CN1218472A - Pharmaceutically useful compounds - Google Patents

Pharmaceutically useful compounds Download PDF

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CN1218472A
CN1218472A CN97194665A CN97194665A CN1218472A CN 1218472 A CN1218472 A CN 1218472A CN 97194665 A CN97194665 A CN 97194665A CN 97194665 A CN97194665 A CN 97194665A CN 1218472 A CN1218472 A CN 1218472A
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pyrazolo
represent
phenyl
methyl
hydroxy
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J·班蒂克
R·邦纳特
P·盖奇
D·多纳德
M·弗伯
S·赫斯特
M·佩里
E·菲利普斯
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BRITISH ASTRA PHARMACEUTICALS Ltd
Astra Pharmaceuticals Ltd
Astra USA Inc
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BRITISH ASTRA PHARMACEUTICALS Ltd
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Priority claimed from GBGB9605803.7A external-priority patent/GB9605803D0/en
Priority claimed from GBGB9610474.0A external-priority patent/GB9610474D0/en
Priority claimed from GBGB9610894.9A external-priority patent/GB9610894D0/en
Priority claimed from GBGB9700862.7A external-priority patent/GB9700862D0/en
Application filed by BRITISH ASTRA PHARMACEUTICALS Ltd filed Critical BRITISH ASTRA PHARMACEUTICALS Ltd
Publication of CN1218472A publication Critical patent/CN1218472A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to 2-arylpyrazolisoquinoline and cinnolinone derivatives, methods for their preparation, their use as medicaments, and pharmaceutical formulations including them.

Description

The compound of pharmaceutically useful
The present invention relates to the compound of pharmaceutically useful, its preparation method, its purposes, and the pharmaceutical preparation that comprises them as medicine.
Some pyrazolo [4,3-c] isoquinoline 99.9-3-ketone is known from J.Chem.Soc.599 (1959) (Hinton etc.).Its purposes as medicine is not discussed as yet.The ability of synthetic and the inhibition radioactivity ligand and the benzodiazepine receptors bind of some pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol has report in detail at J.Med.Chem.35 among 368 (1992) (Allen etc.).Some other pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol is at Gaodeng Xuexiao Huaxue Xuebao 1991,12, and is open among the 1620-1622 (Qian Jian-hua etc.).The pharmaceutical use of the compound of these discussion is all not mentioned.
Found that 2-arylpyrazole isoquinoline 99.9 and cinnoline ketone derivatives show antianaphylaxis and anti-inflammatory activity.Therefore, at first the invention provides formula I compound and pharmaceutically acceptable derivates thereof as medicine:
Figure A9719466500221
Wherein:
B, D, E and G represent CH, CA or N separately, and condition is to be no more than 1 among B, D, E and the G to represent and be no more than 1 among CA and B, D, E and the G and represent N;
X represents C=O, C=S, C=NR 15, CR 3R 6Or NR 4
Y represents N or N +R 7Or CR 18
Z represents OR 8Or O;
R 1Represent OH or C 1-6Alkyl, or and R 2Or R 5Form key;
R 2Represent H, C 1-6Alkyl (can be chosen wantonly by phenyl, COOR 9, NR 10R 11, OR 12Or F replaces) or C 3-7Cycloalkyl or and R 1, R 3Or R 4Form key;
R 3Represent H or and R 2Form key;
R 4Represent C 1-6Alkyl or and R 2Form key;
R 5Representative and R 1Or R 8Key;
R 6Represent H, C 1-6Alkyl (can choose wantonly by phenyl and replace), C 3-7Cycloalkyl, phenyl, halogen, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, cyano group or NR 13R 14
R 7Represent C 1-6Alkyl (can choose wantonly by phenyl and replace) or C 3-7Cycloalkyl, the both can be by halogen, hydroxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, NR 16R 17, COOH, COO (C 1-6Alkyl) or cyano group is optional replaces;
Perhaps R 6And R 7Represent C together 3-5Therefore alkylidene group base, X and Y form a 5-7 unit ring;
R 8Represent H, C 1-6Alkyl or and R 5Form key;
R 9, R 10, R 11, R 12, R 15, R 16, R 17And R 18The independent C that represents 1-6Alkyl or H;
R 13And R 14Independent is C 1-6Alkyl, H or with the nitrogen-atoms that it links form one can choose wantonly contain other optional by C 1-6Sauerstoffatom that alkyl replaces or the 3-7 of nitrogen-atoms unit saturated rings;
Ar 1Represent phenyl, pyridyl, pyrimidyl, 2-[4-morpholinodithio base, 2-or 3-quinolyl or 2-quinoxalinyl, all these groups can be chosen wantonly by being selected from halogen, nitro, cyano group, phenyl, benzenesulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, COOH, COO (C 1-6Alkyl), the C that replaces by phenyl 1-6One or more substituting group of alkyl or phenyl replaces, and wherein any alkyl, alkoxyl group, alkylthio and alkyl sulphinyl can be chosen wantonly by fluorine and replace; With
A represents halogen, cyano group, amino, nitro, C 1-6Alkyl or C 1-6Alkoxyl group; Wherein at R 2, R 6, R 7On phenyl, or as Ar 1On substituent phenyl can choose wantonly by C 1-6Alkyl, halogen or C 1-6Alkoxyl group replaces; Condition is: (ⅰ) represent C=O, C=S or C=NR as X 15The time, then Y represents N; (ⅱ) work as R 4Representative and R 2Key the time, then Y represents N +R 7(ⅲ) represent N as Y +R 7The time, then Z represents O -, R 2Representative and R 3Or R 4Key, and R 1And R 5Form key; (ⅳ) when Y represents N, then Z represents OR 8(ⅴ) work as R 1When representing OH, then X represents C=O, and Y represents N, and Z represents OR 8And R 5Representative and R 8Key; (ⅵ) work as R 1When representing alkyl, R then 5Representative and R 8Key, Y represents N, R 2Do not represent key and X not to represent NR 4(ⅶ) work as R 1Representative and R 2During key, R then 5And R 8Form a key, and if X represents NR 4The time, R then 4Represent alkyl; (ⅷ) work as R 6When representing aryl, halogen, alkoxyl group, sulfane base, R then 2And R 3Form key; (ⅸ) represent N or N as Y +R 7And R 2By NR 10R 11, OR 12Or among the F any be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 2Identical carbon atoms link to each other; (ⅹ) work as R 7By NR 16R 17, OR 12Or in the halogen any one be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 7Identical carbon atoms link to each other; (ⅹ ⅰ) when one was represented N among B, D, E and the G, then X did not represent NR 4(ⅹ ⅱ) represents CR as Y 18The time, then X represents CR 3R 6Its further condition is: wherein: represent CHR when B, D, E and G represent CH, X 3, Y represents nitrogen, R 1And R 5Form key, R 8Represent H and R 2And R 3When representing key together, Ar then 1Do not represent unsubstituted phenyl, 4-chloro-phenyl-, 4-fluorophenyl or 4-p-methoxy-phenyl.
Some formula I compound is a new compound.According to having the present invention further provides formula I compound or its pharmaceutically acceptable derivates:
B, D, E and G represent CH, CA or N separately, and condition is to be no more than 1 among B, D, E and the G to represent and do not play one among CA and B, D, E and the G and represent N;
X represents C=O, C=S, C=NR 15, CR 3R 6Or NR 4
Y represents N or N +R 7Or CR 18
Z represents OR 8Or O;
R 1Represent OH or C 1-6Alkyl, or and R 2Or R 5Form key;
R 2Represent H, C 1-6Alkyl (can be chosen wantonly by phenyl, COOR 9, NR 10R 11, OR 12Or F replaces) or C 3-7Cycloalkyl or and R 1, R 3Or R 4Form key;
R 3Represent H or and R 2Form key;
R 4Represent C 1-6Alkyl or and R 2Form key;
R 5Representative and R 1Or R 8Key;
R 6Represent H, C 1-6Alkyl (can choose wantonly by phenyl and replace), C 3-7Cycloalkyl, phenyl, halogen, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, cyano group or NR 13R 14
R 7Represent C 1-6Alkyl (can choose wantonly by phenyl and replace) or C 3-7Cycloalkyl, the both can be by halogen, hydroxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, NR 16R 17, COOH, COO (C 1-6Alkyl) or cyano group is optional replaces;
Perhaps R 6And R 7Represent C together 3-5Therefore alkylidene group, X and Y form a 5-7 unit ring;
R 8Represent H, C 1-6Alkyl or and R 5Form key;
R 9, R 10, R 11, R 12, R 15, R 16, R 17And R 18The independent C that represents 1-6Alkyl or H;
R 13And R 14Independent is C 1-6Alkyl, H or with the nitrogen-atoms that it links form one can choose wantonly contain other optional by C 1-6Sauerstoffatom that alkyl replaces or the 3-7 of nitrogen-atoms unit saturated rings;
Ar 1Represent phenyl, pyridyl, pyrimidyl, 2-[4-morpholinodithio base, 2-or 3-quinolyl or 2-quinoxalinyl, all these groups can be chosen wantonly by being selected from halogen, nitro, cyano group, phenyl, benzenesulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, COOH, COO (C 1-6Alkyl), the C that replaces by phenyl 1-6One or more substituting group of alkyl or phenyl replaces, and wherein any alkyl, alkoxyl group, alkylthio and alkyl sulphinyl can be chosen wantonly by fluorine and replace; With
A represents halogen, cyano group, amino, nitro, C 1-6Alkyl or C 1-6Alkoxyl group; Wherein at R 2, R 6, R 7On phenyl, or as Ar 1On substituent phenyl can choose wantonly by C 1-6Alkyl, halogen or C 1-6Alkoxyl group replaces; Condition is: (ⅰ) represent C=O, C=S or C=NR as X 15The time, then Y represents N; (ⅱ) work as R 4Representative and R 2Key the time, then Y represents N +R 7(ⅲ) represent N as Y +R 7The time, then Z represents O -, R 2Representative and R 3And R 4Key, and R 1And R 5Form key; (ⅳ) when Y represents N, then Z represents OR 8(ⅴ) work as R 1When representing OH, then X represents C=O, and Y represents N, and Z represents OR 8, R 5Representative and R 8Key; (ⅵ) work as R 1When representing alkyl, R then 5Representative and R 8Key, Y represents N, R 2Do not represent key, and X does not represent NR 4(ⅶ) work as R 1Representative and R 2During key, R then 5And R 8Form key, and if X represents NR 4The time, R 4Represent alkyl; (ⅷ) work as R 6When representing aryl, halogen, alkoxyl group, alkylthio, R 2And R 3Form key; (ⅸ) represent N or N as Y +R 7And R 2By NR 10R 11, OR 12Or among the F any be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 2Identical carbon atoms link to each other; (ⅹ) work as R 7By NR 16R 17, OR 12Or in the halogen any one be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 7Identical carbon atoms link to each other; (ⅹ ⅰ) when one was represented N among B, D, E and the G, then X did not represent NR 4(ⅹ ⅱ) represents CR as Y 18The time, X represents CR 3R 6Its further condition is: (a) represent CHR when B, D, E and G represent CH, X 3, Y represents N, R 1And R 5Form key, R 8Represent H and R 2And R 3When representing key together, Ar then 1Do not represent unsubstituted phenyl, 4-chloro-phenyl-, 4-fluorophenyl or 4-p-methoxy-phenyl; (b) when representing CH, X, B, D, E and G represent CHR 3, Y represents N +R 7, R 1And R 5Form key, R 2And R 3Represent key, R 8Represent H and R 7During represent methylidene, Ar then 1Do not represent unsubstituted phenyl; (c) when representing CH, X, B, D, E and G represent CH 2, Y represents N, R 1And R 5Form key, R 8Represent H and R 2When representing sec.-propyl, Ar then 1Do not represent unsubstituted phenyl or 4-bromophenyl; (d), B, D, E and G represent CH when representing CH, X and Y 2And R 1And R 5When forming key, Ar then 1Do not represent unsubstituted phenyl.
Preferred Ar 1Represent phenyl or pyridyl, phenyl most preferably.Phenyl group Ar 1Preferably having substituting group in contraposition, is Cl, Br, CF in contraposition more preferably 3, C 2F 5, OCF 3, or SCH 3Substituting group particularly is CF in contraposition 3, C 2F 5, OCF 3Or SCH 3Substituting group.
Preferred Y represents N +R 7, and X represents CR 3R 6, R wherein 3With R 2Form key and R 6Represent alkyl.In this case, R 6Preferred branched-chain alkyl.In addition, X can represent NR 4, R wherein 4Representative and R 2Key and Y represent N +R 7
Preferred B represents CA.A preferably represents F in the case.
One is represented under the N situation in B, D, E and G, and preferred D or G represent N.
Preferred R 1Representative and R 2Or R 5Key.In the case, R 1Preferred representative and R 5Key.
The particularly preferred compound of the present invention is included in this illustrational those compounds, comprises its free form and all salt and solvates thereof.
Pharmaceutically acceptable derivates comprises solvate and salt.The special salt that can be mentioned comprises hydrochloride, hydrobromate, benzene sulfonate, tosylate and metilsulfate.
Formula I compound can show tautomerism.Its all tautomers and composition thereof all are included in the scope of the present invention.Formula I compound also can contain 1 or a plurality of unsymmetrical carbon, therefore can demonstrate optics and/or diastereo-isomerism.All diastereomers can separate by common technology, for example chromatography or part recrystallization.Various optically active isomers can be with general technology, as partial crystallization or HPLC, by separately racemize or other mixture of this compound separate.In addition, desired optically active isomer can by with suitable optical activity raw material under the condition that does not cause racemization, as with the acid-respons or the derivatize of single chiral, separate the diastereo-isomerism derivative by common technology (for example HPLC, chromatography on silica gel) then and make.All steric isomers all comprise within the scope of the invention.
All R 1, R 2, R 4, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17And R 18The alkyl that can represent or form Ar at one or more 1Substituted alkyl can be saturated or undersaturated, straight or branched on the aromatic ring of part.C 3-7Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, COO (C 1-6Alkyl) and C 3-5Alkenyl is also explained like this.
The present invention also provides the method for preparation, and it comprises:
(a) (wherein X represents CH to preparation 2Or C=O, Y represents N, and Z represents OR 8, R 5And R 8Form key and R 1And R 2Form key) oxidation that can be by corresponding formula I compound (R wherein 1And R 2Represent H, and B, D, E, G, X, Y, Z, Ar 1And R 5The same definition), for example at room temperature use suitable oxygenant (for example Manganse Dioxide) and suitable organic solvent to carry out;
(b) preparation (wherein B, D, E and G represent CA wherein A represent amino) reduction that can be by corresponding formula I compound (and wherein among B, D, E and the G one represent CA wherein A represent nitro and remaining B, D, E and G, reach X, Y, Z, Ar 1, R 1, R 2And R 5Definition is the same), as under backflow ethanol, carrying out with iron powder and ammonium chloride;
(c) preparation (wherein among B, D, E and the G one represent CA wherein A represent halogen) diazotization that can be by corresponding formula I compound (and wherein among B, D, E and the G one represent CA wherein A represent amino and remaining B, D, E and G reach X, Y, Z, Ar 1, R 1, R 2And R 5Definition is the same) and diazonium salt in the presence of halogen negative ion or (to fluorine) tetrafluoro boron sodium, Decomposition and getting under the backflow in dichlorobenzene;
(d) preparation (wherein among B, D, E and the G one represent CA wherein A represent cyano group) can by corresponding formula I compound (wherein represent one of among B, D, E and the G CA wherein A represent bromine and remaining B, D, E and G, reach X, Y, Z, Ar 1, R 1, R 2And R 5Definition is the same) react with cupric cyanide, get as in N-Methyl pyrrolidone, refluxing;
(e) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkylthio) (wherein X represents CR can to pass through corresponding formula I compound 3R 6, R wherein 6Represent methylthio group or halogen and B, D, E, G, Y, Z, Ar 1, R 1, R 2, R 3And R 5Definition is the same) in the presence of alkali,, in appropriate solvent such as DMF, carry out with the replacement(metathesis)reaction of formula II compound as sodium hydride:
R wherein 6aRepresent C 1-6Alkyl;
(f) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkylthio) (wherein X represents CR can to pass through corresponding formula I compound 3R 6, R wherein 6Represent methylthio group or halogen and B, D, E, G, Y, Z, Ar 1, R 1, R 2, R 3And R 5Definition is the same) in the presence of alkali such as sodium hydride, in appropriate solvent such as DMF, carry out with the replacement(metathesis)reaction of formula III compound:
Figure A9719466500292
R wherein 6aDefinition is the same;
(g) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent NR 13R 14) (wherein X represents CR can to pass through corresponding formula I compound 3R 6, R wherein 6Represent methylthio group or halogen and B, D, E, G, Y, Z, Ar 1, R 1, R 2, R 3And R 5Definition is the same) in the presence of alkali,, in appropriate solvent such as DMF, carry out with the replacement(metathesis)reaction of formula IV compound down at 100 ℃ as sodium bicarbonate:
Figure A9719466500301
R wherein 13And R 14Definition is the same.
(h) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent methylthio group) can (wherein X represents C=S, and Y represents N, and Z represents OH and B, D, E, G, Ar by corresponding formula I compound 1, R 1, R 2And R 5Definition is the same) carry out as under refluxing, reacting with methylating reagent such as methyl iodide;
(i) (wherein X represents C=S to preparation, and Y represents N, and Z represents OH and R 1Representative and R 5Key) can (wherein X represents C=O and B, D, E, G, Y, Z, Ar by corresponding formula I compound 1, R 1, R 2And R 5Definition is the same) reaction as by sulfuration, as use LawessonShi reagent, in appropriate solvent,, under backflow, carry out as diox;
(j) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -And R 6Represent halogen) (wherein X represents C=O, and Y represents N, and Z represents OR can to pass through corresponding formula I compound 8, R 8Representative and R 5Key and B, D, E, G, Ar 1, R 1And R 2Definition is the same) reaction as by halogenation, as with trihalophosporus oxide, as under 100 ℃, carrying out;
(k) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkyl) (wherein X represents C=O, and Y represents N, and Z represents OH, R ' representative and R can to pass through corresponding formula I compound 5Key and B, D, E, G and Ar 1The same and R of definition 2Representative is corresponding to the same R of definition 7Group) as in the presence of mantoquita such as cupric bromide (I), in appropriate solvent such as glycol dimethyl ether, as under refluxing with the nucleophilic alkylating reagent for example, the reaction of formula V compound is carried out:
Figure A9719466500311
R wherein 6The same and Hal of definition represents halogen;
(1) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkyl) (wherein X represents CR can to pass through corresponding formula I compound 3R 6R wherein 6Represent H and B, D, E, G, Y, Z, Ar 1, R 1, R 2And R 5Definition is the same) in appropriate solvent such as THF, carry out as under 0 ℃, carrying out reacting with nucleophilic alkylating reagent formula V as defined above compound;
(m) (wherein X represents C=O to preparation, and Y represents N, and Z represents OR 8, R 1Representative and R 5Key, and R 8Represent alkyl) (wherein Z represents OR can to pass through corresponding formula I compound 8R wherein 8Represent H and B, D, E, G, X, Y, Ar 1, R 1, R 2And R 5Definition is the same) as in the presence of alkali such as sodium hydride, in appropriate solvent such as DMF, react and carry out with formula VI compound;
R 8Hal????(Ⅵ)
R wherein 8The same with the Hal definition;
(n) preparation (R wherein 1Represent OH, X to represent C=O, Y represents N, and Z represents OR 8And R 5Representative and R 8Key) can be by corresponding formula I compound reaction as by use oxygenant, as ceric ammonium nitrate, in appropriate solvent such as acetonitrile, carry out as processing at room temperature that (wherein Z represents O -, R 1And R 5Form key and B, D, E, G, X, Y, Ar 1And R 2Definition is the same);
(o) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key) can (wherein Y represents N, and Z represents OH and B, D, E, G, X, Ar by corresponding formula I compound 1, R 1, R 2And R 5Definition is the same) at alkali such as sodium hydride, in appropriate solvent such as DMF, carry out as at room temperature reacting with formula IX compound;
R 7Hal????(Ⅸ)
R wherein 7The same with the Hal definition;
(p) (wherein X represents C=O to preparation, R 2Do not represent H, Y represents N, and Z represents OH and R 1Representative and R 5Key) can be by corresponding formula I compound (R wherein 2Represent H and B, D, E, G, X, Y, Z, Ar 1, R 1And R 5Definition is the same) in appropriate solvent such as DMF, as at room temperature with alkali such as sodium hydride, and react with formula VII compound and to carry out:
R 2Hal??????????(Ⅶ)
R wherein 2Do not represent H, the Hal definition is the same;
(q) (wherein B, D, E and G represent CH or CA to preparation, and X represents NR 4, Y represents N +R 7, Z represents O -, R 4And R 2Form key and R 1And R 5Form key) but through type VIII compound:
Figure A9719466500321
Wherein A and Ar 1Definition is the same, in appropriate solvent such as DMF, as at room temperature with alkali, react as the formula IX compound of sodium hydride and the same definition and to carry out;
(r) (wherein B, D, E and G represent CH or CA to preparation, and X represents NR 4, Y represents N, and Z represents OR 8, R 2And R 1Form key and R 5And R 8Form key) by as the formula VIII compound of preceding definition in appropriate solvent such as DMF, as at room temperature with alkali, as sodium hydride, and formula X compound reacts and carries out:
R 4Hal????(Ⅹ)
R wherein 4The same with the Hal definition;
(s) (wherein X represents CR to preparation 3R 6, Y represents N, and Z represents OH, R 3And R 2Form key and R 1Representative and R 5Key) can by as under refluxing, handle the formula I compound of correspondence (wherein Y represent N with acid as trifluoroacetic acid +R 7, Z represents O -, R 7Represent CH 2C 6H 4O alkyl and B, D, E, G, X, Ar 1, R 1, R 2And R 5Definition is the same) carry out;
(t) (wherein X represents CR to preparation 3R 6, Y represents N, and Z represents OH, R 3And R 2Form key and R 1Representative and R 5Key) can by as in the presence of catalyzer such as palladium carbon, handle the formula I compound of correspondence (wherein Y represent N with hydrogen +R 7, Z represents O -, R 7Represent CH 2Phenyl (can be chosen wantonly by C 1-6Alkyl or C 1-6Alkoxyl group replaces) and B, D, E, G, X, Ar 1, R 1, R 2And R 5Definition is the same) carry out;
(u) (wherein X represents C=O to preparation, and Y represents N, and Z represents OH, R 2Represent H and R 1Representative and R 5The key that forms) can by as under refluxing, handle the formula I compound of correspondence (wherein Y represent N with acid as trifluoroacetic acid +R 7, Z represents O -, R 7Represent CH 2C 6H 4O alkyl and B, D, E, G, X, Ar 1, R 1, R 2And R 5Definition is the same) carry out;
(v) (wherein X represents CR to preparation 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent H) but through type XI compound:
Figure A9719466500341
Wherein X represents CH 2, R 1Represent H, R 2Representative is corresponding in the formula I compound as the R of preceding definition 7Group, B, D, E and the G definition is the same and R is an alkyl, react with formula XII compound as in dimethylbenzene, refluxing and to carry out:
Ar 1NHNH 2????(Ⅻ)
Ar wherein 1Definition is the same;
(w) (wherein X represents C=O to preparation, R 2Do not represent H, Y represents N, and Z represents OH, and R 1Representative and R 5R 5(wherein X represents C=O, R by the formula XI compound as preceding definition 1Represent H, R 2The same definition and B, D, E, G and R definition are the same) with as the formula XII compound of preceding definition carry out Ar wherein as back flow reaction in dimethylbenzene 1Definition is the same;
(x) (wherein X represents CH to preparation 2, Y represents N, Z represents OR 8, R 8And R 5Form key and R 1Represent alkyl) can by as the formula XI compound of preceding definition (wherein X represents CH 2, R 1Represent alkyl and B, D, E, G, R 2The same with R definition) as in dimethylbenzene, reflux with as the formula XII compound of preceding definition react and carry out, wherein Ar ' definition is the same; Or
(y) (wherein X represents C=O to preparation, and Y represents N, and Z represents OR 8, R 8And R 5Form key and R 1Represent alkyl) can by as the formula XI compound of preceding definition (wherein X represents C=O, R 1Represent alkyl, R 2Represent H or alkyl, and B, D, E, G and R definition are the same) as in dimethylbenzene, refluxing with as the formula XII compound of preceding definition react and carry out, wherein Ar ' definition is the same;
(z) (wherein X represents CR to preparation 3R 6, Y represents CR 18, Z represents OH, R 1And R 5Form key and R 2And R 3Form key) can get by the oxygenizement of corresponding formula I compound, wherein X represents CR 3R 6, Y represents CR 18, Z represents OH, R 2And R 3Represent H, R 1And R 5Form key and B, D, E, G, Ar 1, R 6And R 18Definition is the same; Or
(aa) (wherein X represents CR to preparation 3R 6, Y represents CR 18, Z represents OH, R 2And R 3Form key and R 1And R 5Form key) can by as the formula XII compound of preceding definition and the reaction of formula XX compound carry out:
Figure A9719466500351
Wherein B, D, E, G, R 6, R 18The same with the R definition.
Formula I compound, wherein X represents CHR 3, R 2And R 3Represent key together, R 1And R 5Form key and or:
Y represents N +R 7Represent O with Z -, perhaps
On behalf of N and Z, Y represent OH, can be by being similar to J.Med.Chem.35, and the method for 368 (1992) middle explanations prepares.Formula VIII compound is understood from european patent application No.EP-A-187551, or prepares by the similar method of wherein explanation.But formula XI compound through type X III compound: Wherein B, D, E, G, R, R 2The same and R ' is an alkyl with X definition, with alkali such as sodium hydride, under 60 ℃ in DMSO, reacts in the presence of alcohol and prepares.Formula XI compound, wherein X represents C=O and R 2Represent H, from Japanese Examined PatentPublication No.JP-B-8254152, understand, perhaps can prepare by the similar method of wherein explanation.
Formula X III compound, wherein X represents C=O, but through type X VI compound: Wherein B, D, E, G, R and R 2Definition is the same, in the presence of alkali such as salt of wormwood, as in acetone, preparing as reacting down with formula X VII alkylation in 50 ℃:
(R 1O) 2SO 2(X VII) be R wherein 1Definition is the same.
Formula X III compound, wherein X represents CH 2But, through type X IV compound:
Figure A9719466500362
Wherein B, D, E, G and R definition is the same, and formula X V compound:
Figure A9719466500363
R wherein 1, R 2And R ' definition is the same, in the presence of alkali such as triethylamine, in appropriate solvent such as ether, reacts under backflow and prepares.
But formula X IV compound through type X VIII compound:
Figure A9719466500371
Wherein B, D, E, G and R definition are the same, and with bromizating agent such as NBS, under refluxing in ethylene dichloride, photodissociation irradiation reaction down prepares.
But formula X VI compound through type X IX compound:
Figure A9719466500372
Wherein B, D, E and G definition is the same, with as the formula X V compound of preceding definition (R wherein 1, R 2And R ' definition is the same) in appropriate solvent such as acetone, reaction prepares under 50 ℃.
Formula II, III, IV, V, VI, VII, IX, X, XII, X V, X VI, X VII, X VIII and XX compound or provide by commerce, or know in the document, perhaps obtain with known technology.
The person skilled in the art of this area understands that in the preparation process of above explanation the functional group of midbody compound may need to protect by blocking group.The protection of the functional group step that how goes up explanation in office is carried out before.For example, the nitrogen-atoms of formula XI, X III and X VI compound available suitable protecting group such as benzyl or preferred 4-p-methoxy-phenyl methyl group protection before further reacting.Blocking group can be removed with technology well known in the art (for example acid hydrolysis) with reactions steps or when the reaction process terminal point.
Compound of the present invention has useful pharmacologically active, thereby shows that can be used as medicine is used for medical treatment.
The present invention further provides as medicine as preceding definition but the formula I compound of unrestricted condition (C).
Compound particularly of the present invention has antianaphylaxis and anti-inflammatory activity, shown in the experiment for example described as follows.Therefore show that compound of the present invention can be used for treating the inflammatory disease such as the asthma (for example bronchial asthma, allergic asthma, interior asthma, extrinsic asthma and dust asthma) of supersensitivity air flue, particularly chronic or obstinate asthma (for example late period, asthma and air flue were responsive), bronchitis etc.In addition, show that compound of the present invention can be used for treatment and comprises inflammation/anaphylactic disease such as rhinitis, comprise that all is characterized by the nasal mucosa inflammation, comprise caseous rhinitis as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca, medicamentous rhinitis, mucous membrane rhinitis comprise that croup, fibrin, pseudomembranous rhinitis, lymphoglandula nuclearity nose, seasonal rhinitis comprise nervous rhinitis's (spring fever) and vasomotor rhinitis.
Compound of the present invention is shown that also the eosinophilia that can be used for treating chronic anaphylaxis disease, allergic dermatitis, skin, eosinophilic fasciitis, high 1gE syndromes, vernal conjunctivitis, systemic lupus erythematosus, thyroiditis, leproma leprosy, sezary syndromes (erythroderma), chronic transplanting are to host disease, gravis, essential thrombocytopenia pupura etc.
Compound of the present invention also has the activity of prevention and prophylactic treatment acquired immune deficiency syndrome (AIDS) (AIDS), chronic rejection activity with heteroplastic transplantation that prevention causes by humoral immunization, and treatment autoimmune disease such as multiple sclerosis and rheumatoid arthritis.
The most important thing is compound of the present invention is used for asthma in above indication, especially prevention of asthma, and rhinitis, particularly allergic rhinitis and seasonal rhinitis comprise nervous rhinitis's (spring fever).
Another aspect of the present invention provides the method for treatment or Ammonium Glycyrrhizate or inflammatory disease, this method comprise to infect or the people of these diseases of easy infection treat significant quantity as defined above but (b) or formula I compound (c) or its pharmaceutically acceptable derivates of unrestricted condition.
The administering mode of The compounds of this invention can be partial (as sucking in the lung).Compound of the present invention can pressurize or non-pressurised dry powder form sucks.
In non-pressurised powder composition, the active ingredient of finely divided form is mixed with pharmaceutically acceptable inert support than big scale.Composition can be pressurizeed in addition, and in combination, contain pressurized gas, as nitrogen, or the gas injection agent of liquefaction.In these pressurized compositions, activeconstituents is disperseed well.The composition of this pressurization also can contain tensio-active agent.This pressurized compositions can be prepared by general method.
Compound of the present invention can be by being administered systemically (as by oral to gi tract).Available technology commonly used is made activeconstituents for oral administration to GI tablet or capsule with the auxiliary material of knowing, diluent or carrier.The example that is used for suitable auxiliary material, the diluent or carrier of tablet, capsule and the drageeing of oral administration comprises that Microcrystalline Cellulose, calcium phosphate, diatomite, sugar are as lactose, dextran or mantel, talcum powder, stearic acid, starch, sodium bicarbonate and/or gelatin.
Another aspect of the present invention provides medicinal compositions, and it comprises as preceding definition but formula I compound or its pharmaceutically acceptable derivates of unrestricted condition (c), and mixes with pharmaceutically acceptable auxiliary, diluent or carrier.
The optimal dose that supplies part or oral administration is at 0.01-30mgkg every day -1Between the scope, 0.3mgkg for example -1Every day.
The person skilled in the art of this area understands that some functional group can be with suitable protecting group protection to form the protected derivative of The compounds of this invention in the The compounds of this invention.Do not have described pharmacologically active though should be understood that these protected derivatives yet, after it is taken in vivo metabolism form compound of the present invention with pharmacologically active.Therefore these derivatives are called as " prodrug ".The protected derivative and the prodrug of all formula I compounds all comprise within the scope of the invention.
The present invention illustrates by the following example.General comment:
Column chromatography is gone up at silica gel (35-70 μ m), under the normal atmosphere, carry out under typical 0.5 grating.Following hydrazine is used as intermediate in embodiment subsequently:
5-diazanyl-2-picoline
With the aqueous solution (2ml) of Sodium Nitrite (0.3g) join the 5-amino-2-methyl pyridine that maintains below 5 ℃ (J.Chem.Soc. (C)., 1971,3257) in water (6ml) (3.61g) and the cold soln of concentrated hydrochloric acid (1ml).Mixed solution was stirred 15 minutes down at 0 ℃, and then be cooled to-10 ℃.Drip tin chloride (II) concentrated hydrochloric acid (5ml) solution (0.253g) then.After stirring 10 minutes under-10 ℃, solution is risen to room temperature, add Anhydrous potassium carbonate until generating thick shape slurry.Slurry is stirred with ethyl acetate, and inclining organic phase, is evaporated to oily matter then.With this slurry dilute with water, use dichloromethane extraction (three times) more then.Organic phase is with dried over sodium sulfate, filtration, evaporation, merge with top oily matter again.Through column chromatography purification, use methylene dichloride: methyl alcohol (20: 1) wash-out gets title compound, is beige solid (0.09g), mp68-70 ℃. 1H?NMR(CDCl 3)δ2.47(3H,s),3.60(2H,br?s),5.13(1H,br?s),7.03(1H,d),7.12(1H,dd),8.12(1H.d).
4-(pentafluoroethyl group) phenylhydrazine
By the method for preparing 5-diazanyl-2-picoline, prepare with 4-(pentafluoroethyl group) aniline (J.Chem.Soc.Perkin Trans.1,1990,2293).MS(EI)226(M +) 1HNMR(CDCl 3)δ4.15(2H,br),6.87(2H.d),7.30(2H,d),7.45(1H,br)
2-diazanyl-5-picoline (J.Org.Chem.1966,31,251)
2-chloro-5-hydrazino pyridine (Atti R.Accad.dei Lincei, Roma, 1925,2,125); Chem.Zent.1926,1,672
2-diazanyl pyrimidine J.Chem.Soc.1955,3478 embodiment 13-hydroxyl-4-[(4-p-methoxy-phenyls) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (a) 2-[N-(methoxycarbonyl methyl)-N-(4-p-methoxy-phenyl) methyl) amino] methyl-toluate
Under nitrogen with 2-bromomethyl-benzoic acid methyl ester (23.47g; Press J.Med.Chem., be similar to the method preparation of ethyl ester in 1992,35,368) and triethylamine (15.7ml) be dissolved in the dry ether (200ml).Drip the N-[(4-p-methoxy-phenyl) methyl] glycine methyl ester (23.6g; J.Am.Chem Soc., 1993,115,536).Mixed solution in the heating down 16 hours that refluxes, is chilled to room temperature then.Add entry, separate organic phase.Then with water ethyl acetate extraction (three times).With the organic phase that merges with the salt water washing, use dried over sodium sulfate.Filter, evaporate to remove and desolvate, residue is further purified with column chromatography again, use ethyl acetate: isohexane (1: 9) wash-out gets subtitle compounds, is an oily matter (27.85g); MS (APCI) 358 ((M+H) +) 1H NMR (CDCl 3); δ 3.23 (2H, s), 3.66 (3H, s), 3.71 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.8 (2H, d), 7.2 (2H, d), 7.3 (1H, td), 7.45 (1H, td), 7.6 (1H, dd), 7.75 (1H, dd). (b) 1,2,3,4-tetrahydrochysene-2-(4-p-methoxy-phenyl) methyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate
With 2-[N-(methoxycarbonyl methyl)-N-(4-p-methoxy-phenyl) methyl) amino] methyl-toluate (27.85g; Rapid (a) obtains by previous step) be dissolved in the dry toluene (150ml), be added drop-wise to then in the dry toluene (300ml) and 2-methyl propan-2-ol (2.0ml) suspension of sodium hydride (60% sodium hydride of 4.37g) of the no oil of backflow.Continue heating 12 hours.Then mixed solution is cooled to room temperature, pours into again in the saturated ammonium chloride solution, with ethyl acetate extraction (three times).With the organic layer salt water washing that merges, use dried over sodium sulfate more then.Filter, evaporate, then through column chromatography purification, use ether: isohexane (1: 4) wash-out obtains subtitle compounds, is oily matter (20.41g). 1H NMR (CDCl 3) (principal constituent-enol tautomer) δ 3.60 (2H, s), 3.81 (3H, s), 3.91 (5H, s), 6.86 (2H, d), 7.09 (1H, d), 7.25 (2H, d), 7.35-7.43 (2H, m), 7.77 (1H, d) and 11.58 (1H, s). (c) 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 1,2,3,4-tetrahydrochysene-2-(4-p-methoxy-phenyl) methyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate (1.0g; (b) obtains from above-mentioned steps), the 4-toluenesulphonic acids of 4-(trifluoromethyl) phenylhydrazine (1.08g) and catalytic amount is together 150 ℃ of fusings 10 minutes down.Add dimethylbenzene (20ml) then, continue heating 1 hour.Evaporation is except that desolvating after being cooled to room temperature.Solid residue is obtained title compound (0.5g) with the ether grinding.mp220-221℃。MS (APCI) 450 ((M+H) +) 1H NMR (d 6-DMSO) δ 3.72 (3H, s), 6.08 (2H, s), 6.95 (2H, m), 7.7 (2H, m), 7.8 (3H, m), 7.95 (1H, td), 8.15 (1H, d), 8.35 (1H, d), 8.6 (2H, d), 8.96 (1H, s). embodiment 22-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
In nitrogen with 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.26g; Rapid (c) obtains from previous step) reflux 16 hours trifluoroacetic acid (2ml).Be cooled to steam after the room temperature and desolventize.Toluene is joined in the residue, then evaporation (secondary).Add methyl alcohol and evaporate then, red residue is ground with ethyl acetate.Obtain title compound with ethyl alcohol recrystallization, be red solid (14mg).M.p.＞250 ℃ MS (APCI) 330 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.9 (3H, m), 8.0 (1H, t), 8.3 (4H.m) .9.03 (1H, bs) embodiment 32-(4-chloro-phenyl-)-2,5-dihydro-5-methyl-3H-pyrazolo [4,3-c] cinnoline-3-ketone
In nitrogen with 2-(4-chloro-phenyl-)-2,5-dihydro-pyrazolo [4,3-c] cinnoline-3-ketone (0.33g; The portions of European patent application EP-A-0187551) adds in the suspension of dry dimethyl formamide (5ml) of the nothing oil sodium hydride (60% dispersion of 49mg) that stirs.0.5 drip methyl iodide (0.076ml) after hour, then the solution that generates at room temperature stirred 2 hours.Solution is poured in the salt solution, extracted (three times) with methylene chloride.Organic phase with 2M hydrochloric acid and salt water washing, is used dried over sodium sulfate then, filters, concentrate red solid.(3: 2 ethyl acetate: purifying hexane), recrystallization from dimethyl formamide obtains title compound then, is red crystallization (55mg) through column chromatography.M.p.＞250 ℃ MS (EI) 310.312 (M +) 1H NMR (CDCl 3) δ 4.33 (3H, s), 7.4 (2H, dd), 7.65 (2H, t), 7.75 (1H, td), 8.20 (2H, dd), 8.35 (1H, d). embodiment 42-(4-chloro-phenyl-)-2,3a, 4,5-tetrahydrochysene-3a, 4-dimethyl pyrazole [4,3-c] isoquinoline 99.9-3-ketone (a) 2-[((1-methoxycarbonyl) methylamino ethyl)] methyl-toluate
In nitrogen, 2-bromomethyl-benzoic acid methyl ester (3.51g) and diisopropylethylamine (5.86ml) are dissolved in the ether (30ml), solution are cooled to 0 ℃ then.Dropping is dissolved in the N-methylalanine methyl esters trifluoroacetate (3.89g) in dry ether (10ml) and the dry methylene chloride (5ml), then mixed solution is heated to ambient temperature overnight.Add entry, separate organic phase, use the salt water washing, use dried over sodium sulfate.Filter, evaporate, then through column chromatography (1: 9 ethyl acetate: hexane) get subtitle compounds (2.87g).MS (EI) 265 (M +) (b) 1,2,3,4-tetrahydrochysene-2,3-dimethyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate
In nitrogen with the 2-[((1-methoxycarbonyl) ethyl) methylamino] dry toluene (10ml) drips of solution of methyl-toluate (2g) is added in the suspension of the dry toluene (30ml) of nothing oil sodium hydride (60% dispersion of 0.42g) of backflow and 2-methyl-2-propyl alcohol (5).After the reflux 45 minutes, the ice bath cooling solution is poured in the saturated ammonium chloride solution then, with ethyl acetate extraction (three times).With organic phase salt water washing, use dried over sodium sulfate.Filter, evaporate, through column chromatography (1: 4 ethyl acetate: hexane) get subtitle compounds, be yellow oily liquid (0.95g).MS (EI) 234 ((M+H) +) (c) 2-(4-chloro-phenyl-)-2,3a, 4,5-tetrahydrochysene-3a, 4-dimethyl pyrazole [4,3-c] isoquinoline 99.9-3-ketone
With 1,2,3,4-tetrahydrochysene-2,3-dimethyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate (0.84g), 4-chlorophenyl hydrazine (1.54g) and 4-toluenesulphonic acids (20mg) melted 10 minutes down at 150 ℃ together in nitrogen.Add dimethylbenzene (10ml) then, again mixed solution is heated to 150 ℃ 6 hours.Be cooled to room temperature, evaporation removes and desolvates, and residue is dissolved in the methylene chloride.Solution with 2M hydrochloric acid and salt water washing, is used dried over sodium sulfate then.Filter, evaporation is through column chromatography (1: 99 methyl alcohol: methylene dichloride) get title compound, be colorless solid (50mg).mp?128-129℃。MS (EI) 325,327 (M +) embodiment 52-(4-chloro-phenyl-)-3a, 4-dihydro-3a, 4-dimethyl-2H-pyrazolo [4,3-c] isoquinoline 99.9-3,5-diketone (a) 1,2,3,4-tetrahydrochysene-2,3-dimethyl-1,4-dioxy-3-isoquinoline 99.9 methyl-formiate
Under room temperature in the nitrogen with 1,2-dihydro-4-hydroxy-2-methyl-1-oxygen-(JP-B-82 54,152 for 3-isoquinoline 99.9 methyl-formiate; 1.5g) dry dimethyl formamide (5ml) drips of solution add in dry dimethyl formamide (10ml) suspension of nothing oil sodium hydride (from the dispersion of 0.28g 60%) of stirring.After 30 minutes, drip methyl iodide (0.4ml).Solution was at room temperature stirred 3 hours, pour into then in the 2M hydrochloric acid, with ethyl acetate extraction (three times).With organic phase salt water washing, use dried over sodium sulfate.Filter, evaporation, (1: 1 ether: hexane) purifying obtains subtitle compounds, is yellow oil (0.53g) through column chromatography.MS (ESI) 248 ((M+H) +) (b) 2-(4-chloro-phenyl-)-3a, 4-dihydro-3a, 4-dimethyl-2H-pyrazolo [4,3-c] isoquinoline 99.9-3,5-diketone
With 1,2,3,4-tetrahydrochysene-2,3-dimethyl-1,4-dioxy-3-isoquinoline 99.9 methyl-formiate (0.53g), 4-chlorophenyl hydrazine (0.92g) and 4-toluenesulphonic acids (10mg) are together 150 ℃ of fusings 10 minutes in nitrogen.After being chilled to room temperature, evaporation removes and desolvates, and residue is dissolved in the methylene chloride, with 2M hydrochloric acid, sodium hydrogen carbonate solution and salt water washing.With the solution dried over sodium sulfate, filter evaporation.(1: 9 ethyl acetate: purifying hexane), recrystallization gets title compound from propan-2-ol again, is beige solid (0.13g) through column chromatography.mp192-193℃。MS (EI) 339,341 (M +) embodiment 62-(4-chloro-phenyl-)-2,4-dihydro-3-hydroxy-4-methyl pyrido [4,3-c] isoquinoline 99.9-5-ketone
In nitrogen with 1,2-dihydro-4-hydroxy-2-methyl-1-oxygen-3-isoquinoline 99.9 methyl-formiate (JP8254152; 0.5g), 4-chlorophenyl hydrazine (0.91g) and 4-toluenesulphonic acids (10mg) be together 150 ℃ of fusings 10 minutes down.Add dimethylbenzene (5ml) then, with mixture heating up to 150 ℃ 5 hours.Be cooled to room temperature, filter and collect yellow mercury oxide, wash with ether.(1: 49 methyl alcohol: purifying methylene dichloride), recrystallization gets title compound from ethanol again, is beige solid (0.1g) through column chromatography.mp＞250℃。MS (EI) 325,327 (M +) embodiment 73-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(3-quinolyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), prepare title compound with 3-diazanyl quinoline.mp232-233℃。MS (APCI) 433 ((M+H) +) NMR (d 6-DMSO) δ 3.7 (3H, s), 6.1 (2H, s), 6.7 (2H, d), 7.65 (1H, t), 7.70 (3H, m), 7.80 (1H, t), 8.05 (3H, m), 8.20 (1H, d), 8.40 (1H, d), 9.00 (1H, s), 9.20 (1H, d), 9.90 (1H, d). embodiment 82-(3-quinolyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to method described in the embodiment 2, with 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(3-quinolyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.66g) preparation title compound (0.21g).Mp247-248 ℃ of MS (APCI) 313 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.70 (1H, td), 7.80 (1H, td), 7.90 (1H, bt), 8.00 (1H, t), 8.15 (2H, m), 8.35 (2H, m), 8.90 (1H, d), 9.05 (1H), 9.70 (1H, d), 12.20 (1H, bs) embodiment 92-(3, the 4-dichlorophenyl)-and 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), with 3, the 4-dichloro phenyl hydrazine prepares title compound.Mp 239-240 ℃ MS (APCI) 448,450,452 ((M+H) +) 1H NMR (d 6-DMSO): δ 3.72 (3H, s), 6.06 (2H, s), 6.96 (2H, d), 7.70 (3H, m), 7.79 (1H, and t) 7.97 (1H, t), 8.16 (1H, d), 8.37 (2H, m), 8.72 (1H, d), 8.97 (1H, s). embodiment 102-(3, the 4-dichlorophenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to the method for explanation among the embodiment 2, with 2-(3, the 4-dichlorophenyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.26g) preparation title compound (0.028g), mp＞230 ℃.MS (APCI) 330.332.334 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.82 (1H, d), 7.86 (1H, t), 7.97 (1H, t), 8.13 (1H, dd), 8.24 (1H, d), 8.32 (1H, d), 8.42 (1H, d), 8.94 (1H, s). embodiment 112-([1,1 '-phenylbenzene]-4-yl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol (a) 2-([1,1 '-phenylbenzene]-the 4-yl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to the method for explanation among the embodiment 1 (c), with [1,1 '-phenylbenzene]-4-base hydrazine (seeing J.Chem.Soc.Perkin Trans.I, (1975) 1280) preparation subtitle compounds.(b) 2-([1,1 '-phenylbenzene]-4-yl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to the method described in the embodiment 2, with 2-([1,1 '-phenylbenzene]-4-yl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.29g; Get from previous step (a)) preparation title compound (0.082g).M.p.＞220 ° (decomposition) MS (APCI) 338 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.37 (1H, m), 7.51 (2H, m), 7.75 (2H, m), 7.89 (3H, m), 7.98 (1H, m) .8.05 (2H, m) .8.31 (2H, m), (9.02 1H, s, br) embodiment 123-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-aminomethyl phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
Method according to described in the embodiment 1 (c) prepares title compound with the 4-procarbazine.M.p.＞100 ℃ (decomposition) MS (APCI) 396 ((M+H) +) 1H NMR (d 6-DMSO) δ 2.34 (3H, s), 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, m), 7.26 (2H, m), 7.74 (3H, m), 7.94 (1H, m), 8.13 (1H, d), 8.23 (2H, and d) 8.33 (1H, d), 8.89 (1H, s) embodiment 132-(4-aminomethyl phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to the method described in the embodiment 2, with 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-aminomethyl phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.20g) preparation title compound (0.043g).Mp202-209 ℃ (decomposition).MS (APCI) 276 ((M+H) +) 1H NMR (d 6-DMSO) δ 2.37 (3H, s), 7.37 (2H, d), 7.88 (3H, m), 7.94 (1H, m), 8.29 (2H, m), 9.02 (1H, br), 11.90 (1H, br) methyl embodiment 142-(4-bromophenyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl)]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), prepare title compound with the 4-bromophenyl-hydrazine.Mp＞220 ℃ (decomposition).MS (APCI) 460,462 ((M+H) +). 1H NMR (d 6-DMSO) δ 3.70 (3H, s), 6.08 (2H, s), 6.96 (2H, m), 7.66 (2H, m), 7.76 (2H, m) .7.77 (1H, t), 7.96 (1H, m), 8.15 (1H, d), 8.36 (3H, m), 8.94 (1H, s) embodiment 152-(4-bromophenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to method described in the embodiment 2, with 2-(4-bromophenyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.164g) preparation title compound (0.053g), mp＞250 ℃.MS (APCI) 340,342 ((M+H) +). 1H NMR (d 6-DMSO) δ 7.76 (2H, d), 7.89 (1H, m), 8.02 (3H, m), 8.31 (2H, m), 9.07 (1H, br), (11.92 1H, br) embodiment 162-(3-trifluoromethyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), be prepared into oily matter with the 3-trifluoromethyl phenyl hydrazine, through 2 purifying of column chromatography, use eluent ethyl acetate for the first time, use ether for the second time: the ethyl acetate mixture wash-out, obtain title compound, be oily matter.MS (APCI) 450 ((M+H) -) 1H NMR (CDCl 3) δ 3.81 (3H, s), 6.19 (2H, s), 6.96 (2H, d), 7.45 (1H, m), 7.54 (3H, m), 7.79 (2H, m), 7.86 (1H, t), 8.52 (1H, d), 8.68 (1H, d), 8.72 (1H, s) embodiment 172-(3-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to method described in the embodiment 2, with 2-(3-trifluoromethyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt prepares title compound, 250 ℃ of decomposition of mp.MS (APCI) 330 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.67 (1H, d), 7.81 (1H, t), 7.88 (1H, t), 7.99 (1H, t), 8.42 (3H, m), 8.48 (1H, s), 9.01 (1H, s) embodiment 182-[4-(1, the 1-dimethyl ethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol (a) 3-hydroxyl-2-[4-(1, the 1-dimethyl ethyl) phenyl]-the 4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), use 4-[(1, the 1-dimethyl ethyl) phenyl] hydrazine prepares subtitle compounds, do not need purifying to directly apply to next step.(b) 2-[4-(1, the 1-dimethyl ethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to method described in the embodiment 2, with 3-hydroxyl-2-[4-(1, the 1-dimethyl ethyl) phenyl]-4-(4-anisole ylmethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt prepares title compound.Mp＞210 ℃ (decomposition).MS (APCI) 318 ((M+H) +) 1H NMR (d 6-DMSO) δ 1.33 (9H, s), 7.51 (2H, d), 7.75 (1H, t), 7.84 (1H, t), 8.01 (2H, d), 8.12 (1H, d), 8.25 (1H, d), 8.74 (1H, s) embodiment 192-(4-Trifluoromethoxyphen-l)-2H-pyrazolos [4,3-c] isoquinoline 99.9-3-alcohol (a) 2-(4-Trifluoromethoxyphen-l)-3-hydroxyl-2-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 1 (c), prepare title compound with 4-trifluoromethoxy phenylhydrazine, need not to be further purified, be directly used in next step.(b) 2-(4-Trifluoromethoxyphen-l)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
According to method described in the embodiment 2, with 2-(4-Trifluoromethoxyphen-l)-3-hydroxyl-2-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt prepares title compound.mp＞230℃。MS (APCI) 346 ((M+H) +) 1H NMR (d 6-DMSO) δ 7.58 (2H, d), 7.91 (1H, t), 7.99 (1H, t), 8.14 (2H, d), 8.29 (2H, m), 9.03 (1H, br s). embodiment 202-(4-chloro-phenyl-)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 1,2,3,4-tetrahydrochysene-2-methyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate (0.5g) (I.G.Hinton﹠amp; F.G.Mann, J.Chem.Soc.1959,599), 4-chlorophenyl hydrazine (0.98g) and 4-toluenesulphonic acids (10mg) melted 10 minutes at 150 ℃ under logical nitrogen together.Add dimethylbenzene (10ml) then, again with mixture heating up to 150 ℃ 6 hours.Cool off reaction solution, filter the red precipitate of generation, wash with ether.Recrystallization gets title compound (0.27g) from methyl alcohol.mp?247-248℃。MS (EI) 309,311 (M +). 1H NMR (d 6-DMSO) δ 4.5 (3H, s), 7.5 (2H, d), 7.75 (1H, t), 7.95 (1H, t), 8.1 (1H, d), 8.3 (1H, d), 8.4 (2H, d), 8.6 (1H, s). embodiment 212-(4-chloro-phenyl-)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] cinnoline oxyhydroxide, inner salt
Lead under the nitrogen 2-(4-chloro-phenyl-)-2, (portions of European patent application EP-A-0187551) joins in dry dimethyl formamide (5ml) suspension of nothing oil sodium hydride (from 49mg 60% dispersion) of stirring 5-dihydro-pyrrolo-[4,3-c] cinnoline-3-ketone (0.33g).0.5 drip methyl iodide (0.076ml) after hour, will stir 2 hours under the mixed solution room temperature.Solution is poured in the salt solution, extracted (three times) with the methylene chloride mixed solution.Organic phase with 2N hydrochloric acid and salt water washing, is used dried over sodium sulfate again, filters, concentrate red solid.(2: 3 ethyl acetate: purifying hexane), recrystallization gets title compound from dimethyl formamide again, is purple crystals (65mg) through column chromatography.mp?249-250℃。MS (EI) 310,312 (M +). 1H NMR (CDCl 3) 4.81 (3H, s), 7.40 (2H, d), 7.75 (2H, m), 8.00 (1H, dd), 8.25 (2H, d), 8.35 (1H, dd). embodiment 222-(4-chloro-phenyl-)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
According to method described in the embodiment 20, with 1,2,3,4-tetrahydrochysene-2-(4-p-methoxy-phenyl) methyl-4-oxygen-(latter's compound passes through I.G.Hinton﹠amp to 3-isoquinoline 99.9 methyl-formiate; F.G.Mann, J.Chem.Soc.1959, in 599 similarly method make) the preparation title compound.mp?227-228℃。MS(EI)416,418((M+H) +). 1H?NMR(d 6-DMSO)3.70(3H,s),6.08(2H,s),6.95(2H,d),7.50(2H,d),7.70(2H,d),7.75(1H,t),7.95(1H,t),8.15(1H,d),8.35(1H,d),8.40(2H,d),8.93(1H,s).
Following compounds, embodiment 23-56 is by being similar to embodiment 20﹠amp; 22 method prepares:
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
23 3-hydroxy-4-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 201- 203 344 (M+H) + 4.51(3H,s),7.80(3H,m), 7.97(1H,t),8.10(1H,d), 8.35(1H,d),8.60(2H,d), 8.66(1H,s)
24 3-hydroxy-4-methyl-2-(3-quinolyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 327 (M+H) + 4.55(3H,s).7.60(1H,td), 7.70(1H,td),7.82(1H,td), 8.00(3H,m),8.10(1H,d), 8.40(1H,d),8.69(1H,s), 9.13(1H,d),9.93(1H,d),
25 2-(6-hydroxyl-3-pyridyl)-3-hydroxyl-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 311/313 (M+H) + 4.50(3H,s),7.61(1H,d), 7.80(1H,t),7.97(1H,t), 8.12(1H,d),8.35(1H,d), 8.68(1H,s),8.74(1H,dd), 9.37(1H,s)
26 2-(3, the 4-dichlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 223- 229 344/346/ 348 (M+H) + 4.49(3H,s),7.70(1H,d), 7.78(1H,t),7.96(1H,t), 8.11(1H,d),8.35(2H,m), 8.67(2H,m)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
27 3-hydroxy-4-methyl-2-(4-aminomethyl phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 247- 248 290 (M+H) - 2.33(3H,s),4.52(3H,s), 7.24(2H,m),7.74(1H,m), 7.93(1H,m),8.09(1H,m), 8.20(2H,m),8.33(1H,d), 8.59(1H,s)
28 2-(4-bromophenyl)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 244 354/356 (M+H) + 4.50(3H,s),7.63(2H,d), 7.76(1H,t),7.96(1H,t), 8.10(1H,d)8.34(3H,m), 8.63(1H,s)
29 3-hydroxy-4-methyl-2-(3-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 222-6 344 (M+H) + 4.51(3H,s),7.53(1H,d), 7.69(1H,t)7.78(1H,t). 7.96(1H,t),8.12(1H,d), 8.35(1H,d),8.63(1H,d), 8.66(1H,s),8.81(1H,s)
30 2-[4-(1, the 1-dimethyl ethyl) phenyl]-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞220 ° (decomposition) 332 (M+H) - 1.35(9H,s),4.65(3H,dt) 7.46(2H,m),7.62(1H,dt), 7.71(1H,s),7.83(2H,m), 8.15(2H,m),8.50(1H,d) (CDCl3?not?DMSO?d6)
31 2-(6-chloro-3-pyridyl)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 223- 224 417/419 (M+H) + 3.72(3H,s),6.07(2H,s), 6.97(2H,d),7.62(1H,d), 7.70(2H,d),7.81(1H,t), 8.00(1H,t),8.16(1H,d), 8.36(1H,d),8.79(1H,dd), 8.98(1H,dd),9.38(1H,d)
32 3-hydroxy-4-methyl-2-(6-methyl-3-pyridyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 291 (M+H) 2.50(3H,s),4.51(3H,s), 7.33(1H,d),7.77(1H,t), 7.98(1H,t),8.10(1H,d), 8.34(1H,d),8.50(1H,dd), 8.64(1H,s),9.38(1H,d)
33 2-(4-trifluoromethyl)-3-hydroxyl-4-(2-hydroxyethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 374 (M+H) + 3.99(2H,m),4.92(2H,m), 5.19(1H,t),7.79(3H,m). 7.99(1H,m),8.20(1H,d), 8.38(1H,d),8.60(2H,d), 8.65(1H,s)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
?34 3-hydroxy-4-methyl-2-(5-methyl-2-pyridyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 237- 240 291 (M+H) + 2.34(3H,s),4.50(3H,s), 7.75(2H,m),7.98(1H,t), 8.11(1H,d),8.18(1H,d), 8.36(1H,d),8.40(1H,d), 8.59(1H,s)
35 3-hydroxy-4-methyl-2-[4-(1-methylethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 171- 172 318 (M+H) + 1.25(6H,d),2.92(1H,m), 4.53(3H,s),7.34(2H,d), 7.78(1H,t),7.97(1H,t), 8.14(3H,m),8.35(1H,d), 8.69(1H,s)
36 3-hydroxy-4-methyl-2-(4-nitrophenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞230 321 (M+H) - 3.93(3H,s),7.79(1H,t), 7.99(1H,t),8.12(1H,d), 8.33(3H,m),8.62(2H,d), 8.71(1H,s)
37 2-(4-cyano-phenyl)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 225- 227 301 (M+H) + 4.49(3H,s),7.79(1H,t), 7.89(2H,t),7.95(1H,t), 8.00(1H,d),8.34(1H,d), 8.56(2H,d),8.67(1H,s).
38 2-(4-carboxyl phenyl)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞230 320 (M+H) + 4.51(3H,s),7.78(1H,t), 7.99(1H,t),8.01(2H,d), 8.12(1H,d),8.09(1H,d), 8.47(2H,d),8.64(1H,s), 12.74(1H,s).
39 2-(4-chloro-3-trifluoromethyl)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞230 378/380 (M+H) + 4.50(3H,s),7.81(2H,m), 8.00(1H,t),8.13(1H,t), 8.38(1H,d),8.59(1H,dd), 8.68(1H,s),8.98(1H,d)
40 2-(4-Trifluoromethoxyphen-l)-3-hydroxy-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 195- 196 360 (M+H) + 4.51(3H,s),7.46(2H,d), 7.79(1H,t),7.96(1H,t), 8.12(1H,d),8.35(1H,d), 8.45(2H,d),8.64(1H,s)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
41 3-hydroxy-4-methyl-2-(4-methylthio group phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 197- 198 322 (M+H) + 2.50(3H,s),4.51(3H,s), 7.33(2H,d),7.72(1H,t), 7.91(1H,t),8.08(1H,d), 8.27(2H,d),8.31(1H,d), 8.60(1H,s)
42 4-cyclopropyl-3-hydroxyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt salt ＞250 370 (M+H) + 1.33(2H,m),1.54(2H,m), 5.03(1H,m),7.78(3H,m), 7.96(1H,m),8.15(1H,d), 8.34(1H,d),8.61(2H,m), 8.65(1H,s)
43 4-encircles Nei Ji-3-hydroxyl-2-(6-methyl-3-pyridyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 226- 240 ?317 (M+H) + 1.32(2H,d),1.54(2H,m), 2.51(3H,s),5.08(1H,m), 7.33(1H,d),7.56(1H,td), 7.94(1H,td),8.13(1H,d), 8.32(1H,d),8.54(1H,dd), 8.62(1H,s),9.40(1H,d)
44 4-[(1,1-dimethyl-2-hydroxyl) ethyl]-3-hydroxyl-2-[(4-trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞220 402 (M+H) + 1.94(6H,s),4.28(2H,d), 5.15(1H,t),7.79(3H,m), 8.00(1H,m),8.37(2H,t), 8.62(2H,d),8.77(1H,s)
45 3-hydroxyl-4-(2-methoxy ethyl)-2-[(4-trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 195- 197 388 (M+H) - 3.28(3H,s),3.96(2H,t), 5.06(2H,t),7.79(3H,m), 7.99(1H,m),8.18(1H,d), 8.37(1H,d),8.58(2H,d), 8.71(1H,s)
46 2-(4-chloro-phenyl-)-3-hydroxyl-4-[2-(methylthio group) ethyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 187- 188 370/372 (M+H) + 2.19(3H,s),3.20(2H,t), 5.03(2H,t),7.50(2H,m), 7.79(1H,m),7.99(1H,m), 8.15(1H,d),8.38(3H,m), 8.77(1H,s)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
47 3-hydroxyl-4-[2-(methylthio group) ethyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 193- 195 404 (M+H) + 2.20(3H,s),3.21(2H,t), 5.04(2H,t),7.81(3H,m), 8.01(1H,m),8.17(1H,d), 8.39(1H,d),8.59(2H,d), 8.80(1H,s)
48 4-cyclopropyl-2-(4-Trifluoromethoxyphen-l)-3-hydroxyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 188- 189 386 (M+H) + 1.34(2H,m),1.54(2H,m), 5.08(1H,m),7.46(2H,d), 7.78(1H,t),7.95(1H,t), 8.15(1H,d),8.31(1H,d), 8.46(2H,d),8.62(1H,s)
49 2-(4-chloro-3-trifluoromethyl)-4-cyclopropyl-3-hydroxyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞220 404/406 (M+H) + 1.33(2H,m),1.53(2H,m), 4.98(1H,m),7.78(2H,m), 7.97(1H,t)8.17(1H,d), 8.36(1H,d),8.62(1H,dd), 8.67(1H,s),9.03(1H,dd)
50 4-cyclopropyl-3-hydroxyl-2-(4-methylthio group phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 166- 167 348 (M+H) + 1.30(2H,m),1.51(2H,m), 2.51(3H,s),5.24(1H,m), 7.37(2H,d),7.74(1H,t), 7.93(1H,t),8.14(1H,d), 8.33(3H,m),8.58(1H,s)
51 3-hydroxy-4-phenyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 255 406 (M+H) - 7.69(3H,m),7.76(2H,m), 7.82(3H,m),8.05(1H,m), 8.25(1H,d),8.45(1H,d), 8.53(2H,m),8.85(1H,s)
52 4-ethyl-3-hydroxyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 192- 198 358 (M+H) + 1.63(3H,d),4.88(2H, quart),7.75(1H,t),7.79 (2H,d),7.96(1H,t),8.09 (1H,d),8.33(1H,d),8.59 (2H,d),8.76(1H,s)
53 2-(4-trifluoromethyl)-4-(1-ethoxy carbonyl methyl)-3-hydroxyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 167- 169 416 (M+H) + 1.27(3H,t),4.27(2H,q), 5.83(2H,s),7.82(2H,d), 7.82(1H,t),8.04(1H,t), 8.17(1H,d),8.39(1H,d), 8.54(2H,d),8.71(1H,d)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
54 3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-phenyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt Foam 382 (M+H) + 3.72(3H,s),6.10(2H,s), 6.95(2H,d),7.20(1H,t), 7.48(2H,t),7.75(3H,m), 7.95(1H,t),8.15(1H,d), 8.35(3H,m),8.91(1H,s)
55 3-hydroxyl-4-(1-methylethyl)-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 201- 203 372 (M+H) + 1.70(6H,d),6.26(1H,br?s), 7.79(1H,t),7.79(2H,d), 7.98(1H,t),8.22(1H,d), 8.38(1H,d),8.62(2H,d), 8.93(1H,d)
56 3-hydroxyl-4-(1-methylethyl)-2-(3-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 220- 222 372 (M+H) - 1.71(6H,d),6.27(1H,br?s), 7.54(1H,d),7.70(1H,t), 7.78(1H,t),7.96(1H,t). 8.22(1H,d),8.40(1H,d), 8.64(1H,d),8.85(1H,s), 8.94(1H,s)
Embodiment 573-hydroxyl-2-(4-iodophenyl)-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 1,2,3,4-tetrahydrochysene-2-methyl-4-oxygen-3-isoquinoline 99.9 methyl-formiate (0.485g) and 4-iodobenzene hydrazine (1.053g) mix in ethanol (15ml), reflux 20 hours.Cool off solid precipitation, recrystallization from ethanol gets title compound (0.054g) with the propan-2-ol recrystallization again.mp＞260℃。MS(+ve?ESI)402((M+H) +). 1H?NMR(d 6-DMSO):δ4.50(3H,s),7.76(1H,t),7.77(2H,d),7.94(1H,t),8.09(1H,d),8.19(2H,d),8.32(1H,d),8.62(1H,s)
Following compounds, embodiment 58-60 is according to similar approach used among the embodiment 2
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
58 2-(6-chloro-3-pyridyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 ?297/ ?299 ?(M+H) + 7.71(1H,d),7.89(1H,t),8.00 (1H,t),8.31(2H,m),8.56(1H,br d),9.00(1H,br?s),9.13(1H,s)
59 2-[4-(1-methylethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol 218- 219 ?304 ?(M+H) + 1.25(6H,d),2.97(1H,m),7.42 (2H,d),7.93(4H,m),8.27(2H, m),9.00(1H,s)
60 2-(4-pentafluoroethyl group phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol 219- 223 ?380 ?(M+H) + 7.68(1H,t),7.76(3H,m),8.02 (1H,d),8.24(1H,d),8.54(3H, m)
Following compounds, embodiment 61-68 prepares according to similar approach used among the embodiment 6:
Embodiment Title m.p/℃ ?MS 1H?NMR(d 6-DMSO)δ
?61 2,4-dihydro-3-hydroxy-4-methyl-2-(2-pyrimidyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞250 ?294 (M+H) - 3.79(3H,s),7.48(1H,t), 7.75(1H,t),7.89(1H,t), 8.18(1H,d),8.35(1H,d). 8.92(2H,d)
62 2-([1,1 '-two phenyl]-4-yl)-2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone 241-244 368 (M+H) - 3.83(3H,s),7.39(1H,m), 7.50(2H,t),7.75(3H,m), 7.9l(3H,m),8.05(3H, m).8,38(1H,d)
63 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞250 ?360 (M+H) - 3.81(3H,s),7.77(1H,t), 7.94(3H,m),8.05(1H,d), 8.18(2H,d),8.37(1H,d), 11.37(1H,s)
64 2-(6-chloro-3-pyridyl)-2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞250 ?327/329 (M+H) - 3.79(3H,s),7.73(1H,d), 7.76(1H,t),7.92(1H，t), 8.02(1H,d),8.38(2H,m), 8.97(1H,d)
Embodiment Title m.p/℃ ?MS 1H?NMR(d 6-DMSO)δ
?65 2,4-dihydro-3-hydroxyl-2-(4-iodophenyl)-4-methyl-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞250 ?418 (M+H) - 3.80(3H,s),7.74(3H,m), 7.89(3H,m),8.02(1H,d), 8.36(1H,d)
?66 2,4-dihydro-3-hydroxyl-4-(4-anisole ylmethyl)-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞230 (decomposition) 466 ?(M+H) - 3.68(3H,s),5.59(2H,s), 6.83(2H,d),7.40(2H,d), 7.75(1H,t),7.90(3H,m), 8.07(1H,d),8.20(2H,d), 8.38(1H,d),11.50(1H,s)
67 2,4-dihydro-3-hydroxyl-4-(1-methylethyl)-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone 228-230 (decomposition) 388 (M+H) - 1.59(6H,d),5.85(1H, brs),7.76(1H,t),7.92 (3H,d),8．04(1H,d),8.18 ?(2H,d),8.36(1H,d)
?6S 2,4-dihydro-3-hydroxy-4-methyl-2-[4-(1-methylethyl phenyl]-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone 238-240 ?334 (M+H) - 1.25(6H,d),2.96(1H, hept),3.81(3H,s),7.42 (2H,d),7.72(1H,t),7.78 (2H,d),7.89(1H,c),8.01 (1H,d),8.36(1H,d)
Embodiment 692,4-dihydro-3-hydroxyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-C] isoquinoline 99.9-5-ketone
(4ml) joins 2 with trifluoroacetic acid, 4-dihydro-3-hydroxyl-4-(anisole ylmethyl)-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-C] isoquinoline 99.9-5-ketone (embodiment 66) (425mg) in, mixture heating up was refluxed 12 hours.Evaporation is except that desolvating after being chilled to room temperature, and the residue of generation gets yellow solid after using the methanol recrystallization, gets title compound (150mg) through grinding purifying with isohexane again.mp＞200℃。MS(APCI)346((M+H) +), 1H?NMR(d 6-DMSO)δ7.76(1H,t),7.92(3H,m),8.02(1H,d),8.18(2H,d),8.34(1H,d),11.20(1H,s)
The following example prepares with the method for similar embodiment 69:
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
70 2,4-dihydro-3-hydroxyl-2-[4-(1-methylethyl) phenyl]-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone ＞250° 320 (M+H) + 1.24(6H,d),2.95(1H,m), 7.40(2H,d),7.70(1H,t),7.78 (2H,d),7.88(1H,t),7.99(1H, d),8.32(1H,d),11.00(1H,s)
71 2,4-dihydro-3-hydroxyl-2-([1,1 '-two phenyl]-4-yl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone 273 (decomposition) 354 (M+H) + 7.39(1H,t),7.50(2H,t),7.74 (3H,d),7.87(3H,m),8.01 (3H,m),8.34(1H,d),11.13 (1H,s),11.76(1H,s)
Embodiment 72
2-(4-chloro-phenyl-)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-5-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
Ether (2.0ml) drips of solution of the methyl-magnesium-bromide of 3M is added to ice-cold 2-(4-chloro-phenyl-)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (embodiment 22) is (0.5g) and in cupric bromide (I) dry tetrahydrofuran (20ml) suspension (17mg).The mixed solution cooling was stirred 1 hour down, add saturated aqueous ammonium chloride and ethyl acetate.With stirring 16 hours under the mixed solution room temperature, use ethyl acetate extraction (three times) water then.With organic phase salt water washing, use dried over sodium sulfate, filter evaporation.(99: 1 methylene dichloride: methyl alcohol) purifying gets purple solid (0.38g) to solid residue through column chromatography.Sample (0.1g) recrystallization from ethanol is got title compound (31mg).mp?212-216℃。MS (APCI) 430,432 ((M+H) +) 1H NMR (d 6-DMSO) δ 2.88 (3H, s), 3.71 (3H, s), (6.50 2H, br s), 6.93 (2H, d), 7.32 (2H, d), 7.51 (2H, d), 7.76 (1H, t), 7.98 (1H, t), 8.32 (1H, d), 8.43 (3H, m). embodiment 732-(4-chloro-phenyl-)-5-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
With 2-(4-chloro-phenyl-)-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-5-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.29g) is dissolved in (10ml) in the trifluoroacetic acid, and reflux is 2 hours under the logical nitrogen.Be cooled to room temperature, evaporation removes and desolvates, residue toluene coevaporation (three times).Through column chromatography (20: 1 methylene dichloride: purifying methyl alcohol), with methyl alcohol grind title compound, be orange solids (0.07g).m.p.＞250℃MS(APCI)310,312((M+H) +) 1H?NMR(d 6-DMSO)δ2.77(3H,s),7.47(2H,d),7.68(1H,t),7.77(1H,t),8.10(1H,d),8.25(1H,d),8.31(2H,d).
The following example is pressed the method preparation of embodiment 72:
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
74 4-cyclopropyl-3-hydroxy-5-methyl base-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 384 (M+H) + 1.32(2H,m),1.48(2H,m), 3.07(3H,s),4.04(1H,m), 7.76(3H,m),7.95(1H,t), 8.36(2H,m),8.62(2H,d)
75 3-hydroxyl-4-(2-methoxy ethyl-5-methyl-2-[(4-trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 202- 204 402 (M+H) + 3.00(3H,s),3.29(3H,s),4.08 (2H,t),5.37(2H,br?s),7.68 (3H,m),7.88(1H,t),8.10 (1H,d),8.56(3H,m)
Embodiment 762-(4-chloro-phenyl-)-3-hydroxyl-4,5-dimethyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 2-(4-chloro-phenyl-)-2,4-dihydro-3-hydroxy-4-methyl pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (0.48g) (embodiment 6) is miscible in drying 1, in the 2-glycol dimethyl ether (150ml).Add methyl-magnesium-bromide solution (3ml 3M diethyl ether solution), with mixed solution reflux 0.75 hour.Add methyl-magnesium-bromide (1ml) again, continue heating 3 hours.Reaction is cooled to room temperature, slowly adds the dilute hydrochloric acid termination reaction then.Mixed solution is alkalized with sodium bicarbonate aqueous solution, with ethyl acetate extraction (three times).Organic layer is washed with salt, used dried over mgso, filter, evaporation.Residue through chromatography (silica gel, 97: 3-95: 5 methylene dichloride: methyl alcohol) purifying gets red solid, with ether grind title compound (0.060g).mp＞250℃。MS(APCI)324/326((M+H) +), 1H?NMR(d 6-DMSO)δ2.90(3H,s),4.63(3H,s),7.49(2H,d),7.77(1H,t),7.95(1H,t),8.39(4H,m).
The following example is pressed the method preparation of embodiment 76:
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
77 5-ethyl-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 372 (M+H) + 1.45(3H,t),3.32(2H,q),4.78 (3H,s),7.68(3H,m),7.88 (1H,td),8.03(1H,d),8.54 (2H,d),8.58(1H,dd)
78 3-hydroxy-5-methyl base-4-(1-methylethyl)-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 205- 210 386 (M+H) + 1.76&1.90(6H,2×m. roramers),3.07(3H,s),5.42& 7.40(1H,2×br,rotamers) 7.77(3H,m),7.97(1H,t), 8.41(2H,m),8.62(2H,m),
79 4-methyl-5-(1-methylethyl)-3-hydroxyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 236- 238 386 (M+H) + 1.61(6H,d),4.05(1H,br), 4.75(3H,s),7.76(1H,t),7.80 (2H,d),7.94(1H,t),8.43(1H, dd),8.52(1H,d),8.60(2H,d)
80 3-hydroxyl-4,5-dimethyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 358 (M+H) + 2.87(3H,s),4.72(3H,s),7.66 (3H,m),7.86(1H,t),8.01 (1H,d),8.53(3H,m)
Embodiment 815-chloro-2-(4-trifluoromethyl)-2H-pyrazoles [4,3-c] isoquinoline 99.9-3-alcohol
(5ml) joins 2 with phosphoryl chloride, 4-dihydro-3-hydroxyl-4-(anisole ylmethyl)-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (embodiment 66) (350mg), reflux 1 hour.After the cooling room temperature, remove and to desolvate, residue is used isohexane through column chromatography purification: ethyl acetate: acetate (80: 20: 2) wash-out, with acetonitrile grind title compound (25mg).Mp＞250 ℃ decomposition.MS (APCI) 364/366 ((M+H) +). 1H NMR (d 6-DMSO) δ 7.96 (5H, m), 8.07 (1H, t), 8.25 (1H, d), 8.43 (1H, d) embodiment 823a, 4-dihydro-3a-hydroxyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3,5-diketone
Under the room temperature ceric ammonium nitrate (700mg) is added 2, in 4-dihydro-3-hydroxyl-4-(anisole ylmethyl)-2-(trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (embodiment 66) acetonitrile (4ml) and the suspension of water (1ml) (200mg).After 2 hours mixed solution is added in the silica gel, through column chromatography purification, use isohexane: propan-2-ol (9: 1) wash-out, again through HPLC, use isohexane: ethyl acetate (4: 1) wash-out gets title compound (50mg).mp?175-185℃。MS (ESI) 360 (M-H) + 1H NMR (d 6-DMSO) δ 7.7-8.0 (5H, m), (4H, m), 9.78 (1H, s), embodiment 832,4-dihydro-3-methoxyl group-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone for 8.08-8.12
With 2, dry dimethyl formamide (5ml) drips of solution of 4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (0.2g) (embodiment 63) is added in dry dimethyl formamide (1ml) suspension of 0 ℃ of nothing oil sodium hydride (0.022g 60% dispersion) that stirs down.0.5 add methyl iodide (0.038ml) after hour.Continue to stir 16 hours.With the mixed solution dilute with water, use the dilute hydrochloric acid acidifying, with ethyl acetate extraction (three times).Organic phase with salt washing (seven times), is used dried over mgso then, filter, concentrate.(25: 75-50: 50 ethyl acetate: methylene dichloride is 30: 70 ethyl acetate then: isohexane) purifying gets title compound, is colorless solid (0.015g) through chromatography.M.p.163-164 ℃ of MS (APCI) 374 ((M+H) +) 1H NMR (CDCl 3) δ 3.78 (3H, s), 3.83 (3H, s), 7.60 (1H, td), 7.74 (1H, td), 7.80 (2H, d), 8.04 (2H, d), 8.27 (1H, dd), 8.48 (1H, dd). embodiment 842-(4-chloro-phenyl-)-4-(2-(N, the N-dimethylamino) ethyl }-3-hydroxyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
2-(4-chloro-phenyl-)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol (0.3g) is joined in dry dimethyl formamide (5ml) suspension of the nothing oil sodium hydride (81mg 60% dispersion) that stirs under the logical nitrogen.After 30 minutes, add 2-methylamino ethyl chloride hydrochloride (0.15g), will stir 16 hours under the mixture room temperature.With the mixture dilute with water, with ethyl acetate extraction (three times).Dried over sodium sulfate is used in organic phase salt water washing then, filters, concentrate the purple solid.(20: 1 methylene dichloride: purifying ethanol), again from 4: 1 hexanaphthenes: recrystallization gets title compound the ethyl acetate, red solid (125mg) through column chromatography.mp173-174℃。MS (APCI) 367,369 ((M+H) +). 1H NMR (d 6-DMSO) δ 2.32 (6H, s), 3.02 (2H; t), 5.03 (2H, t); 7.4 (2H, d), 7.65 (1H; t), 7.85 (3H, m); 8.30 (2H, d), 8.50 (1H; d). embodiment 853-hydroxy-4-methyl-2-(4-methylsulfinyl phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 3-hydroxy-4-methyl-2-(4-methylthio group phenyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.10g) (embodiment 41) is dissolved in the methylene dichloride (15ml), is cooled to-78 ℃.Add 3-chlorine peroxybenzoic acid (0.055g), mixed solution was stirred 10 minutes, pour into again in the sodium metabisulfite aqueous solution, with ethyl acetate extraction (three times).With extracting solution and the sodium bicarbonate aqueous solution jolting that merges, use dried over sodium sulfate, evaporate residue, (3: 2 ethyl acetate: methyl alcohol) purifying gets title compound, is red powder (0.012g) through column chromatography.mp＞230℃。MS (APCI): 338 (M+H) +). 1H NMR (d 6-DMSO): δ 2.77 (3H, s), 4.52 (3H.s) .7.80 (3H; m), 7.96 (1H, t); 8.13 (1H, d), 8.37 (1H; d), 8.57 (2H, d); 8.64 (1H; s). embodiment 862-(4-chloro-phenyl-)-3-hydroxyl-4-[2-(methylsulfinyl) ethyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
Under-78 ℃, 3-chlorine peroxybenzoic acid (0.86g) is dissolved in (20ml) in the methylene dichloride.The drips of solution that 6ml is generated is added to 2-(4-chloro-phenyl-)-3-hydroxyl-4-[2-(methylthio group) ethyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, in inner salt (embodiment 46) dichloromethane solution (0.43g).Add the sodium metabisulfite aqueous solution after 30 minutes, then reaction mixture is distributed between water and methylene dichloride.Organic phase is washed with aqueous sodium hydroxide washes, and dry (sal epsom) then filters, evaporation.Residue is through chromatography, is eluent with the dichloromethane solution of methyl alcohol (2-6% volume ratio), purple solid (0.46g).
M.p.228-230 ℃ of MS (APCI+) 386,388 ((M+H) +) 1H NMR (d 6-DMSO) δ 2.69 (3H, s), 3.47 (1H, m); 3.64 (1H, m), 5.11 (1H, m); 5.34 (1H, m), 7.50 (2H, m); 7.79 (1H, m), 7.99 (1H, m); 8.17 (1H, d), 8.38 (3H, m); 8.83 (1H, s). embodiment 873-hydroxyl-4-[2-(methylsulfinyl) ethyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 3-hydroxyl-4-[2-(methylthio group) ethyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (embodiment 47) gets title compound by the method for embodiment 86, is the purple solid.mp?241-243℃。MS (APCI+) 420 ((M+H) +) 1H NMR (d 6-DMSO) δ 2.70 (3H, s), 3.47 (1H, m), 3.64 (1H, m), 5.11 (1H, m), 5.36 (1H, m), 7.81 (3H, m), 8.01 (1H, m), 8.19 (1H, d), 8.38 (1H, d), 8.60 (2H, d), 8.86 (1H, s), embodiment 885-[2-(4-p-methoxy-phenyl) ethyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol, sodium salt
With methyl-magnesium-bromide (in the 3M ether, 8.6ml) slowly add to stir 2,4-dihydro-3-hydroxyl-4-(4-anisole ylmethyl)-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (embodiment 66) (500mg) and cupric bromide (I) (15mg) 1, in the suspension of 2-glycol dimethyl ether (50ml), be heated to then 100 ℃ 24 hours.After being cooled to room temperature, mixed solution is poured in the refrigerative dilute hydrochloric acid, then with sodium bicarbonate and sodium hydroxide alkalization.The water ethyl acetate extraction.With the organic phase salt water washing that merges, use dried over mgso.Filter, evaporation, again through column chromatography purification, use isohexane continuously: ethyl acetate (1: 1), and ethyl acetate: methyl alcohol (9: 1) wash-out, obtain title compound, be red solid (90mg).Mp＞200 ℃ decomposition.MS (APCI) 464 ((M+H) +) 1H NMR (d 6-DMSO/TFA) δ 3.08 (2H, t), 3.59 (2H, t), 3.73 (3H, s), 6.87 (2H, d), 7.25 (2H, d), 7.92 (3H, m), 8.05 (1H, t), 8.33 (2H, d), 8.40 (1H, d), 8.50 (1H, d), 12.05 (TFA/water/1H) embodiment 899-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (a) 2,6-two fluoro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide
With 2, dry methylene chloride (100ml) drips of solution of 6-difluoro benzoyl chloride (20g) is added in dry methylene chloride (150ml) solution that keeps ice-cooled 2-amino-2-methyl propyl alcohol (20.2g) below 5 ℃ in nitrogen.Remove ice bath after dropwising, at room temperature continue to stir other 16 hours.With the organic phase dilute with water, separate.Then with water dichloromethane extraction (secondary).With the organic phase salt water washing that merges, use dried over sodium sulfate, filter evaporation.With hexane grind subtitle compounds (24.65g).MS (APCI) 230 ((M+H) +) 1H NMR (CDCl 3): δ 1.41 (6H, s), 3.70 (2H, d), 3.95 (1H, t), 6.00 (1H, br s), 6.95 (2H, m), 7.38 (1H, m). (b) 2-(2, the 6-difluorophenyl)-4,5-dihydro-4,4-two first base oxazoles
Under the logical nitrogen thionyl chloride (12.6ml) is added drop-wise to ice-cold 2, in dry methylene chloride (100ml) solution of 6-two fluoro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide (24.65g).Remove ice bath after dropwising, continue at room temperature to stir 1 hour.Evaporation removes and desolvates then, and residue grinds with ether.The gained solid is dissolved in the little water (80ml), alkalizes with sodium hydrate particle then.Use ethyl acetate extraction alkali phase (three times) again.Merge organic extracting solution,, use dried over sodium sulfate with salt washing, filtration, evaporate oily matter, (4: 1 hexanes: ethyl acetate) purifying gets subtitle compounds (20.86g) through column chromatography.MS (EI) 211 (M +). 1H NMR (CDCl 3): δ 1.42 (6H, s), 4.14 (2H, s), 6.95 (2H, m), 7.40 (1H, m). (c) 4,5-dihydro-2-(2-fluoro-6-aminomethyl phenyl)-4,4-two first base oxazoles
Under the logical nitrogen tetrahydrofuran (THF) (86ml) drips of solution of 3M methylmagnesium-chloride is added to 0 ℃ 2-(2, the 6-difluorophenyl)-4,5-dihydro-4 is in dry tetrahydrofuran (60ml) solution of 4-Er Jia Ji oxazole (18.23g).Solution was stirred 1 hour at room temperature 16 hours then down at 0 ℃.The saturated ammonium chloride solution of careful adding is used ethyl acetate extraction (three times) reaction mixture then.With the salt water washing of organic extracting solution, use dried over sodium sulfate, filter, evaporate subtitle compounds, be light yellow oily liquid (18.18g).MS (APCI) 208 ((M+H) +) 1H NMR (CDCl 3): δ 1.42 (6H, s), 2.40 (3H, s), 4.12 (2H, s), 6.93 (1H, t), 7.00 (1H, d), 7.26 (1H, m). (d) 2-fluoro-6-tolyl acid
With 4,5-dihydro-2-(2-fluoro-6-aminomethyl phenyl)-4,4-Er Jia Ji oxazole (18.18g) and excess iodine methane (20ml) reflux 4 hours in acetonitrile (150ml) is cooled to room temperature then.Evaporation removes and desolvates, and solid residue is ground with ether.Then the gained solid is dissolved in the mixed solution of methyl alcohol (80ml) and 10% sodium hydroxide solution (80ml) reflux 4 hours.Mixed solution is cooled to room temperature, steams then and remove methyl alcohol.Water washs (three times) with ethyl acetate, and being acidified to pH with dilute hydrochloric acid then is 1.Ethyl acetate extraction (three times) is used in acid mutually.Organic phase is washed with salt, uses dried over sodium sulfate, filter, evaporate 2-chloro-6-tolyl acid (10.85g).With sample (0.27g) from 4: 1 hexanes: recrystallization obtains subtitle compounds (0.15g) the ethyl acetate.mp?123-124℃。MS (EI) 154 (M +). 1H NMR (CDCl 3) δ 2.52 (3H, s), 7.02 (2H, m), 7.35 (1H, m). (e) 2-fluoro-6-methyl-toluate
Under the logical nitrogen cerous carbonate (16g) and methyl iodide (4.6ml) are joined in dry dimethyl formamide (25ml) solution of 2-fluoro-6-tolyl acid (3.78g) of stirring.Continue under the room temperature to stir 16 hours, then with the reaction solution dilute with water, with ethyl acetate extraction (three times).Organic phase is used dilute hydrochloric acid, saturated sodium bicarbonate, salt water washing continuously, uses dried over sodium sulfate, filter, evaporate subtitle compounds, be yellow oil (4.07g). 1H NMR (CDCl 3), δ 2.40 (3H, s), 3.94 (3H, s), 6.94 (1H, t), 7.01 (1H, d), 7.30 (1H, m), (f) 2-(brooethyl)-6-fluorophenyl carbamate
Two (isopropyl cyanide) dry methylene chloride (150ml) suspensions (2g) of 2-fluoro-6-methyl-toluate (35.53g), N-bromine succinimide (37.6g) and azepine were shone (100W halogen lamp) 4 hours under logical nitrogen.Gained solution is poured in 10% sodium hydroxide solution, with dichloromethane extraction (three times).Organic phase is washed with salt, uses dried over sodium sulfate, filter, evaporate the mixture of subtitle compounds and initial substance (52.33g), be yellow oil.MS (EI) 246/248 (M -) 1H NMR (CDCl 3) δ 3.99 (3H, s), 4.66 (2H, s), 7.06 (1H, t), 7.23 (1H, d), 7.40 (1H, m). (g) 2-fluoro-6-{[(2-methoxyl group-2-oxygen ethyl)-(4-anisole ylmethyl) amino] methyl } methyl benzoate
N-(4-anisole ylmethyl) glycine methyl ester (10.2g) is added drop-wise in dry ether (50ml) solution of 2-(the brooethyl)-6-fluorophenyl carbamate (11g) of stirring and triethylamine (6.8ml).With mixed solution reflux 16 hours under logical nitrogen.The cooling reaction solution, dilute with water is used ethyl acetate extraction (three times) again.With organic phase salt water washing, use dried over sodium sulfate, filter evaporation.(20: 1 hexanes: ethyl acetate) purifying gets subtitle compounds to residue, is colorless oil (8.82g) through column chromatography.MS (APCI) 376 ((M+H) +) 1H NMR (CDCl 3): δ 3.21 (2H, s), 3.67 (3H, s), 3.68 (2H, s), 3.78 (3H, s), 3.88 (3H, s), 4.01 (2H, s), 6.82 (2H, d), 7.05 (1H, t), 7.18 (3H, m), 7.35 (1H, m). (h) the 5-fluoro-1,2,3,4-tetrahydrochysene-2-(4-anisole ylmethyl)-4-oxygen-3-isoquinoline 99.9 methyl-formiate
In nitrogen with 2-fluoro-6-{[(2-methoxyl group-2-oxygen ethyl)-(4-anisole ylmethyl) amino] methyl dry toluene (50ml) drips of solution of methyl benzoate (8.82g) is added in dry toluene (100ml) suspension of the sodium hydride (1.32g 60% dispersion, do not have oil) of reflux and the trimethyl carbinol (1ml).Continue heating again and then reaction solution was cooled to room temperature in 12 hours.Then mixed solution is poured in the saturated aqueous ammonium chloride solution, with ethyl acetate extraction (three times).Organic phase is washed with salt, uses dried over sodium sulfate, filter, evaporate subtitle compounds (7.96g).MS (APCI) 344 ((M+H) +). 1H NMR (CDCl 3): δ 3.60 (2H, s), 3.81 (3H, s), 3.89 (2H, s), 3.92 (3H, s), 6.86 (3H, m), 7.05 (1H, m), 7.22 (2H, m), 7.38 (1H, m), 11.83 (1H, s). (i) 9-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 5-fluoro-1,2,3,4-tetrahydrochysene-2-(4-anisole ylmethyl)-4-oxygen-3-isoquinoline 99.9 methyl-formiate (1.0g), 4-trifluoromethyl phenyl hydrazine (1.03g) and tosic acid (20mg) melted 15 minutes at 150 ℃ under logical nitrogen together.Add dimethylbenzene 20ml then, continue heating 2 hours again.Be cooled to room temperature, evaporation removes and desolvates, and (99: 1 methylene dichloride: methyl alcohol) purifying gets title compound to solid residue, is purple spicule (0.425g) through column chromatography.MS (APCI) 468 ((M+H) +) 1H NMR (d 6-DMSO) δ 3.72 (3H, s), 6.10 (2H, s), 6.96 (2H, d), 7.70 (2H, d), 7.80 (4H, m), 8.00 (1H, dd), 8.59 (2H, d), 8.98 (1H, s). embodiment 909-fluoro-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
With 9-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt (0.43g) is dissolved in the trifluoroacetic acid (5ml), and reflux is 16 hours under the logical nitrogen.Evaporation removes and desolvates residue and toluene coevaporation (three times) after the cooling room temperature.Residue is ground with methyl alcohol and ether continuously, recrystallization gets title compound from ethyl acetate at last, is red solid (0.08g) again.mp＞250℃。NMS(APCI)348((M+H) -). 1H?NMR(d 6-DMSO)δ7.86(2H,m),7.95(2H,d),8.14(1H,d),8.24(2H,br?d),9.09(1H,br?s),11.85(1H,br?s).
The following example is according to the method preparation of similar embodiment 90.
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
?91 2-(4-chloro-phenyl-)-7-fluoro-3-hydroxyl-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 ?328/ ?330 ?(M+H) + 4.51(3H,s),7.46(2H,d),7.77 (1H,td),7.87(1H,dd),8.36 (3H,m),8.45(1H,s)
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
92 7-fluoro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 362 (M+H) + 4.51(3H,s),7.75(2H,d),7.80 (1H,m),7.87(1H,dd),8.38 (1H,dd),8.47(1H,s),8.54 (2H,d)
93 2-(4-chloro-phenyl-)-4-cyclopropyl-9-fluoro-3-hydroxyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞214 ?217 354/ 356 (M+H) + 1.35(2H,m),1.54(2H,m), 5.11(1H,m),7.51(2H,d), 7.75(2H,m),7.95(1H,dd), 8.38(2H,d),8.63(1H,s),
94 4-cyclopropyl-9-fluoro-3-hydroxyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 388 (M+H) + 1.36(2H,m),1.55(2H,m), 5.06(1H,m),7.77(4H,m), 7.97(1H,m),8.58(2H,d), 8.66(1H,s)
95 2-(4-chloro-phenyl-)-9-fluoro-3-hydroxyl-4-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 328/ 330 (M+H) + 4.51(3H,s),7.51(2H,d),7.76 (2H,m),7.91(1H,m),8.35 (2H,d),8.65(1H,s)
96 2-(4-chloro-phenyl-)-9-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 434/ 436 (M+H) + 3.72(3H,s),6.10(2H,s),6.95 (2H,d),7.54(2H,d),7.70 (2H,d),7.77(2H,m),7.97 (1H,m),8.39(2H,d),8.96 (1H,s)
97 9-fluoro-3-hydroxy-4-methyl-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt ＞250 362 (M+H) + 4.51(3H,s),7.77(4H,m), 7.93(1H,m),8.56(2H,d), 8.68(1H,s)
Following compounds (embodiment 98-100) prepares by the method for embodiment 2:
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
?98 2-(4-chloro-phenyl-)-9-fluoro-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 ?314/316 ?(M+H) + 7.63(2H,d),7.82(2H,br?m), 8.01(2H,d),8.11(1H,br?d), 9.05(1H,br?s),11.80(1H,br?s)
99 7-fluoro-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 ?348 ?(M+H) + 7.93(3H,d),8.14(1H,d),8.28 (2H,d),8.41(1H,dd),9.02(1H, br?s)
100 2-(4-chloro-phenyl-)-7-fluoro-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 ?314/316 7.63(2H,d),7.91(1H,br?t), 8.05(2H,d),8.13(1H,d),8.40 (1H,dd),9.00(1H,br?s),12.00 (1H,br?s)
Following compounds prepares by the method for embodiment 69:
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
101 9-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl]-5-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 225-227 ?482 ?(M+H) + 2.86(3H,s),3.73(3H,s), 6.53(2H,s),6.92(2H,d), 7.30(2H,d),7.74(4H,m), 8.11(1H,d),8.58(2H,d)
102 2-(4-chloro-phenyl-)-9-fluoro-3-hydroxyl-4-[(4-p-methoxy-phenyl) methyl-5-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt 222-223 ?448/450 ?(M+H) - 2.85(3H,s),3.73(3H,s), 6.53(2H,s),6.91(2H,d), 7.29(2H,d),7.44(2H,d), 7.70(2H,m),8.08(1H,d), 8.37(2H,d)
Following compounds is pressed the method preparation of embodiment 2:
Embodiment Title m.p./℃ MS 1H?NMR(d 6-DMSO)δ
?103 9-fluoro-5-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 362 (M+H) - 2.80(3H,s),7.79(2H,m), 7.88(2H,d),8.10(1H,d), 8.32(2H,d)
?104 2-(4-chloro-phenyl-)-9-fluoro-5-methyl-2H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol ＞250 328/330 (M+H) + 2.89(3H,s),7.58(2H,d), 7.79(2H,br?m),8.08(3H, br?m)
Embodiment 1052,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-thioketones
With 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-ketone (embodiment 63) (0.25g) and diox (20ml) solution stirring of LawessonShi reagent (0.7g) and heating 18 hours under refluxing.With the mixed solution cooling, absorb with silica gel.(1: 99-3: 97 methyl alcohol: methylene dichloride) purifying gets title compound, and recrystallization gets yellow solid (0.075g) from ethanol again through chromatography.mp255-259℃。MS (APCI) 376 ((M+H) +) 1H NMR (D 2O/NaOD) δ 8.47 (1H, d), 7.71 (2H, d), 7.61 (3H, m), 7.34 (1H, t), 7.22 (1Ht), 4.08 (3H, s). embodiment 1063-hydroxy-4-methyl-5-methylthio group-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 2, acetone (50ml) solution stirring of 4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethyl)-5H-pyrazolo [4,3-c] isoquinoline 99.9-5-thioketones (0.46g) (embodiment 105) and methyl iodide (0.095ml) also heated 4 hours under refluxing.Add salt of wormwood (0.170g), with mixed solution reheat 2 hours.The vacuum concentration mixed solution.(2: 98 methyl alcohol: methylene dichloride) purifying gets title compound to residue, is purple solid (0.375g) through chromatography.MS (APCI) 390 ((M+H) +) 1H NMR (CDCl 3) δ 8.54 (4H, m), 7.86 (1H, t), 7.72 (3H, m), 4.98 (3H, s), 2.52 (3H, s), embodiment 1072-(4-trifluoromethyl)-2,4-dihydro-5-imino--4-methyl-5H-pyrazolo [4,3-c] isoquinoline 99.9-3-alcohol
With 3-hydroxy-4-methyl-5-methylthio group-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, the ethanol (7ml) of inner salt (0.013g) (embodiment 106) and ammonia solution (0.880 proportion; Suspension 15ml) stirred 24 hours down at 20 ℃.With the mixed solution dilute with water, use ethyl acetate extraction.With organic phase salt water washing, use dried over mgso, vacuum concentration.(5: 95-10: 90 methyl alcohol: methylene dichloride) purifying gets title compound to residue, is orange solids (0.043g) through chromatography.mp253-255℃。MS (APCI) 717 ((2M+H) +), 359 ((M+H) -), 1H NMR (d 6-DMSO) δ 8.60 (2H, d), 8.46 (1H, d), 8.29 (3H, m), 7.90 (1H, t), 7.71 (3H, m), 4.19 (3H, s) embodiment 1083-hydroxyl-4-(4-p-methoxy-phenyl) methyl-2-(4-trifluoromethyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridines oxyhydroxide, inner salt
(a) 2-(brooethyl)-nicotinic acid methyl ester
2-methylnicotinic acid methyl esters (10.0g) and N-bromine succinimide (14.9g) 1, are mixed in the 2-ethylene dichloride (80ml).Add acetate (3.8ml) and add 2 again, 2 '-azepine two (2-methyl propionitrile) (1.0g), is heated to backflow with mixture under with the 500W light irradiation.Postcooling reaction in 2 hours is poured mixed solution in the sodium hydrogen carbonate solution into again.Organic phase is separated, washes secondary with salt, dry then, filter, evaporate oily matter (18.2g), be used for next step immediately.(b) methyl N-[(4-p-methoxy-phenyl)]-N-[(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester
Press the method for embodiment 1 step (a), with ether (100ml) the formulations prepared from solutions subtitle compounds (3.20g) of 2-(brooethyl) nicotinic acid methyl ester (9.10g), N-(4-p-methoxy-phenyl) methylglycine methyl esters (10.2g) and triethylamine (5.5ml).MS (DESC SI) 358 (M -) 1H NMR (d 6-DMSO) 3.17 (s.2H), 3.34 (s, 3H), 3.58 (s, 2H), 3.71 (s, 3H), 3.82 (s, 3H), 4.23 (s, 2H), 6.82 (d, 2H), 7.04 (d, 2H), 7.43 (dd, 1H), 8.03 (dd, 1H), 8.61 (dd, 1H) (c) 7,8-dihydro-5-hydroxyl-7-(4-p-methoxy-phenyl) methyl [1,7] naphthyridines-6-methyl-formiate
Press the method for embodiment 1 step (b), use the N-[(4-p-methoxy-phenyl) methyl]-N-[(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester (1.00g), sodium hydride (60% dispersion is in oil) (160mg), 2-methyl propan-2-ol (0.10ml) and toluene (15ml) make subtitle compounds (790mg).MS (APCI) 327 ((M+H) +) 1H NMR (d 6-DMSO) 3.65-3.97 (m, 10H), 6.79 (m, 2H), and 7.11-7.39 (m, 3H), 7.86-8.25 (m, 1H), 8.52-8.75 (m, 1H), 11.25 (s, 1H) (d) 3-hydroxyl-4-(4-p-methoxy-phenyl) methyl-2-(4-trifluoromethyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridines oxyhydroxide, inner salt
Press the method for embodiment 1 step (c), with 7,8-dihydro-5-hydroxyl-7-(4-p-methoxy-phenyl) methyl isophthalic acid, 7-naphthyridines-6-methyl-formiate (200mg), 4-trifluoromethyl phenyl hydrazine (1.00g) and ethanol (3ml) prepare title compound (21mg).mp201-203℃。MS (APCI) 451 ((M+H) -) 1H NMR (d 6-DMSO) 3.72 (s, 3H), 6.13 (s, 2H), 6.96 (d, 2H), 7.76 (d, 2H), 7.84 (d, 2H), 7.88 (dd, 1H), 8.59 (d, 2H), 8.72 (dd, 1H), 9.00 (s, 1H), 9.05 (dd, 1H) embodiment 1092-(4-trifluoromethyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridines-3-alcohol
Press the method for embodiment 2, with 3-hydroxyl-4-(4-p-methoxy-phenyl) methyl-2-(4-trifluoromethyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridines oxyhydroxide, inner salt (135mg) and trifluoroacetic acid (5ml) preparation title compound (19mg).Mp 239-241 ℃ (decomposition).MS(APCI)331((M+H) +) 1H?NMR(d 6-DMSO)7.94(d,2H),7.95(m,1H),8.28(d,2H),8.74(d,1H),9.01(br,1H),9.16(d,1H)
The following example method that is similar to embodiment 109 prepares with 2-(brooethyl) nicotinic acid methyl ester, sarkosine methyl esters and suitable hydrazine:
Embodiment Title m.p./℃ ?MS 1H?NMR(d 6-DMSO)δ
110 3-hydroxy-4-methyl-2-(4-trifluoromethyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridines oxyhydroxide, inner salt ＞260 ?345 ?(M+H) - 4.56(s,3H),7.82(d, 2H),7.88(dd.1H),8.56 (d,2H),8.70(s,1H), 8.73(5,1H),9.05(d,1H)
111 2-(4-chloro-phenyl-)-3-hydroxy-4-methyl-2H-pyrazolo [3,4-f] [1,7] naphthyridines oxyhydroxide, inner salt ＞260 ?311/313 ?(M+H) - 4.56(5,3H),7.51(d, 2H),7.88(dd,1H),8.35 (d,2H),8.68(s,1H), 8.70(dd,1H),9.03(dd, 1H)
Embodiment 1123-hydroxy-4-methyl-5-(dimethylamino)-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 3-hydroxy-4-methyl-5-methylthio group-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, the acetone (10ml) of inner salt (0.39g) (embodiment 106) and the solution of 40% dimethylamine agueous solution (2ml) stirred 24 hours down at 20 ℃.The dense place of vacuum reaction solution.(1: 99-2.5: 97.5 methyl alcohol: methylene dichloride) purifying gets title compound to residue, is red solid (0.129g) through chromatography.mp?256-259℃。MS (APCI) 387 ((M+H) +). 1H NMR (CDCl 3) d 3.19 (6H, s), 4.52 (3H, s), 7.64 (3H, m), 7.84 (1H, td), 7.95 (1H, d), 8.54 (3H, d) embodiment 1133-hydroxy-4-methyl-5-morpholinyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 3-hydroxy-4-methyl-5-methylthio group-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, the dry tetrahydrofuran (7ml) of inner salt (0.52g) (embodiment 106) and morpholine (2.3ml) solution be heated to 70 ℃ 12 hours, then 95 ℃ 2 hours.The vacuum concentration mixed solution.(5: 95 methyl alcohol: methylene dichloride) purifying obtains title compound to residue, is red solid (0.165g) through chromatography.mp278-281℃。MS (APCI) 429 ((M+H) -). 1H NMR (d 6-DMSO) d 3.49 (4H, m), 3.87 (4H, m), 4.49 (3H, s), 7.77 (2H, m), 7.94 (1H, t), 8.28 (1H, d), 8.38 (1H, d), 8.59 (2H, d). embodiment 1143-hydroxy-4-methyl-5-piperazinyl-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, inner salt
With 3-hydroxy-4-methyl-5-methylthio group-2-(4-trifluoromethyl)-2H-pyrazolo [4,3-c] isoquinoline 99.9 oxyhydroxide, the toluene solution (20ml) of inner salt (0.29g) (embodiment 106) is added drop-wise to being heated in 110 ℃ toluene (50ml) solution of piperazine (1.28g) of stirring.Mixed solution was stirred 6 hours down at 110 ℃.At room temperature stirred then 16 hours.The vacuum concentration mixed solution.(5: 95-10: 90 methyl alcohol: purifying methylene dichloride), crystallization gets title compound to residue from ethanol again, is red solid (0.107g) through chromatography.mp260-262℃。MS (APCI) 428 ((M+H) +). 1H NMR (DMSO) d 2.96 (4H, m), 3.37 (4H, m), 4.44 (3H, s), 7.76 (3H, m), 7.93 (1H, t), 8.27 (1H, d), 8.37 (1H, d), 8.59 (2H, d). embodiment 1154,5-dihydro-2-[4-(trifluoromethyl) phenyl]-2H-benzo [g] indazole-3-alcohol
With 1-oxygen naphthane-2-methyl-formiate (Mander, L.N and Sethi, S.P; TetrahedronLett, 1983,24,5425-8) (2.0g) and 4-trifluoromethyl phenyl hydrazine (3.47g) heated 8 hours under refluxing in toluene (15ml).With reaction mixture cooling, filtration product then.With ether washing, drying, recrystallization gets title compound from toluene, is colourless crystallization (1.45g) with solid.mp?189-190℃。MS (APCI) 331 ((M+H) +) 1H NMR (d 6-DMSO) d 2.67 (2H, m), 2.90 (2H, m), 7.29 (3H, m), 7.75 (1H, m), 7.84 (2H, d), 8.10 (2H, d), 11.70 (br), embodiment 1164 for 1H, s, 5-dihydro-2-(5-methyl-2-pyridyl)-2H-benzo [g] indazole-3-alcohol
1-oxygen naphthane-2-methyl-formiate (2.18g) and 2-diazanyl-5-picoline (2.85g) were heated 6 hours under refluxing in dimethylbenzene (15ml) together.To react cooling, filtration product then, drying.Recrystallization gets title compound from ether/isohexane, is light brown spicule (0.69g).mp112℃。MS (APCI) 278 ((M+H) +). 1H NMR (d 6-DMSO) d 2.36 (3H, s), 2.73 (2H, t), 2.95 (2H, t), 7.29 (3H, m), 7.68 (1H, dd), 7.92 (1H, d), 7.94 (1H, m), 8.07 (1H, s), 12.73 (1H, s, br). embodiment 1172-[4-(trifluoromethyl) phenyl]-2H-benzo [g] indazole-3-alcohol
With 4,5-dihydro-2-[4-(trifluoromethyl) phenyl]-2H-benzo [g] indazole-3-alcohol (0.30g) and palladium charcoal (0.10g) in N,N-DIMETHYLACETAMIDE (5ml) and hexanaphthene (5ml) reflux 1 hour title compound (0.26g).Mp＞235 ℃ (decomposition).MS (APCI) 329 ((M+H) +). 1H NMR (d 6-DMSO) d 7.70 (4H, m), 7.85 (2H, d), 8.07 (1H, m), 8.27 (2H, d), 8.30 (1H, m), 11.70 (1H, s, br). embodiment 1182-(5-methyl-2-pyridyl)-2H-benzo [g] indazole-3-alcohol
With 4,5-dihydro-2-(5-methyl-2-pyridyl)-2H-benzo [g] indazole-3-alcohol (0.40g) and 10% palladium charcoal (0.20g) heated 8 hours under refluxing in N,N-DIMETHYLACETAMIDE (15ml) and hexanaphthene (15ml).Reaction solution is cooled to room temperature, filters.With (100 ℃/1mmHg), residue recrystallization from ethyl acetate gets title compound, be light orange crystallization (0.12g) of filtrate distillations.mp214℃。MS (APCI) 276 ((MH) -) 1H NMR (d 6-DMSO) d 2.36 (3H, s), 7.52 (1H, d), 7.66 (3H, m), 7.82 (1H, dd), 8.02 (1H, d), 8.41 (1H, s, br), 8.53 (2H, m). the chronic transplanting of pharmacological datum test A-is tested the host
The pharmacologically active of The compounds of this invention can confirm [J.Clin.Exp.Immunol., 1991, vol.83,133-6 with the method for J.M.Doutrelepont etc.; The chronic transplanting of mouse is to the inhibition of host (c-GVH) disease].With testing compound salt solution and tween-80 suspension form every day subcutaneously to give mouse 21 days.The inhibition of test B-eosinophilia
The compounds of this invention to the influence of mouse lung inflammatory cell by Brusselle etc., Clin.Exp.Allergy, 1994,24, the following method of adapting among the 73-80 is determined.Mensuration as the oxyphie peroxidase of oxyphie number marker adopts Cheng etc., J.Pharmacol Exp.Ther.1993,264, the method for 922-929.
The Balb/c mouse that will grow up is used ovalbumin/Al (OH) 3Mixture swashs quick.
Swash and begin to take compound after quick 14 days to mouse.Compound is with the suspension of 5% tween-80 or solution form (according to dosage and compound dissolution degree and decide) every day or oral or subcutaneous administration.
Swash after quick 17 days, after giving compound the 4th time 1 hour, mouse is put into the synthetic glass chamber that is sprayed with ovalbumin solution (2%w/v).Allow mouse suck ovalbumin 30-40 minute.The same time of every day repeats this test and carried out 3 or 7 days again.
In test in 4 days, a day of administration is in the end given the ovalbumin 4 hours of test more in addition after the administration for the first time.
Put to death animal in second day, following inhibition parameter is by relatively recording with control animal:
(1) number, the especially eosinophil (after the administration 4 days) of inflammatory cell in bronchoalveolar lavage (bronchioalveolar lavage), have been increased.
(2) eosinophil is assembled in the lung tissue, measures (after the administration 8 days) according to increasing by oxyphie peroxidase activity in the lung tissue of homogenizing.
(3) antibody titer that presents in the blood plasma that obtains from whole blood (1gE, 1gGl and 1gG2a) increases (after the administration 8 days).
Some compd E D of the present invention 50In the 0.1-10mg/kg scope, show the activity of chronic transplanting to host's test and inhibition eosinophilia test.

Claims (16)

1. as the formula I compound and the pharmaceutically acceptable derivates thereof of medicine:
Figure A9719466500021
Wherein:
B, D, E and G represent CH, CA or N separately, and condition is to be no more than 1 among B, D, E and the G to represent and be no more than 1 among CA and B, D, E and the G and represent N;
X represents C=O, C=S, C=NR 15, CR 3R 6Or NR 4
Y represents N or N +R 7Or CR 18
Z represents OR 8Or O;
R 1Represent OH or C 1-6Alkyl, or and R 2Or R 5Form key;
R 2Represent H, C 1-6Alkyl (can be chosen wantonly by phenyl, COOR 9, NR 10R 11, OR 12Or F replaces) or C 3-7Cycloalkyl or and R 1, R 3Or R 4Form key;
R 3Represent H or and R 2Form key;
R 4Represent C 1-6Alkyl or and R 2Form key;
R 5Representative and R 1Or R 8Key;
R 6Represent H, C 1-6Alkyl (can choose wantonly by phenyl and replace), C 3-7Cycloalkyl, phenyl, halogen, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, cyano group or NR 13R 14
R 7Represent C 1-6Alkyl (can choose wantonly by phenyl and replace) or C 3-7Cycloalkyl, the both can be by halogen, hydroxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, NR 16R 17, COOH, COO (C 1-6Alkyl) or cyano group is optional replaces;
Perhaps R 6And R 7Represent C together 3-5Therefore alkylidene group base, X and Y form a 5-7 unit ring;
R 8Represent H, C 1-6Alkyl or and R 5Form key;
R 9, R 10, R 11, R 12, R 15, R 16, R 17And R 18The independent C that represents 1-6Alkyl or H;
R 13And R 14Independent is C 1-6Alkyl, H or with the nitrogen-atoms that it links form one can choose wantonly contain other optional by C 1-6Sauerstoffatom that alkyl replaces or the 3-7 of nitrogen-atoms unit saturated rings;
Ar 1Represent phenyl, pyridyl, pyrimidyl, 2-[4-morpholinodithio base, 2-or 3-quinolyl or 2-quinoxalinyl, all these groups can be chosen wantonly by being selected from halogen, nitro, cyano group, phenyl, benzenesulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, COOH, COO (C 1-6Alkyl), the C that replaces by phenyl 1-6One or more substituting group of alkyl or phenyl replaces, and wherein any alkyl, alkoxyl group, alkylthio and alkyl sulphinyl can be chosen wantonly by fluorine and replace; With
A represents halogen, cyano group, amino, nitro, C 1-6Alkyl or C 1-6Alkoxyl group; Wherein at R 2, R 6, R 7On phenyl, or as Ar 1On substituent phenyl can choose wantonly by C 1-6Alkyl, halogen or C 1-6Alkoxyl group replaces; Condition is: (ⅰ) represent C=O, C=S or C=NR as X 15The time, then Y represents N; (ⅱ) work as R 4Representative and R 2Key the time, then Y represents N +R 7(ⅲ) represent N as Y +R 7The time, then Z represents O -, R 2Representative and R 3Or R 4Key, and R 1And R 5Form key; (ⅳ) when Y represents N, then Z represents OR 8(ⅴ) work as R 1When representing OH, then X represents C=O, and Y represents N, and Z represents OR 8, R 5Representative and R 8Key; (ⅵ) work as R 1When representing alkyl, R then 5Representative and R 8Key, Y represents N, R 2Do not represent key and X not to represent NR 4(ⅶ) work as R 1Representative and R 2During key, R 5And R 8Form key, and if X represents NR 4The time, R then 4Represent alkyl; (ⅷ) work as R 6When representing aryl, halogen, alkoxyl group, sulfane base, R then 2And R 3Form key; (ⅸ) represent N or N as Y +R 7And R 2By NR 10R 11, OR 12Or among the F any be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 2Identical carbon atoms link to each other; (ⅹ) work as R 7By NR 16R 17, OR 12Or in the halogen any one be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 7Identical carbon atoms link to each other; (ⅹ ⅰ) when one was represented N among B, D, E and the G, then X did not represent NR 4(ⅹ ⅱ) represents CR as Y 18The time, X represents CR 3R 6Its further condition is: represent CHR when B, D, E and G represent CH, X 3, Y represents nitrogen, R 1And R 5Form key, R 8Represent H and R 2And R 3When representing key together, Ar then 1Do not represent 4-chloro-phenyl-, 4-fluorophenyl or 4-p-methoxy-phenyl.
2. formula I compound or its pharmaceutically acceptable derivates: Wherein:
B, D, E and G represent CH, CA or N separately, and condition is to be no more than 1 among B, D, E and the G to represent and be no more than one among CA and B, D, E and the G and represent N;
X represents C=O, C=S, C=NR 15, CR 3R 6Or NR 4
Y represents N or N +R 7Or CR 18
Z represents OR 8Or O;
R 1Represent OH or C 1-6Alkyl, or and R 2Or R 5Form key;
R 2Represent H, C 1-6Alkyl (can be chosen wantonly by phenyl, COOR 9, NR 10R 11, OR 12Or F replaces) or C 3-7Cycloalkyl or and R 1, R 3Or R 4Form key;
R 3Represent H or and R 2Form key;
R 4Represent C 1-6Alkyl or and R 2Form key;
R 5Representative and R 1Or R 8Key;
R 6Represent H, C 1-6Alkyl (can choose wantonly by phenyl and replace), C 3-7Cycloalkyl, phenyl, halogen, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, cyano group or NR 13R 14
R 7Represent C 1-6Alkyl (can choose wantonly by phenyl and replace) or C 3-7Cycloalkyl, the both can be by halogen, hydroxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulfinyl, NR 16R 17, COOH, COO (C 1-6Alkyl) or cyano group is optional replaces;
Perhaps R 6And R 7Represent C together 3-5Therefore alkylidene group, X and Y form a 5-7 unit ring;
R 8Represent H, C 1-6Alkyl or and R 5Form key;
R 9, R 10, R 11, R 12, R 15, R 16, R 17And R 18The independent C that represents 1-6Alkyl or H;
R 13And R 14Independent is C 1-6Alkyl, H or form one with the nitrogen-atoms that it links and to choose wantonly and contain that another is optional by C 1-6Oxygen that alkyl replaces or the 3-7 of nitrogen-atoms unit saturated rings;
Ar 1Represent phenyl, pyridyl, pyrimidyl, 2-[4-morpholinodithio base, 2-or 3-quinolyl or 2-quinoxalinyl, all these groups can be chosen wantonly by being selected from halogen, nitro, cyano group, phenyl, benzenesulfonyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, COOH, COO (C 1-6Alkyl), the C that replaces by phenyl 1-6One or more substituting group of alkyl or phenyl replaces, and wherein any alkyl, alkoxyl group, alkylthio and alkyl sulphinyl can be chosen wantonly by fluorine and replace; With
A represents halogen, cyano group, amino, nitro, C 1-6Alkyl or C 1-6Alkoxyl group; Wherein at R 2, R 6, R 7On phenyl, or as Ar 1On substituent phenyl can choose wantonly by C 1-6Alkyl, halogen or C 1-6Alkoxyl group replaces; Condition is: (ⅰ) represent C=O, C=S or C=NR as X 15The time, then Y represents N; (ⅱ) work as R 4Representative and R 2Key the time, then Y represents N +R 7(ⅲ) represent N as Y +R 7The time, then Z represents O -, R 2Representative and R 3And R 4Key, and R 1And R 5Form key; (ⅳ) when Y represents N, then Z represents OR 8(ⅴ) work as R 1When representing OH, then X represents C=O, and Y represents N, and Z represents OR 8, and R 5Representative and R 8Key; (ⅵ) work as R 1When representing alkyl, R then 5Representative and R 8Key, Y represents N, R 2Do not represent key, and X does not represent NR 4(ⅶ) work as R 1Representative and R 2During key, R then 5And R 8Form key, and if X represents NR 4The time, R 4Represent alkyl; (ⅷ) work as R 6When representing aryl, halogen, alkoxyl group, alkylthio, R then 2And R 3Form key; (ⅸ) represent N or N as Y +R 7And R 2By NR 10R 11, OR 12Or among the F any be when replacing, on the ring of then described substituting group and Y nitrogen-atoms can not with R 2Identical carbon atoms link to each other; (ⅹ) work as R 7By NR 16R 17, OR 12Or when any one replaces in the halogen, on the ring of then described substituting group and Y nitrogen-atoms can not with R 7Identical carbon atoms link to each other; When (ⅹ ⅰ) represented N when B, D, E and G one, then X did not represent NR 4(ⅹ ⅱ) represents CR as Y 18The time, X represents CR 3R 6Its further condition is: (a) represent CHR when B, D, E and G represent CH, X 3, Y represents N, R 1And R 5Form key, R 8Represent H and R 2And R 3When representing key together, Ar then 1Do not represent unsubstituted phenyl, 4-chloro-phenyl-, 4-fluorophenyl or 4-p-methoxy-phenyl; (b) when representing CH, X, B, D, E and G represent CHR 3, Y represents N +R 7, R 1And R 5Form key, R 2And R 3Represent key, R 8Represent H and R 7During represent methylidene, Ar then 1Do not represent unsubstituted phenyl; (c) when representing CH, X, B, D, E and G represent CH 2, Y represents N, R 1And R 5Form key, R 8Represent H and R 2When representing sec.-propyl, Ar then 1Do not represent unsubstituted phenyl or 4-bromophenyl; (d), B, D, E and G represent CH when representing CH, X and Y 2And R 1And R 5When forming key, Ar then 1Do not represent unsubstituted phenyl.
3. claim 1 or 2 formula I compound, wherein Ar 1Represent phenyl or pyridyl.
4. the formula I compound of claim 3, wherein Ar 1Represent phenyl.
5. claim 3 or 4 formula I compound, wherein Ar 1To substd.
6. the formula I compound of claim 5, wherein Ar 1In contraposition Cl, Br, CF are arranged 3, C 2F 5, DCF 3Or SCH 3Substituting group.
7. the formula I compound of above any claim, wherein Y represents N +R 7, and X represent CR 3R 6R wherein 3With R 2Form key and R 6Represent alkyl.
8. the formula I compound of claim 7, wherein R 6Represent branched-chain alkyl.
9. each formula I compound among the claim 1-6, wherein X represents NR 4R wherein 4Representative and R 2Key and Y represents N +R 7
10. the formula I compound of above any claim, wherein B represents CA.
11. the formula I compound of claim 10, wherein A represents F.
12. the formula I compound of above any claim, wherein D or G represent N.
13. the formula I compound of above any claim, wherein R 1Representative and R 2Or R 5The key that forms.
14. according to the formula I compound of claim 13, wherein R 1Representative and R 5The key that forms.
15. The compound according to claim 2 and a pharmaceutically acceptable derivative thereof, which is: 3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, inner salt, 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - chlorophenyl) -2,5 - dihydro-5 - methyl-3H-pyrazolo [4,3-c] cinnolin-3 - one, 2 - (4 - chlorophenyl) -2,3 a, 4,5 - tetrahydro-3a, 4 - dimethyl-pyrazolo [4,3-c] isoquinoline-3 - one, 2 - (4 - chlorophenyl)-3a, 4 - dihydro-3a, 4 - dimethyl-2H-pyrazolo [4,3-c] isoquinoline-3, 5 - two Ketones, 2 - (4 - chlorophenyl) -2,4 - dihydro-3 - hydroxy - 4 - methyl-pyrido [4,3-c] isoquinolin-5 - one, 3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -2 - (3 - quinolyl)-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 2 - (3 - quinolyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (3,4 - dichlorophenyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 2 - (3,4 - dichlorophenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - ([1,1 '- biphenyl]-4 - yl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -2 - (4 - methyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 2 - (4 - methyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - bromophenyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl]-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 2 - (4 - bromophenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (3 - (trifluoromethyl) phenyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl]-2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, inner salt, 2 - (3 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - [4 - (1,1 - dimethylethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - trifluoromethoxy-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner Salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] cinnoline onium hydroxide, inner salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 3 - hydroxy - 4 - methyl - 2 - (3 - quinolyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner Salt, 2 - (6 - hydroxy - 3 - pyridyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 2 - (3,4 - dichlorophenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Inner salt, 3 - hydroxy - 4 - methyl - 2 - (4 - methyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner Salt, 2 - (4 - bromophenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner Salt, 3 - hydroxy - 4 - methyl - 2 - (3 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 2 - [4 - (1,1 - dimethylethyl) phenyl] -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 2 - (6 - chloro-3 - pyridyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl]-2H-pyrazolo [4,3-c] iso- Quinolinium hydroxide, inner salt, 3 - hydroxy - 4 - methyl - 2 - (6 - methyl-3 - pyridinyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 2 - (4 - (trifluoromethyl) phenyl) -3 - hydroxy-4 - (2 - hydroxy-ethyl)-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 3 - hydroxy - 4 - methyl - 2 - (5 - methyl - 2 - pyridinyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 3 - hydroxy - 4 - methyl - 2 - [4 - (1 - methylethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 3 - hydroxy - 4 - methyl - 2 - (4 - nitrophenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, inner Salt, 2 - (4 - cyano-phenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner Salt, 2 - (4 - carboxyphenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner Salt, 2 - (4 - chloro -3 - (trifluoromethyl) phenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Oxides, inner salt, 2 - (4 - (trifluoromethoxy) phenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [4,3-c] isoquinolinio hydroxide Compounds, inner salt, 3 - hydroxy - 4 - methyl - 2 - (4 - (methylthio) phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Inner salt, 4 - cyclopropyl-3 - hydroxy-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 4 - cyclopropyl-3 - hydroxy-2 - (6 - methyl-3 - pyridinyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 4 - [(1,1 - dimethyl-2 - hydroxy) ethyl] -3 - hydroxy-2 - [(4 - trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner salt, 3 - hydroxy - 4 - (2 - methoxy-ethyl) -2 - [(4 - trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - [2 - (methylthio) ethyl]-2H-pyrazolo [4,3-c] isoquinolinio hydrogen Oxides, inner salt, 3 - hydroxy - 4 - [2 - (methylthio) ethyl] -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 4 - cyclopropyl-2 - (4 - (trifluoromethoxy) phenyl) -3 - hydroxy-2H-pyrazolo [4,3-c] isoquinolinio hydrogen Oxides, inner salt, 2 - (4 - chloro-3 - trifluoromethylphenyl) -4 - cyclopropyl-3 - hydroxy-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 4 - cyclopropyl-3 - hydroxy-2 - (4 - (methylthio) phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 3 - hydroxy - 4 - phenyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 4 - ethyl - 3 - hydroxy-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 2 - (4 - trifluoromethyl-phenyl) -4 - (1 - ethoxycarbonyl-methyl) -3 - hydroxy-2H-pyrazolo [4,3-c] iso- Quinolinium hydroxide, inner salt, 3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -2 - phenyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 3 - hydroxy - 4 - (1 - methylethyl) -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 3 - hydroxy - 4 - (1 - methylethyl) -2 - (3 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 3 - hydroxy -2 - (4 - iodo-phenyl) -4 - methyl-2H-pyrazolo [4,3-c] isoquinoline hydroxide, inner salt, 2 - (6 - chloro-3 - pyridinyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - [4 - (1 - methylethyl) phenyl]-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - pentafluoroethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2,4 - dihydro-3 - hydroxy - 4 - methyl - 2 - (2 - pyrimidinyl)-5H-pyrazolo [4,3-c] isoquinolin-5 - one, 2 - ([1,1 - bis-phenyl] -4 - yl) -2,4 - dihydro-3 - hydroxy - 4 - methyl-5H-pyrazolo [4,3-c] isoquinoline - 5 - one, 2,4 - dihydro-3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] isoquinoline - 5 - one, 2 - (6 - chloro-3 - pyridyl) -2,4 - dihydro-3 - hydroxy - 4 - methyl-5H-pyrazolo [4,3-c] isoquinolin-5 - Ketones, 2,4 - dihydro-3 - hydroxy-2 - (4 - iodo-phenyl) -4 - methyl-5H-pyrazolo [4,3-c] isoquinolin-5 - one, 2,4 - dihydro-3 - hydroxy - 4 - (4 - methoxyphenyl)-2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] isoquinolin-5 - one, 2,4 - dihydro-3 - hydroxy - 4 - (1 - methylethyl) -2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] Isoquinolin-5 - one, 2,4 - dihydro-3 - hydroxy - 4 - methyl - 2 - [4 - (1 - methyl-ethyl-phenyl]-5H-pyrazolo [4,3-c] isoquinoline -5 - one, 2,4 - dihydro-3 - hydroxy-2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] isoquinolin-5 - one, 2,4 - dihydro-3 - hydroxy-2 - [4 - (1 - methylethyl) phenyl]-5H-pyrazolo [4,3-c] isoquinolin-5 - Ketones, 2,4 - dihydro-3 - hydroxy-2 - ([1,1 '- biphenyl]-4 - yl)-5H-pyrazolo [4,3-c] isoquinolin-5 - one, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - [(4 - methoxyphenyl) methyl] -5 - methyl-2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, inner salt, 2 - (4 - chlorophenyl) -5 - methyl-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 4 - Cyclopropyl-3 - hydroxy - 5 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 3 - hydroxy - 4 - (2 - methoxy-ethyl-5 - methyl-2 - [(4 - trifluoromethyl) phenyl]-2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, inner salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 ,5 - dimethyl-2H-pyrazolo [4,3-c] isoquinoline hydroxide, inner Salt, 5 - ethyl - 3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 3 - hydroxy - 5 - methyl - 4 - (1 - methylethyl) -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] iso- Quinolinium hydroxide, inner salt, 4 - methyl-5 - (1 - methylethyl) -3 - hydroxy-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] iso- Quinolinium hydroxide, inner salt, 3 - hydroxy-4 ,5 - dimethyl-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 5 - chloro -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 3a, 4 - dihydro-3a-hydroxy-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3, 5 - two Ketones, 2,4 - dihydro-3 - methoxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] isoquinoline 5 - one, 2 - (4 - chlorophenyl) -4 - {2 - (N, N-dimethylamino) ethyl} -3 - hydroxy-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 3 - hydroxy - 4 - methyl - 2 - (4 - methylsulfinyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Oxides, inner salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - [2 - (methylsulfinyl) ethyl]-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 3 - hydroxy - 4 - [2 - (methylsulfinyl) ethyl] -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] Isoquinolinium hydroxide, inner salt, 5 - [2 - (4 - methoxyphenyl) ethyl] -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline 3 - ol, sodium salt, 9 - fluoro-3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner salt, 2 - (4 - chlorophenyl) -7 - fluoro-3 - hydroxy - 4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Inner salt, 7 - fluoro-3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Oxides, inner salt, 2 - (4 - chlorophenyl) -4 - ring propyl-9 - fluoro-3 - hydroxy-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Material, inner salt, 4 - ring propyl-9 - fluoro-3 - hydroxy-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium Hydroxide, inner salt, 2 - (4 - chlorophenyl)-9 - fluoro-3 - hydroxy - 4 - methyl-2H-pyrazolo [4,3-c] isoquinolinium hydroxide, Inner salt, 2 - (4 - chlorophenyl)-9 - fluoro-3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl]-2H-pyrazolo [4,3-c] iso- Quinolinium hydroxide, inner salt, 9 - fluoro-3 - hydroxy - 4 - methyl - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinolinium hydroxide Compounds, inner salt, 2 - (4 - chlorophenyl)-9 - fluoro-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 7 - fluoro-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - chlorophenyl) -7 - fluoro-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 9 - fluoro-3 - hydroxy - 4 - [(4 - methoxyphenyl) methyl] -5 - methyl-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazol Triazolo [4,3-c] isoquinolinio hydroxide, inner salt, 2 - (4 - chlorophenyl)-9 - fluoro-3 - hydroxy - 4 - [(4 - methoxyphenyl) -5 - methyl-2H-pyrazolo [4,3-c] isoquinolinio hydroxide, inner salt, 9 - fluoro-5 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2 - (4 - chlorophenyl)-9 - fluoro-5 - methyl-2H-pyrazolo [4,3-c] isoquinoline-3 - ol, 2,4 - dihydro-3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-5H-pyrazolo [4,3-c] isoquinoline - 5 - thione, 3 - hydroxy - 4 - methyl-5 - (methylthio) -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 2 - (4 - trifluoromethyl-phenyl) -2,4 - dihydro-5 - imino-4 - methyl-5H-pyrazolo [4,3-c] isoquinoline 3 - ol, 3 - hydroxy - 4 - (4 - methoxyphenyl) methyl-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [3,4-f] [1,7] Naphthalene pyridinium hydroxide, inner salt, 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridine-3 - ol, 3 - hydroxy - 4 - methyl - 2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [3,4-f] [1,7] naphthyridin-onium hydroxide Material, inner salt, 2 - (4 - chlorophenyl) -3 - hydroxy-4 - methyl-2H-pyrazolo [3,4-f] [1,7] naphthyridin-ium hydroxide, inner Salt, 3 - hydroxy - 4 - methyl-5 - (dimethylamino) -2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Morpholine onium hydroxide, inner salt, 3 - hydroxy - 4 - methyl-5 - morpholino-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 3 - hydroxy - 4 - methyl-5 - piperazin-2 - (4 - trifluoromethyl-phenyl)-2H-pyrazolo [4,3-c] isoquinoline Onium hydroxide, inner salt, 4,5 - dihydro-2 - [4 - (trifluoromethyl) phenyl]-2H-benzo [g] indazole-3 - ol, 4,5 - dihydro-2 - (5 - methyl - 2 - pyridinyl)-2H-benzo [g] indazole-3 - ol, 2 - [4 - (trifluoromethyl) phenyl]-2H-benzo [g] indazole-3 - ol, 2 - (5 - methyl - 2 - pyridinyl)-2H-benzo [g] indazole-3 - ol, ...
16. the method for the formula I compound of preparation claim 1 or 2 definition, it comprises:
(a) (wherein X represents CH to preparation 2Or C=O, Y represents N, and Z represents OR 8, R 5And R 8Form key and R 1And R 2Form key, the oxidation of the formula I compound by correspondence is carried out, wherein R 1And R 2All represent H, X, Y, Z and R 5Define the same, B, D, E, G and Ar 1As definition in the claim 1;
(b) preparation, wherein B, D, E and G represent CA wherein A represent aminoly, the reduction of the formula I compound by correspondence get, wherein among B, D, E and the G represent CA wherein A represent nitro and remaining B, D, E and G, reach X, Y, Z, Ar 1, R 1, R 2And R 5As definition in the claim 1;
(c) preparation, wherein among B, D, E and the G represent CA wherein A represent halogen, the diazotization of the formula I compound by correspondence, wherein among B, D, E and the G represent CA wherein A represent amino and remaining B, D, E and G, and X, Y, Z, Ar 1, R 1, R 2And R 5As definition in the claim 1, and diazonium salt decomposes in the presence of the material in halogen negative ion or its source and gets;
(d) preparation, wherein among B, D, E and the G represent CA wherein A represent cyano group, formula I compound reaction by correspondence get, wherein among B, D, E and the G represent CA wherein A represent bromine and remaining B, D, E and G, reach X, Y, Z, Ar 1, R 1, R 2And R 5By definition in the claim 1;
(e) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkylthio, by the formula I compound of correspondence, wherein X represents CR 3R 6, R wherein 6Represent methylthio group or halogen, Y, Z, R 1, R 2, R 3And R 5Define the same and B, D, E, G and Ar 1By definition in the claim 1, carry out replacement(metathesis)reaction with the compound of formula II and get: R wherein 6aRepresent C 1-6Alkyl;
(f) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Representation alkoxy, by the formula I compound of correspondence, wherein X represents CR 3R 6, R wherein 6Represent methylthio group or halogen, Y, Z, R 1, R 2, R 3And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1, carry out replacement(metathesis)reaction with formula III compound and get:
Figure A9719466500161
R wherein 6aDefinition is the same;
(g) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent NR 13R 14, by the formula I compound of correspondence, wherein X represents CR 3R 6, R wherein 6Represent methylthio group or halogen, Y, Z, R 1, R 2, R 3And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1, carry out replacement(metathesis)reaction with formula IV compound and get:
Figure A9719466500162
R wherein 13And R 14By definition in the claim 1;
(h) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent methylthio group, by the formula I compound of correspondence, wherein X represents C=S, and Y represents N, and Z represents OH, R 1, R 2And R 5Define the same and B, D, E, G and Ar 1By definition in the claim 1, get with the methylating reagent reaction;
(i) preparation, wherein X represents C=S, and Y represents N, and Z represents OH and R 1Representative and R 5The key that forms, the formula I compound by correspondence carries out sulfuration and gets, and wherein X represents C=O, Y, Z, R 1And R 5Define the same and B, D, E, G, Ar 1And R 2As definition in the claim 1;
(j) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -And R 6Represent halogen, the formula I compound by correspondence carries out halogenation and gets, and wherein X represents C=O, and Y represents N, and Z represents OR 8, R 8Representative and R 5Key and B, D, E, G, Ar 1, R 1And R 2As definition in the claim 1;
(k) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkyl, by the formula I compound of correspondence, wherein X represents C=O, and Y represents N, and Z represents OH, R 1Representative and and R 5The key that forms, B, D, E, G and Ar 1As definition and R in the claim 1 2Representative is corresponding to the R of definition in the claim 1 7, get with the nucleophilic alkylating reagent reaction that comprises formula V compound: R wherein 6Define the same and Hal represents halogen or corresponding to R 6The negative ion in other source;
(1) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent alkyl, by the formula I compound of correspondence, wherein X represents CR 3R 6R wherein 6Represent H, Y, Z, R 1, R 2And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1, get with the reaction of nucleophilic alkylating reagent, described nucleophilic alkylating reagent comprises formula V compound as defined above, or corresponding to R 6The negative ion in other source;
(m) preparation, wherein X represents C=O, and Y represents N, and Z represents OR 8, R 1Representative and R 5The key that forms, and R 8Represent alkyl, by the formula I compound of correspondence, wherein Z represents OR 8R wherein 8Represent H, X, Y, R 1And R 5Define the same and B, D, E, G, Ar 1And R 2As definition in the claim 1, get with the reaction of formula VI compound:
R 8Hal (VI) is R wherein 8Represent alkyl and Hal definition the same;
(n) preparation, wherein R 1Represent OH, X to represent C=O, Y represents N, and Z represents OR 8And R 5Representative and R 8The key that forms, by the formula I compound with correspondence, wherein Z represents O -, R 1And R 5Form key, X, Y and R 2Define the same and B, D, E, G and Ar 1As definition in the claim 1, get with the oxidizer treatment reaction;
(o) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key, by the formula I compound of correspondence, wherein Y represents N, and Z represents OH, X, R 1, R 2And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1, get with the reaction of formula IX compound:
R 7Hal (IX) is R wherein 7The Hal definition is the same by definition in the claim 1;
(p) preparation, wherein X represents C=O, R 2Do not represent H, Y represents N, and Z represents OH and R 1Representative and R 5The key that forms is by the formula I compound of correspondence, wherein R 2Represent H, X, Y, Z, R 1And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1, get with the reaction of formula VII compound:
R 2Hal (VII) is R wherein 2Do not represent H, the Hal definition is the same by definition in the claim 1;
(q) preparation, wherein B, D, E and G represent CH or CA, and X represents NR 4, Y represents N +R 7, Z represents O -, R 4And R 2Form key, and R 1And R 5Form key, through type VIII compound:
Wherein A and Ar 1By definition in the claim 1, with formula IX compound reaction as defined above and get;
(r) preparation, wherein B, D, E and G represent CH or CA, and X represents NR 4, Y represents N, and Z represents OR 8, R 2And R 1Form key and R 5And R 8Form key, get by formula VIII compound and the reaction of formula X compound as preceding definition:
R 4Hal (X) is R wherein 4The Hal definition is the same by definition in the claim 1;
(s) preparation, wherein X represents CR 3R 6, Y represents N, and Z represents OH, R 3And R 2Form key and R 1Representative and R 5The key that forms gets by formula I compound and acid-respons with correspondence, and wherein Y represents N +R 7, Z represents O -, R 7Represent CH 2C 6H 4The O alkyl, X, R 1, R 2And R 5Define the same and B, D, E, G and Ar 1As definition in the claim 1;
(t) preparation, wherein X represents CR 3R 6, Y represents N, and Z represents OH, R 3And R 2Form key and R 1Representative and R 5Key, get by formula I compound and hydrogen treat correspondence, wherein Y represents N +R 7, Z represents O -, R 7Represent CH 2Phenyl (can be chosen wantonly by C 1-6Alkyl or C 1-6Alkoxyl group replaces), X, R 1, R 2And R 5Define the same, and B, E, G and Ar 1As definition in the claim 1;
(u) preparation, wherein X represents C=O, and Y represents N, and Z represents OH, R 2Represent H and R 1Representative and R 5The key that forms gets by formula I compound and acid treatment with correspondence, and wherein Y represents N +R 7, Z represents O -, R 7Represent CH 2C 6H 4The O alkyl, X, R 1, R 2And R 5Define the same, and B, D, E, G and Ar 1As definition in the claim 1;
(v) preparation, wherein X represents CR 3R 6, Y represents N +R 7, Z represents O -, R 3And R 2Form key, R 1And R 5Form key and R 6Represent H, through type XI compound:
Figure A9719466500191
Wherein X represents CH 2, R 1Represent H, R 2Representative is corresponding to the R that defines as claim 1 in the formula I compound 7Group, definition in B, D, E and G such as the claim 1 and R is an alkyl, with formula XII compound reaction and get:
Ar 1NHNH 2(XII) be Ar wherein 1By definition in the claim 1;
(w) preparation, wherein X represents C=O, R 2Do not represent H, Y represents N, and Z represents OH, and R 1Representative and R 5Key, by as the formula XI compound of preceding definition, wherein X represents C=O, R 1Represent H, R 2Definition in the same definition and B, D, E and G such as the claim 1, with formula XII compound reaction as defined above and get, Ar wherein 1As definition in the claim 1;
(x) preparation, wherein X represents CH 2, Y represents N +R 7, Z represents OR 8, R 8And R 5Form key and R 1Represent alkyl, by the formula XI compound as preceding definition, wherein X represents CH 2, R 1Represent alkyl, R as above defines and B, D, E, G and R 2By definition in the claim 1, with formula XII compound reaction as defined above and get, Ar wherein 1The same definition;
(y) preparation, wherein X represents C=O, and Y represents N, and Z represents OR 8, R 8And R 5Form key and R 1Represent alkyl, by the formula XI compound as preceding definition, wherein X represents C=O, R 1Represent alkyl, R 2Represent H or alkyl, as above definition in definition and B, D, E and G such as the claim 1 of R, with formula XII compound reaction as defined above and get, Ar wherein 1The same definition;
(z) preparation, wherein X represents CR 3R 6, Y represents CR 18, Z represents OH, R 1And R 5Form key and R 2And R 3Form key, the oxygenizement of the formula I compound by correspondence gets, and wherein X represents CR 3R 6, Y represents CR 18, Z represents OH, R 2And R 3Represent H, R 1And R 5Form key and B, D, E, G, Ar 1, R 6And R 18As definition in the claim 1; Or
(aa) preparation, wherein X represents CR 3R 6, Y represents CR 18, Z represents OH, R 2And R 3Represent H and R 1And R 5Form key, react by formula XII compound and formula XX compound as defined above and get:
Figure A9719466500211
Wherein R as above defines and B, D, E, G, R 6And R 18By definition in the claim 1.
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