preparation 13
6-(2-Oxo-2-phenylethyl)-3(2H)-pyridazinone
Mass ESI(+) 215(M+1)
1HNMR(300MHz, DMSO-d6)d 4.43 (2H, s) , 6.87 (IH, d, J=9.9Hz) ,
7.38 (IH, d, J=9.9Hz), 7.57 (2H, t, J=8.1Hz), 7.69 (IH, t, J=8.1Hz), 8.03 (2H, d, J=8.4Hz).
Preparation 14
6- [2-(3-Methylphenyl) -2-oxoethyl] -3(2H)-pyridazinone Mass ESI(+) 229(M+1) 1H NMR(300MHz, DMSO-d6)d 2.40 (3H, s) 4.41 (2H, s) 6.86 (IH, d, J=9.6Hz) 7.37 (IH, d, J=9.6Hz) 7.41-7.52 (IH, m) 7.80-7.85 (2H, m) . ,
Preparation 15 To a mixture of 6- [2-(4-fluorophenyl)-2-oxoethyl] - 3(2H)-pyridazinone (17g) and AcOH (1.3ml) in dic.hloromethane (136ml) was added pyridinium tribromide ('28.Ig) at room temperature. After stirring for 3h, the mixture was washed with water, 2%, aqueous sodium thiosulfate and brine, dried over Na2SO4 and concentrated to afford 6- [l-bromo-2-(4-fluorophenyl) -2-oxoethyl]- 3(2H) -pyridazinone (27.2g) as a brown oil. Mass ESI(+). 464(M+1)
1H NMR(300MHz, CDCl3)d 6.15 (IH, s), 7.04 (IH, d, J=9.9Hz), 7.21 (2H, t, J=8.7Hz), 7.76 (IH, d, J=9.9Hz), 8.05-8.14 (2H, m) .
The following compounds were obtained in a similar manner to that of Preparation 15.
Preparation 16
6-[l-Bromo-2-oxo-2-(2-thienyl)ethyl] -3(2H) -pyridazinone 1H NMR (200MHz, DMSO-d6) d 6.87(lH, s), 6.98(1H, d, J=IO.0 Hz), 7.3O(1H, t, J=4.4Hz), 7.66(1H, d, J=IO-OHz), 8.15(2», d, J=4.4 Hz), 13.19(IH, brs).
Preparation 17
6-{1-Bromo-2-oxo-2- [3-(trifluoromethy1)phenyl]ethyl}-
3(2H) -pyridazinone 1H NMR (200MHz, DMSO-d6) d 6.04(1H, s), 6.93(1H, d, J=9.8 Hz), 7.52(1H, d, J=9.8Hz), 7.78(1H, t, J=8.0Hz), 8.02(1H, d, J=7.6 Hz), 8.21-8.31(2H, m) , 12.94(1H, brs).
Preparation 18 6-[1-Bromo-2-(2-fluorophenyl)-2-oxoethyl]-3(2H) - pyridazinone
1HNMR (200MHz, DMSO-d6) d6.71(lH, s), 6.98(1H, dd, J=I."4,
9.8Hz), 7.30-7.48(2H, m) , 7.60-7.80(2H, m) , 7.92-8.06(IH, m), 13.12(1H, brs).
Preparation 19
6-[1-Bromo-2-(4-fluoro-3-methylphenyl)-2-oxoethyl]-2-
(2-methylphenyl)-3(2H)-pyridazinone
1H NMR (200MHz, DMSOd6) d 1.89(3H, s), 2.29(3H, d, J=I.6 Hz), 7.04(1H, s ) ; 7.15-7.42(5H, m) , 7.79(1H, d, J=9.7 Hz),
7.90-8.09(2H, m) .
Preparation 20
6- [1-Bromo-2-(2-chloro-4-fluorophenyl) -2-oxoethyl]-2- (2-methylphenyl) -3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 1.88(3H, s), 6.94(IH, s), 7.13-7.50(5H, m) , 7.57-7.72(2H, m) , 7.96-8.08(IH, m) .
Preparation 21 6- [l-Bromo-2-(4-fluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3(2H)-pyridazinone
1H NMR (200MHz, DMSOd6) d 1.89(3H, s), 7.08(1H, s),
7.15-7.48(7H, m) , 7.80(IH, d, 3=9.1 Hz), 7.08-8.20(2H, m) .
Preparation 22
6-(l-Bromo-2-oxo-2-phenylethyl) -3(2H) -pyridazinone ' Mass ESI(+) 336(M+1)
1H NMROOOMHZ, DMSO-d5)d 6.99 (IH, d, J=9.9Hz), 7.03 (IH, s), 7.56 (2H, t, J=7.8Hz), 7.62-7.76 (2H, m) , 8.05 (2H, d, J=8.1Hz).
Preparation 23
A mixture of 6- [l-bromo-2-(4-fluorophenyl) -2-oxoethyl] -
3(2H)-pyridazinone (27.Og) and thiourea (7.93g) in EtOH (200ml) was refluxed for 4h. After cooling to room temperature, the mixture was diluted with H2O (100ml) and adjusted with aqueous 2M Na2CO3 to pH 3 to give a solid that was collected to afford 6- [2-amino-4- (4-fluorophenyl) - l,3-thiazol-5-yl] -3(2H)-pyridazinone (9.74g) as a first crop. Additionally, mother liquorwas adjustedwith aqueous 2M Na2CO3 to pH 6 to give 6- [2-amino-4-(4-fluorophenyl) - l,3-thiazol-5-yl] -3(2H) -pyridazinone (8.67g) as a second crop. Mass ESI(+) 289(M+1) 1H NMR(SOOMHZ, DMSO-d6)d 6.69 (IH, d, J=9.9Hz), 6.89 (IH, d, J=9.9Hz), 7.23 (2H, t, J=9Hz), 7.37-7.54 (4H, m) .
The following compounds were obtained in a similar manner to that of Preparation 23.
Preparation 24
6-[2-[3- (Dimethylamino) -1-pyrrolidinyl] -4-(2-thienyl)- l,3-thiazol-5-yl] -3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 1.80-2.00(IH, m) , 2.19(6H, s), 2.80-2.89(IH, m) , 3.14-3.70(5H, m) , 6.79(IH, d, J=IO.OHz) , 7.03-7.10(1H, m) , 7.18-7.26(2H, m) , 7.62(IH, dd, J=I.0, 5.1 Hz), 13.1O(1H, brs).
Preparation 25 6-[2-[3-(Dimethylamino)-l-pyrrolidinyl]-4-(4- fluorophenyl)-1,3-thiazol-5-yl]-3(2H)-pyridazinone 1H NMR (200MHz, DMSO-d6) d 1.79-1.98(IH, m) , 2.19(6H, s), 2.81-2.96(1H, m) , 3.13-3.72(5H, m) , 6.7O(1H, d, J=9.9,Hz), 6.86(1H, d, J=9.9Hz), 7.26(2H, t, J=8.9Hz), 7.48-7.58(2H, m), 13.00(IH, brs).
Preparation 26
6-{2- [3- (Dimethylamino) -1-pyrrolidinyl] -4-phenyl-1,3- thiazol-5-yl}-4-methyl-3(2H)-pyridazinone Mass ESI (+) 382 (M+l) 1H NMR (200MHz, DMSO-d6) d 1.78-2.00( IH, m) , 2.19(6H, s), 2.80 -2.98 (IH, m) , 3.14-3.71 (8H, m) , 6.72 (IH, d, J=I.3 Hz) , 7.38-7.52(5H, m) , 12.89(1H, brs) .
Preparation 27
6-{2-[3-(Dimethylamino)-1-pyrrolidinyl] -4- [3- (trifluororaethyl)phenyl] -1,3-thiazol-5-yl}-3(2H)- pyridazinone
1H NMR (200MHz, DMSO-d6) d 1, 79-2.02(IH, m) , 2.19(6H, s), 2.80-2.99(IH, m) , 3.16-3.73(5H, m) , 6.71(IH, d, J=9.9 Hz) , 6.89(IH, d, J=9.9 Hz) , 7.60-7.70(IH, m) , 7.72-7.'83(2H, m) , 13.07(lH, brs).
Preparation 28 6-[2-[3-(Dimethylamino) -1-pyrrolidinyl] -4-(3- methylphenyl)-1,3-thiazol-5-yl] -3(2H)-pyridazinone 1H NMR (200MHz, DMSO-dβ) d 1.78-2.00(IH, m) , 2.19(6H, s), 2.33(3H, s), 2.79-2.97(lH, m) , 3.13-3.27(1H, m) , 3.30-3.27(4H, m) , 6.66(1H, d, J=IO.0 Hz), 6.82(1H, d, J=IO-O Hz), 7.18-7.37(4H, m) , 12.97(1H, s) .
Preparation 29
6- [2- [3-(Dimethylamino)-1-pyrrolidinyl] -4-(2- fluorophenyl)-1,3-thiazol-5-yl] -3(2H) -pyridazinone Mass ESI (+) 386 (M+l) 1H NMR (200MHz, DMSOd6) d 1.73-1.98( IH, m) , 2.20(6H, s), 2.73-2.92 ( IH, m) , 3.15-3.81 (5H, m) , 6.51 (IH, dd, J=I.6, 9.8 Hz), 6.71-7.04(2H, m) , 7.08-7.59(2H, m) , 7.73-7.86( IH, m) , 12.62(1H, brs).
Preparation 30
6-[2-(4-morpholinyl)-4-phenyl-l,3-thiazol-5-yl]-3(2H)- pyridazinone
Mass ESI(+) 341(M+1), 382 1H NMR (300MHz, CDCl3Jd 3.57 ( 4H, t, J=5.2 Hz), 3.84(4H, t, J= 5.2 Hz) , 6.67 (IH, d, J= 9.9 Hz) , 6.93 (IH, d, J= 9.9 Hz) , 7.35-7.55(5H, m) , 11.00(1H, br s).
Preparation 31 A mixture of 6- ( l-bromo-2-oxo-2-phenylethyl) -3(2H) - pyridazinone (250mg) and 4-methyl-3-thiosemicarbazide (98.7mg) in EtOH (5ml) was stirred for 6h at 90 °C. After cooling to room temperature, to the mixture was added potassium tert-butoxide (479mg) and DMF (ImI). The mixture was stirred for 2days at room temperature, diluted with brine and adjustedwith 6N HCl to pH 7 to give a precipitate. The obtained suspension was diluted with EtOAc-hexane and collected to give 6- [5-(methylamino) -3-phenyl-lH- pyrazol-4-yl]-3(2H) -pyridazinone (96mg) as brown solid. Mass ESI(+) 268(M+1) 1H NMR(300MHz, DMSO-d6)d 2.83 (3H, d, J= 6Hz), 6.71 (IH, d, J=9.7Hz), 7.91 (IH, d, J=9.7Hz), 7.46-7.50 (5H, m) .
The following compounds were obtained in a similar manner to that of Preparation 31.
Preparation 32
Ethyl { [1-methyl-4-(6-oxo-1,6-dihydro-3-pyridazinyl) -
3-phenyl-IH-pyrazol-5-yl]amino}acetate Mass ESI 354 (+) (M+l)
1H NMR (200MHz, DMSO-d6) d l.lO(3H, t, J=7.1 Hz), 3.73(3H, s), 3.86-4.02(4H, m) , 6.06(1H, t, J=6.7 Hz), 6.73(1H, dd,
J=2.09.7 Hz) , 6.93(IH, d, J=9.7 Hz) , 7.28(5H, m) , 13.02(IH, brs) .
Preparation 33
6 - [ 5 - ( Cyclohexylamino ) - 3 -phenyl- lH-pyrazol- 4 -yl ] - 3 ( 2H ) - pyridazinone
Mass ESI (+) 336 (M+l) 1H NMROOOMHZ, DMSO-d6)d 1.14-1.42 (5H, m) , 1.51-1.75 (3H, m) , 1.92-2.04 (2H, m) , 3.39-3.50 (IH, m), 6.69 (IH, d,
J=9.9Hz), 6.87 (IH, d, J=9.9Hz), 7.36-7.50 (5H, m) .
Preparation 34 6-[5-(Isopropylamino) -3-phenyl-lH-pyrazol-4-yl]-3(2H) - pyridazinone Mass ESI(+) 296 (M+l)
1H NMR(SOOMHZ, DMSO-d6)d 1.17 (6H, d, J=6.4Hz), 3.66-3.87 (IH, m) , 5.03-5.80 (IH, m) , 6.70 (IH, d, J=9.9Hz) , 6.89 (IH, d, J=9.9Hz), 7.36-7.54 (5H, m) , 12.21 (IH, brs) , 12.80 (IH, brs) .
Preparation 35
6-[1-Methyl-5-(methylamino)-3-phenyl-lH-pyrazol~4-yl]- 3(2H)-pyridazinone
Mass ESI(+) 282(M+1)
1H NMROOOMHZ, DMSO-d6)d 2.64 (3H, d, J=5.1Hz), 3.69 (3H, s), 5.50 (IH, q, J=5.1Hz), 6.76 (IH, d, J=9.9Hz), 7.09 (IH, d, J=9.9Hz), 7.25-7.37 (5H, m) .
Preparation 36
6-(5-{[2-(4-Morpholinyl)ethyl]amino}-3-phenyl-IH- pyrazol-4-yl) -3(2H) -pyridazinone
Mass ESI(+) 367(M+1) 1H NMR(SOOMHZ, CDCl3Jd 2.57-2.67 (4H, m) , 2.72 (2H, t, J=
6Hz), 3.38-3.46 (2H, m) , 3.78-3.87 (4H, m) , 6.69 (IH, d,
J= 9Hz), 6.98 (IH, d, J=9Hz), 7.39-7.48 (5H, m) .
Preparation 37 6-(5-Anilino-3-phenyl-lH-pyrazol-4-yl)-3(2H)~ pyridazinone Mass ESI(+) 330(M+l)
1H NMROOOMHZ, DMSO-d6)d 5.34 (IH, s), 6.76-6.84- (2H, m) , 7.01-7.13 (2H, m) , 7.23 (2H, t, J=8Hz), 7.41-7.60 (6H, m) , 8.36 (IH, brs) .
The following compounds were obtained in a similar manner to that of Example 35.
Preparation 38
6-{ [2-(4-Fluorophenyl) -1,3-dioxolan-2-yl]methyl}-2-
(2-methylphenyl)-3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 1.83(3H, s), 3.17(2H, s),
3.71-3.81(2H, m) , 3.95-4.04(2H, m) , 6.95-7.50(6H, m) .
Preparation 39
6-{ [2-(4-Fluoro-3-methylphenyl)-1,3-dioxolan-2-yl] - methyl}-2-(2-methylphenyl)-3(2H)-pyridazinone
Mass ESI (+) 381 (M+l) 1H NMR (200MHz, DMSO-d6) d 1.84(3H, s), 2.20(3H, d, J=I.7
Hz), 3.15(2H, s), 3.69-3.79(2H, m) , 3.91-4.01(2H, m) ,
6.95-7.37(8H, m), 7.46(1H, d, J=9.6 Hz).
Preparation 40 6-{[2-(2-chloro-4-fluorophenyl)-1,3-dioxolan-2-yl]- methyl}-2-(2-methylphenyl)-3(2H) -pyridazinone , Mass ESI (+) 401 (M+l)
1H NMR (200MHz, DMSO-(I6) d 1.83(3H, s), 3.36(2H, s), 3.69-3.85(2H, m) , 3.90-4.05(2H, m) , 6.93-7.04(2H, m) , 7.09-7.53(7H, m) .
Preparation 41
To a solution of 6-(5-amino-3-phenyl-lH-pyrazol-4-yl)-
3(2H)-pyridazinone hydrόbromide (571mg) in EtOH (6ml) was added 12N HCl (20.5mg) and malonaldehyde bis(dimethyl acetal) (309mg) at room temperature. After stirring for 4h at 700C, the mixture was diluted with H2O, adjusted with aq.3% NaHCO3 to pH 7 and extractedwith EtOAc. The separated organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica column chromatography elutingwith 2 to 5% methanol in CHCl3 to give 6-(2-phenylpyrazolo[l,5-a]pyrimidin-3-yl)-3(2H)- pyridazinone (280mg) as an amorphous solid. Mass ESI(+) 290(M+l) xH NMR(300MHz, DMSO-d6)d 6.99 (IH, d, J=9.9Hz), 7.18-7.25 (IH, m) , 7.41-7.52 (3H, m) , 7.62-7.23 (2H, m) , 7.30 (IH, d, J=8Hz), 8.65-8.70 (IH, m) , 9.22-9.28 (IH, m)..
Preparation 42 A mixture of 6-(l-bromo-2-oxo-2-phenylethyl) ~3(2H) - pyridazinone (300mg) and 4-ethyl-3-thiosemicarbazide (134mg) in AcOH (3ral) was stirred for 5h at 1000C. After cooling to room temperature, the mixture was diluted with EtOH (3ml) . The obtained suspension was aged for 30min with stirring on an ice bath, collected andwashedwith EtOH to give 6- [5- (ethylamino) -3~phenyl-lH-pyrazol-4-yl] - 3(2H) -pyridazinone hydrobromide (327mg) as a off-white solid.
Mass ESI(+) 282(M+1) 1H NMR(SOOMHZ, DMSO-d6)d 1.21 (3H, t, J=7.2Hz), 3.31 (2H, q, J=7.2Hz), 6.79 (IH, d, J=9.6Hz), 6.95 (IH, d, J=9.6Hz), 7.42-7.55 (5H, m) .
The following compounds were obtained in a similar manner to that of Preparation 42.
Preparation 43
6-[5-(Ethylamino)-3-(2-thienyl)-lH-pyrazol-4-yl]-3(2H)- pyridazinone hydrobromide 1H NMR (200MHz, DMSO-d6) d l.l8(3H, t, J= 7.5Hz), 3.25(2H, q, J=7.5Hz), 6.85(1H, d, J=9.5Hz), 7.12-7.23(2H, m) , 7.26-7.34(1H, m) , 7.69(1H, dd, J=I.0, 5.0Hz), 13.06(1H, brs) .
Preparation 44 6-[5-(Isobutylamino)-3-phenyl-lH-pyrazol-4-yl]-3(2H)~ pyridazinone hydrobromide Mass ESI(+) 310(M+l)
1H NMR(SOOMHZ, DMSO-d6)d 0.94 (6H, d, J=6.6Hz), 1.83-1.96 (IH, m) , 3.07 (2H, d, J=6.9Hz), 6.77 (IH, d, J=9.9Hz), 6.93 (IH, d, J=9.9Hz), 7.43-7.54 (5H, m) .
Preparation 45
6- [3-(4-Fluorophenyl)-5-(methylamino) -lH-pyrazol-4-yl] - 3(2H)-pyridazinone hydrobromide
Mass ESI(+) 286(M+1)
1HNMROOOMHZ, DMSO-d6)d 2.88 (3H, s) , 6.79 (IH, d, J=9.9Hz) ,
6.96 (IH, d, J=9.9Hz), 7.35 (2H, t, J=8.7Hz), 7.51 (2H, dt ,
J=3, 8.7Hz).
Preparation 46
6- [5-(Ethylamino) -3-(4-fluorophenyl) -lH-pyrazol-4-yl] -
3(2H)-pyridazinone hydrobromide
Mass ESI(+) 300(M+l) 1H NMROOOMHZ, DMSO-d6)d 1.20 (3H, t, J=7.2Hz), 3.29 (2H, q, J=7.2Hz), 6.79 (IH, d, J=9.9Hz), 6.95 (IH, d, J=9.9Hz),
3.35 (t, J=8.7Hz), 7.46-7.55 (2H, m) .
Preparation 47 6-{3- (4-Fluorophenyl)-5- [ (2-methoxyethyl)amino]-IH- pyrazol-4-yl}-3(2H) -pyridazinone hydrobromide
Mass ESI (+) 330 (M+l) , . 1H NMR(300MHz, DMSO-d6)d 3.29 (3H, s), 3.40 (2H, d, J=5Hz),
3.52 (2H, d, J=5Hz), 6.76 (IH, d, J=9.9Hz), 6.90 (IH, d, 5 J=9.9Hz), 7.34 (2H, t, J=9Hz), 7.46-7.55 (2H, m) .
Preparation 48
6- (5-Amino-3-phenyl-lH-pyrazol-4-yl) -3 (2H) ^pyridazinone hydrobromide 0 Mass ESI(+) 254(M+1)
1H NMROOOMHZ, DMSO-d6)d 6.82 (IH, d, J=8.9Hz), 7.01 (IH, d, J=8.9Hz), 7.34-7.55 (5H, m) .
Preparation 49 5 To a suspension of 6-(phenylethynyl)-3(2H)-pyridazinone (2.58g) in DMF (20ml) was added potassium tert-butoxide (1.55g) with ice cooling. After stirring for 15min, to this was added bromomethylcyclohexane (2.33g) and catalytic amount of tetrabuthylammonium iodide. The mixture was 0 stirred for lday at room temperature, diluted with EtOAc and washed with water. The separated organic layer was washed with aq. 2% citric acid, sat. NaHCO3 and brine, dried over Na2Sθ4 and concentrated in vacuo. The residue was purified by silica column chromatography (eluent; 5 EtOAc/hexane 1/4 to 1/2) to give 2-cyclohexylmethy1-6-(phenylethynyl)-3(2H) -pyridazinone (3;53g) as a brown oil. Mass ESI(+) 293(M+1)
1H NMR(300MHz, CDCl3)U 0.97-1.32 (5H, m) , 1.57-1.78 (5H, m) , 1.85-2.06 (IH, m) , 3.97 (2H, d, J=7.8Hz), 6.90 (IH, d, J= 9.9Hz), 7.25-7.59 (6H, m) .
Preparation 50
A mixture of 2-cyclohexylmethyl-6-(phenylethynyl) -3(2H)- pyridazinόne (3.52g) in methanesulfonic acid (5.08ml) -H2O (0.433ml) was stirred for 2h at 1000C. After cooling to room temperature, to this was added ice-water and EtOAc. The separated organic layer was washed with water, aq. 3% NaHCO3 andbrine, dried overN2SO4 and concentrated in vacuo. The residue was purified by silica column chromatography (eluent; EtOAc/hexane 1/2 to 1/1) to give 2-cyclohexylmethyl-6-(2-phenyl-2-oxoethyl)-3(2H)- pyridazinone (1.65g) as a brown oil. Mass ESI(+) 311(M+1) 1H NMR(300MHz, CDCl3Jd 0.94-1.28 (5H, m) , 1.55-1.75 (5H, m) , 1.84-1.98 (IH, m) , 3.97 (2H, d, J= 7.2Hz), 4.29 (2H, s), 6.90 (IH, d, J= 9.6Hz), 7.19 (IH, d, J= 9.6Hz), 7.50 (2H, t, J= 7.8Hz), 7.60 (IH, t, J=7.8Hz), 8.02 (IH, d, J=7.8Hz). Preparation 51
A mixture of 2~cyclohexylmethyl-6~(2-phenyl-2-oxoethyl) - 3(2H)-pyridazinone (1.14g) and N,N-dimethylformamide dimethylacetal (4.88ml) was stirred for 5h at 900C and concentrated in vacuo to give 6- [ (E) -1-benzoyl-2- (dimethylamino)vinyl] -2-(cyclohexylmethyl)-3(2H) - pyridazinone (1.68g) as a brown oil that was used to next reaction without further purification. Mass ESI(+) 366(M+1)
Preparation 52
A mixture of 6- [ (E)-l-benzoyl-2-(dimethylamino)vinyl]- 2-(cyclohexylmethyl)-3(2H) -pyridazinone (880mg) and N,N-dimethylformamide dimethylacetal (6.76g) was refluxed for 12h and concentratedinvacuo. The residuewas dissolved
in toluene (10ml). To this was addedNH2OH'HCl(591mg) . After reflux for Ih, the mixture was cooled to room temperature, washedwith 3% aq. NaHCO3, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc/hexane, 1/1) to give
2-(cyclohexylmethyl)-6-(5-phenyl-4-isoxazolyl)-3(2H) - pyridazinone (832mg) as a yellow oil.
Mass ESI(+) 336(M+1)
1H NMR(300MHz, CDCl3Jd 1.01-1.30 (5H, m) , 1.62-1.78 (5H,
m), 1.91-2.05 (IH, m) , 4.05 (2H, d, J= 7.5Hz), 6.87 (IH, d, J=9.9Hz) , 7.17 (IH, d, J=9.9Hz), 7.45-7.55 (3H, m) , 7.67
(2H, dd, 3=2, 8Hz), 8.56 (IH, s) .
Preparation 53 A mixture of 2- (cyclohexylmethyl)-6-(5-phenyl-4- isoxazolyl) -3(2H)-pyridazinone (623mg), IN aq. NaOH (3.71ml) and THF (0.5ml) was stirred for 3h at 50 °C. After cooling to room temperature, the mixture was adjusted with 4N aq. HCl to pH3 and extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4 and evaporatedinvacuo to give 2-[1-(cyclohexylmethyl)-6-oxo- 1,6-dihydro-3-pyridazinyl] -3-oxo-3-phenylpropanenitrile (512mg) as a yellow solid. Mass ESI(+) 336(M+1)
Preparation 54
A solution of ethyl { [3-(dimethylamino) -1-pyrrolidinyl] - carbonothioyl}carbamate ( 3.Og) in cone HCl (24ml) was stirredfor Ih at 100°C. After cooling to room temperature, the mixture was concentrated in vacuo. The residual solid was triturated with MeOH to give 3-(dimethylamino)-1-pyrrolidinecarbothioamide hydrochloride (1.8g) as a white solid. 1H NMR (200MHz, DMSO-d6) d 1.29(3H, t, J=7.0 Hz), 1.84-2.00(1H, m) , 2.07-2.23(1H, m) , 2.26(3H, s), 2.29(3H, s), 2.69-2.93(1H, m) , 3.53-4.08(4H, m) , 4.10-4.30(2H, m) , 7.29-7.40(1H, m) .
Preparation 55 A mixture of 6-[5-(ethylamino)-3-phenyl-lH-pyrazol-4- yl] -3(2H)-pyridazinone hydrobromide (20Omg) , di-tert-butyl dicarbonate (241mg) and IN NaOH (1.66ml) in dioxane (2ml) was stirred for 14h at room temperature. After dilution with EtOAc, the mixture was washed with 3% NaHCO3 and brine, dried and concentrated in vacuo. The residual oil was purified by column chromatography on SiO2 (eluent; 1% to 2% methanol in dichlorometahne) to afford tert-butyl 5-(ethylamino)-4-(6-oxo-1,6-dihydro-3- pyridazinyl) -3-phenyl-lH-pyrazole-l-carboxylate (176mg) as an amorphous solid. ESI(+) 382 (M+l)
1H NMR (200MHz, DMSO-d6) d l.20(3H, t, J=7.1 Hz), 1.58(9H, s), 3.20-3.37(2H, m) , 6.8O(1H, d, J=9.9 Hz), 6.89(1H, d, J=9.9 Hz), 7.40-7.54(5H, m) , 12.37(1H, brs).
Preparation 56
The mixture of 6- [2-(4-fluorophenyl)-2-oxoethyl]-3(2H)- pyridazinone (4.8g), ethylene glycol (9.6ml) and toluenesulfonic acid hydrate (393mg) in toluene (96ml) was refluxed for 6h with azeotropic removal of water. After concentration, the residue was partitioned between EtOAc ' and sat. NaHCO3. The organic layer was washed with brine, dried and evaporated in vacuo. The residual oil was diluted with hexane, collected and dried in vacuo to give 5 6-{[2-(4-fluorophenyl)-l,3-dioxolan-2-yl]methyl}-3(2H)- pyridazinone (3.04g) as a white solid.
1H NMR (200MHz, DMSO-d6) d 3.10(2H, s), 3.67-3.74(2H, m) , 3.89-3.97(2H, m) , 6.76(IH, d, J=9.8 Hz) , 7.11-7.20(2H, m) , 7.28(1H, d, J=9.8 Hz), 7.33-7.40(2H, m) , 12.76(IH, s). 10
The following compounds were obtained in a similar manner to that of Preparation 56.
Preparation 57 15 6-{[2-(4-Fluoro-3-methylphenyl)-l,3-dioxolan-2-yl]- methyl}-3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d.2.22(3H, d, J=I.7 Hz), 3.09(2H, s), 3.64-3.75(2H, m) , 3.85-3.96(2H, m) , 6.77(1H, d, J=9.7
Hz), 7.02-7.20(2H, m) , 7.22-7.31(2H, m) , 12.76(1H, brs). 20
Preparation 58
6-{[2-(2-Chloro-4-fluorophenyl)-1,3-dioxolan-2-yl] - methyl}-3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 3.30(2H, s), 3.66-3.81(2H, m) ,
25 3.85-4.00(2H, m) , 6.77(IH, d, J=9.7 Hz), 7.17(1H, dt, J=2.9, 8 . 2 Hz ) , 7 . 30 ( IH , d , J=9 . 7 Hz ) , 7 . 40 - 7 . 51 ( 2H , m) , 12 . 74 ( IH , brs ) .
Preparation 59 To a solution of 6-{ [2-(4-fluorophenyl) -1,3-dioxolan-2- yl]methyl}-2-(2-methylphenyl) -3(2H) -pyridazinone (2.16g) in THF (20ml) was added cone HCl (2ml) at room temperature. After stirring for 14h, the mixture was concentrated and partitioned between EtOAc andwater. The organic layer was washed with 3% NaHCO3 and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (eluent; 30% to 50% EtOAc in dichloromethane) to give 6- [2-(4-fluorophenyl)-2- oxoethyl]-2-(2-methylphenyl)-3(2H)-pyridazinone (1.64g) as pale yellow wax.
1HNMR (200MHz, DMSO-d6) d2.01(3H, s) , 4.51(2H, s) , 7.08(1H, d, J=9.6 Hz), 7.20-7.47(4H, m) , 7.53(1H, d, J=9.6 Hz), 8.05-8.18(2H, m) .
The following compounds were obtained in a similar manner to that of Preparation 59.
Preparation 60
6- [2-(4-Fluoro-3-methylphenyl)-2-oxoethyl]-2-(2- methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 337 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.30(3H, d, J=I.6 Hz), 4.49(2H, s), 7.08(1H, d, J=9.6 Hz), 7.20-7.40(5H, m) , 7.52(1H, d, J=9.6 Hz), 7-87-8.04(2H, m) .
Preparation 61
6-[2-(2-Chloro-4-fluorophenyl) -2-oxoethyl] -2-(2- methylphenyl) -3(2H) -pyridazinone
1HNMR (200MHz, DMSO-d6) dl.99(3H, s) , 4.43(2H, s), 7.09(1H, d, J=9.7 Hz), 7.19-7.46(5H, m) , 7.52(1H, d, J=9.7 Hz), 7.6O(1H, dd, J=2.5, 9.0 Hz), 7.91-8.02(IH, m) .
Preparation 62
A mixture of 6-{3-(4-fluorophenyl) -5- [ (2-methoxyethyl)- amino] -lH-pyrazol-4-yl}-3(2H) -pyridazinone hydrobromide (310mg), di-tert-butyl dicarbonate (330mg) and IN NaOH (2.27ml) in dioxane (3ml) was stirred for 14h at room temperature. After dilution with EtOAc, the mixture was washed with 3% NaHCO3 and brine, dried over Na2SO4 and , concentrated in vacuo. The residue was purified by column chromatography on SiO2 (eluent: 1% to 2% methanol to dichloromethane) to give tert-butyl
3-(4-fluorophenyl) -5- [ (2-methoxyethyl)amino] -4-(6-oxo- l,6-dihydro-3-pyridazinyl) -lH-pyrazole-1-carboxylate (162mg) as a yellow amorphous solid. ESI(+) 430 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.58(9H, s), 3.27(3H, s), 3.31-3.59(4H, m) , 6.81(1H, d, J=IO.0 Hz), 6.88(1H, d, J=IO.0 Hz) , 7.28- 7.40 (2H, m) , 7.48-7.59 (2H, m) , 12.40 (IH,
brs) .
Preparation 63
A mixture of 4-fluoro-3-methylbenzoic acid (15.2g) and
H2SO4 (4.5ml) in methanol (150ml) was refluxed for 4h. After cooling to room temperature, the mixture was poured into a mixture of diisopropyl ether (200ml) and cold water (400ml) with stirring. The separated aqueous layer was extratedwith diisopropylether. The combined organic layer was washedwith saturatedNaHCO3 andbrine, dried over Na2SO4 and concentrated in vacuo to afford methyl
4-fluoro-3-methylbenzoate (17.Ig) as a pale yellow oil. 1HNMR (200MHz, DMSO-d6) d2.29(3H, d) , 3.84(3H, s) , 7.28(1H, t, J=9.3 Hz), 7.79-7.97(2H, m) .
The following compound was obtained in a similar manner to that of Preparation 63.
Preparation 64
Methyl 2-chloro-4-fluorobenzoate 1H NMR (200MHz, DMSO-d6) d 3.84(3H, s), 7.28(1H, t, J=9.3 Hz ) , 7 . 80 - 7 . 98 ( 2H , m) .
Preparation 65
A suspension of tert-butyl 1-piperazinecarboxylate (200mg) and N-methyl-N-phenylhydrazinecarbothioamide (195mg) in acetonitril (ImI) was refluxed for 6h. After cooling at room temperature, a separated solid was collected and washed with acetonitril to give tert-butyl 4-(hydrazinocarbonothioyl)-1-piperazinecarboxylate (96mg).
1H NMR (200MHz, DMSO-d6) d 1.41(9H, s), 2.80-2.89(IH, m) , 3.18-3.52(4H, m) , 3.65-3.79(4H, m) .
Preparation 66 To a solution of ethyl isothiocyanatidocarbonate (2.76g) in THF (18ml) was added dropwise N,N-dimethyl-3- pyrrolidinamine (2.4g) with ice cooling. After Ih with stirring at ambient temperature, the mixture was diluted with hexane (12ml) to give a solid. The suspension was aged for 30min, collected and dried in vacuo to afford ethyl { [3-(dimethylamino)-1-pyrrolidinyl]carbonothioyl}- carbamate (3.55g) as a tan solid (3.55g). 1H NMR (200MHz, DMSO-d6) d 1.21(3H, dt, J=O.7, 7.1 Hz), 1.65-1.92(1H, m), 2.01-2.22(6H, m) , 2.67-2.85(IH, m) , 3.28-3.88(5H, m) , 4.09(2H, dq, J=I.6, 7.1 Hz), 9.91(1H, brs) .
The following compounds were obtained in a similar manner to that of Preparation 42.
Preparation 67
6-[5-(Methylamino)-3-(3-methylphenyl)-lH-pyrazol-4-yl] -
3(2H)-pyridazinone hydrobromide
Mass ESI(+) 282(M+1)
Preparation 68
6-[5-(Ethylamino)-3-(3-methylphenyl)-lH-pyrazol-4-yl]-
3(2H) -pyridazinone hydrobromide
Mass ESI(+) 296(M+l)
Preparation 69
To the stirring solution of 6- [2-(3-methylphenyl) -2- oxoethyl]-3(2H) -pyridazinone (16 g) in ethyl acetate (240 mli) and AcOH (3.2 mL) was added pyridinium tribromide (24.7 g) at 50C. After 0.5 h, ethyl acetate and NaCO3aq were added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in EtOH (240 mL) and to this was added thiourea (5.34 g) and the mixture warmed to 800C. After Ih, the reaction mixture was neutralized with NaHCO3 aq and concentrated. Water was added and the mixture was filtered to give 6- [2-amino-4-(3-methylphenyl) -1,3-thiazol-S- yl] -3(2H) -pyridazinone (17 g). Mass ESI(+) 285(M+1) 1H NMR (DMSO-d6,d) : 2.31(3H, s), 6.66(1H, d, J= 9.5 Hz), 6.87(1H, d, J= 9.5 Hz) , , 7.15-7.35(4H, m) , 7.4Q(2H, br s), 12.93(1H, br s) .
The following compounds were obtained in a similar manner to that of Preparation 69.
Preparation 70
6-[2-(Methylamino)-4-phenyl-l,3-thiazol-5-yl]-3(2H)- pyridazinone Mass ESI(+) 285(M+1)
1H NMR (DMSO-d6,d): 2.86(3H, d, J= 4.6 Hz), 6.66(1H, br d, J= 9.9 Hz), 6.84(1H, d, J= 9.9 Hz), 7.35-7.55(5H, m) , 7.95(1H, q, J= 4.6 Hz), 12.6(1H, br s).
Preparation 71
5-(6-Methoxy-3-pyridazinyl)-4-(4-methylphenyl) -1,3- thiazol-2-amine
Mass ESI(+) 299(M+l)
1H NMR (CDCl3,d) : 2.40(3H, s) , 4.12(3H, s) , 5.28(2H, br s) , 6.67(1H, d, J= 9.5 Hz), 7.13(1H, d, J= 9.5 Hz), 7.2O(1H, d , J= 7 . 7 Hz ) , 7 . 38 ( 1H , d , J= 7 . 7 Hz ) .
Preparation 72
To the stirring solution of p-methylacetophenone (7.89 g) in THF (150 mL) was addedNaOtBu (3.99 g) at room temperature and the mixture was stirred for 20min. To this was added BINAP (2,2' -bis(diphenylphosphino) -1,1' -binaphtyl) (1.08 g), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium) (792 mg) under argon. After 10 min, 3-chloro-6-methoxypyridazine (5 g) was added. The reaction mixture was warmed to 750C and stirred for Ih. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The residue was purified by Si02-chromatogaphy (hexane: ethyl acetate=2: 1- 1: 1) to give 2-(6-Methoxy-3-pyridazinyl)-1- (4-methylphenyl)ethanone (4 g) . Mass ESI(+) 243(M+1)
1HNMR (CDCl3,d): 2.39(1.5H, s), 2.42(1.5H, s), 4.03(1.5H, s), 4.12(1.5H, s), 6.88(1H, d, J= 9.2 Hz), 6.95(1H, d, J= 9.2 Hz), 7.17(1H, d, J= 9.2 Hz), 7.22(1H, d, J= 7.6 HZ), 7.28(1H, d, J= 7.6 Hz), 7.42(1H, d, J= 9.2 Hz), 7.76(1H, d, J= 8.0 Hz), 7.99 (IH, d, J= 8.0 Hz).
Preparation 73 To a stirring solution 5-(6-methoxy-3-pyridazinyl)-4-(4- methylphenyl) -1,3-thiazol-2-amine (0.13 g) in dioxane (0.78 mL) was added, cone. HCl (0.39 mL) at rt. The solution was stirred for 6h at 500C. NaHCO3aq was added and the reaction mixture was extracted with ethyl acetate, dried over Na2SO4 and concentrated to give 6- [2-amino-4-(4- methylphenyl) -1,3-thiazol-5-yl] -3(2H)-pyridazinone (48 mg) .
Mass ESI(+) 285(M+l)
1H NMR (DMSO-d5,d): 2.34(3H, s), 6.66(1H, d, J= 10.0 Hz), 6.89(1H, d, J= 10.0 Hz), 7.20(2H, d, J= 8.2 Hz), 7.34(2H, d, J= 8.2 Hz), 7.38 (2H, br s), 12.92(1H, br s).
The following compound was obtained in a similar manner to that of Preparation 63.
Preparation 74
6-[2~Amino-4-(2-methylphenyl)-l,3-thiazol-5-yl]-3(2H)- pyridazinone
Mass ESI(+) 285(M+l) 1H NMR (DMSO-d6,d): 2.15(3H, s), 6.45(1H, d, J= 9.8 Hz),
6.69(1H, d, J= 9.8 Hz), 7.15-7.40(4H, m) , 7.42(2H, br s),
12.88(1H, br s) .
Example 1 A mixture of 1- (2-phenylpyrazolo[1,5-a]pyridin-3~ yl)ethanone (1.0Og) and glyoxylic acid monohydrate (l:56g)in 1,2-dimethoxyethane (3ml) was refluxed for 15h. The mixture was concentrated in vacuo and taken up EtOAc (5ml) and water (4ml) . The aqueous layer was extracted with EtOAc (3ml) . The combined organic layer were washed with water (3ml) and concentrated in vacuo to give an oil. To , the oil was added hydrazine monohydrate (1.36g) , EtOH (3ml) and AcOH (3ml) and the mixture was stirred for 8h at 100 0C. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The separated organic layer was washed with sat. NaHCO3 and brine, dried and evaporated in vacuo. The obtained residue was purified by silica column chromatography (eluent; EtOAc/hexaήe 1/2 to 1/1) and preparative TLC (eluent; EtOAc/hexane 1/1) followedby crystallization byEtOAc-hexane (1/3) to afford 2-(2,6-dichloropheny1)-6-(2-phenylpyrazolo[1,5-a] - pyridin-3-yl)-3(2H)-pyridazinone (38.5mg) as a yellow solid. Mass ESI(+) 433(M+1) 1H NMR(300MHz, CDCl3Jd 6.89 (IH, t, J=8Hz), 6.92 (IH, d, J=9.8Hz), 7.12 (IH, d, J=9.8Hz), 7.26 (IH, t, J=8Hz), 7.36-7.43 (IH, m) , 7.45-7.56 (5H, m) , 7.64-7.71 (2H, m) , 7.95 (IH, d, J=8.3Hz), 8.56 (IH, d, J=8.3Hz).
The following compounds were obtained in a similar manner to that of Preparation 23.
Example 2
6- [2-Amino-4- (4-fluorophenyl) -l,3-thiazol-5-yl] -2- (2-methγlphenyl)-3(2H) -pyridazinone
Mass ESI (+) 379 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.08(3H, s), 6.9O(1H, d, J=9.9
Hz) , 7.03(1H, d, J=9.,9 Hz) , 7.20-7.41(6H, m) , 7.45-7.62(4H, m) .
Example 3
6- [2-Amino-4- (4-fluoro-3-methylphenyl) -1,3-thiazol-5- yl] -2-(2-methylphenyl) -3(2H)-pyridazinone
Mass ESI (+) 393 (M+l) 1H NMR (200MHz, DMSO-d5) d 2.08(3H, s), 2.26(3H, d, J=I.5
Hz), 6.89(1H, d, J=9.9Hz), 7.05(1H, d, J=9.9 Hz), 7.18(1H, t, J=9.6 Hz), 7.30-7.51(8H, m) .
Example 4 6- [4- (4-Fluorophenyl)-2-(4-methyl-1-piperazinyl) -1,3- thiazol-5-yl] -2-(2-methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 462. (M+l)
1H NMR (200MHz, DMSO-d5) d 2.08(3H, s), 2.21(3H, s), 2.34-2.46(4H, m), 3.40-3.52(4H, m), 6.92(1H, d, J=9.8 Hz) , 7.03(1H, d, J=9.8 Hz) , 7.21-7.42(6H, m) , 7.52-7.64(2H, m) . Example 5
6- [2-Amino-4-(2-chloro-4-fluorophenyl)-1,3-thiazol-5- yl] -2-(2-methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 413 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.04(3H, s), 6.77(1H, d, 3=9.9 Hz), 6.90(IH, d, J=9.9 Hz) , 7.21-7.40(4H, m) , 7.45-7.64(3H, m) .
Example 6
A mixture of 6- [2-amino-4-(4-fluorophenyl)-1,3-thiazol- 5-yl] -3(2H) -pyridazinone (17.4g), l-oxaspiro[2.5]octane (9.14g) and IN NaOH (72ml) in dioxane (210ml) was refluxed for 5h. After cooling to room temperature, the mixture was diluted with water (100ml) to give a solid. The crude solid was recrystallized from EtOH (450ml) and H2O (60ml) to give 6- [2ramino-4-(4-fluorophenyl) -1,3-thiazol-5-yl]-2-[ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone (16.7g) as pale yellow crystals. Mass ESI(+) 401(M+l)
1H NMR(300MHz, CDCl3Jd 1.28-1.76 (1OH, m) , 4.06 (IH, s), 4.28 (2H, s), 5.28 (2H, s), 6.74 (IH, d, J=9.6Hz), 6.94 (IH, d, J=9.6Hz), 7.11 (2H, t, J=8Hz), 7.43-7.51 (2H, m) .
The following compounds were obtained in a similar manner to that of Example 6.
Example 7
6-[2-[3-(Dimethylamino) -1-pyrrolidinyl] -4-(2-thienyl) - 1,3-thiazol-5-yl] -2- [ (1-hydroxycyclohexyl)methyl] - 3(2H)-pyridazinone Mass ESI (+) 486 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.08-1.68(1OH, m) , 1.79-2.00(IH, m), 2.19(6H, s), 2.8O-2.98(1H, m) , 3.14-3.70(5H, m) , 4.06(2H, s), 4.43(1H, s), 6.85(1H, d, J=9.7 Hz),
7.03-7.11(1H, m) , 7.18-7.27(3H, m) , 7.65(IH, dd, J=O.9, 5.0 Hz).
Example 8 6-[2-[3-(Dimethylamino)-l-pyrrolidinyl]-4-(4- fluorophenyl) -1,3-thiazol-5-yl] -2-(2-hydroxy-2- methylpropyl)-3(2H) -pyridazinone
Mass ESI (+) 458 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.13(6H, s), 1.78-2.02(IH, m) , 2.19(6H, s), 2.8O-2.99(1H, m) , 3.14-3.72(5H, m) , 4.03(2H, s), 4.67(1H, s), 6.76(1H, d, J=9.8 Hz), 6.86(1H, d, J=9.8
Hz), 7.26(2H, t, J.=8.9 Hz), 7.49-7.60(2H, m) .
Example 9 6-{2-[3-(Dimethylamino) -1-pyrrolidinyl] -4-[3- (trifluoromethyl)phenyl] -1,3-thiazol-5-yl}-2-[ (1- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone 1HNMR (200MHz, DMSO-d6) d 1.04-1.63(1OH, m) , 1.80-2.01(IH, m), 2.19(6H, s), 2.80-2.98(IH, m) , 3.16-3.73(5H, m) , 4.04(2H, s), 4.41(1H, s), 6.78(iH, d, J=9.7 Hz), 6.91(1H, d, J=9.7 Hz), 7.59-7.70(1H, m) , 7.74-7.83(3H, m) .
Example 10
2-[ (1-Hydroxycyclohexyl)methyl] -6-[5-(methylamino)-3- phenyl-lH-pyrazol-4-yl] -3(2H) -pyridazinone
Mass ESI(+) 380(M+l)
1H NMR(SOOMHZ, CDCl3Jd 1.28-1.75 (1OH, m) , 3.02 (3H, s) ,
4.31 (2H, s), 6.71 (IH, d, J=9.7Hz), 6.91 (IH, d, J=9.7Hz),
7.37-7.50 (5H, m) .
Example 11
2-[ (1-Hydroxycyclohexyl)methyl] -6-(2-phenylpyrazolo-
[l,5-a]pyrimidin-3-yl) -3(2H) -pyridazinone
Mass ESI(+) 402(M+l)
1H NMROOOMHZ, DMSO-d6)d 0.98-1.55 (1OH, m) , 3.99 (2H, s),
4.48 (IH, s), 7.07 (IH, d, J=9.9Hz), 7.19-7.25 (IH, m) ,
7.41-7.50 (3H, m), 7.65-7.72 (2H, m) , 7.84 (IH, d, J=9.9Hz) ,
8.65-8.70 (IH, m) , 9.23-9.28 (IH, m) .
Example 12 6-(2-Amino-4-phenyl-1,3-thiazol-5-yl) -2- [ (1- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone Mass ESI(+) 383(M+1)
1H NMR (300MHz, DMSO-d6)d 1.00-1.70 (1OH, m) , 4.04(2H, s), 4.44(IH,s) , 6.73(IH, d, J= 9.5 Hz) , 6.86(IH, d, J= 9.5 Hz) , 7.35-7.55(7H, m) .
Example 13 6-[2-Amino-4-(4-methylphenyl)-l,3-thiazol-5-yl]-2- [ (1-hydroxycyclohexyl)methyl] -3(2H) -pyridazinone Mass ESI(+) 397(M+1)
1H NMR (300MHz, DMSO-d6)d 1.00-1.70 (1OH, m) , 2.34(3H, s), 4.04(2H, S), 4.44(1H, s), 6.74(1H, d, J= 9.8 Hz), 6.9O(1H, d, J= 9.8 Hz), 7.21 (2H, d, J= 8.4 Hz), 7.36(2H, d, J= 8.4 Hz) 7.41(2H, br s) .
Example 14
6- [2-Amino-4-(3-methylphenyl)-1,3-thiazol-5-yl] -2-[ (1- hydroxycyclohexyl)methyl]-3(2H)-pyridazinone Mass ESI(+) 397(M+1)
1H NMR (300MHz, DMSO-d6)d 1.10-1.70 (1OH, m) , 2.37(3H, s), 4.10(2H, s), 4.5O(1H, s), 6.79(1H, d, J= 9.6 Hz), 6.94(1H, d, J= 9.6 Hz), 7.20-7.40(4H, m) , 7.48(2H, br s).
Example 15 6-[2-Amino-4-(2-methylphenyl)-l,3-thiazol-5-yl]-2-[ (1- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone Mass ESI(+) 397(M+1)
1H NMR (300MHz, DMSO-d6)d 1.00-1.70 (1OH, m) , 2.16(3H, s), 4.00(2H, s), 4.43(1H, s), 6.45(1H, d, J= 9.6 Hz), 6.67(1H, d, J= 9.6 Hz), 7.15-7.40(4H, m) , 7.43(2H, br s).
Example 16
2- [ (1-Hydroxycyclohexyl)methyl] -6- [2-(methylamino) -4- phenyl-l,3-thiazol-5-yl] -3(2H)-pyridazinone Mass ESI(+) 397(M+1)
1H NMR (300MHz, DMSO-d6)d 1.10-1.70(1OH, m) , 2.86(3H, d, J= 4.8 Hz), 4.04(2H, s), 4.43(1H, s), 6.73(1H, d, J= 9.8 Hz), 6.85(1H, d, J= 9.8 Hz), 7.40-7.55(5H, m) , 7.95(1H, q, J= 4.8 Hz) .
Example 17
2- [ (1-Hydroxycyclohexyl)methyl] -6- [2-(4-morpholinyl) -4- phenyl-1,3-thiazol-5-yl] -3(2H)-pyridazinone Mass ESI(+) 453(M+1)
1H NMR (300MHz, CDCl3Jd 1.20-1.80(1OH, m) , 3.57(4H, t, J= 5.2 Hz), 3.83(4H, t, J= 5.2 Hz) , 4.18(1H, s), 4.28(2H, s), 6.68(IH, d, J= 9.8 Hz), 6.91(IH, d, J= 9.8 Hz) , 7.35-7.55(5H, m). Example 18
6-(5-Anilino-3-phenyl-lH-pyrazol-4-yl)-2-[ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone Mass ESI(+) 442(M+1) 1H NMROOOMHZ, DMSO~d6)d 1.15-1.66 (1OH, m) , 4.19 (2H, s),
4.84 (IH, s), 6.75-6.85 (2H, m) , 6.92 (IH, d, J=9.8Hz), 7.22
(2H, t, J=8Hz) , 7.46-7.54 (5H, m) , 7.64-7.75 (2H, m) , 8.52
(IH, s) .
Example 19
6- [5-(Cyclohexylamino) -3-phenyl-lH-pyrazol-4-yl] -2-[ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone -
Mass ESI(+) 448(M+l)
1HNMROOOMHZ, DMSO~d6)d 1.20-1.84 (18H, m) , 2.07-2.19 (2H, m), 3.47-3.62 (IH, m) , 4.15 (IH, s), 4.30 (2H, s), 5.70-5.84
(IH, m) , 6.72 (IH, d, J=9.8Hz), 6.93 (IH, d, J=9.8Hz),
7.37-7.51 (5H, m) .
Example 20 2- [ (1-Hydroxycyclohexyl) methyl] -6- [ 5- (isoprόpylamino) - 3-phenyl-lH-pyrazol-4-yl] -3(2H) -pyridazinone Mass ESI(+) 408(M+l)
1HNMROOOMHZ, CDCl3Jd 1.30 (6H, d, J=6.6Hz), 1.45-1.75 (1OH, m), 3.78-3.92 (IH, m) , 4.05 (IH, brs), 4.30 (2H, s), 5.66 (IH, brs), 6.72 (IH, d, J=9.8Hz), 6.92 (IH, d, J=9.8Hz), 7.38-7.50 (5H, m) .
Example 21
2- [ (1-Hydroxycyclohepty1)methyl] -6- [5-(methylamino)-3- phenyl-lH-pyrazol-4-yl] -3(2H) -pyridazinpne
Mass ESI(+) 394(M+1)
1H NMR(300MHz, DMSO-d6)d 1.28-1.70 (7H, m) , 2.83 (3H, d,
J=5Hz), 4.12 (2H, s), 4.77 (IH, brs) , 6.74 (IH, d, J=9.8Hz),
6.84 (IH, d, J=9.8Hz), 7.35-7.50 (5H, m) .
Example 22
2- [ (1-Hydroxycyclohexyl)methyl] -6- [1-methyl-5-(methyl- amino) -3-phenyl-lH-pyrazol-4-yl]-3(2H)-pyridazinone
Mass ESI(+) 394(M+1) 1H NMR(300MHz, CDCl3Jd 1.28-1.77 (1OH, m) , 2.86 (3H, d,
J=6Hz), 3.83 (IH, s), 3.87 (3H, s), 4.32 (2H, s), 5.64 (IH, q, J=6Hz), 6.75 (IH, d, J=9.9Hz), 6.94 (IH, d, J=9.9Hz),
7.36-7.97 (5H, m) .
Example 23
2-[ (1-Hydroxycyclohexyl)methyl]-6-(5-{[2-(4- morpholinyl)ethyl]amino}-3-phenyl-lH-pyrazol-4-yl) - 3(2H)-pyridazinone Mass ESI(+) 479(M+1) 1HNMR(SOOMHZ, DMSO-d6)d 1.30-1.65 (1OH, m), 2.36-2.59 (8H, m) , 3.59 (4H, t, J=3.8Hz) , 4.13 (2H, s), 4.57 (IH, s), 6.75
(IH, d, J=9.8Hz), 6.84 (IH, d, J=9.8Hz), 7.36-7.50 (5H, m) .
Example 24 2- [ (1-Hydroxycyclohexyl)methyl] -6-(2-phenylpyrazolo- [l,5-a]pyridin-3-yl)-3(2H)-pyridazinone Mass ESI(+) 401(M+l)
1H NMR(300MHz, CDCl3Jd 1.30-1.80 (1OH, m) , 4.37 (IH, s), 4.40 (2H, s), 6.83 (IH, d, J=9.6Hz), 6.90-6.96 (IH, m) , 7.06 (IH, d, J=9.6Hz), 7.29-7.36 (IH, m) , 7.43-7.50 (3H. m) , 7.55-7.63 (2H, m) , 7.97 (IH, d, J=9Hz), 8.54 (IH, d, J=7.5Hz) .
Example 25 To a solution of 6- [2-amino~4~(4-fluorophenyl) ~1,3- thiazol-5-yl] -2-[ (1-hydroxycyclohexyl)methyl] -3(2H) - pyridazinone (200mg) in pyridine (1.58g) was added ethyl chloroformate (190mg) at room temperature. After 12h, the mixture was concentrated and triturated with water to give a crude solid (170mg) . The solid was dissolved in EtOAc and washed with IN HCl, sat. NaHCO3 and brine, dried and evaporated in vacuo. The residue was crystallized from EtOH-H2O (3ml-ImI) to give ethyl (4-(4-fluorophenyl)-5- {1- [ (1-hydroxycyclohexyl)methyl] -6-oxo-1,6-dihydro-3- pyridazinyl}-l,3-thiazol-2-yl)carbamate (91mg) as a pale yellow solid. Mass ESI(+) 473(M+1)
1HNMROOOMHZ, CDCl3Jd 1.31 (3H, t, J=6.9Hz), 1.35-1.74 (IOH, m), 4.04 (IH, s) , 4.22-4.33 (2H, m) , 6.79 (IH, d, J= 9.6Hz) , 6.98 (IH, d, =9.6Hz) , 7.12 (2H, t, J= 8.4Hz) , 7.44-7.52 (2H, m), 8.74 (IH, brs).
The following compounds were obtained in a similar manner to that of Example 25.
Example 26
N- [5-{l- [ (1-Hydroxycyclohexyl)methyl] -6-oxo-l,6- dihydro-3-pyridazinyl}-4-(3-methylphenyl) -1,3-thiazol-
2-yl]acetamide Mass ESI(+) 439(M+1)
1H NMR (300MHz, CDCl3Jd 1.20-1.80(1OH, m) , 1.82(3H, s),
2.37(3H, s), 4.09(1H, s), 4.33(2H, s), 6.77(1H, d, J= 9.6
Hz), 7.01(1H, d, J= 9.6 Hz), 7.20-7.40(4H, m) , 1O.59(1H, br s) .
Example 27 ethyl [5-{l- [ (1-Hydroxycyclohexyl)methyl] -6-oxo-l,6- dihydro-3-pyridazinyl}-4-(3-methylphenyl) -1,3-thiazol-
2-yl]carbamate Mass ESI(+) 469(M+1) 1HNMR (300MHz, CDCl3)d 1.30(3H, t, J= 7.1 Hz) , 1.30-1.80(1OH, m) , 2.37(3H, s), 4.12(1H, s), 4.26(2H, q, J= 7.1 Hz), 4.31(2H, s) , 6.74(IH, d, J= 9.9 Hz) , 6.99(IH, d, J= 9.9 Hz) , 7.20-7.35(4H, m) , 8.7O(1H, br s).
The following compounds were obtained in a similar manner to that of Preparation 31.
Example 28 6- [3-(4-Fluorophenyl)-1-methyl-5-(methylamino)-IH- pyrazol-4-yl]-2-(2-methylphenyl)-3(2H)-pyridazinone
Mass ESI (+) 390 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.05(3H, s), 2.66(3H, d, J=5.4
Hz), 3.66(3H, s), 5.53(1H, q, J=5.4 Hz), 7.00(1H, d, J=9.6 Hz), 7.13-7.49(9H, m) .
Example 29
6-(3-(4-Fluorophenyl) -5-{ [2-(4-morpholinyl)ethyl] - amino}-lH-pyrazol-4-yl)-2-(2-methylphenyl)-3(2H)- pyridazinone
Mass ESI (+) 475 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.12(3H, s), 2.13-2.28(4H, m) , 2.34-2.48(2H, m) , 3.14-3.33(6H, m) , 5.34-5.57(IH, m) , 6.9O(1H, d, J=9.8Hz), 7.00(1H, d, J=9.8Hz), 7.24-7.42(6H, m) , 7.47-7.59(2H, m) , 12.22-12.46(IH, m) . Example 30
6- [5- (Ethylamino)-3-(4-fluorophenyl)-lH-pyrazol-4-yl] -
2-(2-methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 390 (M+l)
1H NMR (200MHz, DMSO-d6) d l.lO(3H, t, J=7.1 Hz), 2.10(3H, s), 3.09-3.24(2H, m) , 5.18-5.31(2/3H, m) , 5.78-5.95(1/3H, m) , 6.94(IH, d, J=9.7 Hz) , 7.01-7.16(IH, m) , 7.21-7-41(6H, m) , 7.45-7.59(2H, m) , 12.23-12.42(IH, m) .
Example 31
6- [5-(Ethylamino)-3-(4-fluoro-3-methylphenyl) -IH- pyrazol-4-yl]-2-(2-methylphenyl)-3(2H) -pyridazinone
Mass ESI (+) 404 (M+l) 1H NMR (200MHz, DMSO-d6) d l.06(3H, t, J=7.1 Hz), 2.10(3H, s), 2.26(3H, d, J=I.1 Hz) , 3.08-3.24(2H, m) , 5.19-5.30(0.6H, m) , 5.82-5.97(0.4H, m) , 6.87-6.98(IH, m) , 7.01-7.46(8H, m) ,
12.23(0.5H, brs), 12.34(0.5H, brs).
Example 32 tert-Butyl 4-{3-(4-fluorophenyl)-4- [1-(2-methylphenyl) - 6-oxo-1,6-dihydro-3-pyridazinyl] -lH-pyrazol-5-yl}-1- piperazinecarboxylate Mass ESI (+) 531 (M+l) 1H NMR (200MHz, DMSOd6) d 1.41(9H, s), 1.99(3H, s), 2.90-3.01(4H, m) , 3.28-3.43(4H, m) , 7.06(1H, d, J=9.6 Hz) , 7.15-7.38(6H, m) , 7.42-7.53(2H, m) , 7.61(IH, d, J=9.8 Hz) , 12.72(1H, brs).
Example 33
6- [3-(2-Chloro-4-fluorophenyl)-5- (ethylamino)-IH- pyrazol-4-yl] -2-(2-methylphenyl) -3(2H)-pyridazinone Mass ESI (+) 424 (M+l)
1H. NMR (200MHz, DMSO-d6) d 1.06(3H, t, J=7.0 Hz), 2.06(3H, s), 3.09-3.27(2H, m) , 5.35-5.49(0.5H, m) , 6.00-6.13(0.5H, m) , 6.79-6.99(2H, m) , 7.23-7.46(5H, m) , 7.48-7.74(2H, m) , 12.31(0.5H, brs), 12.46(0.5H, brs).
Example 34 6- [5-(tert-Butylamino)-3-(4-fluorophenyl)-lH-pyrazol-4- yl] -2-(2-methylphenyl)-3(2H) -pyridazinone
Mass ESI (+) 418 (M+l)
1HNMR (200MHz, DMSO-d6) dl.23(9H, s) , 2.12(3H, s) , 5.62(IH, brs), 6.91(1H, d, J=9.8 Hz), 7.01(1H, d, J=9.8 Hz), 7.28-7.45(6H, m) , 7.48-7.60(2H, m) , 12.29(1H, brs).
Example 35
A mixture of 6-(2-phenylpyrazolo[l,5-a]pyridin-3-yl) -
3(2H)-pyridazinone (lOOmg), (2-chlorophenyl)boronic acid (190mg), copper (II) acetate (6.3mg) and pyridine (96mg) in DMF (3ml) was stirred for 2days at room temperature and partitioned between EtOAc and water. The separated organic layer was washed with aq. 3% NaHCO3 and brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica column chromatography, eluting with 0.5 to 1% methanol in CHCI3 followed by crystallization from EtOAc/hexane (1/2) to give 2-(2-chlorophenyl) -6-(2- phenylpyrazolo[1,5-a]pyridin-3~yl)-3(2H)-pyridazinone (67mg) as pale yellow crystals. Mass ESI(+) 399(M+1)
1H NMR(300MHz, CDCl3)d 6.86-6.92 (2H, m) , 7.12 (IH, d, J=9.9Hz), 7.22-7.30 (IH, m) , 7.42-7.71 (9H, m) , 7.97 (IH, d, J=9Hz), 8.51 (IH, d, J=6.9Hz).
The following compounds were obtained in a similar manner to that of Example 35.
Example 36
2-(2-Methylphenyl) -6-(2-phenylpyrazolo[1,5-a]pyridin-3- yl)-3(2H)-pyridazinone Mass ESI (+) 379 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.50(3H, t, J=3.4 Hz), 7.00-7.11(2H, m) , 7.26(IH, d, J=9.8 Hz), 7.34-7.59(7H, m) , 7.61-7.71(2H, m) , 7.79(1H, d, J=9.8 Hz), 8.34(1H, d, J=6.8 Hz). Example 37
2-(2-Chlorophenyl) -6-[2- [3-(dimethylamino)-1- pyrrolidinyl] -4- (4-fluorophenyl)-1,3-thiazol-5-yl]- 3(2H)-pyridazinone ESI(+) 496 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.78-2.00(IH, m) , 2.17(6H, s), 2.76-2.95(IH, m) , 3.12-3.72(5H, m) , 6.92(IH, d, J=IO.0 Hz) , 7.00(1H, d, J=10.0Hz), 7.31(2H, t, J=8.9Hz), 7.47-7.72(6H, m) .
Example 38
6- [2- [3-(Dimethylamino) -1-pyrrolidinyl] -4- (4- fluorophenyl) -1,3-thiazol-5-yl] -2-(2-methylphenyl)- 3(2H) -pyridazinone ESI(+) 476 (M+l)
1H NMR (200MHz, DMSO-d6) d i.74-1.98(IH, m) , 2.08(3H, s), 2.'17(6H, s), 2.74-2.91(lH, m) , 3.10-3.69(5H, m) , 6.9O(1H, d, J=?.9 Hz), 6.99(1H, d, J=9.9 Hz), 7.25-7.42(6H, m) , 7.53-7.63(2H, m) .
Example 39
6-[2- [3-(Dimethylamino)-1-pyrrolidinyl] -4- (4- fluorophenyl) -1,3-thiazol-5-yl] -2-(2-methoxyphenyl)- 3(2H)-pyridazinone ESI(+) 492 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.74-1.98(IH, m) , 2.17(6H, s), 2.76-2.94(1H, m) , 3.11-3.69(5H, m) , 3.76(3H, s), 6.84(1H, d, J=9.8 Hz), 6.95(1H, d, J=9.8 Hz), 7.02-7.12(1H, m) , 7.17-7.38(4H, m) , 7.41-7.62(3H, m) .
Example 40
6-{2-[3-(Dimethylamino) -1-pyrrolidinyl] -4-phenyl-1,3- thiazol-5-yl}-2-(2-methoxyphenyl)-4-methyl-3(2H)- pyridazinone
Mass ESI(+) 488 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.76-1.98(IH, m) , 2.17(6H, s), 2.75-2.93(1H, m) , 3.12-3.24(1H, m) , 3.28-3.69(7H, m) , 3.76(3H, s), 6.81(1H, d, J=I.3 Hz), 7.06(1H, t, J=7.7 Hz), 7.19(1H, d, J=7.7 Hz), 7.32(1H, dd, J=I.6 7.7 Hz), 7.40-7.55(6H, m) .
Example 41
Ethyl ({4- [1- (2-methoxyphenyl) -6-oxo-l,6-dihydro- 3-pyridazinyl]-1-methyl-3-phenyl-lH-pyrazol-5- yl}amino)acetate Mass ESI (+) 460 (M+l)
1H NMR (200MHz, DMSO-d6) d l.lO(3H, t, J=7.1 Hz), 3.71(3H, s), 3.78(3H, s), 3.90-4.02(4H, m) , 6.00-6.10(1H, m) , 6.88(1H, d, J=9.6 Hz), 7.01(1H, d, J=9.6 Hz), 7.1O(1H, t, J=7 . 6 Hz ) , 7 . 22 01H , d, J=7 . 6 Hz ) , 7 . 31 - 7 . 52 ( 7H , m) .
Example 42
,6- [2- [3-(Dimethylamino)-l-pyrrolidinyl] -4-(4- fluorophenyl) -1,3-thiazol-5-yl] -2-(2-ethylphenylj - 3(2H) -pyridazinone Mass ESI (+) 490 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.07(3H, t), 1.75-1.98(IH, m) , 2.16(6H, s), 2.33-2.54(2H, m) , 2.75-2.94(IH, m) , 3.10-3.70(5H, m) , 6.90(IH, d, J=9.8 Hz) , 6.99(IH, d, J=9.8 Hz), 7.22-7.47(6H, m) , 7.52-7.65(2H, m) .
Example 43
6-{2- [3-(Dimethylamino)-1-pyrrolidinyl]-4-[3- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}-2-(2- methylpheny1)-3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 1.75-1.98(IH, m) , 2.08(3H, s), 2.17(6H, s), 2.76-2.94(1H, m) , 3.12-3.27(1H, m) , 3.31-3.70(4H, m) , 6.91(1H, d, J=9.9 Hz), 7.03(1H, d, J=9.9 Hz), 7.30-7.42(4H, m) , 7.63-7.74(IH, m) , 7.78-7.89(3H, m) .
Example 44
6- [2- [3-(Dimethylamino)-1-pyrrolidinyl]-4-(4- fluorophenyl)-1,3-thiazol-5-yl] -2-(2-phenoxyphenyl) - 3(2H) -pyridazinone Mass ESI (+) 554 (M+l)
1H NMR (200MHz, DMSO-d5) d 1.76-2.00(IH, m) , 2.18(6H, s), 2.78-2.93(1H, m) , 3.09-3.22(1H, m) , 3.28-3.67(4H, m) , 6.75(1H, d, J=9.8 Hz), 6.84(1H, d, J=9.8 Hz), 6.94(2H, d, J=7.6 Hz), 7.03-7.13(2H, m) , 7.21-7.40(5H,. m) , 7.44-7.59(4H, m) .
Example 45
6- [2- [3-(Dimethylamino)-1-pyrrolidinyl] -4-(4- fluorophenyl) -1,3-thiazol-5-yl]-2-(2,3-dimethylphenyl) -
3(2H) -pyridazinone
Mass ESI (+) 490 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.74-1.98(4H, m) , 2.17(6H, s),
2.32(3H, s), 2.76-2.93(lH, m) , 3.1O-3.24(1H, m) , 3.30-3.69(4H, m) , 6.89(1H, d, J=9.9,Hz), 6.99(1H, d, J=9.9
Hz), 7.10-7.37(5H, m) , 7.54-7.64(2H, m) .
Example 46
6-[2-[3- (Dimethylamino) -1-pyrrolidinyl]-4-(4- fluorophenyl) -1,3-thiazol-5-yl]-2-(2,5-dimethylphenyl) - 3(2H) -pyridazinone Mass ESI (+) 490 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.79-1.96(IH, m) , 2.02(3H, s), 2.17(6H, s), 2.32(3H, s), 2.77-2.93(IH, m) , 3.11-3.25(1H, m), 3.28-3.69(4H, m) , 6.89(1H, d, J=9.9 Hz), 6.99(1H, d, 3=9 . 9 Hz ) , 7 . 10 - 7 . 36 ( 5H , m) , 7 . 53 - 7 . 63 ( 2H , m) .
Example 47
6- [2- [3-(Dimethylamino) -1-pyrrolidinyl] -4-(4- fluorophenyl)-l,3-thiazol-5-yl] -2-[2-
- (trifluoromethyl)phenyl]-3(2H)-pyridazinone Mass ESI (+) 530 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.76-1.98(IH, m) , 2.16(6H, s), 2.74-2.92(1H, m) , 3.1O-3.23(1H, m) , 3.29-3.69(4H, m) , 6.9O(1H, d, J=IO-O Hz), 6.99(1H, d, J=IO.0 Hz), 7.31(2H, t, J=7.6 Hz), 7.50-7.61(2H, m) , 7.66-7.98(4H, m) .
Example 48 i
6- [2- [3-(Dimethylamino) -1-pyrrolidinyl] -4- (3- methylphenyl) -1,3-thiazol-5-yl]-2-(2-methylphenyl)-
3(2H)-pyridazinone
Mass ESI (+) 472 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.74-1.98(IH, m) , 20.8(3H, s),
2.17(6H, s), 2.36(3H, s), 2.77-2.93(IH, m) , 3.11-3.23(1H, m), 3.30-3.69(4H, m) , 6.87(1H, d, J=9.9 Hz), 6.96(1H, d,
J=9.9 Hz), 7.23-7.42(8H, m) .
Example 49
6- [2- [3-(Dimethylamino) -1-pyrrolidinyl] -4-(4- fluorophenyl)-1,3-thiazol-5-yl] -2-(2,4-dimethylphenyl)- ,3(2H) -pyridazinone Mass ESI (+) 490 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.80-1.95 ( IH, m) , 2.04(3H, s), 2.17(6H, s), 2.34(3H, s), 2.78-2.97 ( IH, m) , 3.12-3.26(1H, m), 3.30-3.68(4H, m) , 6.88(1H, d, J=9.9 Hz), 6.98(1H, d, J=9.9 Hz), 7.10-7.23(3H, m) , 7.26(2H, t, J=8.9 Hz). 7.54-7.66(2H, m) .
Example 50 6-[2- [3-(Dimethylamino)-l-pyrrolidinyl]~4-(2- fluorophenyl)-1,3-thiazol-5-yl] -2- (2-methylphenyl) -
3(2H)-pyridazinone
Mass ESI (+) 476 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.73-1.99(1H, m) , 2.06(3H, s), 2.16(6H, s), 2.75-2.93(1H, m) , 3.1O-3.24(1H, m) ,
3.28-3.68(4H, m) , 6.92(2H, s), 7.24-7.40(6H, m) ,
7.48-7.62(2H, m) .
Example 51 2-[3-[2-[3-(Dimethylamino)-l-pyrrolidinyl]-4~(4- fluorophenyl)-1,3-thiazol-5-yl] -6-oxo-l(6H)- pyridazinyl]benzaldehyde ESI(+) 490 (M+l) 1H NMR (200MHz, DMSO-d6) d 1.76-1.98(IH, m) , 2.17(6H, s), 2.74-2.96(IH, m) , 3.11-3.69(5H, m) , 6.91(IH, d, J=9.9 Hz) , 7.02(1H, d, J=9.9 Hz), 7.30(2H, t, J=8.9 Hz), 7.53-7.74( 4H,
m), 7.80-8.01(2H, m) , 9.92(1H, s) .
Example 52 A mixture of 2- [ (1-hydroxycyclohexyl)methyl] -6-(2- phenylpyrazolo[1,5-a]pyridin-3-yl) -3(2H)-pyridazinone (200mg) and palladium hydroxide (lOOmg, 20% wt. on carbon) in EtOH (20ml) was stirred for lday under the pressure of 3atm of hydrogen. After filtration of catalyst through the celite pad, the filtrate was concentrated in vacuo and crystallized from EtOH (2ml) and hexane (ImI) .to afford 2- [ (1-hydroxycyclohexyl)methyl] -6-(2-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-yl) -3(2H)- pyridazinone (39mg) as white crystals. Mass ESI'(+) 405(M+l)
1H NMROOOMHZ, CDCl3Jd 1.28-1.73 (1OH, m) , 1.87-1.97 (2H, m), 2.05-2.15 (2H, m) , 2.93 (2H, t, J=6.8Hz), 4.24 (2H, t,
J=6.8Hz), 4.35 (2H, s), 4.42 (IH, s), 6.78 (IH, d, J=9.8Hz) ,
6.94 (IH, d, J=9.8Hz), 7.33-7.46 (5H, m) .
Example 53
To a suspension of 2-[ (1-hydroxycyclohexyl)methyl] -6- (2- phenylpyrazolo[1,5-a]pyrimidin-3-yl) -3(2H) -pyridazinone (220mg) in EtOH (2.5ml) was added NaBH4 (20.7mg) at room temperature. After stirring for Ih at 60°C, the mixture was cooled to ambient temperature and quenched with IN HCl (2:5ml) . The mixturewas stirred for 30min andmade alkaline with 2M Na2CO3 and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated in vacuo. The residue was purified by silica column chromatography, eluting with 1 to 3% methanol in CHCl3 followed by crystallization from diethyl ether to give 2- [ (1-hydroxyeyelohexyl)methyl] -6-(2-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-3(2H)- pyridazinone (72mg) as pale yellow crystals. Mass ESI(+) 406(M+l)
1HNMROOOMHZ, DMSO-d6)d 1.16-1.62 (1OH, m) , 2.04-2.15 (2H, m), 3.25-3.42 (2H, m) , 4.06 (2H, t, J=7.5Hz), 4.13 (2H, s), 4.73 (IH, s), 6.73 (9.9Hz), 6.77-6.86 (2H, m) , 7.34-7.46 (5H, m) .
Example 54
A mixture of 6-[5-(ethylamino)-3-phenyl-lH-pyrazol~4- yl]-3(2H) -pyridazinone hydrobromide (200mg), l-oxaspiro[2.5]octane (99.1mg) and potassium carbonate (305mg) in amixture of H2O (0.8ml) and DMF (2ml) was stirred for 12h at 80 °C. After cooling to room temperature, the mixture was diluted with water and EtOAc. A separated solid was collected and washed with EtOAc and water to give 6- [5-(ethylamino) -3-phenyl-lH-pyrazol-4-yl]-2-[ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone (95mg) as a pale yellow solid. Mass ESI(+) 394(M+1)
1H NMROOOMHZ, DMSO-d6)d 1.18 (3H, t, J=7.2Hz), 1.30-1.63 (1OH, m), 3.18-3.30 (2H, m) , 4.12 (2H, s), 4.62 (IH, brs), 6.74 (IH, d, J=9.8Hz), 6.83 (IH, d, J=9.8Hz), 7.37-7.50 (5H, m) .
The following compounds were obtained in a similar manner to that of Example 54.
Example 55
6-[5-(Ethylamino)-3-(2-thienyl)-lH-pyrazol-4~yl]-2-[(l- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone Mass ESI (+) 400 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.16(3H, t, J=7.1 Hz), 1.21-1.70(1OH, m), 3.12-3.38(2H, m) , 4.12(2H, s), 4.63(1H, s) , 6.81(IH, d, J=9.7 Hz) , 7.01-7.20(3H, m) , 7.56-7.69(IH, m) , 12.28(1H, brs).
Example 56
2-[ (1-Hydroxycyclohexyl)methyl]-6-[5-(methylamino) -3- (3-methylphenyl) -lH-pyrazol-4-yl]-3(2H) -pyridazinone Mass ESI(+) 394(M+1) 1H NMR (300MHz, CDCl3)d 1.30-1.80(1OH, m) , 2.39(3H, s), 2.95-3.10(3H, m) , 3.88(IH, br s) , 4.3l(2H, s) , 5.60-5.80(IH, m), 6.71(1H, d, J= 9.9 Hz), 6.94(1H, d, J= 9.9 Hz), 7.15-7.40(4H, m) .
Example 57
6-[5-(Ethylamino)-3-(3-methylphenyl)-lH-pyrazol-4-yl]- 2-[ (1-hydroxycyclohexyl)methyl] -3(2H)-pyridazinone Mass ESI(+) 408(M+l)
1HNMR (300MHz, CDCl3)d 1.31(3H, t, J= 7.4Hz) , 1.30-1.80(1OH, m), 2.39(3H, s), 3.38(2H, dq, J= 5.5, 7.4Hz), 3.95(1H, br s), 4.31(2H, s) , 5.60-5.75(IH, m) , 6.71(IH, d, J= 10.0 Hz) , 6.94(1H, d, J= 10.0 Hz), 7.15-7.40(4H, m) .
Example 58 2- [ (1-Hydroxycyclohexyl)methyl] -6- [5-(isobutylamino) -3- phenyl-lH-pyrazol-4-yl]-3(2H) -pyridazinone
Mass ESI(+) 422(M+l) xHNMR(300MHz, CDCl3Jd 1.02 (6H, d, J=6.9Hz) , 1.20-1.75 (1OH, m), 1.87-2.04 (IH, m) , 3.16 (2H, t, J=7.5Hz), 4.12 (IH, brs), 4.30 (2H, s), 5.86 (IH, brs), 6.72 (IH, d, J=9.9Hz), 6.93
(IH, d, J=9.9Hz), 7.37-7.51 (5H, m) .
Example 59
6-[3- (4-Fluorophenyl) -5-(methylamino) -lH-pyrazol-4-yl] - 2-[ (1-hydroxycyclohexyl)methyl]-3(2H)-pyridazinone Mass ESI(+) 398(M+l)
1H NMR(300MHz, DMSO-d6)d 1.14-1.63 (1OH, m) , 2.83 (3H, d, J=5.4Hz), 4.13 (2H, s), 4.67 (IH, s), 6.75 (IH, d, J=9.8Hz), 6.85 (IH, d, J=9.8Hz), 7.29 (2H, t, J=9Hz), 7.47 (2H, dt, J=3, 9Hz).
Example 60
6- [3-(4-Fluorophenyl)-5- (methylamino)-lH-pyrazol-4-yl] -
2- [ (1-hydroxycycloheptyl)methyl] -3(2H)-pyridazinone Mass ESI(+) 412(M+1)
1H NMROOOMHZ, DMSO-d6)d 1.28-1.69 (12H, m) , 2.83 (3H, d,
J=5.4Hz), 4.11 (2H, s), 4.78 (IH, s), 6.76 (IH, d, J=9.8Hz),
6.85 (IH, d, J=9.8Hz), 7.30 (2H, t, J=9Hz), 7.43-7.53 (2H, m) .
Example 61
6-{3-(4-Fluorophenyl)-5-[ (2-methoxyethyl)amino] -IH- pyrazol-4-yl}-2- [ (1-hydroxycyclohexyl)methyl] -3(2H) - pyridazinone Mass ESI(+) 442(M+l)
1H NMROOOMHZ, DMSOd6 )d 1.12-1.64 (1OH, m) , 3.31-3.42 (3H,
s), 3.31-3.42 (2H, m) , 3.46-3.56 (2H, m) , 4.11 (2H, s), 4.57
(IH, s), 6.75-6.90 (3H, m) , 7.25-7.40 (2H, m), 7.44-7.54 (2H, m) . Example 62
To a stirring solution of CuBr2 (2.1 g) in CH3CN (31 mL) was dropwise added t-butyl nitrate (1.47 mL) in CH3CN (15 mL) at 50C followed by addition of 6-[2-amino-4-(4-fluorophenyl) -1,3-thiazol-5-yl]-2-
[ (1-hydroxycyclohexyl)methyl] -3(2H)-pyridazinone (3.1 g) over 5min. After 3 hours at 50C, the reaction mixture was concentrated and to this was added IN hydrochloric acid. The mixture was extracted with CHCl3. The organic layer was washed with brine, dried over Na2S(Xi and concentrated. The residue was purified by silica gel chromatography (6Og, CHCl3: EtOAc= 15: 1) to give 6- [2-bromo-4-(4- fluorophenyl)-1,3-thiazol-5-yl] -2- [ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone (2.1 g) as a yellow solid.
Mass ESI(+) 464(M+l)
1H NMR (300MHz, CDCl3Jd 1.30-1.80(1OH, m) , 3.71(1H, s), 4.30(2H, s), 6.82(1H, d, J= 10.0 Hz), 6.99(1H, d, J= 10.0 Hz), 7.14(2H, t, J= 8.4 Hz), 7.51(2H, dd, J= 5.1, 8.4 Hz).
The following compound was obtained in a similar manner to that of Example 62.
Example 63 6-(2-Bromo-4-phenyl-l,3-thiazol-5-yl)-2- [ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone Mass ESI(+) 447(M+1)
1H NMR (300MHz, CDCl3)d 1.30-1.80(1OH, m) , 3.79(1H, s), 4.31(2H, s) , 6.78(IH, d, J= 9.8 Hz), 6.99(IH, d, J= 9.8 Hz), 7.40-7.55(5H, m) .
Example 64
To a stirring solution of 6- [2-bromo-4-(4-fluorophenyl) - l,3-thiazol-5~yl] -2-[ (1-hydroxycyclohexyl)methyl] - 3(2H)-pyridazinone (0.3g) in dioxane (4.5 ml) was added N-methylpiperazine (0.358 ml) at rt. After 24h at 80 °C, the reaction mixture was concentrated and to this was added H2O. The mixture was extractedwith EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was dissolved in combined solvent of EtOH(5ml)- H2O(4ml) at 900C. The mixture was filtered and then stirred at rt. The precipitate was filtered and dried in vacuo at 50 °C to give 6- [4-(4-fluorophenyl) -2-(4-methyl-l- piperazinyl) -1,3-thiazol-5-yl] -2- [ (1- hydroxycyclohexyl)methyl] -3(2H)-pyridazinone (0.26 g) as yellow crystals. Mass ESI(+) 484(M+1)
1H NMR (300MHz, CDCl3Jd 1.30-1.80(1OH, m) , 2.36(3H, s), 2.53(4H, t, J= 5.1 Hz), 3.59(4H, t, J= 5.1 Hz), 4.16(1H, s), 4.27(2H, s), 6.7O(1H, d, J= 10.0 Hz), 6.90 (IH, d, J= 10.0 Hz) , 7.10(2H, dd, J= 8.5 , 8.7 Hz) , 7.49(2H, dd, J= 5.5,
8.5 Hz) .
The following compounds were obtained in a similar manner to that of Example 64.
Example 65
N-[l-(4-(4-Fluorophenyl)-5-{1- [ (1-hydroxycyclohexyl) - methyl] -6-oxo-1,6-dihydro-3-pyridazinyl}-1,3-thiazol-2- yl)-3-pyrrolidinyl] -N-methylacetamide Mass ESI (+•) 526 (M+l)
1HNMR (200MHz, DMSO-d6) d 1.00-1.69(1OH, m) , 1.94-2.29(5H, m) , 2.68-2.96(3H, m) , 3.19-3.76(5H, m) , 4.04(2H, s), 4.41(1H, s), 6.77(1H, d, J=9.8 Hz), 6.89(1H, d, J=9.8 Hz), 7.27(2H, t, J=8.8 Hz), 7.47-7.60(2H, m) .
Example 66
2- [ (1-Hydroxycyclohexyl)methyl] -6-[4-phenyl-2-(1- piperazinyl)-l,3-thiazol-5-yl] -3(2H) -pyridazinone Mass ESI(+) 452(M+1)
1H NMR (300MHz, CDCl3Jd 1.3,0-1.80(1OH, m) , 2.99(4H, t, J= 5.0 Hz), 3.55(4H, t, J= 5.0 Hz), 4.23(1H, m) , 4.27(2H, s), 6.66(IH, d, J= 9.8 Hz) , 6.90(IH, d, J= 9.8 Hz) , 7.35-7.55(5H, m) . Example 67
2-[(l-Hydroxycyclohexyl)methyl]-6-{2-[(2- hydroxyethyl)amino]-4-phenyl-1,3-thiazol-5-yl}-3(2H) - pyridazinone Mass ESI(+) 427(M+1)
1H NMR (300MHz, CDCl3)d 1.30-1.80(1OH, m) , 3.52(2H, dt, J= 4.9, 5.1 Hz) , 3.85(2H, t, J= 5.1 Hz) , 4.17(1H, s) , 4.27(2H, s) , 5.79(IH, m) , 6.68(IH, d, J= 9.5 Hz) , 6.92(IH, d, J= 9.5 Hz) , 7.35-7.50(5H, m) .
Example 68
6- [2- (Dimethylamino) -4-(4-fluorophenyl)-1,3-thiazol-5- yl] -2- [ (1-hydroxycyclohexyl)methyl] -3(2H)-pyridazinone Mass ESI(+) 429(M+l) 1H NMR (300MHz, CDCl3Jd 1.30-1.80(1OH, m) , 3.17(6H, s), 4.2O(1H, s), 4.27(2H, s), 6.69(1H, d, J= 9.8 Hz), 6.88(1H, d, J= 9.8 Hz) , 7.10(2H, t, J= 8.8 Hz), 7.50(2H, dd, J= 5.5, 8.8 Hz) .
Example 69
6- [2-(Dimethylamino) -4-phenyl-l,3-thiazol-5-yl]-2- [ (1- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone
Mass ESI(+) 411(M+l)
1H NMR (300MHz, CDCl3Jd 1.30-1.80(1OH, m) , 3.17(6H, s), 4.27(3H, m) , 6.65(IH, d, J= 9.8 Hz) , 6.88(IH, d, J= 9.8 Hz), 7.45-7.55(5H, m) .
Example 70
6- [2-{ [2-(Dimethylamino)ethyl]amino}-4-(4- fluorophenyl) -l,3-thiazol-5-yl] -2- [ (1- hydroxycyclohexyl)methyl] -3(2H) -pyridazinone Mass ESI(+) 472(M+l)
1H NMR (300MHz, CDCl3)d 1.30-1.80(1OH, m) , 2.30(6Hf s),
2.61(2H, t, J= 5.8 Hz), 3.38(2H, m) , 4.17(1H, s), 4.27(2H,
s), 6.16(1H, m) , 6.70 (IH, d, J= 9.9 Hz ) , 6.91 (IH, d, J= 9.9
Hz), 7.10(2H, t, J= 8.3 Hz), 7.48(2H, dd, J= 5.5, 8.3 Hz) .
Example 71
6- [2- [3-(Dimethylamino) -1-pyrrolidinyl] -4-(4- fluorophenyl)-l,3-thiazol-5-yl]-2-[(l- hydroxyeyelohexyl)methyl] -3(2H)-pyridazinone
Mass ESI(+) 498(M+1)
1H NMR (300MHz, CDCl3Jd 1.30-1.80(1OH, m) , 1.90-2.10( IH, m) , 2.20-2.40(7H, m) , 2.80-2.88 ( IH, m) , 3.34 (IH, dd, J= 8.7 , 9.9 Hz) , 3.50 (IH, ddd, 6.9,9.9, 10.4 Hz) , 3.62-3.84 ( IH, m) ,
4.2O(1H, s), 4.27(2H, s), 6.68(1H, d, J= 9.8 Hz), 6.85(1H, d, J= 9.8 Hz), 7.11(2H, t, J= 8.7 Hz), 7.49(2H, dd, J= 5.4,
8.7 Hz) .
The following compound was obtained in a similar manner to those of Preparation 51 and Example 73.
Example 72
6-[3-(4-Fluorophenyl)-lH-pyrazol-4-yl]-2-(2- methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 347 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.03(3H, s), 7.08(1H, d, J=9.6 Hz), 7.09-7.41(6H, m) , 7.52-7.67(3H, m) , 7.83-8.37(IH, m) , 13.36(1H, brs).
Example 73
A mixture of 2-cyclohexylmethyl~6-(l-benzoyl-2- dimethylaminoethenyl)-3(2H)-pyridazinone (1.44g) and hydrazine monohydrate (0.287ml) in EtOH (12ml) was stirred for 2h at 900C. After cooling to room temperature, the mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The separated organic layer was washed with aqueous 2% aqueous citric acid and brine, dried and concentrated in vacuo. The residue was purified by silica column chromatography (eluent; 1 to 2% methanol in chloroform) to afford 2-(cyclohexylmethyl)-6-(3-phenyl- lH-pyrazol-4-yl) -3(2H)-pyridazinone (904mg) as a yellow amorphous solid. Mass ESI(+) 335(M+1) 1H NMR(SOOMHZ, CDCl3Jd 0.95-1.30 (5H, m) , 1.55-1.76 (5H, m), 1.84-1.99 (IH, m) , 3.99 (2H, d, J= 7.2Hz), 6.81 (IH,
d, J=9.6Hz), 7.08 (IH, d, J=9.6Hz), 7.40-7.54 (5H, m) , 7.89
(IH, s) .
Example 74
A mixture of 2- [1-(cyclohexylmethyl)-6-oxo-l,6-dihydro- 3-pyridazinyl] -3-oxo-3-phenylpropaneriitrile (300mg) , hydrazinemonohydrate (45mg) andhydrazine dihydrochloride (469mg) in EtOH (6ml) and H2O (ImI) was refluxed for 6h and concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The separated organic layer was washed with brine, driedoverNa2SO4 and evaporated invacuo. The residue was purified by silica gel chromatography (eluent: 1% MeOH in CHCI3) to give 6-(5-amino-3-phenyl-lH-pyrazol-4- yl) -2-(cyclohexylmethyl)-3(2H)-pyridazinone (180mg) as an amorphous solid. Mass ESI(+) 350(M+l)
1H NMR(SOOMHZ, DMSO-d6)d 0.94-1.23 (5H, m) , 1.55-1.72 (5H, m), 1.80-1.91 (IH, m) , 3.93 (2H, d, J=7.5Hz), 6.75 (IH, d, J=9.8Hz), 6.91 (IH, d, J=9.8Hz), 7.37-7.44 (5H, m) .
Example 75
A mixture of tert-butyl 5- (ethylamino) -4-(6-oxo-l,6- dihydro-3-pyridazinyl) -3-phenyl-lH-pyrazole-1- carboxylate (lOOmg), (2-methoxyphenyl)boronic acid (120mg), copper(II) acetate (9.5mg) and pyridine (104mg) in DMF (3ml) was stirred for 14h at room temperature under air. The mixture was partitioned between EtOAc and water. The organic layer was washed with IM citric acid, 3% NaHCO3 and brine, dried and concentrated in vacuo. The residue was treated with 4N hydrogen chloride in dioxane (ImI) for Ih at room temperature, then poured into water and extracted with AcOEt. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2Sθ4 and concentrated in vacuo. The residue was purified by prepared TLC (solvent; 7% methanol in dichloromethane) . An obtained oil was triturated with diisopropyl ether to give 6- [5-(ethylamino) -3-phenyl-lH- pyrazol-4-yl] -2-(2-methoxyphenyl) -3(2H) -pyridazinone (22mg) as pale yellow solid. ESI(+) 388 (M+l)
1HNMR (200MHz, DMSO-d6) d 1.01-1.26(3H, m) , 3.09-3.38(2H, m), 3.47(2H, s), 3.79(1H, s), 6.66(1H, s), 6.83-7.52(10H, m), 12.20-12.36(1/3H, m) , 12.89(2/3H, brs) .
The following compounds were obtained in a similar manner to that of Example 75.
Example 76
6- [5-(Ethylamino)-3-phenyl-lH-pyrazol-4-yl] -2-(2- methylphenyl)-3(2H) -pyridazinone Mass ESI (+) 372 (M+l)
1H NMR (200MHz, DMSO-d6) d 1.07(3H, t, J=7.1 Hz), 2.11(3H, s), 3.16(2H, q, J=7.1 Hz), 6.92(1H, d, J=9.8 Hz), 7.08(1H, d, J=9.8 Hz), 7.30-7.51(9H, m) , 12.29(1H, brs).
Example 77
2-(2-Ethoxyphenyl) -6- [5-(ethylamino)-3-phenyl-IH- pyrazol-4-yl] -3(2H)-pyridazinone
Mass ESI (+) 402 (M+l) 1H NMR (200MHz, DMSO-d6) d 1.08(3H, t, J=7.1 Hz), 1.20(3H, t, J=6.9 Hz), 3.10-3.27(2H, m) , 4.07(2H, q, J=6.9 Hz), 5.19-5.42(2/3H, m) , 5.78-5.98(1/3H, m) , 6.87(1H, d, J=9.8 Hz), 6.99(1H, d, J=9.8 Hz) , 7.07(IH, t, J=7.7Hz), 7.22(1H, d, J=7.7 Hz), 7.32-7.55(7H, m) , 12.27(1H, brs).
Example 78
6-{3-(4-Fluorophenyl)-5- [ (2-methoxyethyl)amino]-IH- pyrazol-4-yl}-2-(2-methylphenyl)-3(2H)-pyridazinone Mass ESI (+) 420 (M+l) 1H NMR (200MHz, DMSO-d6) d 2.11(3H, s), 3.09(3H, s),
3.21-3.45(4H, m) , 5.52(1H, brs), 6.92(1H, d, J=9.8 Hz), 7.02(1H, d, J=9.8Hz), 7.22-7.43(6H, m) , 7.46-7.60(2H, m) , 12.28-12.46(1H, m) .
Example 79 To a suspension of 2- [3-[2- [3-(dimethylamino)-1- pyrrolidinyl] -4-(4-fluorophenyl) -1,3-thiazol-5-yl] -6- oxo-l(6H)-pyridazinyl]benzaldehyde (41mg) in THF (2ml) was added a solution of NaBH4 (6.3mg) in H2O (0.3ml) at room temperature. After stirring for 2h, the mixture became clear solution and was quenched with cone. HCl (pH 3) . After Ih with stirring, the mixture was made alkaline with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by prepared TLC (solvent; 5% methanol in dichloromethane) to give an oil that was triturated with diisopropyl ether to give 6- [2- [3-(dimethylamino)-1- pyrrolidinyl] -4-(4-fluorophenyl) -1,3-thiazol-5-yl] -2- f2-(hydroxymethyl)phenyl] -3(2H)-pyridazinone (18mg) as a pale yellow solid.
1H NMR (200MHz, DMSO-d6) d 1.75-2,01(IH, m) , 2.17(6H, s), 2.77-2.93(1H, m) , 3.11-3.26(1H, m) , 3.29-3.69(4H, m) , 4.35(2H, d, J=5.6 Hz), 5.22(1H, t, J=5.6 Hz), 6.88(1H, d, J=9.8 Hz), 6.98(1H, d, J=9.8 Hz), 7.22-7.68(8H, m) .
Example 80 tert-Butyl 4-{3- (4-fluorophenyl)-4- [1-(2-methylphenyl) - 6-oxo-l,6-dihydro-3-pyridazinyl] -lH-pyrazol-5-yl}-l- piperazinecarboxylate (48mg) was dissolved in 4N hydrogen chloride in dioxane (ImI) and methanol (0.5ml), and stirred for 2h at room temperature. The mixture was concentrated in vacuo and triturated with AcOEt to afford 6-[3-(4-fluorophenyl) -5-(1-piperazinyl)-lH-pyrazol-4- yl]-2-(2-methylphenyl)-3(2H)-pyridazinone hydrochloride (38mg) as a yellow solid. Mass ESI (+) 431 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.08(3H, s), 3.03-3.30(8H, m) , 7.07(1H, d, J=9.6 Hz) , 7.13-7.40(6H, m) , 7.41-7.62(3H, m) , 9.13(1H, brs).
The following compound was obtained in a similar manner to that of Example 62.
Example 81 6-[2-Bromo-4-(4-fluorophenyl)-l,3-thiazol-5-yl]-2-(2- methylphenyl) -3(2H) -pyridazinone
1H-NMR (500MHz, CDCl3) d 2.21 (3H, s) , 6.90 (IH, d, J=IO.5Hz) ,
7.05 (IH, dd, J =4.IHz, 10.5 Hz), 7.16 (2H, dd, J=8.3Hz,
8.3Hz), 7.29-7.40 (4H, m) , 7.56 (2H, dd, J=5.3Hz, 8.3 Hz).
The following compound was obtained in a similar manner to that of Example 64.
Example 82 6- [4-(4-Fluorophenyl) -2-(3-hydroxy-1-pyrrolidinyl) -1,3- i thiazol-5-yl] -2-(2-methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 449 (M+l)
1H-NMR (500MHz, CDCl3) d l.66 (IH, brs), 2.15-2.2,0 (IH, m) , 2.21-2.30 (IH, m) , 2.21 (3H, s), 3.54-3.60 (2H, m) , 3.64-3.70 (2H, m) , 4.64 (IH, m) , 6.76 (IH, d, J
=9.6 Hz), 6.93 (IH, d, J=9.6Hz), 7.13 (2H, dd, J=8.2Hz, 8.2Hz) , 7.32-7.35 (4H, m) , 7.55 (2H, dd, J=5.5Hz, 8.2 Hz) .
Example 83 6-[4-(4-Fluorophenyl) -2-(5-methyl-2,5-diazabicyclo-
[2.2.1]hept-2-yl) -1,3-thiazol-5-yl] -2-(2-methylphenyl)-
3(2H)-pyridazinone
Mass ESI (+) 474 (M+l)
1H-NMR (500MHz, CDCl3) d 1.87-1.89 (IH, m) , 2.00-2.02 (IH,
m) , 2.21(3H, s) , 2.42(3H, s), 2.71-2.73 (IH, m) , 2.97-2.99
(IH, m) , 3.36-3.38 (IH, m) , 3.52-3.60 (IH, m) , 3.60-3.62
(IH, m) , 4;30-4.45 (IH, m) , 6.77 (IH, d, J=IO.5Hz),
6.94 (IH, d, J=IO.5Hz), 7.13 (2H, dd, J=8.2Hz, 8.2Hz),
7.32-7.36 (4H, m) , 7.55 (2H, dd, J=5.5Hz, 8.2 Hz) .
Example 84
6- [4-(4-Fluorophenyl) -2,- (8-methyl-3,8-diazabicyclo-
[3.2. l]oσt-3-yl)-1,3-thiazol-5-yl] -2- (2-methylphenyl)-
3(2H) -pyridazinone Mass ESI (+) 488 (M+l) 1H-NMR (500MHz, CDCl3) d 1.70 (2H, m) , 2.04 (2H, m) , 2.20
(3H, s) , 2.34 (3H,s) , 3.22 (2H, m) , 3.34 (2H, d, J=Il.5 Hz) ,
3.58 (2H, d, J=Il.5 Hz), 6.78 (IH, d, J = 10.5Hz) , 6.96 (IH,
d, J=IO.5Hz), 7.12 (2H, dd, J=8.2Hz, 8.2Hz), 7.32-7.35 (4H,
m) , 7.55 (2H, dd, J=5.5Hz, 8.2 Hz) .
The following compound was obtained in a similar manner to that of Preparation 1.
Preparation 75
2-(6-Chloro-3-pyridazinyl)-1-(2,4-difluorophenyl)- ethanone
1HNMR (200MHz, DMSO-d5) d4.74(1.6H, d, J=2.5Hz) , 6.25(0.2H, s), 7.18-7.37(1H, m) , 7.39-7.56(IH, m) , 7.75-7.87(1.2H, m) , 7.88-8.11(2H, m) .
The following compounds was obtained in a similar manner to that of Preparation 7.
Preparation 76
6-[2-(2,4-Difluorophenyl) -2-oxoethyl] -3(2H) - pyridazinone
1H NMR (200MHz, DMSO-d6) d 4.32(2H, d, J=3.0 Hz), 6.86(1H, dd, J=I.5, 10.0 Hz), 7.27(1H, dt, J=2.5, 8.0 Hz), 7.38(1H, d, J=IO.OHz) , 7.40-7.53(IH, m) , 7.91-8.08(IH, m) , 12.91(IH, brs) .
The following compound was obtained in a similar manner to that of Preparation 15.
Pxeparation 77
6-[l-Bromo-2-(2,4-difluorophenyl)-2-oxoethyl]-2-(2- methylphenyl) -3(2H) -pyridazinone
1H NMR (200MHz, DMSOd6) d 1.81(3H1 s), 6.76(1H, s), 6.99-7.58(7H, m) , 7.80(IH, d, J=9.7 Hz), 7.98-8.14(IH, m) .
The following compound was obtained in a similar manner to that of Example 35.
Preparation 78
6-{[2-(2,4-Difluorophenyl)-1,3-dioxolan-2-yl]methyl}-2-
(2-methylphenyl) -3(2H)-pyridazinone
1H NMR (200MHz, DMSO-d6) d 1.81(3H, s), 3.24(2H, s),
3.74-3.90(2H, m) , 3.93-4.08(2H, m) , 6.92-7.09(3H, m) , 7.14-7.39(5H, m) , 7.47(1H, d, J=9.6 Hz).
The following compound was obtained in a similar manner to that of Preparation 56.
Preparation 79 6-{[2-(2,4-Difluorophenyl)-1,3-dioxolan-2-yl]methyl}- 3(2H) -pyridazinone
1H NMR (200MHz, DMSO-d6) d 3.19(2H, s), 3.72-3.87(2H, m) , 3.88-4.02(2H, m) , 6.76(1H, d, J=IO.0 Hz), 7.01(1H, dt, J=2.5, 8.5 Hz), 7.17-7.42(3H, m) , 12.73(1H, brs) .
The following compound was obtained in a similar manner to that of Preparation 59.
Preparation 80
6- [2-(2,4-Difluorophenyl) -2-oxoethyl] -2-(2-methyl- phenyl) -3(2H) -pyridazinone
1H NMR (200MHz, DMSO-d6) d 2.00(3H, s), 4.40(2H, d, J=2.6
Hz) , 7.08(1H, d, J=9.6 Hz) , 7.19-7.58(7H, m) , 7.94-8.09(IH, m) .
Preparation 81 To a solution of tert-butyl methyl(3-pyrrolidinyl)carbamate (5.Og) in H2O-EtOH (5ml-25ml) was added potassium cyanate (3.4g) and the mixture was adjusted to pH7 with IN HCl (25ml) at room temperature. After stirring for 4h, the mixture was diluted with EtOAc, washedwith 0.IN HCl and brine, dried over MgSO4 and concentrated in vacuo to give tert-butyl [1-(aminocarbonyl) -3-pyrrolidinyl]methylcarbamate (5.9g) as a white solid. Mass ESI (+) 244(M+1), 266(M+Na)
1H NMR (200MHz, DMSO-d6) d.1.40 (9H, s), 1.96 (2H, m) , 2.70 (3H, s), 3.02-3.11 (2H, m) , 3.13-3.21 (2H, m) , 4.50 (IH, m) , 5.76 (2H, brs) .
The following compound was obtained in a similar manner to that of Example 35.
Example 85
6- [3-(4-Fluorophenyl)-1-methyl-5-(methylamino)-IH- pyrazol-4-yl] -2-(2-methoxyphenyl) -3(2H)-pyridazinone
Mass ESI (+) 406 (M+l)
1H NMR (200MHz, DMSO-d6) d 2.67(3H, d, J=5.5 Hz), 3.67(3H, s), 3.77(3H, s), 5.55(1H, q, J=5.5 Hz), 6.93(1H, d, J=IO.0
Hz) , 7.06(1H, dt, J=I.5, 7.5 Hz) , 7.13-7.27(4H, m) , 7.35(IH, dd, J=2.0, 7.5 Hz), 7.38-7.52(3H, m) .
Example 86 A mixture of 6- [l-bromo-2-(2,4-difluorophenyl)-2- oxoethyl]-2-(2-methylphenyl)-3(2H)-pyridazinone (3.7g) and tert-butyl [1-(aminocarbonyl)-3-pyrrolidinyl] - methylcarbamate (3.8g) in xylene (21 ml) was stirred at 140 °C for 5h. After cooling to room temperature, the reaction mixture was diluted with H2O (50ml) and extracted with EtOAc (50ml) two times. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO2 (eluent: CH2Cl2/Me0H 100:1-100:2-10:1) to give tert-butyl
(1-{4-(2,4-difluorophenyl) -5- [1-(2-methylphenyl)-6-oxo- l,6-dihydro-3-pyridazinyl]
Figure imgf000100_0001
pyrrolidinylJmethylcarbamate (3.0 g) as a pale brown oil. Mass ESI (+) 564(M+1), 586(M+Na) 1H NMR (200MHz, CDCl3) d 1.47 (9H, s), 2.00 (3H, s), 2.82 (3H, s), 2.00-2.22 (2H, m) , 3.43-3.49 (IH, m) , 3.49-3.57 (IH, m) , 3.75-3.84 (2H, m) , 4.32 (IH, m) , 6.91-7.32 (2H, m), 6.92 (IH, d, J = 10 Hz), 7.24-7.35 (5H, m) , 7.59 (IH, m).
Example 87
To a solution of tert-butyl
(l-{4-(2,4-difluorophenyl)-5- [1-(2-methylphenyl)-6-oxo- 1,6-dihydro-3-pyridazinyl]-1,3-oxazol-2-yl}-3- pyrrolidinyl)methylcarbamate (3.Og) in CH2Cl2 (30ml) was added TFA (3.0ml) at 00C. The reaction mixture was stirred at 00C for Ih, then poured into 2N NaOH (50ml) at 00C and extracted CH2Cl2. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by columnchromatography on SiO2 (eluent: CH2Cl2/Me0H 50:1-10:1) to give yellow solid (1.25g). The solid was crystallized from EtOH (15ml) to give 6~{4-(2,4-difluorophenyl)-2-[3-(methylamino) -1- pyrrolidinyl] -1,3-oxazol-5-yl}-2-(2-methylphenyl)- 3(2H)-pyridazinone (l.lg) as yellow crystals. Mass ESI (+) 464(M+1)
1H NMR (200MHz, CDCl3) d 1.93 (IH, m) , 2.12 (3H, s), 2.21 (IH, m) , 2.48 (3H, s) , 3.48 (2H, m) , 3.63 (IH, m) , 3.76 (2H, m) , 6.77 (IH, m) , 6.88 (IH, m) , 6.97 (IH, d, J = 10 Hz), 7.20-7.57 (6H, m) , 7.58 (IH, m) .
Example 88
6-{4-(2,4-Difluorophenyl)-2- [3-(methylamino)-1- pyrrolidinyl] -1,3-oxazol-5-γl}-2-(2-methylphenyl) - 3(2H)-pyridazinone (660mg) and 38% HCHO (8.5ml) in MeOH (6.6ml) and AcOH (1.8ml) was mixed at 0 °C and stirred at room temperature for Ih. To the reaction mixture was added NaBH3CN (178mg) poftionwise. The mixture was stirred at room temperature for 30min, then quenched with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was crystallized from EtOAc (6ml) to give 6-{4-(2,4-difluorophenyl)-2- [3-(dimethylamino) -1- pyrrolidinyl] -1,3-oxazol-5-yl}-2-(2-methylphenyl)- 3(2H)-pyridazinone (510mg) as a yellow solid. Mass ESI ( + ) 478 (M+1 )
1H NMR (200MHz, CDCl3) d 2.02 (IH, m) , 2.12 (3H, s), 2.24 (IH, m), 2.34 (6H, s), 2.91 (IH, m) , 3.46 (IH, m) , 3.57 (IH, m), 3.78-3.79 (2H, m) , 6.78 (IH, ra) , 6.89 (IH, m) , 6.97 (IH, d, J = 10 Hz), 7.27-7.35 (5H, m) , 7.58 (IH, m) .
The following compounds were obtained in a similar manner to that of the above Preparations or Examples from 6- [l-bromo-2-(4-fluorophenyl)-2-oxoethyl] -2- (2-methylphenyl) -3(2H) -pyridazinone.
Example 89
6-{3-(4-Fluorophenyl)-5- [ (3-hydroxypropyl)amino] -1- methyl-lH-pyrazol-4-yl}-2-(2-methylphenyl) -3(2H)- pyridazinone
Mass ESI (+) 434 (M+l)
IH NMR (500MHz,CDC13) <5 1.31 (IH, t, J = 4.5 Hz), 1.62 - 1.67 (IH, m), 2.24 (3H, s), 3.20 (2H, dt, J = 6.4 Hz, 6.4 Hz), 3.57 (2H, dt, J = 5.5 Hz, 10.1 Hz), 3.82 (3H, s) , 5.55 (IH, t, J = 6.5 Hz), 6.85 (IH, d, J = 9.7 Hz), 7.01 (IH, d, J = 9.7 Hz), 7.14 (2H, dd, J = 8.6 Hz, 8.6 Hz), 7.33 - 7.41 (4H, m), 7.48 (2H, dd, J = 5.5 Hz, .8.5Hz) .
Example 90 6-{3-(4-Fluorophenyl)-5- [ (3-hydroxypropyl)amino] -IH- pyrazol-4-yl}-2-(2-methylphenyl) -3(2H)-pyridazinone Mass ESI (+) 420 (M+l)
IHNMR (500MHz,CDC13) d 1.69 - 1.73 (2H, m) , 2.23 (3H, s), 3.42 (2H, brs), 3.63 (2H, t J = 5.5 Hz), 6.81 (IH, d, J = 9.9 Hz), 6.97 (IH, d, J = 9.9 Hz), 7.19 (2H, dd, J = 8.5 Hz, 8.5 Hz), 7.34 - 7.39 (4H, m) , 7.45 (2H, dd, J = 5.2 Hz, 8.7 Hz) .
Example 91 6-{3-(2,4-Difluorophenyl)-5- [ (3-hydroxypropyl)amino] - lH-pyrazol-4-yl}-2-(2-methylphenyl) -3(2H) -pyridazinone was obtained in a similar manner to that of the above Preparations or Examples from 6- [l-bromo-2-(2,4- difluorophenyl)-2-oxoethyl]-2-(2-methylphenyl) -3(2H) - pyridazinone.
Mass ESI (+) 438 (M+l)
IHNMR (500MHz,CDC13) 6 1.70 - 1.75 (2H, m) , 2.22 (3H, s), 3.41 (2H, t, J = 6.0Hz), 3.65 (2H, t, J = 5.6 Hz), 6.85 (IH, d, J = 9.8 Hz), 6.94 - 7.04 (3H, m) , 7.34 - 7.38 (4H, m) , 7.46 (IH, ddd, J = 6.3Hz, 8.3 Hz, 8.3Hz)
Example 92
A mixture of 6-[3-(4-fluorophenyl) -5-(3- hydroxypropylamino)-IH-pyrazol-4-yl] -2-(2-methyl- phenyl)pyridazin-3(2H)-one (117 mg) , triphenylphosphine (110 mg) and diethyl azodicarboxylate (66££l) in tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. To the mixture was added water (20 ml) . The mixture was extracted with ethyl acetate (30 ml). The extract was concentrated under reduced pressure. To the residue was added 10 % hydrochloric acid (25 ml) . The mixture was washed with diethyl ether (30 ml x 4). The aqueous layer was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate (30 ml). The extract was concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution: ethyl acetate/hexane = 25 % to 100 %) to give 6-[2-(4- fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]- pyrimidin-3-yl]~2-(2-methylphenyl)-3(2H)-pyridazinone as yellow amorphous (70 mg) . Mass ESI (+) 402 (M+l)
IH-NMR (500MHz,CDC13) <5 2.15 - 2.20 (2H, m) , 2.23 (3H, s), 3.36 (2H, brs), 4.15 (2H, t, J = 6.1 Hz), 5.81 (IH, brs), 6.80 (IH, d, J = 9.9 Hz), 7.02, (IH, d, J = 9.9 Hz), 7.15 (2H, dd, J = 8.7 Hz, 8.7 Hz) , 7.33 - 7.38 (4H, m) , 7.50 (2H, dd, J=5.4Hz, 8.7Hz).
The following compound was obtained in a similar manner to that of the Example 92 from 6-{3-(2,4-difluorophenyl) - 5-[ (3-hydroxypropyl)amino] -lH-pyrazol-4-yl}-2-(2- methylphenyl) -3(2H) -pyridazinone
Example 93
6- [2- (2,4-Difluόrophenyl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrimidin-3-yl] -2-(2- methylphenyl) -3(2H)-pyridazinone Mass ESI (+) 420 (M+l)
IH-NMR (500MHz,CDC13) 6 2.16 - 2.20 (2H, m) , 2.21 (3H, S) , 3.36 - 3.38 (2H, m),, 4.17 (2H, t, J = 6.1 Hz), 5.90 (IH, brs), 6.83 (IH, d, J = 9.8 Hz), 6.92 - 6.97 (2H, m) , 7.02 (IH, ddd, J = 2.3 Hz, 8.1 Hz, 8.1Hz), 7.34 - 7.38 (4H, m) , 7.54 (IH, ddd, J = 6.5Hz, 8.4 Hz, 8.4 Hz) .
Example 94 To a solution of 6-{2- [3-(dimethylamino) -1-pyrrolidinyl]- 4-(4-fluorophenyl) -1,3-thiazol-5-yl}-2-(2-methylphenyl) -3(2H)-pyridazinone (80mg) in CH2C12 (ImI) was added mCPBA (37.7mg) and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was washed with a mixture of sat.MaHCO3 and brine, 5% Na2S2O3, water and brine, successively. The organic phase was dried over MgSO4 and evaporated in vacuo to give 6-{2-[3-(dimethylnitroryl) -1- pyrrolidinyl] -4-(4-fluorophenyl)-1,3-thiazol-5-yl}-2-(2 -methylphenyl) -3(2H)-pyridazinone (74 mg) . Mass ESI (+) 492 (M+l) IH-NMR (CDC13) δ 2.20 (3H, s) , 2.48-2.60 (IH, m) , 2.63-2.86 (IH, m) , 3.48 (3H, s), 3.51 (3H, s), 3.66-3.78
(IH, m) , 3.87-3.97 (IH, m) , 4.12 (IH, dd, J=Il.8 and 5.60
Hz), 4.52-4.70 (IH, m) , 6.78 (IH, d, J=9.74 Hz) , 6.95 (IH,
d, J=9.76 Hz), 7.09-7.18 (2H, m) , 7.31-7.36 (4H, m) ,
7.50-7.57 (2H, m) .
The following compounds were obtained in a similar manner to that of the above Preparations or Examples from 6- [l-bromo-2-(2,4-difluorophenyl) -2-oxoethyl] -2- (2-methylphenyl)-3(2H) -pyridazinone.
Example 95
6- [4-(2,4-Difluorophenyl)-2-(3-hydroxy-1-pyrrolidinyl)- 1,3-oxazol-5-yl] -2-(2-methylphenyl)-3(2H)-pyridazinone
Mass ESI (+) 451(M+l), 473(M+Na)
IH-NMR (DMSO~d6) δ 1.94 (2H, m) , 2.02 (3H, s), 3.58 (4H, m), 4.38 (IH, m), 5.08 (IH, m) , 7.09 (IH, d, J = 10 Hz),
7.12-7.33 (6H, m) , 7.53 (IH, d, J = 10 Hz), 7.62 (IH, m) .
Example 96
1-{4-(2,4-Difluorophenyl)-5- [1-(2-methylphenyl)-6-oxo- l,6-dihydro-3-pyridazinyl] -l,3-oxazol-2-yl}-4- piperidinyl acetate Mass ESI '(+) 507 (M+l) IH-NMR (CDC13) δ 1.75-1.79 (2H, m) , 1.96-2.00 (2H, m) , 2.08 (3H, s), 2.13 (3H, s), 3.48 (2H, m) , 3.87 (2H, m) , 5.00 (IH, m), 6.79 (IH, m) , 6.91 (IH, m) , 6.98 (IH, d, J = 10 Hz), 7.23-7.33 (5H, m) , 7.60 (IH, m) .
Example 97
6-{4- (2,4-Difluorophenyl) -2- [ (2-hydrόxyethyl)amino] - 1,3-oxazol-5-yl}-2- (2-methylphenyl) -3(2H) -pyridazinone Mass ESI (+) 425 (M+l)
IH-NMR (DMSO-d6) 6 2.02 (3H, s), 3.24-3.33 (2H, m) ,
3.44-3.51 (2H, m) , 4.73 (IH, t, J = 7 Hz), 7.05 (IH, d, J = 10 Hz), 7.14-7.39 (6H, m) , 7.64 (IH, m) , 7.87 (IH, t, J = 7 Hz), 8.61 (IH, brs) .
Example 98 tert-Butyl (l-{4- (2,4-difluorophenyl) -.5- [ 1- (2- methylphenyl) -6-oxo-l,6-dihydro-3-pyridazinyl] -1,3- , oxazol-2-yl}-4-piperidinyl)methylcarbamate Mass ESI (+) 578 (M+l)
IH-NMR (CDC13) δ 1.47 (9H, s), 1.76 (4H, m) , 2.13 (3H, s), 2.73 (3H, s) , 3.08 (2H, m) , 3.67 (2H, m) , 4.28 (IH, m) , 6.79 (IH, m), 6.84 (IH, m) , 7.00 (IH, d, J = 10 Hz), 7.29 (5H, m), 7.60 (IH, m) .
Example 99 6- [2-Amino-4-(2,4-difluorophenyl) -1,3-oxazol-5-yl]-2- (2-methylphenyl) -3(2H)-pyridazinone Mass ESI (+) 381 (M+l)
IH-NMR (DMSO-d6) δ 2.03 (3H, s), 7.06 (IH, d, J = 10 Hz), 7.26 (IH, m), 7.21-7.40 (8H, m) , 7.64 (IH, m) .
Example 100 tert-Butyl 4-({4-(2,4-difluorophenyl)-5- [1-(2- methylphenyl) -6-oxo-l,6-dihydro-3-pyridazinyl]-1,3- oxazol-2-yl}amino)-1-piperidinecarboxylate Mass ESI (+) 586 (M+Na)
IH-NMR (DMSO-d6) δ 1.39 (9H, s), 1.90 (4H, m) , 2.02 (3H, s), 2.94 (4H, m), 3.79 (IH, m) , 7.05 (IH, d, J = 10 Hz), 7.18-7.40 (7H, m) , 7.65 (IH, m) , 7.96 (IH, m) .
Example 101
6-[2-Bromo-4-(2,4-difluorophenyl) -1,3-oxazol-5-yl] -2-
(2-methylphenyl) -3(2H) -pyridazinone
IH-NMR (CDC13) δ 2.11 (3H, s), 6.71-6.84 (IH, m) , 6.86-6.97 (IH, m) , 7.10 (IH, d, J=ICOHz), 7.15-7.37 (4H, m), 7.52 (IH, d, J=IO.OHz), 7.56-7.70 (IH, m) .
Example 102
6-{4-(2,4-Difluorophenyl)-2- [4- (methylamino)-1-piperidi nyl] -1,3-oxazol-5-yl}-2-(2-methylphenyl) -3(2H)-pyridazi none was obtained in a conventional manner from tert-butyl (l-{4-(2,4-difluorophenyl)-5-[1- (2-methylphenyl) -6-oxo- l,6-dihydro-3-pyridazinyl] -l,3-oxazol-2-yl}-4- piperidinyl)methylcarbamate Mass ESI (+) 478 (M+l)
IH-NMR (CDC13) δ 1.47-1.55 (2H, m) , 2.10 (2H, m) , 2.15 (3H, s), 2.51 (3H, s), 2.51-2.72 (IH, m) , 3.11 (2H, tlike, J = 7 Hz), 4.18 (2H, dlike, J = 7 Hz), 6.80 (IH, m) , 6.92 (IH, t), 7.00 (IH, d), 7.23-7.30 (5H, m), 7.60 (IH, m) .
Example 103
6-{4-(2,4-Difluorophenyl)-2-[4-(dimethylamino)-1- piperidinyl] -1,3-oxazol-5-yl}-2-(2-methylphenyl) -3(2H) - pyridazinone was obtained in a conventional manner from 6-{4-(2,4-Difluorophenyl) -2-[4- (methylamino) -1- piperidinyl] -1,3-oxazol-5-yl}-2-(2-methylphenyl)-3(2H)- pyridazinone
Mass ESI (+) 492 (M+l)
IH-NMR (CDC13) δ 1.25-1.75 (4H, m) , 2.13 (3H, S) , 2.57 (6H, brs), 2.57 (IH, m) , 3.06 (2H, t, J = 7 Hz), 4.33 (2H, d, J = 7 Hz) , 6.79 (IH, m) , 6.91 (IH, m) , 6.99 (IH, m) , 7.21-7.33 (5H, m) , 7.59 (IH, m) .
Example 104 6- [4-(2,4-Difluorophenyl)-2-(4-piperidinylamino)-1,3- oxazol-5-yl]-2-(2-methylphenyl)-3(2H)-pyridazinone was obtained in a conventional manner from tert-butyl 4-({4-(2,4-difluorophenyl) -5-[1-(2-methylphenyl)-6-oxo- 1,6-dihydro-3-pyridazinyl] -1,3-oxazol-2-yl}amino) -1- piperidinecarboxylate Mass ESI (+) 464 (M+l)
IH-NMR (DMSO-d6) δ 1.01-1.38 (2H, m) , 1.74-1.95 (2H, m) , 2.02 (3H, s), 2.50-2.54 (2H, m) , 2.78-3.00 (2H, m) , 3.00-3.63 (IH, m) , 7.05 (IH, d, J = 10 Hz), 7.10-7.37 (8H, m) , 7.66 (IH, m) , 7.99 (IH, d, J = 7 Hz).
Example 105
To the solution 6- [4- (2,4-difluorophenyl)-2-(4- piperidinylamino)-1,3-oxazol-5-yl] -2-(2-methylphenyl) - 3(2H)-pyridazinone (50mg) and TEA (22mg) in CH2C12 (0.5ml)
was added MsCl (12mg) at 0°C. The reaction mixture was stirred at 0°C for Ih and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (CH2C12:MeOH=IO:1) and crystallized from diisopropyl ether to give 6- [4-(2,4-difluorophenyl) -2- { [1- (methylsulfonyl) -4-piperidinyl]amino}-1,3-oxazol-5- yl]-2-(2-methylphenyl)-3(2H)-pyridazinone (24mg) as yellow crystals. Mass ESI (+) 564 (M+Na) IH-NMR (DMSO-d6) 6 1.52-1.57 (2H, m) , 2.02 (2H, m) , 2.02 (3H, s), 2.85 (3H, s), 2.80-2.97 (2H, m) , 3.33 (2H, m) , 3.50 (IH, m) , 7.04 (IH, d, J = 10 Hz), 7.17-7.37 (7H, m) , 7.65 (IH, m) , 8.02 (IH, d, J = 7.4 Hz).
Example 106
To a solution l-{4-(2,4-difluorophenyl) -5- [1- (2- raethylphenyl)-6-oxo-1,6-dihydro-3~pyridazinyl]-1,3- oxazol-2-yl}-4-piperidinyl acetate (43mg)in MeOH-H2O(9: 1, 0.43ml) was added K2CO3 (11.7mg) . The reaction mixture was stirred at ambient temperature for 4h. The reaction mixture was adjusted pH7 with IN HCl and was extracted with ethyl acetate. The organic phase was washedwithbrine, dried over MgSO4, filtered and evaporated in vacuo. The syrup was purified by preparative TLC(CH2C12:MeOH=10:1) to give 6-[4-(2,4-difluorophenyl)-2-(4-hydroxy-l-piperidinyl)- 1,3-oxazol-5-yl]-2-(2-methylphenyl)-3(2H) -pyridazinone (6.0mg) as yellow powder. Mass ESI (+) 487 (M+l)
IH-NMR (CDC13) <5 1.63 (2H, m) , 1.96 (2H, m) , 2.13 (3H, s), 3.33-3.39 (IH, m) , 4.09-4.14 (4H, m) , 6.78-6.81 (IH, m) , 6.90 (IH, m), 6.98 (IH, m) , 7.21-7.33 (4H, m) , 7.59 (IH, m) , 8.01 (IH, m) .
Example 107 6-{4-(2,4-Difluorophenyl)-2- [ (4- hydroxycyclohexyl)amino] -1,3-oxazol-5-yl}-2-(2- methylphenyl) -3(2H) -pyridazinone was obtained in a conventional manner from 6-[2-Bromo-4-(2,4- difluorophenyl) -1,3-oxazol-5-yl] -2- (2-methylphenyl)- 3(2H)-pyridazinone Mass ESI (+) 479 (M+l)
IH-NMR (DMSO-d6) δ 1.43 (2H, m) , 1.60-2.20 (8H, m) , 2.13 (3H, s), 3.67 (2H, m) , 6.89 (IH, m) , 6.90 (IH, m) , 7.01 (IH, d, J = 10 Hz), 7.20-7.40 (5H, m) , 7.60 (IH, m) .

Claims

1. A pyridazinone derivative shown by the following formula
(I):
Figure imgf000113_0001
wherein
Figure imgf000113_0002
R1 is lower alkyl substituted with hydroxy, hydroxycyclo(lower)alkyl or cyclo(lower)alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy; R2 is aryl or thienyl, each of which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy; R3 is hydrogen or lower alkyl; A is O or S; R4 is halogen; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula:
Figure imgf000114_0001
wherein R7 is hydrogen, hydroxy, halogen, lower alkyl, lower alkylamino, di(lower)alkylamino, N-lower alkanoyl-N-lower alkylamino, N-lower alkoxycarbonyl-N-lower alkylamino, lower alkanoyloxy or -N+(CH3J2O"; and R8 is hydrogen; or
R7 and R8 are taken together to form lower alkylene;
X is CH2, NH, N(CH3) or O; and n is 0 or 1; and R5 is hydrogen, lower alkyl or hydroxy(lower)alky1;
R6 is hydrogen; amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino- (lower)alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl(lower)alkyl or hydroxy(lower)alkyl; piperazinyl or N-lower alkoxycarbonylpiperazinyl; or R5 andR6 are taken together to form a group of the formula:
(wherein Y is CH or N) , or
Figure imgf000115_0001
(wherein Z is CH2 or NH); provided that R1 is lower alkyl substituted with hydroxyeyeIo(lower)alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
Figure imgf000115_0002
(wherein R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy) ; or
R1 is lower alkyl substituted with hydroxycyclo(lower)- alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
Figure imgf000116_0001
(wherein R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy, and R4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl) ; or a salt thereof.
2. The compound of claim 1, wherein
Figure imgf000116_0002
R1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (Cl-C4)alkyl or (Cl-C4)alkoxy;
R2 is phenyl optionally substituted with substituent(s) selected from the group consisting of (Cl-C4)alkyl and halogen; R5 is hydrogen, (Cl-C4)alkyl or hydroxy(Cl-C4)alkyl; and
R6 is amino substituted with (C1-C4) alkyl which may be substituted with (Cl-C4)alkoxy or morpholino; phenyl; cyclo(C5-C8)alkyl or hydroxy(Cl-C4)alkyl.
3. The compound of claim 2, wherein R1 is phenyl substituted with (Cl-C4)alkyl or
(Cl-C4)alkoχy; .
R2 is phenyl substituted with halogen; and R6 is amino substituted with (Cl-C4)alkyl.
4. The compound of claim 1, wherein
Figure imgf000117_0001
R1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (Cl-C4)alkyl;
R2 is phenyl optionally substituted with substituent(s) selected from the group consisting of (Cl-C4)alkyl and halogen; A is O or S; and R4 is halogen; amino optionally substituted with hydroxy(Cl~C4)alkyl, hydroxycyclo(Cl-C4)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or (Cl-C4)alkylsulfonylpiperidyl;or a group of the formula:
Figure imgf000118_0001
wherein
R7 is hydrogen, hydroxy, (Cl-C4)alkyl,
(Cl-C4)alkylamino, , di(Cl-C4)alkylamino,
(Cl-C4)alkanoyloxy or -N+(CH3J2O'; and R8 is hydrogen; or R7 and R8 are taken together to form (C1-C4) alkylene; X is CH2, NH, N(CH3) or O; and n is 0 or 1.
5. The compound of claim 4, wherein
R1 is phenyl substituted with (Cl-C4)alkyl; R2 is phenyl substituted with (Cl-C4)alkyl or halogen; and R4 is a group of the formula:
Figure imgf000119_0001
wherein
R7 is hydrogen, hydroxy, methyl, methylamino or dimethylamino; and R8 is hydrogen; or
R7 and R8 are taken together to form methylene or ethylene;
X is CH2,, NH, N(CH3) or O; and n is 0 or 1.
6. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
7. A method for preventing or treating a disease selected from the group consisting of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, drug for psoriasis, or the like, which comprises administering any of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal
8. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
9. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an inhibitors of cytokines' production or their transduction.
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Publication number Priority date Publication date Assignee Title
WO2007026950A1 (en) * 2005-09-01 2007-03-08 Astellas Pharma Inc. Pyridazinone derivatives used for the treatment of pain
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US8765949B2 (en) 2009-12-17 2014-07-01 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
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US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
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US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
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US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10213428B2 (en) 2015-07-02 2019-02-26 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
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US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
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US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013067A1 (en) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles for treating cytokine mediated diseases
WO1995018128A1 (en) * 1993-12-29 1995-07-06 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine adenosine antagonists
WO2001040230A1 (en) * 1999-12-02 2001-06-07 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyrazines and their use as adenosine antagonists
WO2003015776A1 (en) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
WO2003039451A2 (en) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Thiazole pyridazinones as adenosine antagonists
WO2003059891A1 (en) * 2002-01-18 2003-07-24 Pharmacia Corporation Substituted pyridazinones as inhibitors of p38
WO2003097062A1 (en) * 2002-05-13 2003-11-27 Merck & Co., Inc. Phenyl substituted imidazopyridines and phenyl substituted benzimidazoles

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013067A1 (en) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles for treating cytokine mediated diseases
WO1995018128A1 (en) * 1993-12-29 1995-07-06 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine adenosine antagonists
WO2001040230A1 (en) * 1999-12-02 2001-06-07 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyrazines and their use as adenosine antagonists
WO2003015776A1 (en) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
WO2003039451A2 (en) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Thiazole pyridazinones as adenosine antagonists
WO2003059891A1 (en) * 2002-01-18 2003-07-24 Pharmacia Corporation Substituted pyridazinones as inhibitors of p38
WO2003097062A1 (en) * 2002-05-13 2003-11-27 Merck & Co., Inc. Phenyl substituted imidazopyridines and phenyl substituted benzimidazoles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COLLETTI, STEVEN L. ET AL: "Hybrid-Designed Inhibitors of p38 MAP Kinase Utilizing N-Arylpyridazinones", JOURNAL OF MEDICINAL CHEMISTRY , 46(3), 349-352 CODEN: JMCMAR; ISSN: 0022-2623, 2003, XP002269334 *

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US7514566B2 (en) 2006-01-18 2009-04-07 Amgen, Inc. Thiazole compounds and methods of use
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CN107207474A (en) * 2014-12-11 2017-09-26 齐尼思表观遗传学有限公司 Substituted heterocycle is used as bromine domain inhibitor
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10568885B2 (en) 2015-07-02 2020-02-25 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-y1)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-citrate
US10213428B2 (en) 2015-07-02 2019-02-26 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
US11147814B2 (en) 2015-07-02 2021-10-19 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p- tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

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