CN1277605A - Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors - Google Patents

Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors Download PDF

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CN1277605A
CN1277605A CN98808322A CN98808322A CN1277605A CN 1277605 A CN1277605 A CN 1277605A CN 98808322 A CN98808322 A CN 98808322A CN 98808322 A CN98808322 A CN 98808322A CN 1277605 A CN1277605 A CN 1277605A
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CN1167687C (en
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L·A·布拉克
A·巴沙
T·克拉萨
M·E·科特
H·刘
C·M·麦卡蒂
M·V·帕特尔
J·J·罗德
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Abstract

The present invention describes pyridazinone compounds which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX/2), COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important 'housekeeping' enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marketed non-steroidal anti-inflammatory drugs (NSAIDs).

Description

Aryl pyridazinone as prostaglandin(PG) born of the same parents endoperoxide H synthase biosynthesis inhibitors
The application is the part continuation application of No. the 08/917th, 023, the U.S. Patent application sequence submitted on August 22nd, 1997, and back one application is based on the provisional application of submitting on August 22nd, 1,997 60/056,733.Technical field
The present invention includes the new pyridazinone compound of the disease that can be used for treating the cyclooxygenase-2 mediation.More particularly, the present invention relates to suppress the biosynthetic method of prostaglandin(PG), particularly suppress inductive prostaglandin(PG) born of the same parents endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) protein biology synthetic method.Background of invention
Prostaglandin(PG) is the extremely effective substance that usually produces multiple biological effect at nanomolar concentration to the picomole concentration range.People have found the prostaglandin(PG) born of the same parents endoperoxide H synthase of two kinds of forms, be isozyme PGHS-1 and PGHS-2, their catalysis causes the biosynthetic arachidonic oxidation of prostaglandin(PG), and this discovery has caused describing the research of the renewal that these two kinds of isozymes act in physiology and pathology.Shown that these isozymes have different generegulation, represented visibly different prostaglandin(PG) biosynthetic pathway.PGHS-1 approach constitutive expression in most cell types.It is in response to prostaglandin(PG) that produce to regulate acute events in the blood vessel homeostasis, also has effect aspect normal stomach and the renal function keeping.The abduction mechanism that the PGHS-2 approach relates to inflammation, mitotic division take place and the ovulation phenomenon interrelates.
Prostaglandin inhibitor provides the treatment for pain, heating and inflammation, is useful therapy in the treatment of rheumatoid arthritis and osteoarthritis.NSAID (non-steroidal anti-inflammatory drug) (NSAID) such as Ibuprofen BP/EP, Naproxen Base and fenamic acid salt suppresses this two kinds of isozymes.The inhibition of composing type enzyme PGHS-1 causes comprising under ulcer and hemorrhage gastrointestinal side-effect and the long-term treatment kidney problems takes place.The inhibition of inductive enzyme PGHS-2 may provide anti-inflammatory activity, and does not have the side effect of PGHS-1 inhibitor.
In the past, the side-effect problem relevant with giving NSAID never solved fully.Tried to reduce stomach toxicity to greatest extent with enteric coated tablets with derivatives of prostaglandins Misoprostol co-administered.Preferably be provided as the compound of inducing isozyme PGHS-2 selective depressant.
The invention discloses novel cpd for the selective depressant of PGHS-2.Summary of the invention
The invention discloses pyridazinone compound for cyclooxygenase-2 (COX-2) selective depressant.Compound of the present invention has formula I:
Figure A9880832200231
Wherein
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R is selected from hydrogen; alkyl; alkenyl; alkynyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; the alkyl sulphonyl aralkyl; alkoxyl group; alkoxyalkyl; carboxyl; carboxyalkyl; the cyano group alkyl; haloalkyl; halogenated alkenyl; the halo alkynyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl group; cycloalkenyl alkyl; aryl; aralkyl; aromatic yl alkenyl; aromatic yl polysulfide yl; alkoxy aryl; the aryl halide substituted alkyl; the aryl hydroxyalkyl; aryloxy; the aryloxy hydroxyalkyl; the aryloxy haloalkyl; aryl alkyl carbonyl; the halogenated alkoxy hydroxyalkyl; heterocyclic radical; the heterocyclic radical alkyl; the heterocyclic radical alkoxyl group; the heterocyclyloxy base;-C (O) R 5,-(CH 2) nC (O) R 5,-R 6-R 7,-(CH 2) nCH (OH) R 5,-(CH 2) nCH (OR d) R 5,-(CH 2) nC (NOR d) R 5,-(CH 2) nC (NR d) R 5,-(CH 2) nCH (NOR d) R 5,-(CH 2) nCH (NR dR e) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-CX ' 3,-(CH 2) n(CX ' 2) m-(CH 2) n-CX ' 3,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8,-(CH 2) n(CX ' 2) m-(CH 2) nR 8,-(CH 2) n(CHX ') m-(CH 2) n-CX ' 3,-(CH 2) n(CHX ') m-(CH 2) n-R 8With-(CH 2) n-R 20,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, halogenated alkenyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;
R wherein 6Be selected from alkylidene group or alkylene group or halo alkylidene group halo alkylene group;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
R dAnd R eBe independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5; R 1, R 2And R 3In at least one is Or
Figure A9880832200242
X wherein 1Be selected from-SO 2-,-SO (NR 10)-,-SO-,-SeO 2-,-PO (OR 11) and-PO (NR 12R 13)-,
R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino ,-NHNH 2,-N=CH (NR 11R 12), dialkyl amido, alkoxyl group, thiol, alkyl sulfide hydroxyl, blocking group and be connected to X by an alkylidene group 1Blocking group;
X 2Be selected from hydrogen, halogen, alkyl, alkenyl and alkynyl;
R 10, R 11, R 12And R 13Be independently selected from hydrogen, alkyl and cycloalkyl, or R 12And R 13Can form the heterocycle of 3-6 atom with the nitrogen that they connect;
R 1, R 2And R 3Two of in the group all the other are independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, the alkylthio alkoxyl group, alkoxyl group, alkoxyalkyl, alkoxyalkyl amino, the alkoxyl group alkoxyl group, amido, amidoalkyl, haloalkyl, the halo alkenyloxy, halogenated alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, the cycloalkenyl group alkoxyl group, cycloalkyl alkoxy, cycloalkyl alkyl amino, cycloalkyl amino, cycloalkyloxy, the cycloalkylidene alkyl, amino, aminocarboxyl, aminoalkoxy, the aminocarboxyl alkyl, the alkylamino aryloxy, dialkyl amido, the dialkyl amido aryloxy, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aralkyl, alkylthio-aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, alkoxy aryl, aryloxy, heterocyclic radical, the heterocyclic radical alkyl, heterocyclic radical (alkyl) amino, the heterocyclic radical alkoxyl group, heterocyclic radical amino, the heterocyclyloxy base, the heterocyclic radical sulfenyl, hydroxyl, hydroxyalkyl, hydroxyalkyl amino, the hydroxyl alkylthio, the hydroxy alkoxy base, the sulfydryl alkoxyl group, the oxo alkoxyl group, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl),
R 16, R 17And R 19Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.Detailed Description Of The Invention
All patents, patent application and the document quoted in this specification sheets all are attached to herein by reference.Under inconsistent situation, be as the criterion to comprise this specification sheets in being defined in.
The invention discloses pyridazinone compound for the selective depressant of cyclo-oxygenase (COX) inhibitor and cyclooxygenase-2 (COX-2).COX-2 is and the derivable isoform of inflammation-related that relative with composing type isoform cyclo-oxygenase-1 (COX-1), in the many tissues that comprise stomach and intestine (GI) road and kidney, COX-1 is important " house keeper " enzyme.
In one embodiment, compound of the present invention has formula I:
Figure A9880832200261
Wherein
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R is selected from hydrogen; alkyl; alkenyl; alkynyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; the alkyl sulphonyl aralkyl; alkoxyl group; alkoxyalkyl; carboxyl; carboxyalkyl; the cyano group alkyl; haloalkyl; halogenated alkenyl; the halo alkynyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl group; cycloalkenyl alkyl; aryl; aralkyl; aromatic yl alkenyl; aromatic yl polysulfide yl; alkoxy aryl; the aryl halide substituted alkyl; the aryl hydroxyalkyl; aryloxy; the aryloxy hydroxyalkyl; the aryloxy haloalkyl; aryl alkyl carbonyl; the halogenated alkoxy hydroxyalkyl; heterocyclic radical; the heterocyclic radical alkyl; the heterocyclic radical alkoxyl group; the heterocyclyloxy base;-C (O) R 5,-(CH 2) nC (O) R 5,-R 6-R 7,-(CH 2) nCH (OH) R 5,-(CH 2) nCH (OR d) R 5,-(CH 2) nC (NOR d) R 5,-(CH 2) nC (NR d) R 5,-(CH 2) nCH (NOR d) R 5,-(CH 2) nCH (NR dR e) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-CX ' 3,-(CH 2) n(CX ' 2) m-(CH 2) n-CX ' 3,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8,-(CH 2) n(CX ' 2) m-(CH 2) nR 8,-(CH 2) n(CHX ') m-(CH 2) n-CX ' 3,-(CH 2) n(CHX ') m-(CH 2) n-R 8With-(CH 2) n-R 20,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, halogenated alkenyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;
R wherein 6Be selected from alkylidene group or alkylene group or halo alkylidene group halo alkylene group;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
R dAnd R eBe independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5; R 1, R 2And R 3In at least one is
Figure A9880832200271
Or
Figure A9880832200272
X wherein 1Be selected from-SO 2-,-SO (NR 10)-,-SO-,-SeO 2-,-PO (OR 11) and-PO (NR 12R 13)-,
R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino ,-NHNH 2,-N=CH (NR 11R 12), dialkyl amido, alkoxyl group, thiol, alkyl sulfide hydroxyl, blocking group and be connected to X by an alkylidene group 1Blocking group;
X 2Be selected from hydrogen, halogen, alkyl, alkenyl and alkynyl;
R 10, R 11, R 12And R 13Be independently selected from hydrogen, alkyl and cycloalkyl, or R 12
And R 13Can form the heterocycle of 3-6 atom with the nitrogen that they connect;
R 1, R 2And R 3Two of in the group all the other are independently selected from hydrogen, hydroxyl, hydroxyl
Alkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkane sulphur
Base, alkylthio alkoxyl group, alkoxyl group, alkoxyalkyl, alkoxyalkyl amino, alkane
Oxygen base alkoxyl group, amido, amidoalkyl, haloalkyl, halo alkenyloxy,
Halogenated alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, cyclenes
Base alkoxyl group, cycloalkyl alkoxy, cycloalkyl alkyl amino, cycloalkyl amino, cycloalkanes
Oxygen base, cycloalkylidene alkyl, amino, aminocarboxyl, aminoalkoxy, aminocarboxyl
Alkyl, alkylamino aryloxy, dialkyl amido, dialkyl amido aryloxy, aryl
Amino, aryl-alkyl amino, ammonia diaryl base, aryl, aralkyl, alkylthio-aryl,
Aromatic yl alkenyl, aromatic yl polysulfide yl, alkoxy aryl, aryloxy, heterocyclic radical, heterocyclic radical
Alkyl, heterocyclic radical alkylamino, heterocyclic radical alkoxyl group, heterocyclic radical amino, heterocyclyloxy
Base, heterocyclic radical sulfenyl, hydroxyl, hydroxyalkyl, hydroxyalkyl amino, hydroxyl alkylthio,
Hydroxy alkoxy base, sulfydryl alkoxyl group, oxo alkoxyl group, cyano group, nitro and-Y-R 14,
Wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,
-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14
Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl,
Hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group,
Aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl),
R 16, R 17And R 19Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, ring
Thiazolinyl, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group,
Alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another embodiment, compound of the present invention has formula II: Wherein Z is the group with following formula: Or
Figure A9880832200293
X wherein 1Be selected from-SO 2-,-SO-,-SeO 2-,-SO (NR 10)-, and R 9Be selected from alkyl,
Alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino ,-NHNH 2, dialkyl amido,
Alkoxyl group, thiol, alkyl sulfide hydroxyl, blocking group and be connected by an alkylidene group
To X 1Blocking group;
R 10Be selected from hydrogen, alkyl and cycloalkyl;
X 2Be selected from hydrogen, halogen, alkyl, alkenyl and alkynyl;
R is selected from hydrogen; alkyl; alkenyl; alkynyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; the alkyl sulphonyl aralkyl; alkoxyl group; alkoxyalkyl; carboxyl; carboxyalkyl; the cyano group alkyl; haloalkyl; halogenated alkenyl; the halo alkynyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl group; cycloalkenyl alkyl; aryl; aralkyl; aromatic yl alkenyl; aromatic yl polysulfide yl; alkoxy aryl; the aryl halide substituted alkyl; the aryl hydroxyalkyl; aryloxy; the aryloxy hydroxyalkyl; the aryloxy haloalkyl; aryl alkyl carbonyl; the halogenated alkoxy hydroxyalkyl; heterocyclic radical; the heterocyclic radical alkyl; the heterocyclic radical alkoxyl group; the heterocyclyloxy base;-C (O) R 5,-(CH 2) nC (O) R 5,-R 6-R 7,-(CH 2) nCH (OH) R 5,-(CH 2) nCH (OR d) R 5,-(CH 2) nC (NOR d) R 5,-(CH 2) nC (NR d) R 5,-(CH 2) nCH (NOR d) R 5,-(CH 2) nCH (NR dR e) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-CX ' 3,-(CH 2) n(CX ' 2) m-(CH 2) n-CX ' 3,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8,-(CH 2) n(CX ' 2) m-(CH 2) nR 8,-(CH 2) n(CHX ') m-(CH 2) n-CX ' 3,-(CH 2) n(CHX ') m-(CH 2) n-R 8With-(CH 2) n-R 20,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, halogenated alkenyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;
R wherein 6Be selected from alkylidene group or alkylene group or halo alkylidene group halo alkylene group;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
R dAnd R eBe independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, the alkylthio alkoxyl group, alkoxyl group, alkoxyalkyl, alkoxyalkyl amino, the alkoxyl group alkoxyl group, amido, amidoalkyl, haloalkyl, the halo alkenyloxy, halogenated alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, the cycloalkenyl group alkoxyl group, cycloalkyl alkoxy, cycloalkyl alkyl amino, cycloalkyl amino, cycloalkyloxy, amino, aminocarboxyl, aminoalkoxy, the aminocarboxyl alkyl, the alkylamino aryloxy, dialkyl amido, the dialkyl amido aryloxy, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aralkyl, alkylthio-aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, alkoxy aryl, aryloxy, heterocyclic radical, the heterocyclic radical alkyl, heterocyclic radical (alkyl) amino, the heterocyclic radical alkoxyl group, heterocyclic radical amino, the heterocyclyloxy base, the heterocyclic radical sulfenyl, hydroxyl, hydroxyalkyl, hydroxyalkyl amino, the hydroxy alkoxy base, the sulfydryl alkoxyl group, the oxo alkoxyl group, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,
-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With
-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, chain
Thiazolinyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group,
Amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl),
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group,
Alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group,
Alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another embodiment, compound of the present invention has formula III:
Figure A9880832200311
Wherein X, X 1, X 2, R, R 1, R 3And R 9Define suc as formula I; Or its pharmacy acceptable salt, ester or prodrug.
In a preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl ,-(CH 2) nC (O) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8With-(CH 2) n-R 20,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, aminocarboxyl alkyl, alkylamino, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aryloxy, heterocyclic radical, heterocyclic radical alkyl, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl),
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl ,-(CH 2) nC (O) R 5With-(CH 2) n-R 20,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
N is 0 to about 10;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkoxyalkyl, alkylthio alkyl, aryloxy alkyl, arylthio alkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, the aminocarboxyl alkyl, alkylamino, the alkylamino alkyl, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, heterocyclic radical, heterocyclic radical (alkyl), cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl) and
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group;
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl and-(CH 2) nC (O) R 5,
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
N is 0 to about 10;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkoxyalkyl, alkylthio alkyl, aryloxy alkyl, arylthio alkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, the aminocarboxyl alkyl, alkylamino, the alkylamino alkyl, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, heterocyclic radical, heterocyclic radical (alkyl), cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl),
R 15, R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group;
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from alkyl, haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from alkoxyl group, alkenyloxy, hydroxy alkoxy base, aryloxy, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl and-Y-R 14, wherein Y be selected from-O-,-S-, C (R 16) (R 17)-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 3Be hydrogen;
R 15, R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-,-SO-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from alkyl, haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from alkoxyl group, alkenyloxy, hydroxy alkoxy base, aryloxy, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from unsubstituted aryl and with being selected from the aryl that of fluorine or chlorine, two or three substituting groups replace, include but not limited to rubigan, to fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl etc.; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be selected from alkyl and amino;
X 2Be selected from hydrogen and halogen;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, halogenated alkoxy, aralkyl, alkyl and aryloxy; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be selected from alkyl and amino;
X 2Be selected from hydrogen and fluorine;
R is selected from haloalkyl, aryl and alkyl;
N is 0 to about 10;
R 1Being selected from isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, aryloxy comprises 4-fluorophenoxy, unsubstituted aryl and with being selected from the aryl that fluorine and chlorine, two or three substituting groups replace, includes but not limited to 4-fluorophenyl, 4-chloro-phenyl-, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1Be selected from-SO 2-and-SO (NR 10)-, and R 9Be alkyl;
X 2Be selected from hydrogen and fluorine;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, alkyl and aryloxy; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be amino;
X 2Be selected from hydrogen and fluorine;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, alkyl and aryloxy; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be methyl;
X 2Be selected from hydrogen;
X is O;
R is selected from the tertiary butyl, 3-chloro-phenyl-, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl and CF 3CH 2-;
R 1Be selected from aryloxy (comprising the 4-fluorophenoxy), isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.
In another preferred embodiment, compound of the present invention has formula III, wherein X 1For-SO 2-, and R 9Be amino;
X 2Be selected from hydrogen;
X is O;
R is selected from the tertiary butyl, 3-chloro-phenyl-, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF 3CH 2-;
R 1Be selected from aryloxy and comprise (4-fluorophenoxy), isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl; With
R 3Be hydrogen; Or its pharmacy acceptable salt, ester or prodrug.The definition of term
Has specific implication in this specification and the used following term of appended claims.
Term " blocking group " comprises " carboxy protective group " and " N-protected group "." carboxy protective group " used herein is meant and is used for sealing or protect carboxylic functionality, carries out the carboxylic acid protection ester group of the reaction that described compound relates to other functional site simultaneously.At Greene, among " Protective Groups in Organic Synthesis " 152-186 (1981) (document is attached to herein by reference) carboxy protective group has been described.In addition, carboxy protective group can be used as prodrug, and this carboxy protective group can for example easily downcut by enzymically hydrolyse in vivo by this, with the delivery of biologically active parent.T.Higuchi and V.Stella are at " Pro-drugs as Novel Delivery Systems ", the 14th volume of A.C.S.Symposium Series, among the American Chemical Society (1975) (document is attached to herein by reference), provide comprehensive discussion of prodrug notion.This class carboxy protective group is well known to those skilled in the art, has been widely used in the protection carboxyl in penicillin and cynnematin field, and as United States Patent (USP) the 3rd, 840, No. 556 and the 3rd, 719, No. 667, its disclosure is attached to herein by reference.The example that can be used as the ester of carboxylated compound prodrug can be at " Bioreversible Carriers in Drug Design:Theory and Application " (E.B.Roche, Pergamon Press, New York (1987)) find in the 14-21 page or leaf, the document is attached to herein by reference.Representational carboxy protective group is C 1-C 8Alkyl (for example methyl, ethyl or the tertiary butyl etc.); Haloalkyl; Alkenyl; The derivative of cycloalkyl and replacement thereof is such as cyclohexyl, cyclopentyl etc.; The derivative of cycloalkylalkyl and replacement thereof is such as cyclohexyl methyl, cyclopentyl-methyl etc.; Aralkyl, for example styroyl or benzyl, and the derivative that replaces are such as alkoxybenzyl or nitrobenzyl etc.; Aromatic yl alkenyl, for example styryl etc.; The derivative of aryl and replacement thereof, for example 5-indanyl etc.; Dialkyl aminoalkyl (for example dimethyl aminoethyl etc.); The alkanoyloxy alkyl is such as acetoxy-methyl, butyryl acyloxy methyl, valeryl oxygen ylmethyl, isobutyl acyl-oxygen ylmethyl, isoamyl acyl-oxygen ylmethyl, 1-(propionyloxy)-1-ethyl, 1-(penta acyloxy)-1-ethyl, 1-methyl isophthalic acid-(propionyloxy)-1-ethyl, oxy acid methyl neopentyl, propionyloxy methyl etc.; Cycloalkanes acyloxy alkyl is such as cyclopropyl carbonyl oxygen ylmethyl, cyclobutyl carbonyl oxygen ylmethyl, cyclopentylcarbonyl oxygen ylmethyl, cyclohexyl-carbonyl oxygen ylmethyl etc.; The aryl acyloxy alkyl is such as benzoyloxy methyl, benzoyloxy ethyl etc.; Aromatic alkyl carbonyl oxygen base alkyl is such as benzyloxycarbonyl group oxygen ylmethyl, 2-benzyloxycarbonyl group oxygen base ethyl etc.; Alkoxy carbonyl alkyl is such as methoxycarbonyl methyl, cyclohexyloxy carbonyl methyl, 1-methoxycarbonyl-1-ethyl etc.; The alkoxy-carbonyl oxy alkyl is such as methoxycarbonyl oxygen ylmethyl, tert-butoxycarbonyl oxygen ylmethyl, 1-ethoxy carbonyl Oxy-1-ethyl, 1-cyclohexyloxy carbonyl Oxy-1-ethyl etc.; The alkoxycarbonyl amino alkyl is such as tert-butoxycarbonyl amino methyl etc.; The alkyl amino-carbonyl aminoalkyl group is such as methylamino carbonylamino methyl etc.; The alkanoyl amido alkyl is such as acetylamino methyl etc.; Heterocyclic radical ketonic oxygen base alkyl is such as 4-methylpiperazine base ketonic oxygen ylmethyl etc.; The dialkyl amino carbonyl alkyl is such as dimethylamino carbonyl methyl, diethylamino carbonyl methyl etc.; (5-(low alkyl group)-2-oxo-1,3-dioxole-4-yl) alkyl is such as (the 5-tertiary butyl-2-oxo-1,3-dioxole-4-ylmethyl etc.; (5-phenyl-2-oxo-1,3-dioxole-4-yl) alkyl is such as (5-phenyl-2-oxo-1,3-dioxole-4-yl) methyl etc.
Term used herein " N-protected group " or " N-protected " are meant at the N-terminal of synthesis step period project protection amino acid or peptide or amino those groups that do not carry out undesirable reaction of protection.At Greene, " Protective Groups in Organic Synthesis " (JohmWiley ﹠amp; Sons, New York (1981), the document is attached to herein by reference) blocking group commonly used disclosed.The N-protected group comprises acyl group, such as formyl radical, ethanoyl, propionyl, pentanoyl, tertiary butyl ethanoyl, 2-chloracetyl, 2-acetyl bromide, trifluoroacetyl group, tribromo-acetyl base, phthaloyl, ortho-nitrophenyl oxygen base ethanoyl, α-chlorobutyryl, benzoyl, 4-chlorobenzene formacyl, 4-benzoyl bromide, 4-nitro benzoyl etc.; Alkylsulfonyl is such as benzenesulfonyl, p-toluenesulfonyl etc.; Carbamate forms group, such as benzyloxycarbonyl, to the chlorine benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, to the bromo-benzyloxy-carbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(to xenyl)-1-methyl ethoxy carbonyl, α, alpha-alpha-dimethyl-3,5-dimethoxy benzyloxycarbonyl, the hexichol methoxycarbonyl, tert-butoxycarbonyl, the di-isopropyl methoxycarbonyl, isopropoxy carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2-trichlorine ethoxy carbonyl, phenyloxycarbonyl, the 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, the cyclopentyloxy carbonyl, the Buddha's warrior attendant alkoxy carbonyl, cyclohexyloxy carbonyl, thiophenyl carbonyl etc.; Alkyl is such as benzyl, trityl group, benzyloxymethyl etc.; And silyl, such as three silyls etc.Preferred N-protected group is formyl radical, ethanoyl, benzoyl, valeryl, tertiary butyl ethanoyl, phenyl sulfonyl, benzyl, tert-butoxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).
Term used herein " alkanoyl " is meant the alkyl that is connected to the previous definition of parent molecular moiety by a carbonyl (C (O)-).
Term used herein " alkanoyl amido " is meant the alkanoyl that is connected to amino previous definition.The example of alkanoyl amido comprises kharophen, propionamido etc.
Term used herein " alkenyl " is meant and contains 2-15 carbon atom, also contains the straight or branched alkyl of at least one carbon-to-carbon double bond.Alkenyl comprises for example vinyl, allyl group (propenyl), butenyl, 1-methyl-2-butene-1-base etc.
Term " alkylene group " is meant and contains 2-15 carbon atom, and also contains the divalent group of the straight or branched hydrocarbon derivative of at least one carbon-to-carbon double bond.The example of alkylene group comprises-CH=CH-,-CH 2CH=CH-,-C (CH 3)=CH-,-CH 2CH=CHCH 2-etc.
Term used herein " alkenyloxy " is that (O-) key is connected to the alkenyl of the previous definition of parent molecular moiety by an oxygen.The example of alkenyloxy comprises propenyloxy group, butenyloxy etc.
Term used herein " alkoxyl group " is meant R 41O-, wherein R 41Low alkyl group for this paper definition.The example of alkoxyl group includes but not limited to oxyethyl group, isobutoxy, isopentyloxy, tert.-butoxy etc.
Term used herein " alkoxy amino amino " is meant the alkoxyl group that is connected to this paper definition of parent molecular moiety by an alkylamino defined herein.The example of alkoxyalkyl amino includes but not limited to ethoxyl methyl amino, isobutoxy ethylamino etc.
Term used herein " alkoxyl group alkoxyl group " is meant R 80O-R 81O-, wherein R 80Be the low alkyl group of above definition, and R 81Be alkylidene group.The representative instance of alkoxyl group alkoxyl group comprises methoxymethoxy, oxyethyl group methoxy base, tert.-butoxy methoxyl group etc.
Term used herein " alkoxy carbonyl " is meant the alkoxyl group that is connected to the previous definition of parent molecular moiety by a carbonyl.The example of alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl etc.
Term used herein " alkoxy carbonyl alkenyl " is meant the alkoxy carbonyl that is connected to the previous definition of parent molecular moiety by an alkylene group.The alkoxy carbonyl non-limiting examples of alkenyls comprises methoxycarbonyl vinylidene, ethoxy carbonyl propenylidene etc.
Term used herein " alkoxy alkoxy alkyl " is meant the alkoxyl group alkoxyl group of the previous definition that is connected to an alkyl.The representative instance of alkoxy alkoxy alkyl comprises methoxyethoxyethyl, methoxymethoxy methyl etc.
Term used herein " alkoxyl group alkoxy alkenyl " is meant the alkoxyl group alkoxyl group of the previous definition that is connected to an alkenyl.The representative instance of alkoxyl group alkoxy alkenyl comprises methoxy ethoxy vinyl, methoxymethoxy methyne etc.
Term used herein " alkoxyalkyl " is meant the alkoxyl group of the previous definition of the alkyl that is connected to a previous definition.The representative instance of alkoxyalkyl includes but not limited to methoxymethyl, methoxy ethyl, isopropoxy methyl etc.
Term used herein " (alkoxy carbonyl) thio alkoxy " is meant the foregoing alkoxy carbonyl that is connected to a thio alkoxy.The representative instance of (alkoxy carbonyl) thio alkoxy comprises methoxycarbonyl sulfo-methoxyl group, ethoxy carbonyl sulfo-methoxyl group etc.
Term used herein " alkyl " and " low alkyl group " are meant the straight or branched alkyl that contains 1-15 carbon atom, include but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methyl amyl, 2,2-dimethyl propyl, n-hexyl etc.
Term used herein " alkylamino " is meant R 51NH-, wherein R 51Be low alkyl group, for example ethylamino, butyl amino etc.
Term used herein " alkylamino alkyl " is meant the low alkyl group that an alkylamino connects.
Term used herein " alkyl amino-carbonyl " is meant by a carbonyl (C (O)-) key and is connected to the alkylamino of the previous definition of parent molecular moiety.The example of alkyl amino-carbonyl comprises amino-carbonyl, B aminocarbonyl, isopropyl amino-carbonyl etc.
Term used herein " alkyl amino-carbonyl alkenyl " is meant the alkenyl that an alkyl amino-carbonyl connects.
Term used herein " alkyl-carbonyl alkyl " is meant R 40-(C (O)-R 41-, R wherein 40Be alkyl, and R 41Be alkylidene group.
Term " alkylidene group " is meant the straight or branched hydrocarbon with 1-15 carbon atom by removing two hydrogen atom deutero-divalent groups, for example-and CH 2-,-CH 2CH 2-,-CH (CH 3)-,-CH 2CH 2CH 2-,-CH 2C (CH 3) 2CH 2-etc.
Term used herein " alkyl sulphonyl " is meant by an alkylsulfonyl (S (O) 2-) group is connected to the alkyl of the previous definition of parent molecular moiety.The example of alkyl sulphonyl comprises methylsulfonyl, ethylsulfonyl, different third alkylsulfonyl etc.
Term used herein " alkyl sulphonyl alkyl " is meant by a sulphonyl alkyl (S (O) 2-R-) group is connected to the alkyl of the previous definition of parent molecular moiety.The example of alkyl sulphonyl alkyl comprises methylsulfonyl methyl, second sulfonymethyl, the different third sulphonyl ethyl etc.
Term used herein " alkyl sulfonyl amino " is meant by a sulfonamido (S (O) 2-NH-) group is connected to the alkyl of the previous definition of parent molecular moiety.The example of alkyl sulfonyl amino comprises methanesulfonamido, ethanesulfonamido, different third sulfonamido etc.
Term used herein " alkyl sulphonyl aralkyl " is meant by a sulphonyl alkyl (S (O) 2-R 45R 33-) group is connected to the alkyl of the previous definition of parent molecular moiety, wherein R 45Be aryl, and R 33Be alkylidene group.The example of alkyl sulphonyl aralkyl comprises methylsulfonyl phenmethyl, ethylsulfonyl phenmethyl, the different third alkylsulfonyl styroyl etc.
Term used herein " alkylthio " is meant R 53S-, wherein R 53Be alkyl.
Term used herein " alkylthio alkyl " is meant the alkylthio that is connected to this paper definition of parent molecular moiety by an alkylidene group.
Term used herein " alkylthio alkoxyl group " is meant the alkylthio that is connected to this paper definition of parent molecular moiety by the alkoxyl group of this paper definition.
Term used herein " alkynyl " is meant and contains 2-15 carbon atom, and also contains the straight or branched alkyl of at least one carbon-to-carbon triple bond.The example of alkynyl comprises-C ≡ C-H-, H-C ≡ C-CH 2-, H-C ≡ C-CH (CH 3)-etc.
Term used herein " amido " is meant R 54-C (O)-NH-, wherein R 54Be alkyl.
Term used herein " amidoalkyl " is meant R 34-C (O)-NHR 35-, R wherein 34Be alkyl, R 35Be alkylidene group.
Term used herein " amino " is meant-NH 2
Term used herein " aminoalkoxy " is meant the amino that is connected to this paper definition of parent molecular moiety by the alkoxyl group of this paper definition.
Term used herein " aminocarboxyl " is meant H 2N-C (O)-.
Term used herein " aminocarboxyl alkyl " is meant the above-mentioned aminocarboxyl that is connected to parent molecular moiety by an alkylidene group.
Term used herein " aminocarboxyl alkenyl " is meant an aminocarboxyl (H 2N-C (O)-) alkenyl connecting of group.
Term used herein " aminocarboxyl alkoxyl group " is meant the H of the alkoxyl group that is connected to previous definition 2N-C (O)-.The example of aminocarboxyl alkoxyl group comprises aminocarboxyl methoxyl group, aminocarboxyl oxyethyl group etc.
Term used herein " aryl acyloxy alkyl " is meant R 32-C (O)-O-R 33-, R wherein 32Be aryl, and R 35Be alkylidene group.The example of aryl acyloxy alkyl comprises benzoyloxy methyl, benzoyloxy ethyl etc.
Term used herein " aryl " is meant monocycle or the bicyclic carbocyclic system with one or two aromatic ring, includes but not limited to phenyl, naphthyl, tetralyl, indanyl, indenyl etc.Aryl can be unsubstituted or replace with being independently selected from following one, two or three substituting groups: low alkyl group, halo, haloalkyl halogenated alkoxy, hydroxyl, oxo (=O), hydroxyalkyl, alkenyloxy, alkoxyl group, alkoxyl group alkoxyl group, alkoxy carbonyl, alkoxy carbonyl alkenyl, (alkoxy carbonyl) thio alkoxy, thio alkoxy, alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, alkyl sulphonyl, dialkyl amido, aminocarboxyl, aminocarboxyl alkoxyl group, alkanoyl amido, aryl, aralkyl, alkoxy aryl, aryloxy, sulfydryl, cyano group, nitro, carboxyl, formaldehyde (carboxaldehyde), methane amide (carboxamide), cycloalkyl, carboxyl alkenyl, carboxyl alkoxyl group, alkyl sulfonyl amino, cyano alkoxy, heterocyclic radical alkoxyl group ,-SO 3H, hydroxy alkoxy base, phenyl and tetrazyl alkoxyl group.Under halogenated situation, aryl can have 5 halo substituting groups of as many as.The example of the aryl that replaces comprises 3-chloro-phenyl-, 3-fluorophenyl, 4-chloro-phenyl-, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-sulfonyloxy methyl phenyl, pentafluorophenyl group etc.
Term used herein " aromatic yl alkenyl " is meant the alkenyl that aryl connects, for example styroyl etc.
Term used herein " aromatic yl polysulfide yl " is meant the alkynyl that aryl connects, for example phenylacetylene base etc.
Term used herein " alkoxy aryl " is meant R 42O-, wherein R 42Be aralkyl, for example benzyloxy etc.
Term used herein " alkoxy aryl alkyl " is meant the low alkyl group that alkoxy aryl connects, for example benzyloxymethyl etc.
Term used herein " aralkyl " is meant the aryl of the previous definition that is connected to low alkyl group, for example benzyl etc.
Term used herein " aryl alkyl amino " is meant the aralkyl that is connected to the previous definition of parent molecular moiety by an amino.
Term used herein " alkylthio-aryl " is meant the aralkyl that is connected to the previous definition of parent molecular moiety by a thiol.
Term used herein " arylamino " is meant R 42NH 2-, R wherein 45Be aryl.
Term used herein " aryl alkyl carbonyl " is meant R 45C (O) R 33-, R wherein 45Be aryl, and R 33Be alkylidene group.
Term used herein " aryl halide substituted alkyl " is meant that the haloalkyl by this paper definition is connected to the aryl of the previous definition of parent molecular moiety.The example of aryl halide substituted alkyl comprises phenyl-2-fluoropropyl etc.
Term used herein " aryl hydroxyalkyl " is meant that the hydroxyalkyl by this paper definition is connected to the aryl of the previous definition of parent molecular moiety.The example of aryl hydroxyalkyl comprises phenyl-2-hydroxypropyl etc.
Term used herein " aryloxy " is meant R 45O-, wherein R 45Be aryl, for example phenoxy group etc.
Term used herein " aryloxy alkyl " is meant the aryloxy of the previous definition that is connected to an alkyl.The example of aryloxy alkyl comprises phenoxymethyl, 2-phenoxy group ethyl etc.
Term used herein " aryloxy haloalkyl " is meant that the haloalkyl by this paper definition is connected to the aryloxy of the previous definition of parent molecular moiety.The example of aryloxy haloalkyl comprises phenoxy group-2-fluoropropyl etc.
Term used herein " aryloxy hydroxyalkyl " is meant that the hydroxyalkyl by this paper definition is connected to the aryloxy of the previous definition of parent molecular moiety.The example of aryloxy hydroxyalkyl comprises phenoxy group-2-hydroxypropyl etc.
Term used herein " formaldehyde " is meant formaldehyde group-C (O) H.
Term used herein " methane amide " is meant-C (O) NH 2
Term used herein " carboxyl " is meant hydroxy-acid group-C (O) OH.
Term used herein " carboxyalkyl " is meant the carboxyl of the previous definition of the alkyl that is connected to a previous definition.The example of carboxyalkyl comprises 2-carboxy ethyl, 3-carboxyl-1-propyl group etc.
Term used herein " carboxyl alkenyl " is meant the carboxyl of the previous definition of the alkenyl that is connected to a previous definition.The carboxyl non-limiting examples of alkenyls comprises 2-carboxy vinyl, 3-carboxyl-1-vinyl etc.
Term used herein " carboxyl alkoxyl group " is meant the carboxyl of the previous definition of the alkoxyl group that is connected to a previous definition.The example of carboxyl alkoxyl group comprises carboxyl methoxyl group, carboxyl oxyethyl group etc.
Term used herein " cyano group " is meant that cyano group (CN).
Term used herein " cyano group alkyl " is meant a cyano group (CN) alkyl of the previous definition of Lian Jieing.The example of cyano group alkyl comprises 3-cyano group propyl group, 4-cyano group butyl etc.
Term used herein " cyano alkoxy " be meant be connected to parent molecular moiety by an alkoxyl group cyano group (CN).The example of cyano alkoxy comprises 3-cyano group propoxy-, 4-cyano group butoxy etc.
Term used herein " cycloalkanes acyloxy alkyl " is meant that the cycloalkanes acyloxy (is R 60-C (O)-, R wherein 60Be cycloalkyl) low alkyl group.
Term used herein " cycloalkyl " is meant the alicyclic ring system with 3-10 carbon atom and 1-3 ring, includes but not limited to cyclopropyl, cyclopentyl, cyclohexyl etc.Cycloalkyl can be unsubstituted, or replaces with being independently selected from following one, two or three substituting groups: hydroxyl, halo, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, alkoxy carbonyl, thio alkoxy, haloalkyl, sulfydryl, carboxyl, formaldehyde, methane amide, cycloalkyl, aryl, aralkyl ,-SO 3H, nitro, cyano group and low alkyl group.
Term used herein " cycloalkenyl group " is meant the alicyclic ring system that has 3-10 carbon atom and 1-3 ring, contains at least one two key in described ring structure.Cycloalkenyl group can be unsubstituted, or replaces with being independently selected from following one, two or three substituting groups: hydroxyl, halo, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, alkoxy carbonyl, thio alkoxy, haloalkyl, sulfydryl, carboxyl, formaldehyde, methane amide, cycloalkyl, aryl, aralkyl ,-SO 3H, nitro, cyano group and low alkyl group.
Term used herein " cycloalkylalkyl " is meant the cycloalkyl that is connected to a low alkyl group, includes but not limited to cyclohexyl methyl.
Term used herein " cycloalkyl alkoxy " is meant the cycloalkyl of the alkoxyl group that is connected to this paper definition, includes but not limited to the cyclohexyl methoxyl group.
Term used herein " cycloalkyl amino " is meant that the amino by this paper definition is connected to the cycloalkyl of parent molecular moiety, includes but not limited to cyclohexyl amino etc.
Term used herein " cycloalkyl alkyl amino " is meant that the alkylamino by this paper definition is connected to the cycloalkyl of parent molecular moiety, includes but not limited to cyclohexyl methyl amino etc.
Term used herein " cycloalkylidene alkyl " is meant by being connected to a two key (=(CH of alkylidene group 2) n-) be connected to the cycloalkyl of parent molecular moiety.Example comprises cyclopropylidene ethyl, inferior cyclobutyl propyl group etc.
Term used herein " cycloalkyloxy " is meant the cycloalkyl that is connected to parent molecular moiety by a Sauerstoffatom, includes but not limited to cyclohexyloxy.
Term used herein " cycloalkenyl alkyl " is meant the cycloalkenyl group that is connected to low alkyl group, includes but not limited to cyclohexenyl methyl etc.
Term used herein " cycloalkenyl group alkoxyl group " is meant the cycloalkenyl group that is connected to alkoxyl group defined herein, includes but not limited to cyclohexenyl methoxyl group etc.
Term used herein " dialkyl amido " is meant R 56R 57N-, wherein R 56And R 57Be independently selected from low alkyl group, for example diethylamino, methyl-propyl amino etc.
Term used herein " dialkyl amido aryloxy " is meant that the aryloxy by this paper definition is connected to the dialkyl amido of parent molecular moiety.
Term used herein " ammonia diaryl base " is meant (R 45) (R 46) N-, wherein R 45And R 46Be independently aryl, for example diphenyl amino etc.
Term used herein " dialkyl aminoalkyl " is meant the low alkyl group that dialkyl amido connects.
Term used herein " dialkyl amino carbonyl " is meant by a carbonyl (C (O)-) key and is connected to the dialkyl amido of parent molecular moiety.The example of dialkyl amino carbonyl comprises dimethylamino carbonyl, diethylamino carbonyl etc.
Term used herein " dialkyl amino carbonyl alkenyl " is meant the alkenyl that dialkyl amino carbonyl connects.
Term used herein " dialkyl amino carbonyl alkyl " is meant R 50-C (O)-R 51-, R wherein 50Be dialkyl amido, and R 51Be alkylidene group.
Term used herein " halo " or " halogen " are meant I, Br, Cl or F.
Term used herein " haloalkyl " is meant alkyl defined above, and it has a halogenic substituent at least, for example chloro methyl, fluoro ethyl, trifluoromethyl or pentafluoroethyl group, 2,3-difluoro amyl group etc.
Term used herein " halogenated alkenyl " is meant the alkenyl with at least one halogenic substituent, for example chloro methyne, fluorinated ethylene base, trifluoro methyne or five fluoride-based, 2,3-difluoro pentenyl etc.
Term used herein " halo alkenyloxy " is meant the halogenated alkenyl that is connected to parent molecular moiety by a Sauerstoffatom.
Term used herein " halo alkynyl " is meant the alkynyl with at least one halogenic substituent, for example; Chloro methyne, Fluoro Substituted Acetylene base, trifluoro methyne or five fluorine ethynyls, 2,3-difluoro pentynyl etc.
Term used herein " halogenated alkoxy " is meant the alkoxyl group that has at least one halogenic substituent defined above, 2-fluorine oxyethyl group, 2,2 for example, 2-trifluoro ethoxy, trifluoromethoxy, 2,2,3,3,3-five fluorine propoxy-etc.
Term used herein " halogenated alkoxy alkyl " is meant the low alkyl group that halogenated alkoxy connects.
Term used herein " halogenated alkoxy hydroxyalkyl " is meant the halogenated alkoxy that is connected to this paper definition of parent molecular moiety by the hydroxyalkyl of this paper definition.
Term used herein " heterocycle ring system " or " heterocyclic radical " or " heterocycle " are meant and contain a heteroatomic 3-or a 4-unit ring that is selected from oxygen, nitrogen and sulphur; Or following 5-, 6-or 7-unit ring: contain one, two or three nitrogen-atoms; A Sauerstoffatom; Sulphur atom, nitrogen-atoms and a sulphur atom, a nitrogen-atoms and a Sauerstoffatom; Two Sauerstoffatoms in non-adjacent position; A Sauerstoffatom and a sulphur atom in non-adjacent position; Or at two sulphur atoms of non-adjacent position.The heterocyclic example includes but not limited to thiophene, pyrroles and furans.5 yuan of rings have 0-2 two key, and 6 yuan of rings and 7 yuan of rings have 0-3 two key.Nitrogen heteroatom can be randomly quaternized.Term " heterocyclic radical " also comprises any and phenyl ring or cycloalkanes or another heterocycle (for example indyl, indolinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, benzofuryl, dihydro benzo furyl, dihydro benzo furyl or benzothienyl) the condensed bicyclic group in the wherein above-mentioned heterocycle.Heterocyclic radical comprises aziridinyl, azetidinyl, pyrryl, pyrrolinyl, pyrrolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, piperidyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thio-morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, oxetanyl, furyl, tetrahydrofuran base, thienyl, thiazolidyl, isothiazolyl, triazolyl, tetrazyl isoxazolyl oxadiazole base, thiadiazolyl group, pyrryl, pyrimidyl and benzothienyl.Heterocyclic radical also comprises formula
Figure A9880832200501
Compound, X wherein *For-CH 2-or-O-, and Y *For-C (O)-or [C (R ") 2-] v, R wherein " and be hydrogen or C 1-C 4Alkyl, and v is 1,2 or 3, such as 1,3-dioxolyl, 1,4-benzodioxan base etc.Heterocyclic radical also comprises the dicyclo such as quinuclidinyl etc.
Heterocyclic radical can be unsubstituted, or replaces with being independently selected from following one, two or three substituting groups: hydroxyl, halo, oxo (=O), alkyl imino (R *N=, wherein R *Be low alkyl group), amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, alkoxy carbonyl, thio alkoxy, haloalkyl, sulfydryl, carboxyl, formaldehyde, methane amide, cycloalkyl, aryl, aralkyl ,-SO 3H, nitro, cyano group and low alkyl group.In addition, nitrogen heterocyclic ring can be by N-protected.
Term used herein " heterocyclic radical alkoxyl group " is meant the heterocyclic radical defined above that is connected to alkoxyl group defined above.The example of heterocyclic radical (alkoxyl group) comprises 4-pyridyl methoxyl group, 2-pyridyl methoxyl group etc.
Term used herein " heterocyclic radical amino " is meant the heterocyclic radical defined above that is connected to amino defined above.The example of heterocyclic radical amino comprises 4-pyridinylamino, 2-pyridinylamino etc.
Term used herein " heterocyclyloxy base " is meant the heterocyclic radical defined above that is connected to parent molecular moiety by a Sauerstoffatom.The example of heterocyclyloxy base comprises 4-pyridyl oxygen base, 2-pyridyl oxygen base etc.
Term used herein " heterocyclic radical alkyl " is meant the heterocyclic radical defined above that is connected to low alkyl group defined above.
Term used herein " heterocyclic radical alkylamino " is meant the heterocyclic radical defined above that is connected to alkylamino defined above.
Term used herein " heterocyclic radical ketonic oxygen base alkyl " is meant R 46-C (O)-O-R 47-, R wherein 46Be heterocyclic radical, and R 47Be alkylidene group.
Term used herein " heterocyclic radical sulfenyl " is meant the heterocyclic radical defined above that is connected to parent molecular moiety by a thiol.The example of heterocyclic radical sulfenyl comprises 4-pyridine sulfenyl, 2-pyridine sulfenyl etc.
Term used herein " hydroxyl " is meant-OH.
Term used herein " hydroxyl alkenyl " is meant the alkenyl that hydroxyl connects.The hydroxyl non-limiting examples of alkenyls comprises 3-hydroxyl propenyl, 3,4-dihydroxyl butenyl etc.
Term used herein " hydroxy alkoxy base " is meant the hydroxyl (OH) alkoxyl group defined above of Lian Jieing.The example of hydroxy alkoxy base comprises 3-hydroxyl propoxy-, 4-hydroxyl butoxy etc.
Term used herein " hydroxyalkyl " is meant the low alkyl group that hydroxyl connects.The example of hydroxyalkyl comprises 1-hydroxypropyl, 4-hydroxybutyl, 1,3-dihydroxyl isopentyl etc.
Term used herein " hydroxyalkyl amino " is meant the hydroxyalkyl that is connected to parent molecular moiety by an amino.The example of hydroxyalkyl amino comprises 1-hydroxyl third amino, 4-hydroxyl fourth amino, 1,3-dihydroxyl isoamylamino etc.
Term used herein " hydroxyl alkylthio " is meant the hydroxyalkyl that is connected to parent molecular moiety by a thiol.The example of hydroxyalkyl amino comprises 1-hydroxyl rosickyite base, 4-hydroxyl butylthio, 1,3-dihydroxyl isoamyl sulfenyl etc.
Term used herein " sulfydryl " or " thiol " are meant-SH.
Term used herein " nitro " is meant-NO 2
Term oxo alkoxyl group is meant the carbonyl that is connected to parent molecular moiety by an alkoxyl group.
Term used herein " sulfydryl alkoxyl group " or " thio alkoxy " are meant R 70S-, wherein R 70Be alkoxyl group.The example of thio alkoxy includes but not limited to methylthio group, ethylmercapto group etc.Term used herein " tetrazyl " is meant formula Group or its tautomer.
Term used herein " tetrazyl alkoxyl group " is meant the tetrazyl that is connected to alkoxyl group defined above.The example of tetrazyl alkoxyl group comprises tetrazyl methoxyl group, tetrazyl oxyethyl group etc.
Term used herein " thio alkoxy alkoxyl group " is meant R 80S-R 81O-, wherein R 80Be low alkyl group defined above, and R 81Be alkylidene group.The representative instance of alkoxyl group alkoxyl group comprises CH 3SCH 2O-, EtSCH 2O-, t-BuSCH 2O-etc.
Term used herein " thio alkoxy alkoxyalkyl " is meant the thio alkoxy alkoxyl group that is connected to alkyl.The representative instance of alkoxy alkoxy alkyl comprises CH 3SCH 2CH 2OCH 2CH 2-, EtSCH 2OCH 2O-etc.
Compound of the present invention can be to be used by mineral acid or organic acid deutero-salt form.These salt include but not limited to following salt: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, undecyl vitriol, esilate, glucoheptose salt, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyl-esilate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picric acid, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosilate and undecylate.In addition, nitrogenous basic group can be used such as following reagent quaternized: low alkyl group halogen, such as methyl, ethyl, propyl group and Butyryl Chloride, bromine and iodine; The sulfuric acid dialkyl is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide is such as decyl, lauryl, myristyl and stearyl chloride, bromine and iodine; Aralkyl halogen is as benzyl and phenethyl bromide; And other reagent.Obtain water-soluble thus or oil soluble or dispersible products.
The example that can be used for forming the acid of pharmaceutically-acceptable acid addition comprises: organic acid, all example hydrochloric acids, sulfuric acid and phosphoric acid; And organic acid, such as oxalic acid, toxilic acid, succsinic acid and citric acid.
In the end separate and purifying formula (I) compound during can the on-site preparation base addition salt, or by making carboxylic acid functional and suitable alkali (such as oxyhydroxide, carbonate or the supercarbonate of pharmaceutically acceptable metallic cation) or preparing base addition salt respectively with ammonia or organic primary amine, secondary amine or reactive tertiary amine.This class pharmacy acceptable salt includes but not limited to: based on the positively charged ion of basic metal and alkaline-earth metal, such as the salt of sodium, lithium, potassium, calcium, magnesium, aluminium salt etc.; And the cationic positively charged ion of nontoxic ammonium, quaternary ammonium and amine, include but not limited to the salt of ammonium, tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, ethamine etc.Other the representative organic amine that can be used for forming base addition salt comprises diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.
Term used herein " pharmaceutically acceptable ester " is meant the ester of hydrolysis in vivo, comprises being easy to decompose those esters that stay parent compound or its salt in human body.Suitable ester group for example comprises by pharmaceutically acceptable aliphatic carboxylic acid (particularly paraffinic acid, alkenoic acid, naphthenic acid and chain docosandioic acid) deutero-ester group, and wherein each moieties or alkenyl part preferably has and is no more than 6 carbon atom.The example of concrete ester comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.
Term used herein " pharmaceutically acceptable prodrug " is meant the prodrug of those The compounds of this invention, they are to be applicable to human to contact with zootic tissue in correct medical judgment scope, and do not have toxicity, stimulation, anaphylaxis etc. improperly and have rational interests/risk ratio and effective to its purpose purposes, when possible the zwitterionic form of The compounds of this invention.Term " prodrug " is meant and transforms the compound that the parent compound with following formula for example is provided by hydrolysis in blood in vivo fast.At T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, the 14th volume of A.C.S.Symposium Series and the Bioreversible Carriers in Drug Design that edits at Edward B.Roche, American Pharmaceutical Association and Pergamon Press, in 1987 (these two documents are attached to herein by reference), provide comprehensive discussion.
The group of cleavable in the used term metabolism in this specification and the appended claims is meant to be easy in vivo from having the compound cracked part of this group, wherein said compound after cracking still for or become medical active arranged.The group of cleavable forms the group of the carboxyl reaction of a class and The compounds of this invention in the metabolism, is well known to those skilled in the art.They include but not limited to such as following group: alkanoyl is ethanoyl, propionyl, butyryl radicals etc. for example; The aroyl that does not replace and replace is such as the benzoyl of benzoyl and replacement; Alkoxy carbonyl is such as ethoxy carbonyl; Trialkylsilanyl is such as TMS and triethyl silyl; An ester that forms with dicarboxylic acid is such as succinyl etc.Because the group of cleavable is easy to cracking in vivo in the metabolism of The compounds of this invention, so have the prodrug that the compound of this class group can be used as other prostaglandin(PG) biosynthesis inhibitor.The advantage that has the compound of cleavable group in the described metabolism is: owing to parent compound relies on the existence of cleavable group in the described metabolism to make solubleness increase and/or the uptake rate raising, they may show the raising of bioavailability.
May there be asymmetric center in the The compounds of this invention.Present invention includes various steric isomers and composition thereof.By beginning by the raw material that contains described chiral centre, or by preparation enantiomorph mixture of products, then for example by being converted into non-enantiomer mixture, separating by recrystallize or chromatographic technique subsequently, or, can prepare each steric isomer of The compounds of this invention by directly on the chiral layers post, separating optically active enantiomorph.Specific stereochemical initial compounds or commercially available perhaps can prepare by the method for following detailed description, and splits by the technology that organic chemistry filed is known.Preferred embodiment
Can be used for implementing compound of the present invention and include, but is not limited to following compounds or its pharmacy acceptable salt, ester or prodrug: 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl-3-butenyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2, two (4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (the 2H)-pyridazinones of 4-; 2-(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-oxopropoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methoxyl group-imino--propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (R)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (S)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (R)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; (S)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-oxo-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-oxo-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; With 2, two (4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of 4-]-3 (2H)-pyridazinones.
The preferred compound of the present invention includes, but is not limited to following compounds or its pharmacy acceptable salt, ester or prodrug: 2-phenyl-4-(4-fluorophenyl)-5-(4-sulfonyloxy methyl phenyl)-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-(4-methyl sulphonyl phenyl)-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; With 2, two (4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (the 2H)-pyridazinones of 4-.The preparation of The compounds of this invention
The compounds of this invention can be by multiple route of synthesis preparation.Below summarized representational method at flow process 1-3.
Below the have formula III general way of The compounds of this invention of (wherein 5 aryl is replaced by an alkylsulfonyl on the pyridazinone ring) has been described in flow process 1.Two chloro-3 (2H)-pyridazinones and benzyl chloride and salt of wormwood are reacted in methyl alcohol.Then, 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone is handled with boric acid such as 4-fluorobenzoic boric acid (showing) and palladium catalyst.The described methoxyl group of Hydrogen bromide hydrolysis with 48% obtains 5-hydroxyl pyridazinone compound.Handle 5-hydroxyl pyridazinone product with trifluoromethanesulfanhydride anhydride, on the pyridazinone ring, replace then with 4-methylthio phenyl boric acid.The methyl sulfide compound of gained and the acetate of peracetic acid and dichloromethane solution reaction obtain the methyl sulfone.Remove benzyl with aluminum bromide or another kind of suitable Lewis acid.Can add the R group by replacing with suitable alkylating agent and alkali.
Flow process 1
Figure A9880832200601
Figure A9880832200611
Another approach of The compounds of this invention with formula III has been described in following flow process 2.Make 4-bromine sulfo-phenylmethylether or another kind of suitable thioether and tri-alkoxy boric acid ester such as trimethoxy boric acid ester or the reaction of triisopropyl boric acid ester, be translated into 4-(methylthio group) phenylo boric acid.With the glycol dimethyl ether solution of four (triphenylphosphine)-palladiums (O), make this boric acid and 2-benzyl-4,5-two bromo-3 (2H)-pyridazinone reaction.With this product and second boric acid such as 4-fluorobenzoic boric acid (shown in) and palladium catalyst reaction, obtain thioether then.The methyl sulfide compound of gained and the dichloromethane solution of metachloroperbenzoic acid (MCPBA) are reacted, the methyl sulfone is provided.Remove benzyl with aluminum bromide or another kind of suitable Lewis acid.Can add the R group by replacing with suitable alkylating agent and alkali.
Flow process 2
Figure A9880832200612
The third approach of The compounds of this invention with formula III has been described in following flow process 3.(Y is CH by making 4-sulphomethyl phenyl aldehyde 3S) with methyl (methyl sulfinyl methyl) sulfide and sodium hydroxide reaction, preparation (4-sulphomethyl phenyl) dimethyl thioketene that contracts ((4-Thiomethylphenyl) dimethylthioketene acetal) one-S-oxide compound.The described thioketene diethyl acetal of THF solution-treated and 4-fluorophenylacetic acid methyl esters or suitable ester (X is a fluorine) with highly basic such as hexamethyl two silicon sodiumazide provide butyric ester.With the direct cyclisation of dithio ketene of will contracting of hydrazine and salt is unsubstituted pyridazinone.With peracetic acid oxidation pyridazinone, provide the alkylsulfonyl pyridazinone.In a kind of alternate approach flow process 3-A, used chloric acid to handle the described thioketene that contracts, the ester-aldehyde as non-enantiomer mixture is provided.Handle oxidation products with hydrazine, use peracetic acid treatment then, obtain the alkylsulfonyl dihydropyridazinone.Can handle by using,, form described pyridazinone described dihydropyridazinone dehydrogenation such as the bromine in the acetate.Can add the R group by replacing with suitable alkylating agent and alkali.
Flow process 3
Figure A9880832200631
Flow process 3A
Figure A9880832200632
Figure A9880832200641
Comprise J.Med.Chem. by being applied in, 1987,30,239-249 and WO 96/36623 (these documents are attached to herein by reference) be the disclosed and method that is shown in flow process 4 in interior multiple source, can finish the preparation of 5-hydroxyl-2 (5H)-furanone.
Flow process 4
Figure A9880832200651
Method IV:
Figure A9880832200652
Below the have formula III general way of The compounds of this invention of (wherein 5 aryl is replaced by an alkylsulfonyl on the pyridazinone ring) has been described in flow process 5.Make the hydrazine reaction that glues hydracid such as Mucobromic acid or mucochloric acid and have required R group, dihalo pyridazinone compound 5A is provided.For example in the presence of sodium hydride or the potassium hydride KH, handle the dihalo compound at alkali, alkoxide 5B is provided with alcohol.(if described alkoxyl group will be at subsequent removal, and then methyl alcohol is preferred alcohol).The reaction of alkoxyl group-halogenide and methylthio phenyl boric acid provides alkoxyl group-pyridazinone 5C.By using the Grignard agent treated, described alkoxyl group is converted into alkyl, thioether 5D is provided.Can form sulfenylation compound 5G or methyl sulphones 5E with oxygenant such as the described thioether of oxidations such as peracetic acid, metachloroperbenzoic acid.Rearrangement and the hydrolysis of sulfenylation compound 5G provide thiophenol.With described thiophenol oxidation, activation and amination are translated into amino-sulfonyl compound 5H then.Perhaps; by handling the methylsulfonyl compound with diazonium dicarboxylic ester such as DBAD, DIAD, DEAD etc. and disilazane negatively charged ion such as HMDS lithium etc.; sodium acetate in the water and hydroxylamine-o-sulfonic acid are handled then; methylsulfonyl compound 5E can be converted into aminosulfonyl based compound 5H, obtain aminosulfonyl based compound 5H.
Flow process 5
Figure A9880832200661
Perhaps, shown in flow process 5A, can be with alkoxyl group-pyridazinone 5C oxidation.The first step with oxygenant such as peracetic acid, metachloroperbenzoic acid etc., forms sulfinyl compound 5G ' or methyl sulphones 5E '.The rearrangement and the hydrolysis of this sulfinyl compound provide thiophenol.With thiophenol oxidation, activation and amination, be translated into amino-sulfonyl compound 5H ' then.At last; by handling the methylsulfonyl compound with diazonium dicarboxylic ester such as DBAD, DIAD, DEAD etc. and disilazane negatively charged ion such as HMDS lithium etc.; sodium acetate in the water and hydroxylamine-o-sulfonic acid are handled then, sulfonyloxy methyl compound 5E ' can be converted into aminosulfonyl compound 5H '.
Flow process 5A
Figure A9880832200671
The preparation of the The compounds of this invention of (wherein alkyl or the alkenyl of 4 group for replacing on the pyridazinone ring) has been described and had formula III to following flow process 6.With halogenating agent for example NBS and superoxide will shown in R96 be the thioether 5E halogenation of alkyl (for example methyl), bromo compound 6A is provided.Make the reaction of bromo compound and pure and mild weak base such as yellow soda ash or salt of wormwood, 4-alkyl-ether 6B is provided.Alkali such as silver carbonate in the presence of, make bromo compound and thio-compounds the reaction, 4-alkyl-thioether 6C is provided.Make the reaction of bromo compound and amine and weak base such as yellow soda ash or salt of wormwood, 4-alkylamino-alkylate 6D is provided.
Flow process 6
Above flow process 6 has been described the have formula III general way of The compounds of this invention of (wherein 4 group can easily replace on the pyridazinone ring).By R 97For the alkoxide 5E ' of methyl begins to synthesize.With alkali such as sodium hydroxide or the described methoxylation compound of potassium hydroxide treatment, provide 4-hydroxyl-pyridazinone 6A.Handle described alcohol with Tosyl chloride, tosyloxy compound 6B is provided.Can be with experiencing S NThe compound R of 2 reactions 92Z ' easily replaces described tosyloxy compound.These examples for compounds are such as the anionic compound of alcohol, mercaptan, amine or alkyl.
Flow process 6A
Figure A9880832200691
As used in this specification and the appended claims, used following abbreviation: ACD represents acid citrate dextrose, CAP represents carrageenan inductive air bag (air pouch) prostaglandin(PG), CIP represents rat carrageenan pleura inflammatory model, COX-2 represents cyclooxygenase-2, CPE represents carrageenan inductive rat pawl oedema, DBAD represents the di-t-butyl azodicarboxylate, DEAD represents the diethylazodicarboxylate, DIAD represents azo-2-carboxylic acid's dipropyl, DMAP represents 4-(dimethylamino) pyridine, DME represents 1, the 2-glycol dimethyl ether, DMF represents N, dinethylformamide, DMSO represents dimethyl sulfoxide (DMSO), EDTA represents ethylenediamine tetraacetic acid (EDTA), and EIA represents enzyme immunoassay, and FAB represents fast atom bombardment(FAB), GI represents stomach and intestine, HMDS, lithium or Li HMDS represent 1,1,1,3,3,3-hexamethyl two silicon Lithium Azides, HWPX representative whole blood platelet cyclo-oxygenase-1, MCPBA represents metachloroperbenzoic acid, NSAID represents NSAID (non-steroidal anti-inflammatory drug), and PEG 400 represents polyoxyethylene glycol, PGE 2Represent PGE 2PGHS represents prostaglandin(PG) born of the same parents endoperoxide H synthase, RHUCX1 represents recombinant human cyclo-oxygenase-1, RHUCX2 represents the recombinant human cyclooxygenase-2, r-hu Cox1 represents recombinant human Cox-1, and TEA represents triethylamine, and TFA represents trifluoroacetic acid, and THF represents tetrahydrofuran (THF), the full cell cyclooxygenase-2 of WISH representative amnion.Following examples are described method of the present invention, for nonrestrictive.
Compound of the present invention includes but not limited to following examples:
Embodiment 14-(methylthio group) phenylo boric acid
(5.0g, anhydrous tetrahydro furan 0.0246mol) (THF) stirred solution is cooled to-78 ℃ under nitrogen atmosphere with 4-bromine sulfo-phenylmethylether.The 2.5M hexane solution of n-Butyl Lithium (12ml.0.030mol) is dropped in the described refrigerative solution.When adding is finished, with reaction mixture in-78 ℃ of stir abouts 45 minutes.Import trimethyl borate (8.5ml, 0.0748) by syringe.Allow the reaction mixture temperature to ambient temperature overnight then.Handle the solution of room temperature continuously with 10% aqueous sodium hydroxide solution (50ml) and water (33.5ml), and under room temperature, stirred 1 hour.With 10% aqueous citric acid solution the pH of reaction mixture is reduced to 4-5, and THF is removed in decompression.Make the residual aqueous solution saturated with sodium-chlor, and use ethyl acetate extraction.Organic extract is also filtered through dried over mgso.Concentrating under reduced pressure filtrate obtains white solid, and it is used hexane wash, obtains described product, is white solid (output: 1.5g; 36%).M.p.170℃。 1H?NMR(300MHz，DMSO-d 6)δ2.47(s，3H)，7.20(d，J＝8Hz，2H)，7.71(d，J＝8Hz，2H)，7.96(br?s，2H)。
Embodiment 22-benzyl-4,5-two bromo-3 (2H)-pyridazinones
With bromotoluene (0.59ml 0.005mol) adds to 4,5-two bromo-3 (2H)-pyridazinones (1.27g, 0.005mol) and salt of wormwood (0.76g is in 20ml anhydrous dimethyl formamide (DMF) stirred solution 0.0055mol).Solution stirred under room temperature spend the night, and be allocated between aqueous citric acid solution and the ethyl acetate.Water layer ethyl acetate extraction 2 times.The organic extract salt water washing that merges is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains beige solid, with it through column chromatography purification (silica gel, 9: 1 hexane/ethyl acetate).Obtain described product (output: 1.32g for white solid; 76.7%).M.p.95-96℃。 1H?NMR(300MHz，CDCl 3)δ5.31(s，2H)，7.29-7.37(m，3H)，7.41-7.47(m，2H)，7.79(s，1H)。MS(DCI-NH 3)m/z?345(M+H) +。IR(KBr)1645cm -1
Embodiment 32-benzyl-4-bromo-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Preparation is according to the boric acid (0.318g of the method preparation of embodiment 1,0.001889mol), according to the dibromo pyridazinone (0.975g of the method for embodiment 2 preparation, 0.002834mol) and four (triphenylphosphine)-palladiums (O) (0.16g, glycol dimethyl ether 0.0142mmol) (30ml) solution.(2.83ml 0.005668mol) adds in the glycol dimethyl ether solution, with mixture heating under refluxing with the 2M aqueous sodium carbonate.After 16 hours, chromatography (TLC) is checked that (9: 1 hexane/ethyl acetate) shows and is still had two kinds of raw materials, adds the new palladium catalyst of equal portions.Reaction mixture was stirred 5 hours down in refluxing again, allow it be cooled to room temperature, during weekend, leave standstill.Volatile matter is removed in decompression, and resistates is allocated between water and the ethyl acetate.The water layer ethyl acetate extraction.The organic extract salt water washing that merges is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains oily matter, with it through column chromatography purification (silica gel, 95: 5 hexane/ethyl acetate).Merge the flow point that contains required product, and concentrating under reduced pressure.With this material chromatography (95: 5 hexane/ethyl acetate) again, obtain the 0.200g beige solid.The crystallization from ether/hexane of described solid obtains white crystal (output: 110mg, 15%).M.p.115-118℃。 1H?NMR(300MHz，CDCl 3)δ2.53(s，3H)，5.40(s，2H)，7.30-7.42(m，7H)，7.49-7.54(m，2H)，7.65(s，1H)。MS(DCI-NH 3)m/z?387(M+H) +。
Embodiment 42-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Product (0.100g with preparation among the embodiment 3,0.000258mol), 4-fluorobenzene boric acid (0.072g, 0.000516mol), four (triphenylphosphine)-palladium (O) (0.015g, 0.000013mol) and 2M aqueous sodium carbonate (0.64ml, the following stirring 16 hours of 30ml glycol dimethyl ether (DME) solution backflow 0.001291mol).The described boric acid that adds new palladium catalyst of equal portions and other a a great deal of.Reactant is kept refluxing 24 hours.Volatile matter is removed in decompression, and resistates is allocated between water and the ethyl acetate.The water layer ethyl acetate extraction.The organic layer salt water washing that merges is through dried over mgso and filtration.Filtrate is adsorbed on the silica gel.Silica gel/product is placed the silicagel column top, with 93: 7 hexane/ethyl acetate eluted product.Merge the flow point and the concentrating under reduced pressure that contain product.This residue is further purified through second column chromatography (silica gel, 95: 5 hexane/ethyl acetate).Concentrating under reduced pressure contains the flow point of product, obtains viscosity oily matter (output: 0.028g, 27%). 1H?NMR(300MHz，CDCl 3)δ2.46(s，3H)，5.39(s，2H)，6.95(t，J＝9Hz，2H)，6.99(d，J＝9Hz，2H)，7.11(d，J＝9Hz，2H)，7.16-7.23(m，2H)，7.30-7.40(m，3H)，7.52-7.40(m，2H)，7.86(s，2H)。MS(DCI-NH 3)m/z?403(M+H) +。
Embodiment 52-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
(0.027g in the stirred solution of cold (0 ℃) methylene dichloride (10ml) 0.000067mol), drips metachloroperbenzoic acid (MPCBA) (0.039g, methylene dichloride 0.00013mol) (5ml) solution to the sulfide for preparing to the method according to embodiment 4.After 5 minutes, TLC (1: 1 hexane/ethyl acetate) shows and exhausts initial sulfide.With sodium sulfite aqueous solution quenching reactant.Organic layer is washed 2 times with aqueous sodium hydroxide washes, with salt water washing 1 time.Dichloromethane solution is through dried over mgso and filtration.Concentrating under reduced pressure filtrate.Resistates obtains required sulfone product through column chromatography (silica gel, 7: 3 hexane/ethyl acetate) purifying.With the further wash-out of 100% ethyl acetate, go out described sulfoxide from this post wash-out.The sulfoxide product stands MCPBA oxidizer treatment (0.04g, 1 hour, 0 ℃) and as above-mentioned processing again.The resistates that obtains mixes with the sulfone that wash-out from first post goes out, with mixture through column chromatography purification (silica gel, 7: 3 hexane/ethyl acetate) purifying.Merge the flow point and the concentrating under reduced pressure that contain product.With resistates crystallization from ether/hexane, obtain described product, be white crystal (output: 13mg, 44.6%).M.p.101-103℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.40(s，2H)，6.95(t，J＝9Hz，2H)，7.12-7.20(m，2H)，7.28-7.41(m，3H)，7.31(d，J＝9Hz，2H)，7.58-7.53(m，2H)，7.84(s，1H)，7.87(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z435(M+H) +。MS (FAB, high resolving power) calculated value: m/z 435.1179 (M+H) +, measured value: m/z 435.1184 (M+H) +
Embodiment 62-benzyl-4-(4-fluorophenyl)-5-methoxyl group-3 (2H)-pyridazinone
Under nitrogen, to according to S.Cho etc. at J.Het.Chem., 1996,33,2-benzyl-5-methoxyl group-4-bromo-3 (2H)-pyridazinone (2.94g of the method preparation of describing among the 1579-1582; 10mmol), 4-fluorobenzoic boric acid (1.54g; 11mmol) and CsF (3.04g; Add Pd (Ph in the anhydrous DME mixture of 25ml 22mmol) 3P) 4(347mg 0.3mmol).After the adding, mixture was heated 18 hours down in 100 ℃ of backflows.Vacuum concentrated mixture is allocated in resistates between ethyl acetate and the water.The salt water washing of acetic ester layer is through dried over mgso and vacuum concentration.Be suspended in ether-hexane solid residue and filtration, obtain solid product (output: 3.1g; About 100%;＞95% purity). 1H?NMR(300MHz，CDCl 3)δ3.90(s，3H)，5.36(s，2H)，7.09(t，J＝9Hz，2H)，7.31(m，3H)，7.50(m，4H)，7.91(s，1H)。MS(DCI-NH 3)m/z?311(M+H) +，328(M+NH 4) +。
Embodiment 7 2-benzyl-4-(4-fluorophenyl)-5-hydroxyl-3 (2H)-pyridazinone
With product (1.24g, 4mmol) the mixture in 20ml acetate of 48% HBr (25ml) processing according to the method preparation of embodiment 6.With mixture backflow heating about 5 hours to about 8 hours (TLC analysis) down.Vacuum concentrated mixture.Product is dissolved in the ethyl acetate, with 10% supercarbonate and salt water washing, vacuum concentration.Handle resistates with ether-hexane (2: 1),, obtain almost pure product (output: 1.16g solid filtering; 98%). 1H NMR (300MHz, DMSO-d 6) δ 5.24 (2H), 7.21 (m, 2H), 7.30 (m, 5H), 7.55 (m, 2H), 7.85 (s, 1H), 11.31 (wide s, 1H).MS(DCI-NH 3)m/z?296(M+H) +，314(M+NH 4) +。
Embodiment 82-benzyl-4-(4-fluorophenyl)-5-(trifluoromethyl sulfonyloxy)-3 (2H)-pyridazinones
Under nitrogen, preparation is according to the product of the method for embodiment 7 preparation (89mg, the 0.3mmol) solution in the 2.5ml anhydrous pyridine, and in 0 ℃ of maintenance.With trifluoromethanesulfanhydride anhydride (Tf2O; 0.06ml; 0.32mmol) drop in this solution.The mixture of gained was stirred 5 hours in 0 ℃, under room temperature, stirred 16 hours.(pyridine and Tf 2O should be pure, to obtain good result.Sometimes the essential Tf that adds additional quantity 2O is so that reaction is finished).Then mixture is inclined and to the cold soln of citric acid, also use ethyl acetate extraction, obtain almost pure product (output: 127mg, about 99%). 1H?NMR(300MHz，DMSO-d 6)δ5.34(s，2H)，7.35(m，7H)，7.60(m，2H)，8.48(s，1H)。MS(DCI-NH 3)m/z?429(M+H) +，446(M+NH 4) +。
Embodiment 92-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Will according to the product of the method for embodiment 8 preparation (154mg, 0.36mmol), 4-(methylthio group) phenylo boric acid (67mg, 0.4mmol), Et 3N (0.11mmol; 0.8mmol) and Pd (Ph 3P) 4(30mg, 0.025mmol) mixture in 15ml toluene heated about 45 minutes under about 100 ℃ of backflows.Vacuum concentrated mixture through column chromatography purification (hexane-ethyl acetate 3: 1), obtains title compound (output: 98mg, 68%) with resistates. 1H?NMR(300MHz，CDCl 3)δ2.47(s，3H)，5.38(s，2H)，6.98(m，4H)，7.12(m，2H)，7.20(m，2H)，7.35(m，3H)，7.54(m，2H)，7.86(s，1H)。MS(DCI-NH 3)m/z?403(M+H) +，420(M+NH 4) +。
Embodiment 102-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
(140mg 0.348mmol) adds peracetic acid (CH in the solution in the 10ml methylene dichloride in 0 ℃ of product for preparing to the method according to embodiment 9 3COOOH; 0.5ml; 30%).Mixture was stirred 90 minutes in 0 ℃.Vacuum is removed methylene dichloride then.Resistates is dissolved in the ethyl acetate, with 10% sodium bicarbonate and salt water washing.Ethyl acetate is removed in decompression.Resistates through chromatography (silica gel, methylene dichloride-ether 19: 1), is obtained title compound (output: 130mg, 86%). 1H?NMR(300MHz，CDCl 3)δ3.04(s，3H)，5.40(s，2H)，6.95(m，2H)，7.16(m，2H)，7.33(m，5H)，7.55(m，2H)，7.86(m，3H)。MS(DCI-NH 3)m/z?434(M+H) +，452(M+NH 4) +。
Embodiment 114-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Will according to the product of the method for embodiment 10 preparation (37mg, 0.085mmol) and AlBr 3(70mg, the 0.26mmol) stir about 15 minutes under about 80 ℃ of backflows of the mixture in 10ml toluene, and be cooled to 0 ℃.Handle the refrigerative mixture with 1N HCl, and use ethyl acetate extraction.Acetic ester layer water, salt water washing and vacuum concentration.Resistates is gone up purifying at silicagel column (ethyl acetate is as eluent), obtains title compound (output: 22mg, 76%). 1HNMR (300MHz, CDCl 3) δ 3.07 (s, 3H), 7.00 (t, J=9Hz, 2H), 7.20 (m, 2H), 7.56 (d, J=9Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9Hz, 2H), 10.94 (wide s, 1H).MS(DCI-NH 3)m/z?345(M+H) +，362(M+NH 4) +。
Embodiment 122-phenyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 12A. 2-phenyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinones
According to S.Cho etc. at J.Het.Chem., 1996,33, the method for describing among the 1579-1582 is begun by N-phenyl-dichloro pyridazinone, preparation 2-phenyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone.With 2-phenyl-4, (1g, 4.1mmol) (580mg, heating was 5 hours under 4.2mmol) mixture in 50ml methyl alcohol refluxed, and vacuum concentration with the finely powdered Anhydrous potassium carbonate for 5-two chloro-3 (2H)-pyridazinones.Resistates is allocated between water and the ethyl acetate.Acetic ester layer water and salt water washing obtain 2-phenyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone (output: 920mg, 95%). 1H?NMR(300MHz，DMSO-d 6)δ4.15(s，3H)，7.50(m，5H)，8.43(s，1H)。MS(DCI-NH 3)m/z?237(M+H) +，254(M+NH 4) +。12B. 2-phenyl-4-(4-fluorophenyl)-5-methoxyl group-3 (2H)-pyridazinone
According to the method for embodiment 6,, obtain 2-phenyl-4-(4-fluorophenyl)-5-methoxyl group-3 (2H)-pyridazinone (output: 1.1g with 2-phenyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone and the coupling of 4-fluorobenzoic boric acid; 96%). 1H?NMR(300MHz，CDCl 3)δ4.00(s，3H)，7.10(t，J＝9Hz，2H)，7.45(m，3H)，7.60(m，4H)，8.06(s，1H)。MS (DCI-NH 3) m/z 297 (M+H) +12C. 2-phenyl-4-(4-fluorophenyl)-5-hydroxyl-3 (2H)-pyridazinone
According to the method for embodiment 7, handle 2-phenyl-4-(4-fluorophenyl)-5-methoxyl group-3 (2H)-pyridazinone product with 48%HBr, obtain 2-phenyl-4-(4-fluorophenyl)-5-hydroxyl-3 (2H)-pyridazinone (output: 957mg, 92%).MS(DCI-NH 3)m/z?283(M+H) +，300(M+NH 4) +。12D. 2-phenyl-4-(4-fluorophenyl)-5-trifluoro-methanesulfonyl oxy-3 (2H)-pyridazinone
According to the method for embodiment 8,, obtain 2-phenyl-4-(4-fluorophenyl)-5-trifluoro-methanesulfonyl oxy-3 (2H)-pyridazinone (output: 1.35g, 96%) with 2-phenyl-4-(4-fluorophenyl)-5-hydroxyl-3 (2H)-pyridazinone product sulfonylation.MS(DCI-NH 3)m/z?415(M+H) +，432(M+NH 4) +。12 E. 2-phenyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
As described in embodiment 9, with 2-phenyl-4-(4-fluorophenyl)-5-trifluoro-methanesulfonyl oxy-3 (2H)-pyridazinone and the coupling of 4-(methylthio group) phenylo boric acid, obtain 2-phenyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinone (output: 915mg, 92%), as described in embodiment 9, immediately it is used the peracetic acid oxidation, at column chromatography (silica gel, 1: 1 hexane-ethyl acetate) and from ether/hexane after the crystallization, obtain title compound (output: 288mg, 69%).M.P.219-220℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.15(t，J＝9Hz，2H)，7.30(m，2H)，7.46(m，1H)，7.56(m，4H)，7.64(m，2H)，7.90(d，J＝9Hz，2H)，8.24(s，1H)。MS(DCI-NH 3)m/z?421(M+H) +，438(M+NH 4) +
Embodiment 134-fluorophenylacetic acid methyl esters
The vitriol oil of catalytic amount (0.5ml) is added to the 4-fluorophenylacetic acid, and (30.8g is in 500ml methanol solution 0.20ml).Solution was stirred 4 hours down in refluxing.Volatile matter is removed in decompression, obtains colorless oil, it is dissolved in ether/ethyl acetate, with 2N aqueous sodium carbonate, salt water washing, through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains oily matter, with its dried overnight (output: 33.6 under high vacuum; 95%). 1H?NMR(300MHz，CDCl 3)δ3.59(s，2H)，3.65(s，3H)，7.01(t，J＝9Hz，2H)，7.20-7.28(m，2H)。MS(DCI-NH 3)m/z?186(M+H) +。
Embodiment 14[4-(methylthio group) phenyl] dimethyl thioketene one-S-oxide compound contracts
(50g, 0.40mol) (3.12g, mixture 0.078mol) stirred 4 hours in 70 ℃ with finely powdered sodium hydroxide with methyl (methylsulfinyl methyl) sulfide.A collection of then adding 4-(methylthio group) phenyl aldehyde (27.4ml.0.195mol), with reaction mixture in 70 ℃ of restir 4 hours.Mixture is cooled to room temperature, is allocated in 10% aqueous citric acid solution and the methylene dichloride.Organic layer is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains brown oil.Oily matter obtains solid through column chromatography purification (7: 3 hexane/ethyl acetate).With this solid crystallization from ether/hexane (output: 24.7g; 72%). 1H?NMR(300MHz，CDCl 3)δ2.33(s，3H)，2.53(s，3H)，2.77(s，3H)，7.17(d，J＝9Hz，2H)，7.57(s，1H)，7.86(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 259 (M+H) +With m/z 276 (M+NH 4) +
Embodiment 152-(4-fluorophenyl)-3-[4-(methylthio group) phenyl]-4-methylthio group-4-methylsulfinyl-methyl butyl
Will according to the ester products of the method for embodiment 13 preparation (16.24g, 50ml THF drips of solution 0.0966mol) add to 1.0M hexamethyl two silicon sodiumazide THF (96.6ml, in stirred solution 0.0966mol), under dry nitrogen atmosphere in 0 ℃ of maintenance.After 30 minutes, will (20.8g, 50ml THF drips of solution 0.0805mol) adds in the reaction mixture as for 0 ℃ of maintenance according to the thioketene that contracts (ketene thioacetal) of the method for example 14 preparation.After 4 hours, reaction mixture is with 10% aqueous citric acid solution acidifying.Water layer washs 2 times with ethyl acetate.Organic extract is merged, use the salt water washing, through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains brown oil, with it through column chromatography purification (85: 15 to 1: 1 dichloromethane/ethyl acetate gradients).Separate and obtain having different R fValue and several products of NMR spectrographic.These compounds have identical mass spectrum.In subsequent reaction, handle the mixture (output: 22.4g of compound; 65%).MS(DCI-NH 3)m/z?444(M+NH 4) +。
Embodiment 162-(4-fluorophenyl)-3-[4-(methylthio group) phenyl]-3-formyl radical-n Propanoic acid methyl esters
Will (9.0g 0.021mol) be dissolved in the acetonitrile (80ml), and is cooled to 0 ℃ according to the mixture of the compound of embodiment 17 preparation.To cross chloric acid (60%; 1.06g, 0.006mol) add in the solution of stirring.In 0 ℃ of stirred reaction mixture 8 hours, with the quenching of 2N sodium bicarbonate aqueous solution.Acetonitrile, the mixture aqueous solution ethyl acetate extraction of gained are removed in decompression.Organic solution is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains yellow oil, with it through column chromatography purification (silica gel, 7: 3 hexane/ethyl acetate).Vacuum concentration makes residue crystallization from methyl alcohol from the flow point of the diastereomer of high Rf that has of product mixtures, obtains title aldehyde-ester cpds, is white crystal (output: 0.27g, 4.0%).M.p.＝112-113℃。 1HNMR(300MHz，CDCl 3)δ2.49(s，3H)，2.46(s，3H)，4.39(s，2H)，7.03(t，J＝9Hz，1H)，7.21(d，J＝9Hz，1H)，7.25(d，J＝9Hz，2H)，7.40-7.47(m，2H)。MS (DCI-NH 3) m/z 333 (M+H) +With m/z 350 (M+NH 4) +Vacuum concentration is from the flow point of the compound with low Rf of product compound, and resistates is accredited as the hydrate (output: 2.6g, 35.2%) of described aldehyde-ester. 1H NMR (300MHz, CDCl 3) δ 2.44 and 2.46 (2s, 3H), 3.56 and 3.48 (2s, 3H), 3.55 and 3.76 (2dd, J=6Hz, J=6Hz, 1H), 3.98 and 4.26 (2d, J=12Hz, 1H), 5.41 and 5.47 (2d, J=6Hz, 1H), 6.96 and 7.00 (t, J=9Hz, 2H), 7.11-7.26 (m, 6H).MS (DCI-NH 3) m/z333 (M+H) +With m/z 350 (M+NH 4) +
The compound identification that Rf is minimum is the hydroxy-lactone (output: 1.1g, 16.4%) that a hydroxyl of described hydrate replaces the methoxyl group formation of described ester. 1H NMR (300MHz, CDCl 3) δ 2.45 (s, 3H), 3.54-3.71 (m, 1H), 3.98-4.21 (m, 1H), 4.61 (wide s, 1H), 5.85-6.01 (m, 1H), 6.98 (t, J=9Hz, 2H), 7.12-7.27 (m, 6H).MS(DCI-NH 3)m/z?336(M+NH 4) +。
Embodiment 174-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-4,5-dihydro-3 (2H)-pyridazinone
With among the embodiment 16 preparation aldehyde-ester, hydrate and hydroxy-lactone (0.10g 3mmol) is dissolved in the 100ml ethanol.(0.15ml 300ml) handles this solution, stirs the solution of gained under refluxing in containing the Soxhlet apparatus of molecular sieve with a hydrazine hydrate.After 18 hours, with the reaction mixture cooling, volatile matter is removed in decompression.Resistates is allocated between the ethyl acetate and the HCl aqueous solution.Water washs 2 times with ethyl acetate.The water layer that merges washs 2 times with ethyl acetate.The organic extract that merges is with salt water washing 2 times, through dried over mgso and filtration.Concentrating under reduced pressure filtrate, resistates obtain title compound (output: 50mg, 53%) through column chromatography purification (4: 1 hexane/ethyl acetate). 1H NMR (300MHz, CDCl 3) δ 2.46 (s, 3H), 3.75 (d, J=12Hz, 1H), 3.87 (d, J=12Hz, 1H), 6.93-7.08 (m, 6H), 7.16 (d, J=9Hz, 2H), 8.71 (s (wide), 1H).MS (DCI-NH 3) m/z 315 (M+H) +With 332 (M+NH 4) +
Embodiment 184-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-4,5-dihydro-3 (2H)-pyridazinone
To according to the sulfide of the method for embodiment 17 preparation (0.050g, 0.16mmol) in the stirred solution, add 32% peracetic acid acetic acid solution (0.4ml, 1.6mmol), and in 0 ℃ of maintenance.Reaction mixture was stirred 5 hours in 0 ℃, then dilute with water.Organic layer is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains oily matter, solidifies when it is ground with ether (output: 47mg, 85%). 1H NMR (300MHz, CDCl 3) δ 3.05 (s, 3H), 3.77 (d, J=12Hz, 1H), 4.05 (d, J=12Hz, 1H), 6.95-7.08 (m, 4H), 7.28 (d, J=9Hz, 2H), 7.90 (d, J=9Hz, 2H), 8.75 (s, wide, 1H).MS(DCI-NH 3)m/z?364(M+NH 4) +。
Embodiment 194-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
(47mg is 0.136mmol) in the solution acetate (25ml) for the dihydropyridazinone product that will prepare according to the method for embodiment 18.(0.025ml 0.16mmol) adds to this solution, and reaction mixture was stirred 20 minutes in 95 ℃ with bromine.The concentrating under reduced pressure reaction mixture.Resistates is allocated between ethyl acetate and the water.Organic layer salt water washing is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains solid, with it by silica gel short column eluent ethyl acetate.Crystallization goes out title compound (output: 35mg, 75%) from ethyl acetate/hexane.M.p.255-256℃。 1H?NMR(300MHz，CDCl 3)δ3.07(s，3H)，6.98(t，J＝9Hz，2H)，7.16-7.23(m，2H)，7.35(d，J＝9Hz，2H)，7.86(s，1H)，7.91(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 345 (M+H) +With 362 (M+NH 4) +
Embodiment 202-(4-luorobenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The unsubstituted pyridazinone product of nitrogen (160mg with preparation among the embodiment 19,0.465mmol), salt of wormwood (193mg, 1.4mmol), 4-luorobenzyl-bromine (0.09ml, 0.7mmol) and NaI (catalytic amount) at the anhydrous N of 10ml, the solution in the dinethylformamide (DMF) stirred under room temperature 18 hours.Reaction mixture 2N HCl quenching, (2 * 20ml) extractions with salt solution and water washing, through dried over mgso, are filtered also vacuum concentration with ethyl acetate.Resistates is through column chromatography purification (2: 2: 6 ethyl acetate/dichloromethane/pentanes).Crystallization from ether/pentane obtains white crystal (output: 110mg, 52%).M.p.153-154℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，2H)，5.36(s，2H)，6.96(t，J＝8.4Hz，2H)，7.04(t，J＝8.7Hz，2H)，7.16(dd，J＝9.1Hz，J＝5.4Hz，2H)，7.31(d，J＝8.5Hz，2H)，7.54(dd，J＝8.8Hz，5.5Hz，2H)，7.84(s，1H)，7.87(d，J＝8.8Hz，2H)。MS(DCI-NH 3)m/z?453(M+H) +。
Embodiment 212-(phenyl propargyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with the phenyl propargyl bromide, the preparation title compound.M.p.100-103℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，5.26(s，2H)，6.97(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，J＝6Hz，2H)，7.31(m，3H)，7.34(d，J＝9Hz，2H)，7.48(m，2H)，7.89(d，J＝9Hz，2H)，7.9(s，1H)。MS(DCI-NH 3)m/z?459(M+H) +。
Embodiment 222-(2, the 4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 2, the 4-difluoro benzyl bromide replaces the 4-fluoro benzyl bromide, the preparation title compound.M.p.179-182℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，5.45(s，2H)，6.87(m，2H)，6.96(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，J＝6Hz，2H)，7.32(d，J＝9Hz，2H)，7.54(m，1H)，7.86(s，1H)，7.88(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?471(M+H) +。
Embodiment 232-(methyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 3-chloro-2-methacrylic, the preparation title compound.M.p.140-142℃。 1H?NMR(CDCl 3，300MHz)δ1.86(s，3H)，3.08(s，3H)，4.83(s，2H)，4.94(t，J＝1Hz，1H)，5.05(t，J＝1Hz，1H)，6.98(t，J＝9Hz，2H)，7.21(dd，J＝9Hz，J＝6Hz，2H)，7.37(d，J＝9Hz，2H)，7.89(s，1H)7.91(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?399(M+H) +。
Embodiment 242-(3-methyl-2-butene base)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 4-bromo-2-methyl-2-butene, the preparation required compound.M.p.169-172℃。 1H?NMR(CDCl 3，300MHz)δ1.78(s，3H)，1.85(s，3H)，3.06(s，3H)，4.86(d，J＝7.5Hz，2H)，5.47(t，J＝7.5Hz，1H)，6.96(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，J＝6Hz，2H)，7.33(d，J＝9Hz，2H)，7.84(s，1H)，7.88(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?413(M+H) +。
Embodiment 252-(2-trifluoromethyl benzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(trifluoromethyl) bromotoluene, the preparation title compound.M.p.87-90℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，5.66(s，2H)，6.97(t，J＝9Hz，2H)，7.21(dd，J＝9Hz，J＝6Hz，2H)，7.26(d，J＝7.7Hz，1H)，7.37(d，J＝9Hz，2H)，7.42(t，J＝7.7Hz，1H)，7.53(t，J＝7.7Hz，1H)，7.73(dJ＝7.7Hz，1H)，7.9(s，1H)，7.91(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?503(M+H) +。
Embodiment 262-(cyclopropyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl) cyclopropane, the preparation title compound.M.p.118-121℃。 1H?NMR(CDCl 3，300MHz)δ0.45-0.52(m，2H)，0.54-0.63(m，2H)，1.40-1.52(m，1H，3.07(s，3H)，4.07(d，J＝7Hz，2H0，6.97(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，J＝6Hz，2H)，7.35(d，J＝9Hz，2H)，7.83(s，1H)，7.88(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 399 (M+H) +With 416 (M+NH 4) +
Embodiment 272-(2-pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl [3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl) pyridine, the preparation title compound.M.p.182-184℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，5.56(s，2H)，6.95(m?2H)，7.17(m，2H)，7.26(m，1H)，7.35(m，2H)，7.46(m，1H)，7.71(m，1H)，7.90(m，3H)，8.63(m?1H)。MS(DCI-NH 3)m/z?436(M+H) +。
Embodiment 282-(4-pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl [3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 4-(brooethyl) pyridine, the preparation title compound.M.p.153-156℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，5.40(s，2H)，6.97(m?2H)，7.17(m，2H)，7.34(m，2H)，7.42(m，2H)，7.90(m，3H)，8.63(m，2H)。MS(DCI-NH 3)m/z?436(M+H) +。
Embodiment 292-(3-pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 3-(brooethyl) pyridine, the preparation title compound.M.p.160-161℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，5.43(s，2H)，6.97(m，2H)，7.15(m，2H)，7.34(m，4H)，7.35(m，2H)，7.87(m，2H)，7.97(s，1H)，8.60(m，1H)，8.81(m，1H)。MS(DCI-NH 3)m/z?436(M+H) +。
Embodiment 302-(6-fluorine quinoline-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(chloromethyl)-6-fluorine quinoline, the preparation title compound.M.p.116-119℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，5.73(s，2H)，6.96(m?2H)，7.18(m，2H)，7.34(m，4H)，7.35(m，2H)，7.46(m，2H)，7.58(m，3H)，7.90(m，3H)，8.12(m，2H)。MS(DCI-NH 3)m/z?504(M+H) +。
Embodiment 312-(quinoline-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(chloromethyl)-quinoline, the preparation title compound.M.p.97-100℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，5.75(s，2H)，6.95(m?2H)，7.19(m，2H)，7.35(m，2H)，7.55(m，2H)，7.73(m，1H)，7.82(m，1H)，7.90(m，3H)，8.15(m，2H)。MS(DCI-NH 3)m/z?386(M+H) +。
Embodiment 322-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinthiones (pyridazinethione)
2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl that will prepare according to the method for embodiment 5]-3 (2H)-pyridazinone (109mg; 0.25mmol) and Lawesson reagent (202mg stirred 48 hours under 0.5mmol) mixture in 15ml toluene refluxes.Vacuum concentrated mixture, resistates obtain title compound (output: 100mg, 88%) through chromatographic separation (silica gel, ethyl acetate).M.p.88-90℃。 1H?NMR(300MHz，CDCl 3)δ3.04(s，3H)，6.05(s，2H)，6.96(m，2H)，7.08(m，2H)，7.26(m，2H)，7.37(m，3H)，7.61(m，2H)，7.84(d，J＝9Hz，2H)，8.13(s，1H)。MS(DCI-NH 3)m/z?451(M+H) +。
Embodiment 332-benzyl-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinone 33A. 2-benzyl-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl] preparation of-3 (2H)-pyridazinones
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl that will prepare according to the method for embodiment 4]-3 (2H)-pyridazinone (450mg, 1.12mmol) drips of solution in methylene dichloride (10ml) adds to hydroxyl (tosyloxy) phenyl-iodide (439mg, 1.12mmol) methylene dichloride (15ml) suspension in, mixture is stirred to obtains clear soln (about 1 hour).Reaction mixture washes and uses dried over mgso with water then.Vacuum is removed solvent, obtains corresponding sulfoxide (output: 485mg, about 100%). 1H?NMR(300MHz，CDCl 3)δ2.72(s，3H)，5.40(s，2H)，6.90(m，2H)，7.15(m，3H)，7.33(m，3H)，7.57(m，3H)，7.71(m，1H)，7.86(s，1H)。MS (DCI-NH 3) m/z 419 (M+H) +With 436 (M+NH 4) +33B. the preparation of 2-benzyl-4-(4-fluorophenyl)-5-(acetoxy-methyl alkylsulfonyl phenyl)-3 (2H)-pyridazinones
At Svn.Lett., described in 1997,375, do following the modification according to M.De Vleeschauwer and J.V.Gauthier, described sulfoxide be converted into sulphonamide:
Will according to the sulfoxide of the method for embodiment 33A preparation (485mg, 1.12mmol) and AcONa (1.4g) at 15ml Ac 2Suspension returning among the O stirred 2 hours down, and vacuum concentration.Resistates is dissolved in the 25ml methylene dichloride with toluene distillation twice, is cooled to 0 ℃, uses CH 3CO 3H (1ml) handles.After 1 hour, mixture saturated sodium bicarbonate and salt solution continuous washing.Vacuum is removed solvent.Resistates obtains required product 2-benzyl-4-(4-fluorophenyl)-5-(acetoxy-methyl alkylsulfonyl phenyl)-3 (2H)-pyridazinones (output: 150mg, 27%) through chromatographic separation (silica gel, 1: 1 hexane-ethyl acetate).MS(DCI-NH 3)m/z?493(M+H) +。33C. 2-benzyl-4-(4-fluorophenyl)-5-[4-(-sulfinic acid sodium) phenyl] preparation of-3 (2H)-pyridazinones
In 0 ℃ to according to the acetoxy-methyl sulfone of the method for embodiment 33B preparation (150mg, 0.305mmol) in 10ml THF and 5ml methanol solution, add 1N NaOH (0.305ml, 0.305mmol).Mixture was stirred 1 hour in 0 ℃.Vacuum concentrated mixture is by the ethanol/toluene azeotropic, methylbenzene azeotropic is removed residual water then.Resistates under high vacuum dry 48 hours obtains described-sulfinic acid sodium (output: 140mg, 96%).MS(DCI-NH 3)m/z?443(M+H) +。33D. 2-benzyl-4-(4-fluorophenyl)-5-[4-(chlorosulfonyl) phenyl] preparation of-3 (2H)-pyridazinones
Methylene dichloride (10ml) solution of described-sulfinic acid sodium (about 0.31mmol) is used SOCl in 0 ℃ 2(0.033ml 0.4mmol) handled 2 hours.Mixture salt water washing with dried over mgso and vacuum concentration, obtains rough SULPHURYL CHLORIDE (output: 145mg, about 100%).MS(DCI-NH 3)m/z?455(M+H) +。33D. 2-benzyl-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl] preparation of-3 (2H)-pyridazinones
The rough muriatic 10ml THF solution that will prepare according to the method for embodiment 33D adds in the 10ml THF solution of 50% ammonium hydroxide, in 0 ℃ of maintenance.Make mixture warm to room temperature in 3.5 hours.Vacuum is removed THF, product ethyl acetate extraction.Vacuum is removed ethyl acetate, and resistates is handled with ether-hexane at 2: 1, obtains described sulphonamide (output: 113mg, 84%).M.p.188-191℃。 1H?NMR(300MHz，DMSO-d 6)δ2.70(dd，J＝15Hz，2H)，5.36(s，2H)，7.13(t，J＝9Hz，2H)，7.22(m，2H)，7.40(m，7H)，7.73(d，J＝9Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z?436(M+H) +。
Embodiment 342-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 2-iodo-1,1, the 1-Halothane replaces the 4-fluoro benzyl bromide, the preparation title compound.M.p.177-179℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，4.88(q，J＝9Hz，2H)，6.98(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，J＝6Hz，2H)，7.35(d，J＝9Hz，2H)，7.89(s，1H)，7.91(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 427 (M+H) +With m/z 444 (M+NH 4) +
Embodiment 352-(3,3-two chloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 1,1, the 3-trichloropropane replaces the 4-fluoro benzyl bromide, the preparation title compound.M.p.150-152℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，4.98(d，J＝7?Hz，2H)，6.25(t，J＝7?Hz，1H)，6.98(t，J＝9?Hz，2H)，7.18(dd，J＝9Hz，J＝6Hz，2H)，7.33(d，J＝9Hz，2H)，7.85(s，1H)，7.89(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 453 (M+H) +With m/z 470 (M+NH 4) +
Embodiment 362-(3-phenyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with cinnamyl bromide, the preparation title compound.M.p.165-167℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，5.01(d，J＝7Hz，2H)，6.48(dt，J＝15Hz，7Hz，1H)，6.79(t，J＝15Hz，2H)，，6.97(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，J＝6Hz，2H)，7.25-7.44(m，5H)，7.37(d，J＝9Hz，2H)，7.86(s，1H)，7.89(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 461 (M+H) +With m/z 478 (M+NH 4) +
Embodiment 372-(4-carboxyl phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with the ester of 4-(brooethyl) methyl benzoate replacement 4-fluoro benzyl bromide and hydrolysis gained, the preparation title compound.M.p.239-241℃。 1H?NMR(CDCl 3，300MHz)δ3.06(s，3H)，5.46(s，2H)，6.96(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，6Hz，2H)，7.33(d，J＝9Hz，2H)，7.63(d，J＝9Hz，2H)，7.87(s，1H)，7.89(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 479 (M+H) +With m/z 496 (M+NH 4) +
Embodiment 382-(5-methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl)-5-methylthiazol, the preparation title compound.M.p.114-116℃。 1H?NMR(d 6-DMSO，300MHz)δ2.64(s，3H)，3.23(s，2H)，5.37(s，2H)，7.13(m，2H)，7.23(m，2H)，7.40(s，1H)，7.47(d，J＝8Hz，2H)，7.87(d，J＝8Hz，2H)，8.10(s，1H)。MS(DCI-NH 3)m/z?356(M+H) +。
Embodiment 392-(5-diuril azoles-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl)-5-diuril azoles, the preparation title compound.M.p.185-186℃。 1H?NMR(d 6-DMSO，300MHz)δ2.32(s，3H)，5.50(s，2H)，7.15(m，2H)，7.24(m，2H)，7.47(m，2H)，7.87(m，3H)，8.14(s，1H)。MS (DCI-NH 3) m/z 476 (M+H) +With m/z 493 (M+NH 4) +
Embodiment 402-(2,3,3,4,4,4-hexafluoro-n-butene-1-yl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 2,2,3,3,4,4,4-seven fluoro-1-butyl iodides replace the 4-fluoro benzyl bromide, the preparation title compound.Under alkylation conditions, eliminate HF, obtain described unsaturated product.M.p.167-169℃。 1H?NMR(CDCl 3，300MHz)δ3.07(s，3H)，7.00(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，6Hz，2H)，7.33(d，J＝9Hz，2H)，7.68(d，J＝24Hz，1H)，7.93(d，J＝9Hz，2H)，8.01(s，1H)。MS (DCI-NH 3) m/z 507 (M+H) +With m/z 524 (M+NH 4) +
Embodiment 412-(2,4 difluorobenzene formyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-chloro-2 ', 4 '-difluoro phenyl methyl ketone, the preparation title compound.M.p.191-192℃。 1H?NMR(CDCl 3，300MHz)δ3.08(s，3H)，5.57(d，J＝3Hz，2H)，6.94-7.07(m，2H)，6.96(t，J＝9Hz，2H)，7.39(dd，J＝9Hz，6Hz，2H)，7.91(s，1H)，7.91(d，J＝9Hz，2H)，8.03-8.12(m，1H)。MS (DCI-NH 3) m/z 499 (M+H) +With m/z 516 (M+NH 4) +
Embodiment 422-(5-chlorothiophene-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl)-5-chlorothiophene, the preparation title compound.M.p.139-141℃。 1H?NMR(d 6-DMSO，300MHz)δ3.23(s，3H)，5.43(s，2H)，7.03?d，J＝4Hz，1H)，7.09-7.29(m，5H)，7.47(d，J＝8Hz，2H)，7.87(d，J＝8Hz，3H)，8.13(s，1H)。MS (DCI-NH 3) m/z 474 (M+H) +With m/z 492 (M+NH 4) +
Embodiment 432-(5-thiotolene-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(brooethyl)-5-thiotolene, the preparation title compound.M.p.172-175℃。 1H?NMR(d 6-DMSO，300MHz)δ3.22(s，3H)，5.49(s，2H)，7.03(m，1H)，7.14(m，2H)，7.23(m，3H)，7.48(m，3H)，7.86(m，2H)，8.11(s，1H)。MS (DCI-NH 3) m/z 441 (M+H) +With m/z 458 (M+NH 4) +
Embodiment 442-(4-diethylamino phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-chloro-4 '-diethylamino phenyl methyl ketone, the preparation title compound.M.p.105-108℃。 1H?NMR(CDCl 3，300MHz)δ1.23(t，J＝7Hz，3H)，3.07(s，3H)，3.44(q，J＝7Hz，2H)，5.61(s，2H)，6.66(d，J＝9Hz，2H)，6.94(t，J＝9Hz，2H)，7.21(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.87-7.94(m，4H)，7.90(s，1H)。MS(DCI-NH 3)m/z?534(M+H) +。
Embodiment 452-(2,3,4,5, the 6-PFBBR)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 2,3,4,5,6-PFBBR bromine replaces the 4-fluoro benzyl bromide, the preparation title compound.M.p.115-116℃。 1H?NMR(CDCl 3，300MHz)3.06(s，3H)，5.50(s，2H)，6.96(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，6Hz，2H)，7.33(d，J＝9Hz，2H)，7.82(s，1H)，7.89(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 525 (M+H) +With m/z 542 (M+NH 4) +
Embodiment 462-(phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with the 2-bromoacetyl benzene, the preparation title compound.M.p.228-230℃。 1H?NMR(CDCl 3，300MHz)3.07(s，3H)，5.68(s，2H)，6.95(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.53(t，J＝7Hz，2H)，7.65(t，J＝7Hz，1H)，7.90(d，J＝9Hz，2H)，7.91(s，1H)，8.04(d，J＝7Hz，2H)。MS (DCI-NH 3) m/z 463 (M+H) +With m/z 480 (M+NH 4) +
Embodiment 472-(4-chlorobenzoyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-bromo-4 '-chloro-acetophenone, the preparation title compound.M.p.186-188℃。 1H?NMR(CDCl 3，300MHz)3.07(s，3H)，5.63(s，2H)，6.95(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.51(d，J＝9Hz，2H)，7.65(t，J＝7Hz，1H)，7.90(d，J＝9Hz，2H)，7.91(s，1H)，7.98(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 497 (M+H) +With m/z 514 (M+NH 4) +
Embodiment 482-(propargyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with propargyl bromide, the preparation title compound.M.p.196-198℃。 1H?NMR(CDCl 3，300MHz)2.42(t，J＝3Hz，1H)，3.06(s，3H)，5.04(d，J＝3Hz，2H)，6.97(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.34(d，J＝9Hz，2H)，7.90(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 383 (M+H) +With m/z 400 (M+NH 4) +
Embodiment 492-(4-cyano group phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-bromo-4 '-cyanoacetophenone, the preparation title compound.M.p.188-189℃。 1H?NMR(CDCl 3，300MHz)3.08(s，3H)，5.64(s，2H)，6.96(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.84(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)，7.93(s，H)，8.14(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?488(M+H) +。
Embodiment 502-(Alpha-Methyl-4-luorobenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with Alpha-Methyl-4-fluoro benzyl bromide, the preparation title compound.M.p.162-164℃。 1H NMR (CDCl 3, 300MHz) 3.06 (s, 3H), 6.40 (t, J=9Hz, 2H), 6.95 (t, J=9Hz, 2H), 7.05 (t, J=9Hz, 2H), 7.15 (dd, J=9Hz and 6Hz, 2H), 7.31 (d, J=9Hz, 2H), 7.53 (dd, J=9Hz and 6Hz, 2H), 7.87 (d, J=9Hz, 1H), 7.88 (s, 1H).MS (DCI-NH 3) m/z467 (M+H) +With m/z 484 (M+NH 4) +
Embodiment 512-styroyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with (2-bromotrifluoromethane) benzene, the preparation title compound.M.p.170-171℃。 1H NMR (CDCl 3, 300MHz) 3.07 (s, 3H), 3.20 (t, J=9Hz, 2H), 4.28 (t, J=9Hz, 2H), 6.98 (t, J=9Hz, 2H), 7.18 (dd, J=9Hz and 6Hz, 2H), 7.22-37 (m, 5H), 7.34 (d, J=9Hz, 2H), 7.83 (s, 1H), 7.89 (d, J=9Hz, 1H).MS (DCI-NH 3) m/z 449 (M+H) +And m/z466 (M+NH 4) +
Embodiment 522-benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the described method of embodiment 6-10, with the 4-fluorobenzoic boric acid among the 3-chloro-4-fluorobenzoic boric acid replacement embodiment 6, preparation title compound.M.p.134-136℃。 1H?NMR(CDCl 3，300MHz)3.06(s，3H)，5.41(s，2H)，6.96-7.02(m，2H)，7.29-7.41(m，3H)，7.33(d，J＝9Hz，2H)，7.51-7.56(m，2H)，7.85(s，1H)，7.91(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 469 (M+H) +With m/z 486 (M+NH 4) +
Embodiment 532-benzyl-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the described method of embodiment 6-10, just with the 4-fluorobenzoic boric acid among the 4-chlorobenzene boric acid replacement embodiment 6, preparation title compound.M.p.157-159℃。 1H?NMR(CDCl 3，300MHz)3.05(s，3H)，5.40(s，2H)，7.11(d，J＝9Hz，2H)，7.24(d，J＝9Hz，2H)，7.28-7.40(m，2H)，7.31(d，J＝9Hz，2H)，7.51-7.57(m，2H)，7.84(s，1H)，7.88(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 451 (M+H) +With m/z 468 (M+NH 4) +
Embodiment 542-(2,2, the 2-trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Go benzylization by the product N-that will prepare in embodiment 52 according to the method for embodiment 11, according to the method 2-iodo-1,1 of embodiment 20, the alkylation of 1-Halothane prepares title compound then.M.p.165-166℃。 1H?NMR(CDCl 3，300MHz)3.07(s，3H)，4.89(q，J＝9Hz，2H)，7.00-7.06(m，2H)，7.31-7.35(m，1H)，7.37(d，J＝9Hz，2H)，7.90(s，1H)，7.94(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 461 (M+H) +With m/z 478 (M+NH 4) +
Embodiment 552-(4-trifluoromethoxy benzoyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-bromo-4 '-trifluoromethoxy phenyl methyl ketone, the preparation title compound.M.p.160-161℃。 1H?NMR(CDCl 3，300MHz)3.08(s，3H)，5.65(s，2H)，6.96(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，6Hz，2H)，7.37(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)，7.93(s，1H)，8.11(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 547 (M+H) +With m/z 564 (M+NH 4) +
Embodiment 562-(4-trifluoromethyl benzoyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-bromo-4 '-trifluoromethyl phenyl methyl ketone, the preparation title compound.M.p.205-206℃。 1H?NMR(CDCl 3，300MHz)3.07(s，3H)，5.66(s，2H)，6.96(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.80(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)，7.92(s，1H)，8.15(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 531 (M+H) +With m/z 548 (M+NH 4) +
Embodiment 572-[2-(benzo [b] thiene-3-yl-)-2-oxoethyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 3-chloracetyl benzo [b] thiophene, the preparation title compound.M.p.183-184℃。 1H?NMR(CDCl 3，300MHz)3.08(s，3H)，5.68(s，2H)，6.96(t，J＝9Hz，2H)，7.21(dd，J＝9Hz，6Hz，2H)，7.39(d，J＝9Hz，2H)，7.42-7.54(m，2H)，7.91(d，J＝9Hz，2H)，7.91(d，J＝7Hz，1H)，7.94(s，1H)，8.53(s，1H)，8.72(d，J＝7Hz，1H)。MS(DCI-NH 3)m/z?519(M+H) +。
Embodiment 582-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Go benzylization by the product N-that will prepare in embodiment 54 according to the method for embodiment 12, according to the method 2-iodo-1,1 of embodiment 20, the alkylation of 1-Halothane prepares title compound then.M.p.55-57℃。 1H?NMR(CDCl 3，300MHz)3.07(s，3H)，4.88(q，J＝9Hz，2H)，7.13(d，J＝9Hz，2H)，7.26(d，J＝9Hz，2H)，7.36(d，J＝9Hz，2H)，7.89(s，1H)，7.92(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 443 (M+H) +With m/z 460 (M+NH 4) +
Embodiment 592-(3,3-dimethyl-2-oxo butyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 1-bromine Pinacolone, the preparation title compound.M.p.168-170℃。 1H?NMR(CDCl 3，300MHz)1.31(s，9H)，3.06(s，3H)，5.21(s，2H)，6.95(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，6Hz，2H)，7.35(d，J＝7Hz，2H)，7.86(s，1H)，7.89(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 443 (M+H) +With m/z 460 (M+NH 4) +
Embodiment 602-(3-thienyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 3-(chloromethyl) thiophene, the preparation title compound.M.p.169-172℃。 1H?NMR(300MHz，DMSO?d 6)δ3.22(s，3H)，5.36(s，2H)，7.18(m，5H)，7.51(m，4H)，7.88(m，2H)，8.08(s，1H)。MS (DCI-NH 3) m/z 441 (M+H) +With m/z 458 (M+NH 4) +
Embodiment 612-(2-benzo [b] thienyl methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 2-(chloromethyl) benzo [b] thiophene, the preparation title compound.M.p.93-96℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.64(s，2H)，6.97(m，2H)，7.18(m，2H)，7.33(m?5H)，7.78(m，2H)，7.86(m，3H)。MS (DCI-NH 3) m/z 491 (M+H) +With m/z 508 (M+NH 4) +
Embodiment 622, two (4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of 4-]-3 (2H)-pyridazinones
Preparation is according to (4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of the method preparation of embodiment 10 in the 20ml pyridine]-3 (2H)-pyridazinone (172mg; 0.5mmol), Cu powder (32mg), Anhydrous potassium carbonate (207mg; 1.5mmol) and 4-fluorine iodobenzene (0.12ml, mixture 1mmol).The solution backflow was stirred 14 hours down.Then mixture is cooled to room temperature, is allocated between water and the ethyl acetate.Ethyl acetate layer is with 10% citric acid, water and salt water washing and vacuum concentration.Through column chromatography for separation (silica gel, methylene dichloride-ether 15: 1), obtain the 190mg raw product.Crystallization from methylene dichloride-ether-hexane obtains title compound (output: 175mg, 79.9%).M.p.168-169℃。 1H?NMR(300MHz，CDCl 3)δ3.07(s，3H)6.98(t，J＝9Hz，2H)，7.20(m，4H)，7.40(d，J＝9Hz，2H)，7.69(m，2H)，7.92(d，J＝9Hz，2H)，7.98(s，1H)。MS(DCI-NH 3)m/z?439(M+H) +，456(M+NH 4) +。C 23H 16F 2N 2O 3S0.25H 2The analytical calculation value of O: C, 62.36; H, 3.75; N, 6.32.Measured value: C, 62.23; H, 3.55; N, 6.26.
Embodiment 634-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
(454mg 1.25mmol) is dissolved in the propyl carbinol (10ml) 5-hydroxy-5-methyl base-2 (the 5H)-furanone that will prepare by method cited above, and (0.3ml 6.2mmol) handles, and the stirring down 18 hours that refluxes with hydrazine hydrate.After the cooling, obtain white crystal (224mg, 50%).M.p.290 ℃ (decomposition). 1H?NMR(300MHz，d 6-DMSO)δ1.99(s，3H)，3.10(s，3H)，7.05(t，J＝9Hz，2H)，7.15(dd，J＝6Hz，J＝9Hz，2H)，7.48(d，J＝9Hz，2H)，7.85(d，J＝9Hz，2H)，13.10(br?s，1H)。MS(DCI-NH 3)m/z?376(M+NH 4) +。C 18H 15N 2FSO 30.25H 2The analytical calculation value of O: C, 59.57; H, 4.30; N, 7.71.Measured value: C, 59.28; H, 4.39; N, 8.39.
Embodiment 642-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-6-methyl-3 (2H)-pyridazinone
With the product of embodiment 63 (100mg 0.28mmol) is dissolved in the dry DMF (3ml), anhydrous sodium carbonate (130mg, 1.2mmol) exist down, in 50-60 ℃ with 1,1, (27.5ml 280mmol) handled 2 hours 1-three fluoro-2-iodoethane.Reaction mixture is allocated between water and the ethyl acetate, obtains required compound, be amorphous solid (60mg, 48%). 1H?NMR(300MHz，CDCl 3)δ2.10(s，3H)，3.10(s，3H)，4.85(q，J＝9Hz，2H)，6.90(m，2H)，7.10(dd，J＝6Hz，J＝9Hz，2H)，7.25(m，2H)，7.95(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?458(M+NH 4) +。C 20H 16N 2F 4SO 3The analytical calculation value: C, 54.54; H, 3.66; N, 6.36.Measured value: C, 54.41; H, 3.56; N, 6.35.
Embodiment 652-benzyl-4-(3, the 4-dichlorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 6, by with 3,4-dichlorobenzene boric acid and 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) coupling, preparation title compound.According to the method for embodiment 7, this product is converted into 5-hydroxyl-derivative.According to the method for embodiment 8, the 5-oxy-compound is converted into 5-trifluoromethyl sulfonyloxy-derivative.According to the method for embodiment 9,4-(methylthio group) phenylo boric acid is coupled to triflate, obtain 5-[4-(methylthio group) phenyl]-intermediate, with its method oxidation, obtain described end product (output: 780mg, 84%) according to embodiment 10.M.p.161-163℃。 1H?NMR(300MHz，DMSO-d 6)δ3.22(s，3H)，5.35(s，2H)，7.08(dd，J＝9Hz，3Hz，1H)，7.32-7.44(m，5H)，7.47(dd，J＝9Hz，3Hz，3H)，7.48(d，J＝3Hz，1H)，7.90(d，J＝9Hz，2H)，8.13(s，1H)。MS(DCI-NH 3)m/z?485(M+H) +。C 24H 18Cl 2N 2O 3The analytical calculation value of S: C, 59.38; H, 3.73; N, 5.77.Measured value: C, 59.28; H, 3.92; N, 5.42.
Embodiment 662-(2,2, the 2-trifluoroethyl)-4-(4-n-propyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 6, by with 4-(n-propyl) phenylo boric acid and 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) coupling, preparation title compound.According to the method for embodiment 7, this product is converted into 5-hydroxyl-derivative.According to the method for embodiment 8, this product is converted into 5-trifluoromethyl sulfonyloxy-derivative.According to the method for embodiment 9,4-(methylthio group) phenylo boric acid is coupled to triflate, obtain 5-[4-(methylthio group) phenyl]-intermediate, with its method oxidation, obtain described end product (output: 220mg, 70%) according to embodiment 10.M.p.64-66℃。 1H?NMR(300MHz，CDCl 3)δ0.91(t，J＝7.5Hz，3H)，1.6(h，J＝7.5Hz，2H)，2.55(q，J＝7.5Hz，2H)，3.05(s，3H)，4.88(q，J＝9Hz，2H)，7.08(s，4H)，7.35(d，J＝9Hz，2H)，7.86(d，J＝9Hz，7.87(s，1H)。MS(DCI-NH 3)m/z?451(M+H) +。C 22H 21F 3N 2O 3The analytical calculation value of S: C, 58.65; H, 4.69; N, 6.21.Measured value: C, 58.71; H, 4.72; N, 6.20.
Embodiment 672-(2,2, the 2-trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 6,, prepare title compound by with 3-fluoro-4-chlorobenzene boric acid and 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone coupling.According to the method for embodiment 7, this product is converted into 5-hydroxyl-compound.According to the method for embodiment 8, this 5-oxy-compound is converted into 5-trifluoromethyl sulfonyloxy-derivative.According to the method for embodiment 9,4-(methylthio group) phenylo boric acid is coupled to triflate, obtain 5-[4-(methylthio group) phenyl]-intermediate, with its method oxidation, obtain described end product (output: 170mg, 84%) according to embodiment 10.M.p.174-175℃。 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H)，4.89(q，J＝9Hz，3H)，6.87(dm，J＝9Hz，1H)，7.09(dd，J＝9Hz，3Hz，1H)，7.30(t，J＝9Hz，1H)，7.39(d，J＝9Hz，2H)，7.91(s，1H)，7.95(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?461(M+H) +。C 19H 13ClF 4N 2O 3The analytical calculation value of S: C, 49.52; H, 2.84; N, 6.07.Measured value: C, 49.66; H, 2.70; N, 5.96.
Embodiment 682-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
With 2-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl] (680mg, trifluoroacetic anhydride 1.53mmol) (30ml) solution stirred under room temperature 1 hour-3 (2H)-pyridazinones.The solvent that vacuum-evaporation is excessive, resistates use the 1N methyl alcohol-NaOH solution (50ml, 4: 1) of deoxidation in 0 ℃ of processing.This solution was stirred under room temperature 2 hours, with the quenching of rare HCl solution until acidity.With the white suspension vacuum concentration that forms, with evaporation methyl alcohol.THF is added in the suspension of gained, until obtaining clear soln.Chlorine is fed in this solution lentamente, in 0 ℃ of maintenance.After 10 minutes, nitrogen was fed in this solution several minutes, to replace residual chlorine.With solution of ammonium hydroxide (30%, 5-10ml) slowly add to this solution (to exhaust all initial SULPHURYL CHLORIDE) in 0 ℃, and under room temperature, stirred 5 minutes.This solution is allocated between water and the ethyl acetate.Organic layer at first washes with water, uses the salt water washing then, through dried over mgso and filtration.Vacuum concentrated filtrate.(40: 60 ethyl acetate/hexane obtain title compound (output: 500mg, 75%) to resistates through the silica gel column chromatography purifying.M.p.193-195℃。 1HNMR(300MHz，CDCl 3)δ4.82(s，2H)，4.88(q，J＝9Hz，2H)，6.98(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.30(d，J＝9Hz，1H)，7.88(d，J＝9Hz，2H)，7.90(s，1H)。MS(DCI-NH 3)m/z?428(M+H) +。C 18H 13F 4N 3O 3The analytical calculation value of S: C, 50.58; H, 3.06; N, 9.83.Measured value: C, 51.04; H, 3.26; N, 9.63.
Embodiment 692-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinone 69A. 2-benzyl-4-chloro-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 77 prepares title compound.According to the method for embodiment 6, with this product and the coupling of 4-chlorobenzene boric acid.According to the method for embodiment 11, product is gone benzylization, and according to the method for embodiment 20 with 2-iodo-1,1, the 1-Halothane is carried out the N-alkylation, obtains sulfide (sulfice) compound.69B. 2-benzyl-4-chloro-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones
Is corresponding sulfoxide with a a great deal of metachloroperbenzoic acid with described sulfide oxidation, obtains corresponding methyl sulfoxide, then according to the method for embodiment 68, is translated into sulphonamide end product (output: 540mg, 70%).M.p.154-156℃。 1H?NMR(300MHz，CDCl 3)δ4.86(s，2H)，4.87(q，J＝9Hz，2H)，7.14(d，J＝9Hz，2H)，7.29(d，J＝9Hz，2H)，7.31(d，J＝9Hz，2H)，7.89(d，J＝9Hz，2H)，8.00(s，1H)。MS(DCI-NH 3)m/z?444(M+H) +。C 18H 13ClF 3N 3O 3The analytical calculation value of S: C, 48.71; H, 2.95; N, 9.46.Measured value: C, 49.05; H, 3.01; N, 9.15.
Embodiment 702-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Methyl sulfide intermediate with the oxidation of a a great deal of metachloroperbenzoic acid prepares in embodiment 83 obtains methyl sulfoxide, then according to the method for embodiment 68, is translated into sulphonamide end product (output: 396mg, 60%).M.p.158-160℃。 1H?NMR(300MHz，CDCl 3)δ1.21(d，J＝6Hz，6H)，4.83(q，J＝7.5Hz，2H)，4.86(s，2H)，5.46(p，J＝6Hz，1H)，7.72(d，J＝9Hz，2H)，7.82(s，1H)，8.03(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?392(M+H) +。C 15H 16F 3N 3O 4The analytical calculation value of S: C, 46.03; H, 4.12; N, 10.73.Measured value: C, 46.08; H, 4.22; N, 10.52.
Embodiment 712-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Methyl sulfide intermediate with the oxidation of a a great deal of metachloroperbenzoic acid prepares in embodiment 76 obtains methyl sulfoxide, then according to the method for embodiment 68, is translated into sulphonamide end product (output: 180mg, 37%).M.p.150-152℃。 1H?NMR(300MHz，CDCl 3)δ4.71(q，J＝7.5Hz，2H)，4.72(s，2H)，6.88(dd，J＝9Hz，4.5Hz，2H)，7.0(t，J＝9Hz，2H)，7.73(d，J＝9Hz，2H)，7.98(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?444(M+H) +。C 18H 13F 4N 3O 4The analytical calculation value of S: C, 48.76; H, 2.95; N, 9.47.Measured value: C, 48.49; H, 2.8; N, 8.95.
Embodiment 722, two (4-fluorophenyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl of 4-]-3 (2H)-pyridazinone 72A-1. 2-fluorine sulfo-phenylmethylethers
With the 2-fluoro thiophenol (10g, 78mmol) the deoxidation solution in dry DMF (10ml) with methyl iodide (4.9ml, 78mmol) and salt of wormwood (10.8g, 78mmol) processing.Reaction mixture was stirred under room temperature 1 hour.Thin-layer chromatography (100% hexane) sample shows to react not to be finished as yet, therefore adds the alkali and the methyl iodide of 1 part of a great deal of again, reaction mixture is stirred under room temperature spend the night.With 10% aqueous citric acid solution acidification reaction thing, and with hexane (2 * 125ml) extraction.The organic extract salt water washing that merges is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains required compound, is faint yellow oily thing (output: 6.68g; 60%).72A-2. 2-fluorine sulfo-phenylmethylether
An alternative method of preparation 2-fluorine sulfo-phenylmethylether is at first to use sulfo-sodium methylate (0.59g, 8mmol) processing 1,2-two fluorobenzene (0.79ml, dry DMF 8mmol) (50ml) solution.Reaction mixture was stirred under room temperature 6 hours, be allocated between hexane and the water.Organic layer salt water washing is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains required compound (1.1g, 100%), and required compound has polluted 1 slightly, two (methylthio group) benzene of 2-, and this is a kind of R fLower material, through chromatography with 100% hexane wash-out with its removal (0.9g, 80%). 1H?NMR(300MHz，CDCl 3)δ2.46(s，3H)，6.98-7.19(m，3H)，2.26(dt，J＝9Hz，3Hz，1H)。72B 4-bromo-2-fluorine sulfo-phenylmethylether
With 2-fluorine sulfo-phenylmethylether (1.42g, 10mmol) and iron powder (0.03g, methylene dichloride 0.5mmol) (20ml) solution is cooled to 0 ℃, (0.5ml 10mmol) handles dripping bromine.When bromine was finished dealing with, TLC (100% hexane) was carried out in sampling from reactant.There is a kind of R fHigher material is not finished as yet but react, and therefore, adds the bromine of a a great deal of and the aluminum chloride of catalytic amount.Reaction mixture stirred under room temperature spend the night.Sodium sulfite aqueous solution is added to reaction mixture, separate organic layer, through dried over mgso and filtration.Filtrate is filtered by silicagel pad, and to remove color, concentrating under reduced pressure obtains described product then, is clarifying colorless oil (output: 1.3g; 60%). 1H?NMR(300MHz，DMSO-d 6)δ2.48(s，3H)，7.31(t，J＝9Hz，1H)，7.43(dd，J＝9Hz，3Hz，1H)，7.54(dd，J＝9Hz，3Hz，1H)。72C 3-fluoro-4-(methylthio group) phenylo boric acid
Under nitrogen atmosphere, (0.5g, dry THF 22.6mmol) (20ml) solution is cooled to-78 ℃ with 4-bromo-2-fluorine sulfo-phenylmethylether.(1.7ml, 27.1mmol) reaction mixture to-40 ℃, keep the mixture temperature 0.5 hour with it then with the hexane solution of 1.6M n-Butyl Lithium.Then reaction mixture is cooled to-78 ℃, and the triisopropyl borate ester of 3 parts of a great deal oves of adding (1.56ml, 67.8mmol).With the reaction mixture temperature to room temperature and stirred 1.5 hours.At this moment, (200ml 360mmol), stirs mixture and to spend the night under room temperature to add the 10%KOH aqueous solution.Then reaction mixture is under agitation inclined to ice/concentrated hydrochloric acid mixture, obtain white precipitate.With this solid dried overnight in vacuum drying oven (65 ℃, 29 in Hg), obtain title compound (output: 0.22g; 52.4%). 1H?NMR(300MHz，DMSO-d 6)δ2.48(s，3H)，7.31(t，J＝9Hz，1H)，7.49(dd，J＝12Hz，1.5Hz，1H)，7.54(dd，J＝9Hz，1.5Hz，1H)。72D. 2, two (4-fluorophenyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl of 4-]-3 (2H)-pyridazinones
According to the method for embodiment 7, with 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) be converted into 5-hydroxyl-analogue,, be translated into 5-trifluoromethyl sulfonyloxy-analogue then according to the method for embodiment 8.Subsequently,, it is coupled to 3-fluoro-4-(methylthio group) phenylo boric acid, obtains 2-benzyl-4-chloro-5-[3-fluoro-4-(methylthio group) phenyl according to the method for embodiment 9]-3 (2H)-pyridazinones.According to the method for embodiment 6, with this intermediate 4 with the coupling of 4-fluorobenzoic boric acid.According to the method for embodiment 11, N-goes benzylization with this product, and according to the method for embodiment 62 4-fluorine iodobenzene N-arylation.The sulfide of gained obtains methyl sulfoxide with the metachloroperbenzoic acid oxidation of a a great deal of, is translated into sulphonamide end product (output: 500mg, 75%) according to the method for embodiment 68.M.P.222-224℃。 1H?NMR(300MHz，CDCl 3)δ506(s，2H)，7.01(t，J＝9Hz，2H)，7.06(d，J＝9Hz，2H)，7.10(d，J＝9Hz，2H)，7.18(t，J＝9Hz，2H)，7.69(dd，J＝9Hz，3Hz，2H)，7.88(t，J＝9Hz，1H)，7.95(s，1H)。MS(DCI-NH 3)m/z?458(M+H) +。C 22H 14F 3N 3O 3The analytical calculation value of S: C, 57.76; H, 3.08; N, 9.18.Measured value: C, 57.5; H, 3.15; N, 8.8.
Embodiment 732-(2,2, the 2-trifluoroethyl)-4-(3-fluoro-4-chloro-phenyl-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 68, the methyl sulfide intermediate of preparation among the embodiment 67 with the metachloroperbenzoic acid oxidation of a a great deal of, is obtained described methyl sulfoxide.According to the method for embodiment 68, described methyl sulfoxide is converted into sulphonamide end product (output: 1.5g, 63%).M.p.180-183℃。 1H?NMR(300MHz，DMSO-d 6)δ5.09(q，J＝9Hz，2H)，7.01(dd，J＝9Hz，3Hz，1H)，7.15(dd，J＝9Hz，3Hz，1H)，7.39(dd，J＝9Hz，3Hz，1H)，7.47(dd，J＝9Hz，3Hz，1H)，7.55(t，J＝9Hz，1H)，7.71(t，J＝9Hz，1H)，7.78(s，2H)，8.37(s，1H)。MS(DCI-NH 3)m/z480(M+H) +。C 18H 11ClF 5N 3O 3The analytical calculation value of S: C, 45.05; H, 2.31; N, 8.75.Measured value: C, 46.19; H, 3.02; N, 7.43.
Embodiment 742-benzyl-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 7, with 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) be converted into 5-hydroxyl-analogue,, be translated into 5-trifluoromethyl sulfonyloxy-analogue then according to the method for embodiment 8.Subsequently,, it is coupled to 4-(methylthio group) phenylo boric acid, obtains 2-benzyl-4 chloro-5-[4-(methylthio group) phenyl according to the method for embodiment 9]-3 (2H)-pyridazinones.With the 4-chloro-intermediate of preparation thus with the 2-propyl alcohol (20ml, 261mmol) and potassium tert.-butoxide (110mg, the 0.98mmol) processing down 45 minutes that refluxes obtains 2-benzyl-4-(2-propoxy-)-5-[4-(methylthio group) amyl group]-3 (2H)-pyridazinones.According to the method for embodiment 10,, obtain title compound (output: 180mg, 80%) with this methyl sulfide oxidation.M.p.109-111℃。 1H?NMR(300MHz，CDCl 3)δ1.18(d，J＝6Hz，6H)，3.12(s，3H)，5.36(s，2H)，5.49(h，J＝6Hz，2H)，7.35(m，3H)，7.47(dd，J＝9Hz，3Hz，1H)，7.74(d，J＝9Hz，2H)，7.79(s，1H)，8.03(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?399(M+H) +。C 21H 22N 2O 4The analytical calculation value of S: C, 63.29; H, 5.56; N, 7.03.Measured value: C, 63.17; H, 5.57; N, 6.95.
Embodiment 752-benzyl-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 74, replace the 2-propyl alcohol with the 4-fluorophenol, preparation title compound (output: 180mg, 99%).M.p.188-190℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，5.26(s，2H)，6.86(dd，J＝9Hz，6Hz，2H)，6.99(t，J＝9Hz，2H)，7.34(m，3H)，7.46(dd，J＝9Hz，3Hz，2H)，7.72(d，J＝9Hz，2H)，7.92(s，1H)，8.02(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?415(M+H) +。C 24H 19FN 2O 4The analytical calculation value of S: C, 63.98; H, 4.25; N, 6.21.Measured value: C, 63.74; H, 4.2; N, 6.12.
Embodiment 762-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 75; with 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 180mg, 63%).M.p.161-164℃。 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H，4.81(q，J＝9Hz，2H)，6.88(dd，J＝9Hz，4.5Hz，2H)，7.0(t，J＝9Hz，2H)，7.78(d，J＝9Hz，2H)，7.79(s，1H)，8.06(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?443(M+H) +。C 19H 14F 4N 2O 4The analytical calculation value of S: C, 51.58; H, 3.18; N, 6.33.Measured value: C, 51.8; H, 3.3; N, 6.22.
Embodiment 772-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 7, with 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) be converted into 5-hydroxyl-analogue,, be translated into 5-trifluoromethyl sulfonyloxy-analogue then according to the method for embodiment 8.Subsequently,, it is coupled to 4-(methylthio group) phenylo boric acid, obtains 2-benzyl-4-chloro-5-[4-(methylthio group) phenyl according to the method for embodiment 9]-pyridazinone.According to the method for embodiment 6, with this intermediate and the coupling of 4-chlorobenzene boric acid.Method according to embodiment 11 goes this product N-to benzylization, and according to the method for embodiment 20, with 2-iodo-1,1, the 1-Halothane is with its N-alkylation.According to the method for embodiment 5, be corresponding sulfoxide with the metachloroperbenzoic acid of a a great deal of with the sulfide oxidation of gained, obtain title compound (output: 130mg, 70%).M.p.154-155℃。 1HNMR(300MHz，CDCl 3)δ2.74(s，3H)，4.88(q，J＝9Hz，2H)，7.14(d，J＝9Hz，2H)，7.26(d，J＝9Hz，2H)，7.31(d，J＝9Hz，2H)，7.61(d，J＝9Hz，2H)，7.82(s，1H)。MS(DCI-NH 3)m/z?427(M+H) +。C 19H 14ClF 3N 2O 2The analytical calculation value of S: C, 53.46; H, 3.3; N, 6.56.Measured value: C, 53.58; H, 3.34; N, 6.42.
Embodiment 782-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, with 2-benzyl-4-chloro-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones (intermediate of preparation in embodiment 77), preparation title compound (output: 180mg, 83%).M.p.166-167℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，5.41(s，2H)，7.37(m，3H)，7.53(dd，J＝9Hz，3Hz，2H)，7.68(d，J＝9Hz，2H)，7.74(s，1H)，8.08(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?375(M+H) +。C 18H 15ClN 2O 3The analytical calculation value of S: C, 57.67; H, 4.03; N, 7.47.Measured value: C, 57.43; H, 4.06; N, 7.35.
Embodiment 792-(2,2, the 2-trifluoroethyl)-4-(4-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 7, with 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) be converted into 5-hydroxyl-analogue,, be translated into 5-(trifluoromethyl) sulfonyloxy-analogue then according to the method for embodiment 8.Subsequently,, it is coupled to 4-(methylthio group) phenylo boric acid, obtains 2-benzyl-4-bromo-5-[4-(methylthio group) phenyl according to the method for embodiment 9]-3 (2H)-pyridazinones.According to the method for embodiment 6, with this intermediate and the coupling of 4-methylphenylboronic acid.Method according to embodiment 11 goes this product N-to benzylization, and according to the method for embodiment 20, with 2-iodo-1,1, the 1-Halothane is with its N-alkylation.According to the method for embodiment 10, be title compound (output: 210mg, 98%) with the sulfide oxidation of gained.M.p.154-156℃。 1H?NMR(300MHz，CDCl 3)δ2.33(s，3H)，3.07(s，3H)，4.89(q，J＝9Hz，2H)，7.08(s，4H)，7.37(d，J＝9Hz，2H)，7.88(s，1H)，7.89(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?423(M+H) +。C 20H 17F 3N 2O 3The analytical calculation value of S: C, 56.86; H, 4.05; N, 6.63.Measured value: C, 56.59; H, 4.11; H, 6.53.
Embodiment 802-(2,2, the 2-trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 7, with 2-benzyl-4-chloro-5-methoxyl group-3 (2H)-pyridazinone (J.Het.Chem., 1996,33,1579-1582) be converted into 5-hydroxyl-analogue,, be translated into 5-(trifluoromethyl) sulfonyloxy-analogue then according to the method for embodiment 8.Subsequently,, it is coupled to 4-(methylthio group) phenylo boric acid, obtains 2-benzyl-4-chloro-5-[4-(methylthio group) phenyl according to the method for embodiment 9]-3 (2H)-pyridazinones.According to the method for embodiment 6, with this intermediate and the coupling of 4-chloro-3-fluorobenzoic boric acid.Method according to embodiment 11 goes this product N-to benzylization, and according to the method for embodiment 20, with 2-iodo-1,1, the 1-Halothane is with its N-alkylation.Is corresponding sulfoxide with the metachloroperbenzoic acid of a a great deal of with the sulfide oxidation of gained, obtains methyl sulfoxide, according to the method for embodiment 68, is translated into sulphonamide end product (output: 500mg, 75%).M.p.214-215℃。 1H?NMR(300MHz，CDCl 3)δ4.82(s，2H)，4.88(q，J＝9Hz，2H)，6.88(m，1H)，7.09(d，J＝9Hz，3Hz，2H)，7.31(d，J＝9Hz，1H)，7.32(d，J＝9Hz，2H)，7.90(s，1H)，7.92(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?462(M+H) +。C 18H 12F 4ClN 3O 3The analytical calculation value of S: C, 46.81; H, 2.61; N, 9.09.Measured value: C, 46.79; H, 2.59; N, 8.86.
Embodiment 812-(2,2, the 2-trifluoroethyl)-4-(3, the 4-dichlorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 11, the product N-described in the embodiment 65 is gone benzylization.According to the method for embodiment 20, with 2-iodo-1,1, the 1-Halothane obtains title compound (output: 165mg, 55%) with described intermediate N alkylation.M.p.197-198℃。 1HNMR(300MHz，CDCl 3)δ3.09(s，3H)，4.88(q，J＝9Hz，2H)，6.98(dd，J＝9Hz，3Hz，1H)，7.37(d，J＝9Hz，4H)，7.91(s，1H)，7.95(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?477(M+H) +。C 19H 13F 3Cl 2N 2O 3The analytical calculation value of S: C, 47.81; H, 2.74; N, 5.86.Measured value: C, 47.94; H, 2.87; N, 5.83.
Embodiment 822-benzyl-4-(2-third amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Make 2-benzyl-4,5-two bromo-3 (2H)-pyridazinone (2g, 6mmol) with 2-aminopropane (2ml, 23.5mmol) and potassium tert.-butoxide (910mg, 6.6mmol) the reaction down 18 hours that refluxes of toluene (40ml) solution, obtain 4-(2-third amino)-derivative behind the column chromatography (silica gel, 92: 8 hexane/ethyl acetate).According to the method for embodiment 6, with this intermediate 5 with the coupling of 4-(methylthio group) phenylo boric acid.According to the method for embodiment 10,, obtain title compound (output: 120mg, 48%) with this methyl sulfide oxidation.M.p.146-147℃。 1H?NMR(300MHz，CDCl 3)δ0.92(d，J＝6Hz，6H)，3.11(m，1H)，3.13(s，3H)，5.34(s，2H)，5.59(m，1H)，7.33(m，3H)，7.42(s，1H)，7.48(dd，J＝9Hz，3Hz，2H)，7.56(d，J＝9Hz，2H)，8.00(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?399(M+H) +。C 21H 23N 3O 3The analytical calculation value of S: C, 63.45; H, 5.83; N, 10.57.Measured value: C, 63.31; H, 5.87; N, 10.44.
Embodiment 832-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 83A. 2-(2,2, the 2-trifluoroethyl)-4,5-two bromo-3 (2H)-pyridazinones
(10g, 38.8mmol) (38.8.mmol) solution in 100ml methyl alcohol will its heating down 3 hours that refluxes for 70% the aqueous solution, 4.88ml with the trifluoroethyl hydrazine for the preparation Mucobromic acid.The vacuum concentration reaction mixture, and be allocated between ethyl acetate and the water.Ethyl acetate layer filters, by silicagel pad and vacuum concentration through dried over mgso.Obtain described product, be little yellow solid (output: 8.8g, 68%). 1H?NMR(300MHz，CDCl 3)δ4.78(q，J＝9Hz，2H)，7.87(s，1H)。MS(DCI-NH 3)m/z?337(M+H) +。83B. 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-bromo-3 (2H)-pyridazinone
With 2-(2,2, the 2-trifluoroethyl)-4, and 5-two bromo-3 (2H)-pyridazinones (2g, 6mmol), (7.2mmol) solution in toluene (40ml) refluxes and heated 5 hours down for 60% dispersion in oil, 290mg for Virahol (3ml) and sodium hydride.Reaction mixture is allocated between ethyl acetate and the water.Ethyl acetate layer is filtered and vacuum concentration.Resistates obtains described product through chromatography purification (95: 5 hexane/ethyl acetate), is slightly greeny oily matter (output: 1.22g, 65%). 1H?NMR(300MHz，CDCl 3)δ1.46(d，J＝7.5Hz，6H)，5.48(h，J＝6Hz，1H)，7.87(s，1H)。MS(DCI-NH 3)m/z?316(M+H) +。83C. 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
With 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-bromo-3 (2H)-pyridazinone (1.2g, 3.8mmol), 4-(methylthio group) phenylo boric acid (704mg, 4.19mmol), tetrakis triphenylphosphine palladium (O) (220mg, 5%mmol) and cesium carbonate (2.72g 8.3mmol) is heated at the solution of 20ml glycol dimethyl ether and refluxed 5 hours.Mixture is allocated between ethyl acetate and the water.Ethyl acetate layer water, salt water washing are through dried over mgso and vacuum concentration.Resistates is through silica gel column chromatography purifying (94: 6 hexane/ethyl acetate).Obtain described product, for slightly being green solid (output: 1.1g, 81%). 1H?NMR(300MHz，CDCl 3)δ1.19(d，J＝7.5Hz，6H)，2.55(s，3H)，4.83(q，J＝9Hz，2H)，5.28(h，J＝6Hz，1H)，7.32(d，J＝9Hz，2H)，7.52(d，J＝9Hz，2H)，7.85(s，1H)。MS(DCI-NH 3)m/z?359(M+H) +。83D. 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 220mg, 100%).M.p.152-153℃。 1H?NMR(300MHz，CDCl 3)δ1.2(d，J＝6Hz，6H)，3.13(s，3H)，4.84(q，J＝9Hz，2H)，5.49(p，J＝6Hz，1H)，7.78(d，J＝9Hz，2H)，7.82(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?391(M+H) +。C 16H 17F 3N 2O 4The analytical calculation value of S: C, 49.22; H, 4.38; N, 7.17.Measured value: C, 49.34; H, 4.25; N, 7.01.
Embodiment 842-(2,2, the 2-trifluoroethyl)-4-cyclohexyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 83, replace the 2-propyl alcohol with hexalin, preparation title compound (output: 250mg, 52%).M.p.129-130℃。 1H?NMR(300MHz，CDCl 3)δ1.1-1.6(m，8H)，1.84(m，2H)，3.12(s，3H)，4.83(q，J＝9Hz，2H)，5.21(h，J＝4.5Hz，1H)，7.77(s，1H)，7.80(d，J＝9Hz，2H)，8.06(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?431(M+H) +。C 19H 21F 3N 2O 4The analytical calculation value of S: C, 53.01; H, 4.91; N, 6.50.Measured value: C, 52.96; H, 4.84; N, 6.45.
Embodiment 852-(2,2, the 2-trifluoroethyl)-4-cyclopentyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 83, replace the 2-propyl alcohol with cyclopentanol, preparation title compound (output: 250mg, 52%).M.p.148-150℃。 1H?NMR(300MHz，CDCl 3)δ1.35-1.55(m，4H)，1.68-1.75(m，4H)，3.12(s，3H)，4.83(q，J＝9Hz，2H)，5.89(h，J＝4.5Hz，1H)，7.75(d，J＝9Hz，2H)，7.83(s，1H)，8.04(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?417(M+H) +。C 18H 19F 3N 2O 4The analytical calculation value of S: C, 51.91; H, 4.59; N, 6.72.Measured value: C, 52.04; H, 4.50; N, 6.65.
Embodiment 862-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 86A. 2-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-bromo-3 (2H)-pyridazinone
According to the method for embodiment 83B, replace the 2-propyl alcohol with the 2-propylamine, preparation title compound (productive rate: 70%).MS(DCI-NH 3)m/z?315(M+H) +。86B. 2-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 83C, replace 2-(2,2, the 2-trifluoroethyl)-4-isopropoxy-5-bromo-3 (2H)-pyridazinone with 2-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-bromo-3 (2H)-pyridazinone, preparation title compound (productive rate: 80%).MS(DCI-NH 3)m/z?358(M+H) +。86C. 2-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(2,2, the 2-trifluoroethyl)-4-(2-third amino)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 180mg, 83%).M.p.173-174℃。 1H?NMR(300MHz，CDCl 3)δ0.95(d，J＝6Hz，6H)，3.13(s，3H)，4.81(q，J＝9Hz，2H)，5.97(s，1H)，7.45(s，1H)，7.59(d，J＝9Hz，2H)，8.03(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?340(M+H) +。C 16H 18F 3N 3O 4The analytical calculation value of S: C, 49.35; H, 4.65; N, 10.79.Measured value: C, 49.29; H, 4.52; N, 10.65.
Embodiment 872-benzyl-4-(4-morpholino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 86, make 2-benzyl-4 according to the method preparation of embodiment 2,5-two chloro-3 (2H)-pyridazinones and morpholine reaction obtain 4-morpholino-derivative.According to the method for embodiment 6, with described morpholino intermediate in 5 with the coupling of 4-(methylthio group) phenylo boric acid.According to the method for embodiment 10, the methyl sulfide of gained is oxidized to title compound (output: 150mg, 69%).M.p.158-160℃。 1H?NMR(300MHz，CDCl 3)δ3.06(t，J＝4.5Hz，3H)，3.12(s，3H)，3.69(t，J＝4.5Hz，3H)，5.33(s，2H)，7.35(m，3H)，7.5(m，4H)，7.58(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?426(M+H) +。C 22H 23N 3O 4The analytical calculation value of S: C, 62.10; H, 5.44; N, 9.87.Measured value: C, 61.74; H, 5.47; N, 9.59.
Embodiment 882-(2,3,3-three fluoro-2-propylene-1-yls)]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 88A. 1-sulfonyloxy methyl oxygen bases-2,3,3-three fluoro-2-propylene
As J.Org.Chem., 1989,54, reported preparation 2,3,3-three fluoro-2-propylene-1-alcohol among the 5640-5642.By making 2,3,3-three fluoro-2-propylene-1-alcohol reacts in ether with methylsulfonyl chloride, obtains methanesulfonates.Obtain described product through the standard processing, this product need not purifying and uses.88B. 2-(2,3,3-three fluoro-2-propylene-1-yls)]-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Begin preparation 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl by the 2-benzyl-pyridazinons that derives from embodiment 9]-3 (2H)-pyridazinones, go this compound to benzylization according to the method for embodiment 11.
With 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl] and-3 (2H)-pyridazinones (250mg, 0.8mmol), Cs 2CO 3(650mg, 2mmol) with 3-sulfonyloxy methyl Oxy-1,1, (1.19mmol) mixture in ethyl acetate (30ml) stirred 1.5 hours in 55 ℃ the 2-trifluoro propene for methanesulfonates, 250mg.Mixture is allocated between ethyl acetate and the water.Organic layer adopts the salt water washing, with dried over mgso and filtration.Vacuum concentrated filtrate.Resistates with 15% ethyl acetate/hexane wash-out, obtains methyl sulfide compound 2-(2 through purification by silica gel column chromatography, 3,3-three fluoro-2-propylene-1-yls)]-and 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, for slightly being green oily matter (output: 175mg, 53%).88C. 2-(2,3,3-three fluoro-2-propylene-1-yls)]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, described methyl sulfide is oxidized to title compound (output: 125mg, 68%).M.P.154-156℃。 1H?NMR(300MHz，CDCl 3)δ3.07(s，3H)，5.1(ddd，J＝21Hz，3Hz，1.5Hz，2H)，6.98(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.35(d，J＝9Hz，2H)，7.89(s，1H)，7.9(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?439(M+H) +。C 20H 14F 4N 2O 3The analytical calculation value of S: C, 54.79; H, 3.21; N, 6.38.Measured value: C, 54.52; H, 3.15; N, 6.21.
Embodiment 892, two (4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl of 4-]-3 (2H)-pyridazinones
Method according to embodiment 68; with 2; two (4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl of 4-]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 118mg, 43%).M.p.213-216℃。 1H?NMR(300MHz，DMSO-d 6)δ7.15(t，2H)，7.27(m，2H)，7.4(m，6H)，7.7(dd，2H)，7.76(d，J＝9Hz，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?440(M+H) +，439.44(M+NH 4) +。C 21H 15FN 2O 3S 2The analytical calculation value: C, 60.13; H, 3.44; N, 9.56.Measured value: C, 59.94; H, 3.37; N, 9.46.
Embodiment 902-(2,2, the 2-trifluoroethyl)-4-cyclo propyl methoxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 90A. 2-(2,2, the 2-trifluoroethyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinones
Method according to embodiment 83B replaces Virahol with methyl alcohol, preparation title compound (productive rate: 78%). 1H?NMR(300MHz，CDCl 3)δ4.3(s，3H)，4.76(q，J＝9Hz，2H)，7.85(s，1H)。MS(DCI-NH 3)m/z?288(M+H) +。90B. 2-(2,2, the 2-trifluoroethyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 83C, replace 2-(2,2, the 2-trifluoroethyl)-4-(2-propoxy-)-5-bromo-3 (2H)-pyridazinone with 2-(2,2, the 2-trifluoroethyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone, preparation title compound (productive rate: 80%). 1H?NMR(300MHz，CDCl 3)δ2.54(s，3H)，4.11(s，3H)，4.82(q，J＝9Hz，2H)，7.33(d，J＝9Hz，2H)，7.48(d，J＝9Hz，2H)，7.84(s，1H)。MS(DCI-NH 3)m/z?331(M+H) +。90C. 2-(2,2, the 2-trifluoroethyl)-4-hydroxyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
With 2-(2,2, the 2-trifluoroethyl)-4-methoxyl group-5-[4-(methylthio group) phenyl] and-3 (2H)-pyridazinones (2g, 6.1mmol) and Hydrogen bromide (40% aqueous solution, acetate 20ml) (40ml) the solution heating down 3 hours that refluxes.Reaction mixture is cooled to room temperature, adds entry (50ml).The crystal that forms is filtered, and the hexane solution washing of water and 5% ethyl acetate is dried to constant weight.Obtain described product, be white solid (output: 1.75g, 91%). 1H?NMR(300MHz，CDCl 3)δ2.54(s，3H)，4.82(q，J＝9Hz，2H)，7.47(d，J＝9Hz，2H)，7.65(d，J＝9Hz，2H)，7.73(br?s，1H)，8.00(s，1H)。MS(DCI-NH 3)m/z?317(M+H) +。90D. 2-(2,2, the 2-trifluoroethyl)-4-cyclo propyl methoxy-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Preparation 2-(2,2, the 2-trifluoroethyl)-and 4-hydroxyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinone (150mg, 0.47mmol), cyclopropyl-carbinol (43ml, 0.52mmol) and triphenylphosphine (124mg, 0.47mmol) solution in new distillatory THF, with its in 0 ℃ drop to diethyl azodiformate (75ml, 0.52mmol) in.The mixture temperature to room temperature, was stirred 5 hours and vacuum concentration.Resistates obtains described product through silica gel column chromatography purifying (95: 5 hexane/ethyl acetate), is colorless oil (output: 140mg, 81%). 1H?NMR(300MHz，CDCl 3)δ0.22(m，2H)，0.48(m，2H)，1.6(m，1H)，2.53(s，3H)，4.26(d，J＝7.5Hz，2H)，4.72(q，J＝9Hz，2H)，7.32(d，J＝9Hz，2H)，7.55(d，J＝9Hz，2H)，7.87(s，1H)。MS(DCI-NH 3)m/z?371(M+H) +。90E. 2-(2,2, the 2-trifluoroethyl)-4-cyclo propyl methoxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(2,2, the 2-trifluoroethyl)-4-cyclo propyl methoxy-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 130mg, 85%).M.p.133-135℃。 1H?NMR(300MHz，CDCl 3)δ0.22(m，2H)，0.5(m，2H)，1.07(m，1H)，3.12(s，3H)，4.4(d，J＝9Hz，2H)，4.83(q，J＝9Hz，2H)，7.79(s，1H)，7.83(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z403(M+H) +。C 17H 17F 3N 2O 4The analytical calculation value of S: C, 50.74; H, 4.25; N, 6.96.Measured value: C, 50.56; H, 4.09; N, 6.88.
Embodiment 912-(2,2, the 2-trifluoroethyl)-4-(3-propylene-1-oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 90, with 2-propylene-1-alcohol substituted ring propyl group methyl alcohol, preparation title compound (output: 120mg, 77%).M.p.121-123℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，4.84(q，J＝12Hz，2H)，5.07(d，J＝6Hz，2H)，5.21(dd，J＝13.5Hz，1Hz，1H)，5.27(dd，J＝15Hz，1Hz，1H)，5.85(m，1H)，7.25(d，J＝9Hz，2H)，7.83(s，1H)，8.06(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?389(M+H) +。C 16H 15F 3N 2O 4The analytical calculation value of S: C, 49.48; H, 3.89; N, 7.21.Measured value: C, 49.24; H, 3.77; N, 7.16.
Embodiment 922-(2,2, the 2-trifluoroethyl)-4-(4-fluoro-Alpha-Methyl benzyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 90, with 4-fluoro-α-Jia Jibenjiachun substituted ring propyl group methyl alcohol, preparation title compound (output: 155mg, 76%).M.p.133-135℃。 1H?NMR(300MHz，CDCl 3)δ1.57(d，J＝6Hz，3H)，3.13(s，3H)，4.75(q，J＝7.5Hz，1H)，4.87(q，J＝7.5Hz，1H)，6.34(q，J＝6Hz，1H)，6.83(t，J＝9Hz，2H)，6.98(dd，J＝9Hz，6Hz，2H)，7.59(d，J＝9Hz)，7.70(s，1H))，8.03(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?471(M+H) +。C 21H 18F 4N 2O 4The analytical calculation value of S: C, 53.61; H, 3.85; N, 5.95.Measured value: C, 53.54; H, 3.73; N, 5.86.
Embodiment 932-[4-(methylthio group) phenyl]-4-(4-fluoro-phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under nitrogen atmosphere; product 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl with embodiment 11]-3 (2H)-pyridazinone (344mg; 1.0mmol), 4-bromine sulfo-phenylmethylether (812mg; 4.0mmol) and copper (70mg, 1.1mmol) solution in the 20ml pyridine stirred 18 hours under refluxing.After being cooled to room temperature, the mixture diluted reaction mixture of water and ethyl acetate.This two-layer Celite that passes through Filter and separation.Organic layer adopts 10% aqueous citric acid solution and salt water washing, through dried over mgso and filtration.Vacuum concentrated filtrate, residue obtains title compound foam (output: 380mg, 81.5%) through column chromatography purification (silica gel, 93: 7 dichloromethane/ethyl acetate). 1H?NMR(300MHz，CDCl 3)δ2.55(s，3H)，3.05(s，3H)，6.98(t，J＝9Hz，2H)，7.22(dd，J＝9Hz，6Hz，2H)，7.38(dd，J＝8Hz，2Hz，4H)，7.64(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)，7.98(s，1H)。MS(DCI-NH 3)m/z?467(M+H) +。C 24H 19FN 2O 3S 20.5H 2The analytical calculation value of O: C, 60.63; H, 4.21; N, 5.90.Measured value: C, 60.72; H, 3.96; N, 5.70.
Embodiment 942, two [4-(methyl sulphonyl) phenyl]-4-(4-fluorophenyl)-3 (the 2H)-pyridazinones of 5-
According to the method for embodiment 10, by the product of oxidation embodiment 93, preparation title compound (output: 156mg, 78%). 1H?NMR(300MHz，CDCl 3)δ3.10(s，3H)，3.12(s，3H)，7.02(m，2H)，7.24(m，2H)，7.42(br?d，J＝9Hz，2H)，7.94(dd，J＝9Hz，2Hz，2H)，8.02(dd，J＝9Hz，2Hz，2H)，8.10(m，3H)。MS(DCI-NH 3)m/z?499(M+H) +，516(M+NH 4) +。C 24H 19FN 2O 5S 20.5H 2The analytical calculation value of O: C, 56.80; H, 3.94; N, 5.53.Measured value: C, 56.50; H, 3.88; N, 5.38.
Embodiment 952-(3-methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 190mg, 43%) with 2-bromo-3 methyl thiophene.M.p.215-217℃。 1H?NMR(300MHz，CDCl 3)δ2.21(s，3H)，3.08(s，3H)，6.90(d，J＝9Hz，1H)，6.98(dd，J＝9Hz，2H)，7.24(dd，J＝9Hz，6Hz，3H)，7.41(d，J＝9Hz，2H)，7.94(d，J＝9Hz，2H)，7.98(s，1H)。MS(DCI-NH 3)m/z?441(M+H) +，458(M+NH 4) +。C 22H 17FN 2O 3S 20.5H 2The analytical calculation value of O: C, 58.80; H, 4.01; N, 6.24.Measured value: C, 58.85; N, 3.78; N, 5.99.
Embodiment 962-(2-trifluoromethyl-5-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 390mg, 73%) with 2-bromo-5-nitro-trifluoromethyl toluene. 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，6.98(t，J＝9Hz，2H)，7.21(dd，J＝9Hz，6Hz，2H)，7.43(d，J＝9Hz，2H)，7.80(d，J＝9Hz，1H)，7.96(d，J＝9Hz，2H)，8.02(s，1H)，8.61(dd，J＝9Hz，3Hz，1H)，8.75(d，J＝3Hz，1H)。MS(DCI-NH 3)m/z?534(M+H) +，551(M+NH 4) +。C 24H 15F 4N 3O 5S0.75H 2The analytical calculation value of O: C, 52.70; H, 3.02; H, 7.69.Measured value: C, 52.42; H, 3.04; N, 6.82.
Embodiment 972-[3-(methylthio group) phenyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 355mg, 76%) with 3-bromine sulfo-phenylmethylether.M.p.196℃。 1H?NMR(300MHz，CDCl 3)δ2.55(s，3H)，3.08(s，3H)，6.99(t，J＝9Hz，2H)，7.23(dd，J＝9Hz，6Hz，2H)，7.28-7.33(m，1H)，7.37-7.49(m，2H)，7.40(d，J＝9Hz，2H)，7.58(m，1H)，7.92(d，J＝9Hz，2H)，7.99(m，1H)。MS(DCI-NH 3)m/z?467(M+H) +，484(M+NH 4) +。C 24H 19FN 2O 3S 2The analytical calculation value: C, 61.80; H, 4.08; N, 6.01.Measured value: C, 61.56; H, 3.93; N, 5.86.
Embodiment 982-[3-(methyl sulphonyl] phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, by the product of oxidation embodiment 97, preparation title compound (output: 98mg, 65.6%).M.p.141-142℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，3.35(s，3H)，7.18(t，J＝9Hz，2H)，7.32(dd，J＝9Hz，6Hz，2H)，7.52(d，J＝9Hz，2H)，7.83(t，J＝9Hz，1H)，7.95(d，J＝9Hz，2H)，8.05(m，1H)，8.25(t，J＝1.5Hz，1H)，8.33(s，1H)。MS(DCI-NH 3)m/z?516(M+NH 4) +。C 24H 19FN 2O 5S 2H 2The analytical calculation value of O: C, 55.81; H, 4.07; N, 5.43.Measured value: C, 56.24; H, 4.29; N, 5.10.
Embodiment 992-(4-fluorophenyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-benzyl pyridazinone by embodiment 53 begins, preparation 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones, according to the method for embodiment 11, go this compound to benzylization.
Method according to embodiment 93; with 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 4-bromine sulfo-phenylmethylether with 1-fluoro-4-iodobenzene; preparation title compound (output: 245mg, 54%).M.p.195-197℃。 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，7.19(m，4H)，7.25(m，2H)，7.41(d，J＝9Hz，2H)，7.70(m，2H)，7.95(d，J＝9Hz，2H)，8.01(s，1H)。MS(DCI-NH 3)m/z?455(M+H) +，472(M+NH 4) +。C 23H 16ClFN 2O 3The analytical calculation value of S: C, 60.78; H, 3.52; N, 6.17.Measured value: C, 60.81; H, 3.53; N, 5.93.
Embodiment 1002-(5-chloro-2-thienyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 4-bromine sulfo-phenylmethylether with 2-bromo-5-chlorothiophene; preparation title compound (output: 150mg, 45%).M.p.249-251℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，6.92(d，J＝9Hz，1H)，7.18(d，J＝9Hz，2H)，7.31(d，J＝9Hz，2H)，7.39(d，J＝9Hz，2H)，7.58(d，J＝6Hz，1H)，7.94(d，J＝9Hz，2Hz，2H)，8.04(s，1H)。MS(DCI-NH 3)m/z?477(M+H) +，494(M+NH 4) +。C 21H 14Cl 2N 2O 3S 2H 2The analytical calculation value of O: C, 50.9; H, 3.03; N, 5.60.Measured value: C, 50.5; H, 2.79; N, 5.26.
Embodiment 1012-(3-trifluoromethyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 4-bromine sulfo-phenylmethylether with 3-iodine phenylfluoroform; preparation title compound (output: 210mg, 59.5%).M.p.103-105℃。 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，7.18(d，J＝9Hz，2H)，7.28(d，J＝9Hz，2H)，7.41(d，J＝9Hz，2H)，7.65(m，2H)，7.95(m，3H)，8.04(m，2H)。MS(DCI-NH 3)m/z?505(M+H) +，525(M+NH 4) +。C 24H 16ClF 3N 2O 3The analytical calculation value of S: C, 57.14; H, 3.17; H, 5.56.Measured value: C, 56.61; H, 3.28; N, 5.38.
Embodiment 1022-(3-chloro-4-fluorophenyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (described in the embodiment 99) replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 4-bromine sulfo-phenylmethylether with 1-bromo-3-chloro-4-fluorobenzene; preparation title compound (output: 330mg, 58.8%).M.p.205℃。 1H?NMR(300MHz，CDCl 3)δ3.10(s，3H)，7.17(d，J＝9Hz，2H)，7.23-7.31(m，1H)，7.28(d，J＝9Hz，2H)，7.41(d，J＝9Hz，2H)，7.65(ddd，J＝9Hz，3Hz，1.5Hz，1H)，7.85(dd，J＝9Hz，3Hz，1H)，7.93(d，J＝9Hz，2H)，8.01(s，1H)。MS(DCI-NH 3)m/z?489(M+H) +，508(M+NH 4) +。C 23H 15Cl 2N 2O 3The analytical calculation value of S: C, 56.44; H, 3.17; N, 5.73.Measured value: C, 56.37; H, 3.19; N, 5.64.
Embodiment 1032-(3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 310mg, 70.8%) with 1-fluoro-3-iodobenzene.M.p.245-247℃。 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，6.98(t，J＝9Hz，2H)，7.14(m，1H)，7.24(dd，J＝9Hz，6Hz，2H)，7.40(m，2H)，7.52(m，3H)，7.92(d，J＝9Hz，2H)，8.01(s，1H)。MS(DCI-NH 3)m/z?439(M+H) +，456(M+NH 4) +。C 23H 16F 2N 2O 3S0.25H 2The analytical calculation value of O: C, 62.34; H, 3.67; N, 6.38.Measured value: C, 62.33; H, 3.68; N, 6.22.
Embodiment 1042-[2-(methylthio group) phenyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 280mg, 60%) with 2-bromine sulfo-phenylmethylether.M.p.206-208℃。 1H?NMR(300MHz，CDCl 3)δ2.49(s，3H)，3.08(s，3H)，6.95(t，J＝9Hz，2H)，7.25(dd，J＝9Hz，6Hz，2H)，7.29-7.51(m，4H)，7.43(d，J＝9Hz，2H)，7.92(d，J＝9Hz，3H)，8.01(s，1H)，7.98(s，1H)。MS(DCI-NH 3)m/z467(M+H) +，484(M+NH 4) +。C 24H 19FN 2O 3S 2H 2The analytical calculation value of O: C, 59.50; H, 4.13; N, 5.79.Measured value: C, 59.62; H, 4.15; N, 5.52.
Embodiment 1052-(5-nitro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 330mg, 70%) with 2-bromo-5-nitrothiophene.M.p.252-253℃。 1H?NMR(300MHz，CDCl 3)δ3.06(s，3H)，7.05(t，J＝9Hz，2H)，7.25(dd，J＝9Hz，6Hz，2H)，7.40(d，J＝9Hz，2H)，7.71(d，J＝6Hz，1H)，7.95(m，3H)8.14(s，1H)。MS(DCI-NH 3)m/z?472(M+H) +，489(M+NH 4) +。C 21H 14FN 3O 5S 20.5H 2The analytical calculation value of O: C, 52.50; H, 3.02; N, 8.75.Measured value: C, 52.79; H, 3.18; N, 8.74.
Embodiment 1062-(2, the 3-difluorophenyl)-4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 4-(4-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and with 1-bromo-3; 4-two fluorobenzene replace 4-bromine sulfo-phenylmethylether; preparation title compound (output: 310mg, 65.7%).M.p.187-188℃。 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H)，7.18(d，J＝9Hz，2H)，7.29(m，3H)，7.41(d，J＝9Hz，2H)，7.52(m，1H)，7.65(m，1H)，7.92(d，J＝9Hz，2H)，8.01(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 23H 15ClF 2N 2O 3S0.5H 2The analytical calculation value of O: C, 57.38; H, 3.33; N, 5.82.Measured value: C, 57.44; H, 3.38; N, 5.52.
Embodiment 1072-(3-benzothienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 185mg, 41%) with 3-bromobenzene thiophthene.M.p.265-267℃。 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H)，7.0(t，J＝9Hz，2H)，7.27(dd，J＝9Hz，6Hz，2H)，7.39-7.47(m，2H)，7.44(d，J＝9Hz，2H)，7.75-7.82(m，1H)，7.87-7.94(m，2H)，7.94(d，J＝9Hz，2H)，8.05(s，1H)。MS(DCI-NH 3)m/z?477(M+H) +，494(M+NH 4) +。C 25H 17FN 2O 3S 2The analytical calculation value: C, 63.03; H, 3.57; N, 5.88.Measured value: C, 62.89; H, 3.55; N, 5.71.
Embodiment 1082-(4-fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 108A.4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 11, use AlBr 3Toluene solution handle 2-benzyl-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 1.8g, 95%).108B. 2-(4-fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 93, by 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones begin, and replace 4-bromine sulfo-phenylmethylether, preparation title compound (output: 60mg, 53%) with 1-fluoro-4-iodobenzene.M.p.83-85℃。 1H?NMR(300MHz，CDCl 3)δ3.10(s，3H)，6.89-7.03(m，4H)，7.15(t，J＝9Hz，2H)，7.65(dd，J＝9Hz，6Hz，2H)，7.83(d，J＝6Hz，2H)，8.07(d，J＝9Hz，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?455(M+H) +，472(M+NH 4) +。
Embodiment 1092-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 1-bromo-3; 4-two fluorobenzene replace 4-bromine sulfo-phenylmethylether; and with 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 108A) replace 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 185mg, 39%).M.p.178-180℃。 1H?NMR(300MHz，CDCl 3)δ3.11(s，3H)，6.89-7.04(m，4H)，7.45-7.52(m，1H)，7.45-7.52(m，1H)，7.61(dt，J＝6Hz，3Hz，1H)，7.82(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 23H 15F 3N 2O 4S0.5H 2The analytical calculation value of O: C, 57.38; H, 3.33; N, 5.83.Measured value: C, 57.17; H, 3.13; N, 5.62.
Embodiment 1102-(3-bromophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 1; the 3-dibromobenzene replaces 4-bromine sulfo-phenylmethylether; and with 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 108A) replace 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 260mg, 50.5%).M.p.208-210℃。 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H)，6.89-7.04(m，4H)，7.34(t，J＝9Hz，1H)，7.53(br?d，J＝9Hz，1H)，7.64(br?d，J＝9Hz，1H)，7.82(d，J＝9Hz，2H)，7.87(t，J＝1.5Hz，1H)，8.08(d，J＝9Hz，2H)，8.09(s，1H)。MS(DCI-NH 3)m/z?517(M+H) +，534(M+NH 4) +。C 23H 16BrFN 2O 4The analytical calculation value of S: C, 53.7; H, 3.11; N, 5.45.Measured value: C, 53.46; H, 2.88; N, 5.18.
Embodiment 1112-(3, the 5-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; with 1-bromo-3; 4-two fluorobenzene replace 4-bromine sulfo-phenylmethylether; and with 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 108A) replace 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 175mg, 37%).M.p.209-211℃。 1H?NMR(300MHz，CDCl 3)δ3.10(s，3H)，6.85(tt，J＝9Hz，3Hz，1H)，6.90-7.04(m，4H)，7.38(dd，J＝9Hz，3Hz，2H)，7.81(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.10(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 23H 15F 3N 2O 4SH 2The analytical calculation value of O: C, 58.47; H, 3.18; N, 5.94.Measured value: C, 58.31; H, 3.15; N, 5.82.
Embodiment 1122-(3-chloro-phenyl-)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 93; replace 4-bromine sulfo-phenylmethylether with 1-bromo-3-chlorobenzene; and with 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 108A) replace 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 25mg, 5.3%).M.p.211-213℃。 1H?NMR(300MHz，DMSO-d 6)δ3.30(s，3H)，7.15(d，J＝9Hz，4H)，7.51-7.64(m，3H)，7.71-7.75(m，1H)，7.91(d，J＝9Hz，2H)，8.06(d，J＝9Hz，2H)，8.41(s，1H)。MS(DCI-NH 3)m/z?471(M+H) +，488(M+NH 4) +。C 23H 16ClFN 2O 4S0.5H 2The analytical calculation value of O: C, 57.62; H, 3.44; H, 5.85.Measured value: C, 57.62; H, 3.52; N, 5.48.
Embodiment 1132-(4-nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 4-nitrobenzyl bromine, preparation title compound (output: 164mg, 58.9%).M.p.183-184℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.47(s，2H)，6.96(t，J＝9Hz，2H)，7.16(dd，J＝9Hz，3Hz，2H)，7.32(d，J＝9Hz，2H)，7.70(d，J＝9Hz，2H)，7.87(s，1H)，7.88(d，J＝9Hz，2H)，8.22(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z480(M+H) +，497(M+NH 4) +。C 24H 18FN 3O 5The analytical calculation value of S: C, 60.12; H, 3.78; N, 8.76.Measured value: C, 59.89; H, 3.83; N, 8.61.
Embodiment 1142-(4-acetoxyl group benzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with acetate 4-(chloromethyl) phenyl ester, preparation title compound (output: 220mg, 76.9%).M.p.172-174℃。 1H?NMR(300MHz，CDCl 3)δ2.30(s，3H)，3.05(s，3H)，5.38(s，2H)，6.95(t，J＝9Hz，2H)，7.06(d，J＝9Hz，2H)，7.16(dd，J＝9Hz，5Hz，2H)，7.31(d，J＝9Hz，2H)，7.60(d，J＝9Hz，2H)，7.81(s，1H)，7.87(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?510(M+NH 4) +。C 26H 21FN 2O 5The analytical calculation value of S: C, 63.40; H, 4.30; N, 5.69.Measured value: C, 63.28; H, 4.41; N, 5.39.
Embodiment 1152-(4-hydroxybenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2-(4-acetoxyl group benzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (0.2g; 4.06mmol) THF (20ml) solution of (embodiment 114) is with lithium hydroxide monohydrate (0.05g, water 1.22mmol) (5ml) solution-treated.Add methyl alcohol (2ml), obtain uniform solution, it is stirred under room temperature spend the night.Then, reaction mixture is used ethyl acetate extraction with 10% aqueous citric acid solution acidifying.Ethyl acetate layer is through dried over mgso and filtration.Vacuum concentrated filtrate obtains white foam shape thing, with it through column chromatography purification (silica gel, 65: 35 hexane/ethyl acetate).The product flow point is merged and vacuum concentration.Resistates crystallization from ethyl acetate/hexane (output: 195mg, 70%).M.p.225-226℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，4.86(s，1H)，5.33(s，2H)，6.80(d，J＝8.5Hz，2H)，6.95(t，J＝9Hz，2H)，7.15(dd，J＝9Hz，5Hz，2H)，7.30(d，J＝8.5Hz，2H)，7.46(d，J＝8.5Hz，2H)，7.83(s，1H)，7.87(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?451(M+H) +。C 24H 19FN 2O 4The analytical calculation value of S: C, 63.99; H, 4.25; N, 6.22.Measured value: C, 63.73; H, 4.16; N, 6.11.
Embodiment 1162-(3-nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 3-nitrobenzyl bromine, preparation title compound (output: 195mg, 70%).M.p.156-157℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.48(s，2H)，6.96(t，J＝9Hz，2H)，7.16(dd，J＝9Hz，5Hz，2H)，7.33(d，J＝8.5Hz，2H)，7.54(t，J＝7Hz，1H)，7.88(s，1H)，7.90(d，J＝8.5Hz，2H)，8.19(br?d，J＝7Hz，1H)，8.37(t，J＝1.7Hz，1H)。MS(DCI-NH 3)m/z?480(M+H) +，497(M+NH 4) +。C 24H 18FN 3O 5The analytical calculation value of S: C, 60.12; H, 3.78; N, 8.76.Measured value: C, 59.98; H, 3.73; N, 8.67.
Embodiment 1172-(3,4,4-three fluoro-3-butenyls)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 4-bromo-1,1,2-three fluoro-1-butylene replace the 4-fluoro benzyl bromide, preparation title compound (output: 38mg, 14.5%).M.p.131-132℃。 1HNMR(300MHz，CDCl 3)δ2.92(br?d，J＝21.7Hz，2H)，3.06(s，3H)，4.47(t，J＝6.6Hz，2H)，6.98(t，J＝9Hz，2H)，7.17(dd，J＝9Hz，5Hz，2H)，7.35(d，J＝8.5Hz，2H)，7.85(s，1H)，7.89(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?453(M+H) +，470(M+NH 4) +。C 21H 16F 4N 2O 3The analytical calculation value of S: C, 55.75; H, 3.56; H, 6.19.Measured value: C, 55.63; H, 3.62; N, 6.10.
Embodiment 1182-(2-hexin base)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 1-chloro-2-hexin, preparation title compound (output: 170mg, 69%).M.p.79-80℃。 1H?NMR(300MHz，CDCl 3)δ0.99(t，J＝7.5Hz，3H)，1.56(h，J＝7.5Hz，2H)，2.21(m，2H)，3.06(s，3H)，5.01(t，J＝3Hz，2H)，6.96(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.34(d，J＝9Hz，2H)，7.88(s，1H)，7.89(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?425(M+H) +。C 23H 21FN 2O 3The analytical calculation value of S: C, 65.07; H, 4.98; N, 6.59.Measured value: C, 64.87; H, 4.90; N, 6.58.
Embodiment 1192-(3,3-two chloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, with 1,1, the 3-tri chloropropene replaces the 4-fluoro benzyl bromide, preparation title compound (output: 1.15g, 68%).M.p.184-185℃。 1H?NMR(300MHz，DMSO-d 6)δ4.39(d，J＝7.5Hz，2H)，6.43(t，J＝7.5Hz，1H)，7.14(t，J＝9Hz，2H)，7.23(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.43(s，2H)，7.73(d，J＝9Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z454(M+H) +。C 19H 14Cl 2F 4N 3O 3The analytical calculation value of S: C, 50.23; H, 3.1; N, 9.24.Measured value: C, 50.28; H, 3.29; N, 9.19.
Embodiment 1202-cyclohexyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with cyclohexyl bromide, preparation title compound (output: 163mg, 76%).M.p.169-171℃。 1H?NMR(DMSO-d 6，300MHz)δ1.23(m，1H)，1.41(m，2H)，1.71(m，3H)，1.87(m，4H)，3.23(s，3H)，4.85(m，1H)，7.11(m，2H)，7.22(m，2H)，7.46(d，J＝9Hz，2H)，7.85(d，J＝9Hz，2H)，8.11(s，1H)。MS (DCI-NH 3) m/z 427 (M+H) +With 444 (M+NH 4) +C 23H 23FN 2O 3S0.5H 2The analytical calculation value of O: C, 63.43; H, 5.55; N, 6.43.Measured value: C, 63.25; H, 5.28; N, 6.28.
Embodiment 1212-cyclopentyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with cyclopentyl bromide, preparation title compound (output: 165g, 80%).M.p.191-193℃。 1H?NMR(DMSO-d 6，300MHz)δ1.67(m，2H)，1.85(m，4H)，2.05(m，2H)，3.23(s，3H)，5.36(m，1H)，7.12(t，J＝9Hz，2H)，7.22(m，2H)，7.45(d，J＝9Hz，2H)，7.85(d，J＝9Hz，2H)，8.13(s，1H)。MS (DCI-NH 3) m/z 413 (M+H) +With 430 (M+NH 4) +C 22H 21FN 2O 3S0.5H 2The analytical calculation value of O: C, 62.69; H, 5.26; N, 6.57.Measured value: C, 62.53; H, 4.93; N, 6.50.
Embodiment 1222-cyclobutyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with the cyclobutyl bromine, preparation title compound (output: 270g, 68%).M.p.202-203℃。 1H NMR (DMSO-d 6, 300MHz) δ 1.85 (m, 2H), 2.32 (m, 2H), 2.50 (m, 2H), 5.40 (quintet, J=7Hz, 1H), 7.11 (t, J=9Hz, 2H), 7.21 (m, 2H), 7.47 (d, J=9Hz, 2H), 7.86 (d, J=9Hz, 2H), 8.16 (s, 1H).MS (DCI-NH 3) m/z 399 (M+H) +With 416 (M+NH 4) +C 21H 19FN 2O 3S0.75H 2The analytical calculation value of O: C, 61.22; H, 5.01; N, 6.80.Measured value: C, 61.19; H, 4.62; N, 6.73.
Embodiment 1232-(3-methyl-2-butene base)-4-(4-fluorophenyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 11, will be according to 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl of the method for embodiment 68 preparation]-3 (2H)-pyridazinones go benzylization.According to the method for embodiment 20, replace the 4-fluoro benzyl bromide with 1-bromo-3-methyl-2-butene and make this intermediate N alkylation, obtain title compound (output: 50mg, 30%).M.p.134-136℃。 1H?NMR(300MHz，CDCl 3)δ1.79(s，3H)，1.86(s，3H)，4.78(s，2H)，4.85(d，J＝7.5Hz，2H)，5.48(t，J＝6Hz，1H)，6.96(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.28(d，J＝9Hz，2H)，7.83(s，1H)，7.85(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?414(M+H) +。C 21H 20FN 3O 3The analytical calculation value of S: C, 61; H, 4.87; N, 10.16.Measured value: C, 60.98; H, 4.66; N, 9.95.
Embodiment 1242-(2, the 4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 123, with 2, the 4-difluoro benzyl bromide replaces 1-bromo-3-methyl-2-butene, preparation title compound (output: 65mg, 24%).M.p.236-238℃。 1HNMR(300MHz，CDCl 3)δ4.78(s，2H)，5.43(s，2H)，6.88(m，2H)，6.97(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.38(d，J＝9Hz，2H)，7.55(m，1H)，7.85(s，1H)，7.86(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z472(M+H) +。C 23H 16F 3N 3O 3The analytical calculation value of S: C, 58.59; H3.42; N, 8.91.Measured value: C, 58.44; H, 3.47; N, 8.72.
Embodiment 1252-(PFBBR)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 123, with 2,3,4,5,6-PFBBR bromine replaces 1-bromo-3-methyl-2-butene, preparation title compound (output: 105mg, 35%).M.p.201-203℃。 1HNMR(300MHz，CDCl 3)δ4.8(s，2H)，5.5(s，2H)，6.98(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.28(d，J＝9Hz，2H)，7.32(s，1H)，7.37(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?526(M+H) +。C 23H 13F 6N 3O 3The analytical calculation value of S: C, 52.57; H, 2.49; N, 7.99.Measured value: C, 52.66; H, 2.68; N, 7.8.
Embodiment 1262-(3-cyclohexenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 123, replace 1-bromo-3-methyl-2-butene, preparation title compound (output: 30mg, 10%) with 3-bromine tetrahydrobenzene.M.p.206-208℃。 1H?NMR(300MHz，CDCl 3)δ1.75-1.85(m，3H)，2.1-2.3(m，3H)，4.8(s，2H)，5.75(m，2H)，6.1(m，1H)，6.97(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，6Hz，2H)，7.28(d，J＝9Hz，2H)，7.86(d，J＝9Hz，2H)，7.90(s，1H)。MS(DCI-NH 3)m/z?426(M+H) +。C 22H 20FN 3O 3The analytical calculation value of S: C, 62.10; H, 4.73; N, 9.87.Measured value: C, 61.27; H, 4.75; N, 9.56.
Embodiment 1272-(3, the 4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 123, with 3, the 4-difluoro benzyl bromide replaces 1-bromo-3-methyl-2-butene, and reacts in DMSO, rather than reacts in DMF, forms by product with prevention, preparation title compound (output: 210mg, 62%).M.p.253-255℃。 1H?NMR(300MHz，DMSO-d 6)δ5.33(s，2H)，7.13(t，J＝9Hz，2H)，7.22(dd，J＝9Hz，6Hz，2H)，7.28(m，1H)，7.39(d，J＝9Hz，2H)，7.42(s，2H)，7.47(m，2H)，7.73(d，J＝9Hz，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?472(M+H) +。C 23H 16F 3N 3O 3The analytical calculation value of S: C, 58.59; H, 3.42; N, 8.91.Measured value: C, 58.05; H, 3.55; N, 8.49.
Embodiment 1282-(2,3-dihydro-1H-indenes-2-yl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The 4-that preparation prepares in embodiment 11 (4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (172mg, 0.5mmol), the 2-indanol (67mg, 0.5mmol) and Ph 3P (262mg, the 1mmol) solution in toluene (20ml) and ethyl acetate (5ml), and drip DIAD (0.2ml, toluene 1mmol) (10ml) solution.Mixture was stirred under room temperature 6 hours and vacuum concentration.Resistates obtains 200mg product (containing reductive DIAD) through chromatographic separation (silica gel, 19: 1 methylene dichloride-ethyl acetate).Column chromatography (hexane-ethyl acetate 1: 1) obtains title product (output: 170mg, 74%) for the second time.M.p.97-100℃。 1H NMR (DMSO-d 6, 300MHz) δ 3.22 (s, 3H), 3.32 (m, 2H), 3.44 (dd, J=9Hz and 15Hz, 1H), 5.83 (m, 1H), 7.25 (m, 4H), 7.34 (m, 4H), 7.46 (d, J=9Hz, 2H), 7.85 (d, J=9Hz, 2H), 8.06 (s, 1H).MS (DCI-NH 3) m/z 461 (M+H) +With 478 (M+NH 4) +
Embodiment 1292-(2,3-dihydro-1H-indenes-1-yl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 128, replace the 2-indanol with the 1-indanol, preparation title product (output: 110mg, 48%).M.p.128-130℃。 1H?NMR(DMSO-d 6，300MHz)δ2.40(m，1H)，2.60(m，1H)，3.00(m，1H)，3.22(s+m，4H)，6.60(dd，J＝9Hz，6Hz，1H)，7.16(m，4H)，7.27(m，4H)，7.47(d，J＝9Hz，2H)，7.85(d，J＝9Hz，2H)，8.02(s，1H)。MS (DCI-NH 3) m/z 461 (M+H) +With 478 (M+NH 4) +
Embodiment 1302-(4-tetrahydrochysene-2H-pyrans-4-yl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 128, replace the 2-indanol with 4-tetrahydropyrans alcohol, preparation title product (output: 140g, 65%).M.p.230-231℃。 1H?NMR(300MHz，DMSO-d 6)δ1.75(m，2H)，1.93(m，2H)，3.14(s，3H)，3.46(m，2H)，3.93(m，2H)，5.02(m，1H)，7.05(t，J＝9Hz，2H)，7.15(m，2H)，7.40(d，J＝9Hz，2H)，7.80(d，J＝9Hz，2H)，8.08(s，1H)。MS (APCI-) m/z 428 (M-H) -With 463 (M+Cl) -C 22H 21FN 2O 4S1.25H 2The analytical calculation value of O: C, 58.59; H, 5.25; N, 6.21.Measured value: C, 58.31; H, 4.75; N, 6.05.
Embodiment 1312-(2-methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 128, replace the 2-indanol with the 2-methylcyclopentanol, preparation title product (output: 230g, 86%).M.p.180-181℃。 1H?NMR(300MHz，DMSO-d 6)δ0.75(d，J＝7Hz，3H)，1.60(m，2H)，1.89(m，2H)，2.10(m，1H)，2.21(m，1H)，2.40(m，1H)，3.23(s，3H)，5.37(q，J＝7Hz，1H)，7.12(t，J＝9Hz，2H)，7.21(m，2H)，7.47(d，J＝9Hz，2H)，7.86(d，J＝9Hz，2H)，8.11(s，1H)。MS (APCI+) m/z 427 (M+H) +(APCI-) 461 (M+Cl) -C 23H 23FN 2O 3The analytical calculation value of S: C, 64.77; H, 5.43; N, 6.56.Measured value: C, 64.71; H, 5.34; N, 6.28.
Embodiment 1322-(2-adamantyl (adamantyl))-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 128, replace the 2-indanol with the 2-adamantanol, preparation title product (output: 75g, 25%).M.p.195-197℃。 1H?NMR(300MHz，DMSO-d 6)δ1.60(m，2H)，1.77(m，2H)，1.94(m，6H)，2.35(m，4H)，3.23(s，3H)，4.83(m，1H)，7.11(t，J＝9Hz，2H)，7.22(m，2H)，7.47(d，J＝9Hz，2H)，7.87(d，J＝9Hz，2H)，8.11(s，1H)。MS (APCI+) m/z 479 (M+H) +(APCI-) m/z 478 (M-H) -, m/z 513 (M+Cl) -C 27H 27FN 2O 3S0.25H 2The analytical calculation value of O: C, 67.13; H, 5.73; N, 5.79.Measured value: C, 67.06; H, 5.76; N, 5.06.
Embodiment 1332-(3-methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 128, replace the 2-indanol with the 3-methylcyclopentanol, preparation title product (output: 155g, 73%).M.p.169-171℃。 1H NMR (300MHz, DMSO-d 6) δ 1.05 (dd, 2: 1,3H), 1.24 (m, 1H), 1.63 (m, 1H), 2.00 (m, 3H), 2.22 (m, 2H), 3.23 (s, 3H), 5.43 (m, 1H), 7.1 (t, J=9Hz, 2H), 7.21 (m, 2H), 7.46 (d, J=9Hz, 2H), 7.86 (d, J=9Hz, 2H), 8.12 (2 s, 2: 1,1H).MS (APCI+) m/z 27 (M+H) +(APCI-) m/z 426 (M-H) -, m/z 461 (M+Cl) -C 27H 27FN 2O 3S0.25H 2The analytical calculation value of O: C, 64.09; H, 5.49; N, 6.49.Measured value: C, 64.27; H, 5.62; N, 6.46.
Embodiment 1342-(1-methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Preparation is according to 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of the method for embodiment 11 preparation]-3 (2H)-pyridazinones (206mg, 0.6mmol), 1-methyl isophthalic acid-cyclopentanol (60mg, 0.6mmol), DMAP (18mg, 0.12mmol) and Ph 3P (262mg, the 1mmol) solution in toluene (30ml) and ethyl acetate (5ml), and it is dropped to DIAD, and (0.2ml is in 10ml toluene solution 1mmol).Mixture was stirred under room temperature 6 hours, then vacuum concentration.Resistates obtains 80mg product (pollution has reductive DIAD) through chromatography purification (silica gel, 19: 1 methylene dichloride-ethyl acetate).Through second column chromatography (hexane-ethyl acetate 1: 1), obtain title product (output: 50mg, 19%).M.p.107-110℃。 1H?NMR(DMSO-d 6，300MHz)δ1.55(s，3H)，1.70(m，4H)，2.08(m，2H)，2.32(m，2H)，3.22(s，3H)，7.10(t，J＝9Hz，2H)，7.20(m，2H)，7.45(d，J＝9Hz，2H)，7.86(d，J＝9Hz，2H)，8.03(s，1H)。MS (APCI+) m/z 427 (M+H) +(APCI-) m/z426 (M-H) -, m/z 461 (M+Cl) -
Embodiment 1352-(3, the 4-difluorophenyl)-4-(4-fluoro-3-ethenylphenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 135A. 5-bromo-2-fluorobenzene ethene
Under nitrogen, with first base three phenyl phosphonium bromides (2.14g, 6mmol) and potassium tert.-butoxide (672mg, 6mmol) mixture in 50ml THF refluxed 30 minutes, then it was cooled to room temperature.Adding 5-bromo-2-fluorobenzaldehyde (1.02g, 5mmol), with 2 hours (the showing that until TLC initial aldehyde disappears) of mixture backflow of gained.With the reactant vacuum concentration, and be allocated between water and the ethyl acetate.Acetic ester layer water and salt water washing.Solution is through dried over mgso and vacuum concentration.Resistates obtains 900mg (90%) 5-bromo-2-fluorobenzene ethene through chromatography purification (silica gel, 15: 1 hexane-ether).135B. 2-(3, the 4-difluorophenyl)-4-(4-fluoro-3-ethenylphenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
The bromstyrol mixture of the above preparation among the 10ml THF is dropped to the magnesium chips of heating, and (120mg, 5mmol) and THF (20ml) solution of several glycol dibromides, its drop rate makes can keep gentle backflow.Mixture was refluxed 30 minutes again, and be cooled to room temperature.This Grignard reagent solution being cooled to-78 ℃, dropping to 2-(3, the 4-difluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl] (540mg is in THF 1.5mmol) (20ml) solution for-3 (2H)-pyridazinones.Make this reaction mixture be warmed to room temperature 12 hours.After this, add saturated ammonium chloride solution, the mixture ethyl acetate extraction obtains the rough sulfide of 320mg.135C. 2-(3, the 4-difluorophenyl)-4-(4-fluoro-3-ethenylphenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The sulfide of above preparation is dissolved in the methylene dichloride (20ml), and uses 30%CH in 0 ℃ 3CO 3H (0.5ml) handles.1.5 after hour, add 10% sodium bicarbonate, the mixture dichloromethane extraction.The vacuum concentration extract, resistates obtains title compound (output: 270mg, 37%) through chromatographic separation (silica gel, 1: 1 hexane-ethyl acetate). 1H NMR (DMSO-d 6, 300MHz) δ 3.22 (s, 3H), 5.37 (d, J=12Hz, 1H), 5.65 (d, J=18Hz, 1H), 6.77 (dd, J=12Hz and 18Hz, 1H), 7.15 (m, 2H), 7.57 (m, 5H), 7.90 (m, 3H), 8.28 (s, 1H).MS (APCI+) m/z 483 (M+H) +(APCI-) m/z 517 (M+Cl) -C 25H 17F 3N 2O 3S0.5H 2The analytical calculation value of O: C, 61.09; H, 3.69; N, 5.69.Measured value: C, 61.04; H, 3.71; N, 5.34.
Embodiment 1362-(3, the 4-difluorophenyl)-4-(6-methyl-3-heptenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2-(2-bromo-ethyl)-1,3-diox (586mg, 3mmol) replace 5-bromo-2-fluorobenzene ethene, to add to 2-(3 in-78 ℃ as the Grignard of preparation among the embodiment 135, the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methylthio group) phenyl] (720mg is in THF 2mmol) (30ml) solution for-3 (2H)-pyridazinones.Mixture is placed room temperature following 14 hours, use the saturated ammonium chloride solution quenching, use ethyl acetate extraction, obtain the rough sulfide of 900mg.
Sulfide product in the middle of described is dissolved in the methylene dichloride (10ml), uses 33%CH in 0 ℃ 3CO 3The CH of H 3CO 2H (0.7ml) solution-treated 1 hour.Vacuum concentrated mixture is allocated in resistates between saturated sodium bicarbonate and the ethyl acetate.The acetic ester layer obtains the rough sulfonyl-derivatives of 950mg through dried over mgso and vacuum concentration.
The sulfonyl compound of above preparation is dissolved in the acetone (50ml), handles with 2N HCl (10ml).The mixture of gained was refluxed 16 hours and vacuum concentration.The resistates ethyl acetate extraction obtains 900mg 2-(3, the 4-difluorophenyl)-4-(2-formyl radical ethyl)-5-[4-(methyl sulphonyl) phenyl] (crude aldehyde, pollute has some unreacted initial dioxane derivatives to-3 (2H)-pyridazinones.
With isopentyl three phenyl phosphonium bromides (414mg, 1mmol) and potassium tert.-butoxide (112mg, 1mmol) mixture in toluene (25ml) refluxed 30 hours, was cooled to room temperature then.Add described crude aldehyde, then mixture was refluxed 14 hours.Then reaction mixture is cooled to room temperature and vacuum concentration.Resistates is dissolved in the ethyl acetate, and water, 10% citric acid and salt water washing, through dried over mgso and vacuum concentration.Through column chromatography purification (silica gel, 1: 1 hexane-ethyl acetate), obtain title compound oily matter (output: 120mg, 13%). 1H?NMR(300MHz，DMSO-d 6)δ0.74(d，J＝7Hz，6H)，1.44(m，1H)，1.70(t，J＝7Hz，2H)，2.22(m，2H)，2.54(m，2H)，3.30(s，3H)，5.29(m，2H)，7.5?1(m，1H)，7.63(m，1H)，7.74(d，J＝9Hz，2H)，7.82(m，1H)，8.02(s，1H)，8.10(d，J＝9Hz，2H)。MS (APCI+) m/z 473 (M+H) +(APCI-) m/z 471 (M-H) -, m/z 507 (M+Cl) -C 25H 26F 2N 2O 3The analytical calculation value of S: C, 63.54; H, 5.54; N, 5.92.Measured value: C, 63.74; H, 5.67; N, 5.58.
Embodiment 1372-(3, the 4-difluorophenyl)-4-(3-cyclopropylidene propyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 136, replace isopentyl three phenyl phosphonium bromides with cyclopropyl three phenyl phosphonium bromides, preparation title compound (output: 55mg, 12%).M.p.128-129℃。 1H?NMR(300MHz，DMSO-d 6)δ0.81(m，2H)，0.97(m，2H)，2.34(m，2H)，2.65(m，2H)，3.32(s，3H)，5.64(m，1H)，7.52(m，1H)，7.73(m，1H)，7.63(d，J＝9Hz，2H)，7.81(m，1H)，8.02(s，1H)，8.10(d，J＝9Hz，2H)。MS (APCI+) m/z 443 (M+H) +(APCI-) m/z 441 (M-H) -, m/z 477 (M+Cl) -C 23H 20F 2N 2O 3S0.5H 2The analytical calculation value of O: C, 61.18; H, 4.68; N, 6.20.Measured value: C, 61.48; H, 4.60; N, 6.02.
Embodiment 1382-(3, the 4-difluorophenyl)-4-(5-methyl-3-hexenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 136, replace isopentyl three phenyl phosphonium bromides with isobutyl-three phenyl phosphonium bromides, be prepared as the title compound (output: 170mg, 74%) of oily matter. 1HNMR(300MHz，DMSO-d 6)δ0.75(d，J＝7Hz，6H)，2.22(m，3H)，2.54(m，2H)，3.32(s，3H)，5.12(m，2H)，7.52(m，1H)，7.60(m，1H)，7.72(d，J＝9Hz，2H)，7.80(m，1H)，8.02(s，1H)，8.10(d，J＝9Hz，2H)。MS (APCI+) m/z 459 (M+H) +(APCI-) m/z 457 (M-H) -, m/z 493 (M+Cl) -C 24H 24F 2N 2O 3The analytical calculation value of S: C, 62.86; H, 5.27; N, 6.10.Measured value: C, 62.57; H, 5.32; N, 5.81.
Embodiment 1392-(3, the 4-difluorophenyl)-4-(5-methyl hexyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 135B, replace 3-fluoro-4-ethenylphenyl magnesium bromide with 5-methyl hexyl magnesium bromide, be prepared as the title compound (output: 28mg, 10%) of oily matter. 1HNMR(300MHz，DMSO-d 6)δ0.77(d，J＝7Hz，6H)，0.88(m，1H)，1.03(m，2H)，1.20(m，1H)，1.46(m，5H)，3.32(s，3H)，7.52(m，1H)，7.62(m，1H)，7.75(d，J＝9Hz，2H)，7.82(m，1H)，8.02(s，1H)，8.11(d，J＝9Hz，2H)。MS (APCI+) m/z 461 (M+H) +(APCI-) m/z 459 (M-H) -, m/z 495 (M+Cl) -
Embodiment 1402-(3-chloro-1-methyl-2E-propenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 1,3-two chloro-1-butylene replace 3,4-difluoro benzyl bromide, preparation title compound (output: 55mg, 30%).M.P.152-154℃。 1H?NMR(300MHz，CDCl 3)δ4.71(dt，J＝15Hz，7.5Hz，2H)，2.28(d，J＝1.5Hz，3H)，3H)，4.8(s，2H)，4.99(d，J＝1Hz，1H)，5.02(d，J＝1Hz，1H)，5.85(td，J＝4Hz，1Hz，1H)，6.98(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.28(d，J＝9Hz，2H)，7.86(s，1H)，7.87(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?434(M+H) +。C 20H 17ClFN 3O 3The analytical calculation value of S: C, 55.36; H, 3.94; N, 9.68.Measured value: C, 54.99; H, 3.83; N, 9.34.
Embodiment 1412-(2,3,3-three fluoro-2-propylene-1-yls)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with the 1-sulfonyloxy methyl oxygen base-2,3 of preparation among the embodiment 88,3-three fluoro-1-propylene (methanesulfonates) replace 3,4-difluoro benzyl bromide, preparation title compound (output: 10mg, 4%).M.p.173-175℃。 1H?NMR(300MHz，CDCl 3)δ4.39(s，2H)，5.09(ddd，J＝26Hz，J＝3Hz，J＝1Hz，2H)，6.98(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，J＝6Hz，2H)，7.29(d，J＝9Hz，2H)，7.78(s，1H)，7.78(d，J＝9Hz，2H)。MS (DCI-NH 3) m/z 440 (M+H) +, MS (FAB, high resolving power) m/z C 19H 14F 4N 3O 3The analytical calculation value of S: 440.0692 (M+H) +Measured value: 440.0695 (M+H) +, (0.7ppm error).
Embodiment 1422-(1,1,2-three fluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
From being used for preparing 2-(2,3,3-three fluoro-2-propylene-1-yls)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl] in the identical reaction mixture (embodiment 141) of-3 (2H)-pyridazinones, (this title compound is S to separate title compound N2 ' the result who attacks) (output: 50mg, 20%).M.p.230-232℃。 1H?NMR(300MHz，CDCl 3)δ4.7(s，2H)，5.28(dd，J＝15Hz，4.5Hz，1H)，5.39(dd，J＝45Hz，4.5Hz，1H)，6.98(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.31(d，J＝9Hz，2H)，7.9(d，J＝9Hz，2H)，7.92(s，1H)。MS(DCI-NH 3)m/z?440(M+H) +。C 19H 13F 4N 3O 3The analytical calculation value of S: C, 51.93; H, 2.98; N, 9.56.Measured value: C, 51.88; H, 3.01; N, 9.15.
Embodiment 1432-(3,3-two fluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 1,3-two bromo-1, the 1-difluoropropane replaces 3, the 4-difluoro benzyl bromide, and use the salt of wormwood of 5 parts of a great deal oves, preparation title compound (output: 220mg, 65%).M.p.191-194℃。 1H?NMR(300MHz，DMSO-d 6)δ4.77(d，J＝7.5Hz，2H)，4.95(dtd，J＝24Hz，7.5Hz，1Hz，1H)，7.12(t，J＝9Hz，2H)，7.23(dd，J＝9Hz，6Hz，2H)，7.49(d，J＝9Hz，2H)，7.50(s，2H)，7.74(d，J＝9Hz，2H)，8.1(s，1H)。MS(DCI-NH 3)m/z?422(M+H) +。C 19H 14F 3N 3O 3The analytical calculation value of S: C, 54.15; H, 3.34; N, 9.97.Measured value: C, 53.88; H, 3.42; N, 9.76.
Embodiment 1442-(Alpha-Methyl-3-luorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, replace 3 with 3-fluoro-α-Jia Jibianji chlorine, 4-difluoro benzyl bromide, preparation title compound (output: 220mg, 65%).M.p.192-194℃。 1HNMR(300MHz，DMSO-d 6)δ1.76(d，6Hz，3H)，6.27(q，J＝7Hz，1H)，7.1(t，J＝9Hz，2H)，7.22(dd，J＝9Hz，6Hz，2H)，7.49(d，J＝9Hz，2H)，7.51(s，2H)，7.72(d，J＝9Hz，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?468(M+H) +。C 24H 19F 2N 3O 3The analytical calculation value of S: C, 61.66; H, 4.09; N, 8.98.Measured value: C, 61.36; H, 3.96; N, 8.86.
Embodiment 1452-(1-cyclohexenyl methyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, replace 3 with 1-brooethyl tetrahydrobenzene, 4-difluoro benzyl bromide, preparation title compound (output: 70mg, 28%).M.p.192-193℃。 1H?NMR(300MHz，DMSO-d 6)δ1.55(m，4H)，1.98(m，4H)，4.64(s，2H)，5.53(s，1H)，7.12(t，J＝9Hz，2H)，7.22(dd，J＝9Hz，6Hz，2H)，7.39(d，J＝9Hz，2H)，7.39(s，2H)，7.72(d，J＝9Hz，2H)，8.07(s，1H)。MS(DCI-NH 3)m/z?440(M+H) +。C 23H 22FN 3O 3The analytical calculation value of S: C, 62.85; H, 5.04; N, 9.56.Measured value: C, 62.47; H, 5.23; N, 9.14.
Embodiment 1462-(alpha-methyl-2,3,4-trifluoro-benzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 2,3,4-three fluoro-α-Jia Jibianji chlorine replace 3,4-difluoro benzyl bromide, preparation title compound (output: 70mg, 50%).M.p.192-194℃。 1H?NMR(300MHz，CDCl 3)δ1.84(d，J＝6Hz，3H)，4.8(s，2H)，6.54(q，J＝7Hz，1H)，6.96(t，J＝9Hz，2H)，6.99(m，1H)，7.18(dd，J＝9Hz，6Hz，2H)，7.2(m?1H)，7.38(d，J＝9Hz，2H)，7.86(d，J＝9Hz，2H)，7.88(s，1H)。MS(DCI-NH 3)m/z?504(M+H) +。C 24H 17F 4N 3O 3The analytical calculation value of S: C, 57.25; H, 3.4; N, 8.34.Measured value: C, 56.84; H, 3.52; N, 7.91.
Embodiment 1472-(Alpha-Methyl-3,5-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 3,5-two fluoro-α-Jia Jibianji chlorine replace 3,4-difluoro benzyl bromide, preparation title compound (output: 80mg, 45%).M.p.139-141℃。 1HNMR(300MHz，CDCl 3)δ1.83(d，J＝6Hz，3H)，4.79(s，2H)，6.32(q，J＝7Hz，1H)，6.84(m，1H)，6.97(t，J＝9Hz，2H)，7.02(dd，J＝6Hz，1.5Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.28(d，J＝9Hz，2H)，7.85(s，1H)，7.9(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?486(M+H) +。C 24H 18F 3N 3O 3The analytical calculation value of S: C, 59.37; H, 3.73; N, 8.65.Measured value: C, 59.00; H, 3.70; N, 8.35.
Embodiment 1482-(Alpha-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 3,4-two fluoro-α-Jia Jibianji chlorine replace 3,4-difluoro benzyl bromide, preparation title compound (output: 200mg, 58%).M.p.214-215℃。 1HNMR(300MHz，CDCl 3)δ1.82(d，J＝6Hz，3H)，4.7(s，2H)，6.35(q，J＝7Hz，1H)，6.96(t，J＝9Hz，2H)，7.16(m，4H)，7.28(d，J＝9Hz，2H)，7.37(m，1H)，7.84(d，J＝9Hz，2H)，7.90(s，1H)。MS(DCI-NH 3)m/z?486(M+H) +。C 24H 18F 3N 3O 3The analytical calculation value of S: C, 59.37; H, 3.73; N, 8.65.Measured value: C, 59.13; H, 3.73; N, 8.54.
Embodiment 1492-(3-luorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, replace 3 with the 3-fluoro benzyl bromide, 4-difluoro benzyl bromide, preparation title compound (output: 160mg, 61%).M.p.220-222℃。 1H?NMR(300MHz，DMSO-d 6)δ5.37(s，2H)，7.12(t，J＝9Hz，2H)，7.22(m，5H)，7.39(m，5H)，7.73(d，J＝9Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z?454(M+H) +。C 23H 17F 2N 3O 3The analytical calculation value of S: C, 60.92; H, 3.77; N, 9.26.Measured value: C, 61.06; H, 4.22; N, 8.88.
Embodiment 1502-(4-luorobenzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, replace 3 with the 4-fluoro benzyl bromide, 4-difluoro benzyl bromide, preparation title compound (output: 85mg, 34%).M.p.237-239℃。 1H?NMR(300MHz，DMSO-d 6)δ5.32(s，2H)，7.12(t，J＝9Hz，2H)，7.22(m，4H)，7.38(m，4H)，7.47(dd，J＝9Hz，6Hz，2H)，7.72(d，J＝9Hz，2H)，8.10(s，1H)。MS(DCI-NH 3)m/z?454(M+H) +。C 23H 17F 2N 3O 3The analytical calculation value of S: C, 60.92; H, 3.77; N, 9.26.Measured value: C, 60.61; H, 3.96; N, 8.74.
Embodiment 1512-(2,4, the 6-trifluoro-benzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 2,4,6-trifluoro-benzyl bromine replaces 3,4-difluoro benzyl bromide, preparation title compound (output: 255mg, 73%).M.p.201-203℃。 1HNMR(300MHz，DMSO-d 6)δ5.38(s，2H)，7.13(t，J＝9Hz，2H)，7.23(m，4H)，7.38(d，J＝9Hz，2H)，7.42(s，2H)，7.70(d，J＝9Hz，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?490(M+H) +。C 23H 15F 4N 3O 3The analytical calculation value of S: C, 56.44; H, 3.08; N, 8.58.Measured value: C, 56.31; H, 3.09; N, 8.40.
Embodiment 1522-(2,4, the 5-trifluoro-benzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 2,4,5-trifluoro-benzyl bromine replaces 3,4-difluoro benzyl bromide, preparation title compound (output: 180mg, 49%).M.p.236-238℃。 1HNMR(300MHz，DMSO-d 6)δ5.35(s，2H)，7.13(t，J＝9Hz，2H)，7.23(dd，J＝9Hz，6Hz，2H)，7.39(d，J＝9Hz，2H)，7.41(s，2H)，7.6(m，2H)，7.72(d，J＝9Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z?490(M+H) +。C 23H 15F 4N 3O 3The analytical calculation value of S: C, 56.44; H, 3.08; N, 8.58.Measured value: C, 56.38; H, 3.28; N, 8.41.
Embodiment 1532-(2,3, the 4-trifluoro-benzyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 127, with 2,3,4-trifluoro-benzyl bromine replaces 3,4-difluoro benzyl bromide, preparation title compound (output: 220mg, 63%).M.p.218-220℃。 1HNMR(300MHz，DMSO-d 6)δ5.40(s，2H)，7.13(t，J＝9Hz，2H)，7.22(dd，J＝9Hz，6Hz，2H)，7.34(m，2H)，7.39(d，J＝9Hz，2H)，7.42(s，2H)，7.73(d，J＝9Hz，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?490(M+H) +。C 23H 15F 4N 3O 3The analytical calculation value of S: C, 56.44; H, 3.08; N, 8.58.Measured value: C, 56.32; H, 3.24; N, 8.31.
Embodiment 1542-(4,4,4-three fluoro-3-methyl-2E-butenyls)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 123, with 1-bromo-3-methyl-4,4,4-three fluoro-2-butylene replace 1-bromo-3-methyl-2-butene, preparation title compound (output: 160mg, 48%).M.p.155-157℃。 1H?NMR(300MHz，CDCl 3)δ2.00(s，3H)，4.8(s，2H)，4.96(d，J＝7.5Hz，2H)，6.33(m，1H)，6.99(t，J＝9Hz，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.29(d，J＝9Hz，2H)，7.65(s，1H)，7.97(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?468(M+H) +。C 21H 17F 4N 3O 3The analytical calculation value of S: C, 53.96; H, 3.66; N, 8.98.Measured value: C, 53.84; H, 3.51; N, 8.77.
Embodiment 1552-(4-xenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.275g, 100%) with the 4-bromo biphenyl.M.p.249-251℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.16(m，2H)，7.30(m，2H)，7.42(m，1H)，7.48-7.58(m，4H)，7.75(m，4H)，7.84(m，2H)，7.91(m，2H)，8.27(s，1H)。MS(DCI-NH 3)m/z?497(M+H) +，514(M+NH 4) +。C 23H 21FN 2O 3The analytical calculation value of S: C, 70.15; H, 4.26; N, 5.64.Measured value: C, 69.81; H, 4.42; N, 5.41.
Embodiment 1562-(4-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 1, the 4-dibromobenzene replaces 4-iodo-1-fluorobenzene, preparation title compound (output: 0.337g, 93%). 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.14(m，2H)，7.28(m，2H)，7.64(m，2H)，7.75(m，2H)，7.90(m，2H)，8.25(s，1H)。MS(DCI-NH 3)m/z?499(M+H) +，518(M+NH 4) +。C 23H 16BrFN 2O 3S0.75H 2The analytical calculation value of O: C, 53.86; H, 3.43; N, 5.46.Measured value: C, 53.92; H, 3.16; N, 5.34.
Embodiment 1572-(4-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.45g, 100%) with 1-iodo-4-oil of mirbane.M.p.110-116℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.17(m，2H)，7.32(m，2H)，7.53(m，2H)，7.91(m，2H)，8.03(m，2H)，8.34(s，1H)，8.40(m，2H)。MS(DCI-NH 3)m/z?466(M+H) +，483(M+NH 4) +。C 23H 16FN 3O 5The analytical calculation value of S: C, 59.35; H, 3.46; N, 9.03.Measured value: C, 59.02; H, 3.62; N, 8.82.
Embodiment 1582-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.667g, 22%) with 4-bromine diphenyl ether.M..p.118-125℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.12(m，5H)，7.15-7.33(m，4H)，7.46(m，2H)，7.52(m，2H)，765(m，2H)，7.90(m，2H)，8.23(s，1H)。MS(DCI-NH 3)m/z?513(M+H) +。C 25H 16FN 2O 4S0.75H 2The analytical calculation value of O: C, 66.21; H, 4.31; N, 5.32.Measured value: C, 65.98; H, 4.25; N, 5.27.
Embodiment 1592-(4-tert-butyl-phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound with 1-bromo-4-tert.-butylbenzene.Do not observe product.With solution for vacuum concentration.The solid of gained is dissolved among the DMF (5ml), and adding CuI (13.3mg, 0.07mmol).Allowing solution reflux spends the night.When finishing, mixture is inclined to 10% citric acid solution, use ethyl acetate extraction.Organic layer washes with water, through dried over mgso and vacuum concentration.Rough solid adopts flash chromatography (SiO 2) purifying, with 5% ether/methylene dichloride wash-out, obtain required product (output: 0.292g, 84%).M.p.132-136℃。 1H?NMR(300MHz，DMSO-d 6)δ1.34(s，9H)，3.24(s，3H)，7.14(m，2H)，7.29(m，2H)，7.54(m，6H)，7.90(m，2H)，8.23(s，1H)。MS(DCI-NH 3)m/z?477(M+H) +，494(M+NH 4) +。C 27H 25FN 2O 3The analytical calculation value of S: C, 68.05; H, 5.29; N, 5.88.Measured value: C, 67.94; H, 5.31; N, 5.67.
Embodiment 1602-(4-chloro-phenyl-)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.254g, 83.5%) with 4-bromo-1-chlorobenzene.M.p.214-216℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.16(m，2H)，7.29(m，2H)，7.52(m，2H)，7.61(m，2H)，7.71(m，2H)，7.91(m，2H)，8.26(s，1H)。MS(DCI-NH 3)m/z?455(M+H) +，472(M+NH 4) +。C 23H 16ClFN 2O 3The analytical calculation value of S: C, 60.73; H, 3.55; N, 6.16.Measured value: C, 60.45; H, 3.41; N, 6.05.
Embodiment 1612-(3-aminomethyl phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.262g, 83%) with the 3-toluene bromide.M.p.213-216℃。 1H?NMR(300MHz，DMSO-d 6)δ2.39(s，3H)，3.24(s，3H)，7.14(m，2H)，7.28(m，3H)，7.43(m，3H)，7.53(m，2H)，7.80(m，2H)，8.22(s，1H)。MS(DCI-NH 3)m/z435(M+H) +，452(M+NH 4) +。C 24H 19FN 2O 3The analytical calculation value of S: C, 66.35; H, 4.41; N, 6.45.Measured value: C, 66.00; H, 4.16; N, 6.23.
Embodiment 1622-(3-ethenylphenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.202g, 62%) with the 3-bromstyrol.M.p.182-183℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，5.35(d，J＝12Hz，1H)，5.92(d，J＝15Hz，1H)，6.82(m，1H)，7.15(m，2H)，7.30(m，2H)，7.50-7.60(m，4H)，7.74(m，2H)，7.91(m，2H)，8.24(s，1H)。MS(DCI-NH 3)m/z?447(M+H) +，464(M+NH 4) +。C 25H 19FN 2O 3S0.50H 2The analytical calculation value of O: C, 65.92; H, 4.42; N, 6.14.Measured value: C, 65.86; H, 4.40; N, 6.07.
Embodiment 1632-(2-formyl radical phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.196g, 60%) with the 2-bromobenzaldehyde.M.p.234-236℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.15(m，2H)，7.27(m，2H)，7.54(m，2H)，7.64-7.75(m，2H)，7.86-7.95(m，3H)，8.01(m，1H)，8.29(s，1H)，10.02(s，1H)。MS(DCI-NH 3)m/z?449(M+H) +。C 24H 17FN 2O 4S0.50H 2The analytical calculation value of O: C, 63.01; H, 3.96; N, 6.12.Measured value: C, 63.04; H, 3.82; N, 5.88.
Embodiment 1642-(2-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.307g, 90.8%) with 1-bromo-2-oil of mirbane.M.p.236-239℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.12-7.27(m，4H)，7.56(m，2H)，7.7-8.01(m，5H)，8.18(m，1H)，8.35(s，1H)。MS(DCI-NH 3)m/z?466(M+H) +，483(M+NH 4) +。C 23H 16FN 3O 5S0.25H 2The analytical calculation value of O: C, 58.78; H, 3.53; N, 8.94.Measured value: C, 58.63; H, 3.54; N, 8.88.
Embodiment 1652-(3-chloro-phenyl-)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.255g, 77%) with 1-bromo-3-chlorobenzene.M.p.232-235℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，7.14(m，2H)，7.29(m，2H)，7.49-7.58(m，4H)，7.66(m，1H)，7.79(m，1H)，7.90(m，2H)，8.25(s，1H)。MS(DCI-NH 3)m/z?455(M+H) +，472(M+NH 4) +。C 23H 16ClFN 2O 3The analytical calculation value of S: C, 60.73; H, 3.55; N, 6.16.Measured value: C, 60.40; H, 3.43; N, 5.98.
Embodiment 1662-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 1, the 3-dibromobenzene replaces 4-iodo-1-fluorobenzene, preparation title compound (output: 0.216g, 60%).M.p.210-212℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，7.15(m，2H)，7.29(m，2H)，7.48-7.55(m，3H)，7.69(m，2H)，7.90(m，3H)，8.26(s，1H)。MS(DCI-NH 3)m/z?499(M+H) +，519(M+NH 4) +。C 23H 16BrFN 2O 3The analytical calculation value of S: C, 55.32; H, 3.23; N, 5.61.Measured value: C, 55.12; H, 3.12; N, 5.51.
Embodiment 1672-(4-cyano-phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.349g, 100%) with the 4-bromobenzylcyanide.M.p.273-278℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.11-7.21(m，2H)，7.25-7.35(m，2H)，7.52(m，2H)，7.88-7.96(m，4H)，8.04(m，2H)，8.31(s，1H)。MS(DCI-NH 3)m/z?445(M+H) +。C 24H 16FN 3O 3The analytical calculation value of S: C, 64.71; H, 3.62; N, 9.43.Measured value: C, 64.50; H, 3.53; N, 9.35.
Embodiment 1682-(5-methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.200g, 62%) with 2-bromo-5-thiotolene.M.p.219-224℃。 1H?NMR(300MHz，DMSO-d 6)δ2.45(s，3H)，3.23(s，3H)，6.80(m，1H)，7.17(m，2H)，7.29(m，2H)，7.52(m，2H)，7.89(m，2H)，8.33(s，1H)。MS(DCI-NH 3)m/z?441(M+H) +，458(M+NH 4) +。C 22H 17FN 2O 3S 2The analytical calculation value: C, 59.99; H, 3.89; N, 6.36.Measured value: C, 59.90; H, 3.91; N, 6.26.
Embodiment 1692-(3-xenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.28g, 78%) with the 3-bromo biphenyl.M.p.126-134℃。 1H?NMR(300MHz，DMSO-d 6)δ3.24(s，3H)，7.15(m，2H)，7.31(m，2H)，7.37-7.45(m，1H)，7.51(m，4H)，7.64(m，2H)，7.68-7.79(m，3H)，7.92(m，3H)，8.27(s，1H)。MS(DCI-NH 3)m/z?497(M+H) +，514(M+NH 4) +。C 29H 21FN 2O 3The analytical calculation value of S: C, 70.15; H, 4.26; N, 5.64.Measured value: C, 69.91; H, 4.33; N, 5.74.
Embodiment 1702-(3, the 5-3,5-dimethylphenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 4-iodo-1-fluorobenzene, preparation title compound (output: 0.152g, 46.5%) with 5-bromo-m-xylene.M.p.130-134℃。 1H?NMR(300MHz，DMSO-d 6)δ2.34(s，6H)，3.23(s，3H)，7.07-7.12(m，2H)，7.15(m，1H)，7.21-7.32(m，4H)，7.52(m，2H)，7.90(m，2H)，8.29(s，1H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 25H 21FN 2O 3The analytical calculation value of S: C, 66.95; H, 4.72; N, 6.25.Measured value: C, 66.81; H, 4.57; N, 6.07.
Embodiment 1712-(3, the 4-difluorophenyl)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 11; with 2-benzyl-4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones begin; preparation 4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (output: 0.3319g, 83%).
Method according to embodiment 62; with 4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and with 1-bromo-3; 4-two fluorobenzene replace 4-iodo-1-fluorobenzene; preparation title compound (output: 0.085g, 54%).M.p.157-159℃。 1H?NMR(300MHz，DMSO-d 6)δ3.30(s，3H)，3.88(bs，2H)，7.04(m，4H)，7.49-7.66(m，2H)，7.70(m，2H)，7.81(m，1H)，8.12(s，1H)。MS(DCI-NH 3)m/z?471(M+H) +，488(M+NH 4) +。C 24H 17F 3N 2O 3S0.25H 2The analytical calculation value of O: C, 60.69; H, 3.71; N, 5.84.Measured value: C, 6.39; H, 3.76; N, 5.81.
Embodiment 1722-(3-chloro-4-fluorophenyl)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 62; with 4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 4-iodo-1-fluorobenzene with 4-bromo-2-chloro-1-fluorobenzene; preparation title compound (output: 0.110g, 74%).M.p.153-156℃。 1H?NMR(300MHz，DMSO-d 6)δ3.30(s，3H)，3.89(bs，2H)，7.02-7.07(m，4H)，7.59(m，1H)，7.65-7.72(m，4H)，8.07(m，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?487(M+H) +，504(M+NH 4) +。C 24H 17ClF 2N 2O 3S0.25H 2The analytical calculation value of O: C, 58.65; H, 3.58; N, 5.64.Measured value: C, 58.41; H, 3.56; N, 5.36.
Embodiment 1732-(2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 98mg, 40%) with the 2-bromothiophene.M.p.215-217℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.18(m，J＝9Hz，3H)，7.29(m，2H)，7.42(d，2H)，7.75(d，1H)，7.93(d，J＝9Hz)，8.4(s，1H)。MS(DCI-NH 3)m/z427(M+H) +，444(M+NH 4) +。C 21H 15FN 2O 3S 2The analytical calculation value: C, 59.14; H, 3.54; N, 6.57.
Embodiment 1742-(4-trifluoromethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 185mg, 64%) with 1-bromo-4-trifluoromethylbenzene.M.p.171-173℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.18(t，2H)，7.29(m，2H)，7.52(d，J＝9Hz，2H)，7.91(d，J＝9Hz，2H)，7.93(s，4H)，8.32(s，1H)。MS(DCI-NH 3)m/z?489(M+H) +，506(M+NH 4) +。C 24H 16F 4N 2O 3The analytical calculation value of S: C, 59.02; H, 3.3; N, 5.74.Measured value: C, 58.75; H, 3.35; N, 5.69.
Embodiment 1752-[4-(1-pyrryl) phenyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene with 1-(4-iodophenyl) pyrroles, preparation title compound (output: 140mg, 50%).M.p.229-231℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，6.3(t，2H)，7.18(t，2H)，7.29(m，2H)，7.46(t，2H)，7.53(d，J＝9Hz，2H)，7.75(s，4H)，7.91(t，J＝9Hz，2H)，8.27(s，1H)。MS(DCI-NH 3)m/z?486(M+H) +，504(M+NH 4) +。C 27H 20FN 3O 3S0.5H 2The analytical calculation value of O: C, 66.79; H, 4.15; N, 8.65.Measured value: C, 65.21; H, 4.29; N, 8.12.
Embodiment 1762-(5-chloro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 225mg, 93%) with 1-bromo-5-chlorothiophene.M.p.190-192℃。 1H?NMR(300MHz，DMSO-d 6)δ2.38(s，3H)，3.25(s，3H)，7.15(t，2H)，7.29(m，4H)，7.5(D，4H)，7.91(d，J＝9Hz，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z435(M+H) +，452(M+NH 4) +。C 24H 19FN 2O 3The analytical calculation value of S: C, 66.35; H, 4.41; N, 6.45.Measured value: C, 66.15; H, 4.37; N, 6.3.
Embodiment 1772-(4-aminomethyl phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 79mg, 31%) with 1-bromo-4-methylbenzene.M.p.190-192℃。 1H?NMR(300MHz，DMSO-d 6)δ2.38(s，3H)，δ3.25(s，3H)，7.15(t，2H)，7.29(m，4H)，7.5(D，4H)，7.91(d，J＝9Hz，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z435(M+H) +，452(M+NH 4) +。C 24H 19FN 2O 3The analytical calculation value of S: C, 66.35; H, 4.41; N, 6.45.Measured value: C, 66.15; H, 4.37; N, 6.3.
Embodiment 1782-(4-fluorophenyl)-4-(2-ethyl-1-hexyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under room temperature; to 2-ethyl-1-hexanol (65mg; 0.5mmol) THF (15ml) solution in add NaH (60% oil suspension) (20mg.0.5mmol); after 10 minutes; add 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl] and-3 (2H)-pyridazinones (193mg, 0.5mmol).With the mixture of gained restir 2 hours under room temperature.Mixture is used ethyl acetate extraction with 10% citric acid quenching.Dried over mgso is used in extract water, salt water washing, and through chromatography purification (silica gel, 2: 1 hexane-ethyl acetate), obtains required product (output: 140mg, 60%).M.p.120-122℃。 1H NMR (300MHz, DMSO-d 6) δ 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quintet, J=7Hz, 2H), 1.44 (m, 1H), 3.27 (s, 3H), 4.30 (d, J=6Hz, 2H), 7.37 (t, J=9Hz, 2H), 7.65 (m, 2H), 7.89 (d, J=9Hz, 2H), 8.06 (d, J=9Hz, 2H), 8.18 (s, 1H).MS(APCI+)m/z?473(M+H) +；(APCI-)m/z?507(M+Cl) -。C 25H 29FN 2O 4S0.5H 2The analytical calculation value of O: C, 62.35; H, 6.27; N, 5.87.Measured value: C, 62.22; H, 6.14; N, 6.22.
Embodiment 1792-(3-thienyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 225mg, 93%) with 3 bromo thiophene.M.p.200-202℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.15(t，2H)，7.29(m，2H)，7.5(d，J＝9Hz，2H)，7.6(M，1H)，7.66(dd，1H)，7.91(d，J＝9Hz，2H)，8.13(dd，1H)，8.25(s，1H)。MS(DCI-NH 3)m/z?427(M+H) +，444(M+NH 4) +。C 21H 15FN 2O 3S 2The analytical calculation value: C, 55.07; H, 4.07; N, 6.11.Measured value: C, 54.63; H, 3.47; N, 6.01.
Embodiment 1802-(3, the 5-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 3,5-difluoro bromobenzene replaces 1-bromo-4-fluorobenzene, preparation title compound (output: 250mg, 96%).M.p.166-168℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，δ7.15(t，2H)，7.27(m，2H)，7.4(m，1H)，7.41(m，2H)，7.51(d，J＝9Hz，4H)，7.9(d，J＝9Hz，2H)，8.3(s，1H)。MS(DCI-NH 3)m/z?457(M+H) +，474(M+NH 4) +。C 23H 15F 3N 2O 3The analytical calculation value of S: C, 60.13; H, 3.31; N, 6.14.Measured value: C, 60.49; H, 3.31; N, 6.03.
Embodiment 1812-(2,4 difluorobenzene base)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 2,4-difluoro bromobenzene replaces 1-bromo-4-fluorobenzene, preparation title compound (output: 40mg, 15%).M.p.245-247℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，δ7.15(t，2H)，7.3(t，2H)，7.54(m，2H)，7.57(m，2H)，7.75(m，1H)，7.9(d，J＝9Hz，2H)，8.27(s，1H)。MS(DCI-NH 3)m/z?457(M+H) +，474(M+NH 4) +。C 28H 15F 3N 2O 3The analytical calculation value of S: C, 60.52; H, 3.31; N, 6.03.
Embodiment 1822-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 3,4-difluoro bromobenzene replaces 1-bromo-4-fluorobenzene, preparation title compound (output: 170mg, 70%).M.p.109-110℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，δ7.15(t，2H)，7.3(t，2H)，7.25(m，2H)，7.59(m，4H)，7.83(m，1H)，7.9(d，J＝9Hz，2H)，8.27(s，1H)。MS(DCI-NH 3)m/z?457(M+H) +，474(M+NH 4) +。C 23H 15F 3N 3O 3The analytical calculation value of S: C, 60.52; H, 3.31; N, 6.14.Measured value: C, 60.60; H, 3.48; N, 5.89.
Embodiment 1832-(3-furyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 175mg, 73%) with 3-bromine furans.M.p.239-242℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.09(d，1H)，7.15(t，2H)，7.29(m，2H)，7.5(d，J＝9Hz，2H)，7.8(t，1H)，7.91(d，J＝9Hz，2H)，8.3(s，1H)，8.58(s，1H)。MS(DCI-NH 3)m/z?411(M+H) +，428(M+NH 4) +。C 21H 15FN 2O 4S0.5H 2The analytical calculation value of O: C, 61.46; H, 3.68; N, 6.83.Measured value: C, 59.91; H, 3.54; N, 6.54.
Embodiment 1842-(3-fluoro-4-p-methoxy-phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 230mg, 85%) with 3-fluoro-4-methoxyl group bromobenzene.M.p.97-101℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，3.9(s，3H)，7.16(d，1H)，7.29(m，3H)，7.5(m，4H)，7.91(d，J＝9Hz，2H)，8.23(s，1H)。MS(DCI-NH 3)m/z?469(M+H) +，491(M+NH 4) +。C 24H 18F 2N 2O 4S0.5H 2The analytical calculation value of O: C, 61.53; H, 3.87:N, 5.98.Measured value: C, 61.18; H, 4.01; N, 5.58.
Embodiment 1852-(2-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 195mg, 75%) with the 2-bromofluorobenzene.M.p.96-103℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，δ7.15(t，2H)，7.3(m，3H)，7.55(m，5H)，7.9(d，J＝9Hz，2H)，8.27(s，1H)。MS(ESI)m/z?437(M-H) +。C 23H 16F 2N 2O 3The analytical calculation value of S: C, 63.01; H, 3.68; N, 6.39.Measured value: C, 62.19; H, 4.06; N, 5.99.
Embodiment 1862-[4-(amino-sulfonyl) phenyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound with 4-amino-sulfonyl-1-bromobenzene.M.p.213-216℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.15(t，2H)，7.29(m，2H)，7.53(s，2H)，7.55(s，1H)，7.7(dd，2H)，7.91(t，4H)，7.98(d，2H)，8.3(s，1H)。MS(DCI-NH 3)m/z499(M+H) +，517(M+NH 4) +。C 23H 18FN 3O 5S 20.5H 2The analytical calculation value of O: C, 55.30; H, 3.63; N, 8.41.Measured value: C, 54.4; H, 3.79; N, 7.78.
Embodiment 1872-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 320mg, 78%) with 3-chloro-4-fluoro-1-bromobenzene.M.p.155-157℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，δ7.15(t，2H)，7.3(t，2H)，7.25(m，2H)，7.53(d，J＝9Hz，2H)，7.59(t，1H)，7.73(m，1H)，7.9(d，J＝9Hz，2H)，7.96(m，1H)，8.27(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 23H 15ClF 2N 2O 3The analytical calculation value of S: C, 58.42; H, 3.2; N, 5.92.Measured value: C, 58.23; H, 2.87; N, 5.70.
Embodiment 1882-(3, the 5-dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, with 3,5-dichloro bromobenzene replaces 1-bromo-4-fluorobenzene, preparation title compound (output: 360mg, 78%).M.p.289-294℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，δ7.15(t，2H)，7.27(m，2H)，7.51(d，J＝9Hz，4H)，7.75(t，1H)，7.83(d，2H)，7.9(d，J＝9Hz，2H)，8.3(s，1H)。MS(DCI-NH 3)m/z?490(M+H) +，507(M+NH 4) +。C 23H 15Cl 2FN 2O 3S0.5H 2The analytical calculation value of O: C, 56.45; H, 3.09; N, 5.72.Measured value: C, 55.36; H, 3.00; N, 5.50.
Embodiment 1892-(4-fluoro-3-aminomethyl phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 275mg, 71%) with 1-bromo-4-fluoro-3-methylbenzene.M.p.168-170℃。 1H?NMR(300MHz，DMSO-d 6)δ2.3(s，3H)，δ3.25(s，3H)，7.15(t，2H)，7.3(m，3H)，7.56(m，4H)，7.9(d，2H)，8.23(s，2H)。MS(DCI-NH 3)m/z?453(M+H) +，471(M+NH 4) +。C 24H 18F 2N 2O 3The analytical calculation value of S: C, 63.71; H, 4.01; N, 6.01.Measured value: C, 63.53; H, 4.06; N, 5.92.
Embodiment 1902-(4-chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 220mg, 80%) with 4-bromo-1-chloro-2-fluorobenzene.M.p.102-110℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，7.11-7.19(m，2H)，7.25-7.32(m，2H)，7.51(d，J＝5.6Hz，2H)，7.58-7.64(m，1H)，7.75-7.87(m，2H)，7.91(d，J＝5.6Hz，2H)，8.28(s，1H)。MS(APCI+)m/z?473(M+H) +。
Embodiment 1912-(the fluorine-based phenyl of 4-chloro-2-)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, replace 1-bromo-4-fluorobenzene, preparation title compound (output: 65mg, 24%) with 1-bromo-4-chloro-2-fluorobenzene.M.p.250-260℃。 1H?NMR(300MHz，DMSO-d 6)δ3.21(s，3H)，7.12-7.19(m，2H)，7.25-7.32(m，2H)，7.49-7.58(m，3H)，7.68-7.78(m，2H)，7.91(d，J＝8.7Hz，2H)，8.29(s，1H)。MS(APCI+)m/z?473(M+H) +。C 23H 15ClF 2N 2O 3The analytical calculation value of S: C, 58.41; H, 3.19; N, 5.92.Measured value: C, 58.69; N, 3.45; N, 5.78.
Embodiment 1922-(1-Buddha's warrior attendant carbalkoxy)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Preparation is according to 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of the method for embodiment 11 preparation]-3 (2H)-pyridazinones (200mg, 0.58mmol) solution in methylene dichloride (8ml) and with its stirring.Add 1-adamantyl fluoro manthanoate (172mg, 0.87mmol), dimethyl aminopyridine (14mg, 0.011mmol) and triethylamine (0.12ml.0.87mmol).Reaction mixture stirred under room temperature spend the night.Reaction mixture is with methylene dichloride (50ml) dilution, with 10% citric acid (50ml) and salt solution (50ml) washing, through dried over mgso and vacuum concentration.The rough resistates flash chromatography (SiO of gained 2, with 15: 1 methylene dichloride: the purifying ether wash-out) obtained required product (output: 55mg, 18%). 1H?NMR(300MHz，DMSO-d 6)δ1.66(bs，6H)，2.25(bd，10H)，3.21(s，3H)，7.15(t，2H)，7.24(m，2H)，7.6(dd，2H)，7.88(d，J＝9Hz，2H)，8.15(s，1H)。MS (ESI) m/z 521 (M-H) +, C 21H 15FN 2O 3S 2Analytical calculation value: C, 64.35; H, 5.20; N, 5,36.
Embodiment 1932-(2,2, the 2-trifluoroethyl)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 193A.2-(2,2, the 2-trifluoroethyl)-4,5-two chloro-3 (2H)-pyridazinones
((70% the aqueous solution, 35.0g's 2-trifluoroethyl hydrazine 0.307mol), reflux them 5 hours for 51.88g, ethanol 0.307mol) (300ml) solution-treated 2,2 with mucochloric acid.The vacuum concentration solvent.The crystal that obtains washes with water and air-dry (output: 50g, 67.5%). 1H?NMR(300MHz，CDCl 3)d?4.8(q，J＝9Hz，2H)，7.85(s，1H)。MS(DCI-NH 3)m/z264(M+NH 4) +。193B. 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-hydroxyl-3 (2H)-pyridazinone
With 2-(2,2, the 2-trifluoroethyl)-4, (10g 72.4mmol) mixes with water (500ml), and refluxes and stirred 6 hours down for 5-two chloro-3 (2H)-pyridazinones (15.0m 60.7mmol) and salt of wormwood.TLC (1: 1: 2 dichloromethane/hexane/ethyl acetate) shows that all raw materials exhaust.Reaction mixture is cooled to room temperature.With hydrochloric acid (15%) pH of reaction mixture is transferred to about 4.Product extracts with ethyl acetate (700ml).Organic phase salt water washing is through anhydrous magnesium sulfate washing and filtration.Concentrating under reduced pressure filtrate.Obtaining described oxy-compound is light brown solid (output: 13.1g, 94%). 1H?NMR(300MHz，DMSO-d 6)δ4.92(q，J＝9Hz，2H)，7.9(s，1H)。MS(DCI-NH 3)m/z?229(M+NH 4) +。193C. 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-(trifluoromethyl sulfonyloxy)-3 (2H)-pyridazinones
(9.04m 85.32mmol) places the 500ml round-bottomed flask, adds anhydrous methylene chloride (200ml) with anhydrous sodium carbonate.Reaction mixture is cooled to 0 ℃ under nitrogen.The halogenated hydroxyl pyridazinone for preparing among the embodiment 193B is dissolved in the methylene dichloride (100ml), it is added to also to stir in the flask lentamente spend the night.With the slow ground temperature of reactant to room temperature.(TLC (2: 1 hexane/ethyl acetate) demonstration reaction is finished).The quenching of reactant water.Separate the organic phase that contains described product, with the salt water washing and through dried over mgso.Concentrating under reduced pressure gained filtrate.Isolate described raw product, be dark red brown resistates.With silicagel column (30: 70 ethyl acetate/pentanes) purifying, obtain title compound garnet resistates (14.3m, 70%). 1H?NMR(300MHz，CDCl 3)δ4.85(q，J＝9Hz，2H)，7.9(s，1H)。MS(DCI-NH 3)m/z?378(M+H) +。193D. 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
With the triflate (1.56g for preparing among the embodiment 193C, 4.3mmol), 4-(methylthio group) phenylo boric acid (870mg, 5.16mmol), four (triphenylphosphine)-palladium (O) (250mg, 5%mmol) and triethylamine (1.44ml, heating was 1 hour under 10.32mmol) solution in toluene refluxed.Mixture is allocated between ethyl acetate and the water.Ethyl acetate layer washes with water, uses the salt water washing then, then through dried over mgso and filtration.Vacuum concentrated filtrate.Resistates is through column chromatography purification (silica gel, 92: 8 hexane/ethyl acetate), the shallow yellow-green colour solid (output: 500mg, 35%) that slightly is of the intermediate that obtains coupling.M.p.130-139℃。 1H?NMR(300MHz，CDCl 3)δ2.55(s，3H)，4.87(q，J＝9Hz，2H)，7.37(d，J＝9Hz，2H)，7.48(d，J＝9Hz，2H)，7.82(s，1H)。MS(DCI-NH 3)m/z?335(M+H) +。193E. 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, with intermediate replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl of the coupling for preparing among the embodiment 193D]-3 (2H)-pyridazinones, preparation title compound (output: 440mg, 81%).M.p.221-222℃。 1H?NMR(300MHz，DMSO-d 6)δ3.33(s，3H)，5.10(q，J＝9Hz，2H)，7.90(d，J＝9Hz，2H)，8.12(d，J＝9Hz，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?367(M+H) +。193F. 2-(2,2, the 2-trifluoroethyl)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Magnesium chips (500mg) is placed exsiccant 250ml round-bottomed flask.Under room temperature nitrogen, add anhydrous diethyl ether (20ml), add fluoro benzyl bromide (3ml) and stirring then.Reactant was heated 2 hours in 40 ℃.All magnesium exhaust, and obtain the shallow yellow-brownish solution that slightly is.With 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl for preparing among the embodiment 193E]-3 (2H)-pyridazinones are dissolved among the exsiccant THF (25ml), and are transferred in the Grignard solution.With mixture heating up 3 hours.TLC (2: 1 hexane/ethyl acetate) shows that the pyridazinone raw material exhausts.) reactant is cooled to room temperature, use the saturated ammonium chloride solution quenching.Described product extracts with ethyl acetate (250ml), and organic layer adopts saturated ammonium chloride solution and salt water washing.Ethyl acetate solution is through dried over mgso and filtration.Concentrating under reduced pressure filtrate.Isolate described product, be orange residue.With silicagel column (20: 80 ethyl acetate/pentanes) purifying, obtain title compound, be pale yellow powder (output: 140mg, 28%). 1H?NMR(300MHz，CDCl 3)δ3.13(s，3H)，4.85(m，2H)，6.93(m，4H)，7.49(d，J＝9Hz，2H)，7.72(s，1H)，8.08(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?441(M+H) +。C 20H 16F 4N 2O 3S0.5H 2The analytical calculation value of O: C, 53.45; H, 3.81; N, 6.23.Measured value: C, 53.45; H, 3,81; N, 6.23.
Embodiment 1942-(4-fluorophenyl)-4-(4-fluorophenoxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 194A. 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones
(5.0g 19.4mol) handles with 4-fluorobenzene hydrazine HCl, and the bath temperature of heterogenetic mixture in 115 ℃ refluxed 15 hours will to be dissolved in Mucobromic acid in the acetate (110ml).During reaction, mixture becomes uniform dark red solution, when being cooled to 23 ℃, forms crystalline precipitate.Incline solution to frozen water (1000ml) and stirred 20 minutes.Huang/brown crystal is leached,, obtain 5.8g (86%) product with extra cold water washing and vacuum-drying.(J.Het.Chem.，1993，30，1501；Heterocycles?1985，23，2603)。 1H?NMR(300MHz，DMSO-d 6)δ7.31-7.41(m，2H)，7.57-7.64(m，2H)，8.29(s，1H)。MS (DCI+) m/z 347 (Br 79Br 79M+H) +, m/z 349 (Br 79Br 81M+H) +, m.z 364 (Br 79Br 79M+NH 4) +And m/z 366 (Br 79Br 81, M+NH 4) +194B. 2-(4-fluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone
With the 2-(4-fluorophenyl)-4 of above preparation, 5-two bromo-3 (2H)-pyridazinones (7.18g, 20.6mmol) the 23 ℃ of homogeneous solution methyl alcohol (0.843ml in tetrahydrofuran (THF) (322ml), 20.8mmol) handle, handle with NaH (0.833g, 20.8mmol, 60% oil suspension) after 5 minutes.This exothermic heat of reaction number minute continues reaction 8 hours (noting: finished several reactions this moment) in 23 ℃ then.Reaction is not finished as yet, therefore temperature is risen to backflow and carries out 4 hours again.Reaction remains unfulfilled.As mentioned above in other flask, with the NaOMe solution of 0.1 part of a great deal of of material refabrication of following amount: 32ml tetrahydrofuran (THF), 0.084ml methyl alcohol and 83mg 60% NaH oil suspension.By syringe this NaOMe solution is added in the reaction mixture that is cooled to 23 ℃, temperature is risen to refluxed 4 hours then.Reaction remains unfulfilled, and therefore, the NaOMe solution of 0.1 part of a great deal of of refabrication with its adding, refluxes reactant as mentioned above.After 4 hours, reaction is finished.Mixture is cooled to 23 ℃ and be diluted with water to 2000ml.Huang/the white precipitate that forms is leached,, obtain 5.39g (88%) product with extra water washing and vacuum concentration.(J.Het.Chem.，1988，25，1757)。 1H?NMR(300MHz，DMSO-d 6)δ4.13(s，3H)，7.30-7.40(m，2H)，7.56-7.62(m，2H)，8.22(s，1H)。MS (APCI+) m/z 299 (Br 79M+H) +With m/z 301 (Br 81M+H) +194C. 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 6, replace 2 benzyls-4-bromo-5-methoxyl group-3 (2H)-pyridazinone with 2-(4-fluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone, and, prepare title compound (output: 70mg, 61%) with 4-(methylthio group)-phenylo boric acid replacement 4-fluorobenzoic boric acid. 1H?NMR(300MHz，DMSO-d 6)δ2.54(s，3H)，4.02(s，3H)，7.35(dd，J＝9.0，9.0Hz，2H)，7.39(d，J＝8.5Hz，2H)，7.61(d，J＝8.5Hz，2H，7.65(dd，J＝9.0，5.0Hz，2H)，8.14(s，1H)。MS(APCI+)m/z?343(M+H) +。194D. 2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with methyl-magnesium-bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 0.83g, 87%). 1H?NMR(300MHz，CDCl 3)δ2.25(s，3H)，2.55(s，3H)，7.17(dd，J＝8.8，8.8Hz，2H)，7.31(d，J＝8.7Hz，2H)，7.38(d，J＝8.7Hz，2H)，7.61-7.68(m，2H).7.82(s，1H)。MS(APCI+)m/z?327(M+H) +。194E. 2-(4-fluorophenyl)-4-methyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 473mg, 86%). 1H?NMR(300MHz，CDCl 3)δ2.24(s，3H)，3.14(s，3H)，7.19(d，J＝8.8，8.8Hz，2H)，7.61(d，J＝8.4Hz，2H)，7.63-7.69(m，2H)，7.80(s，1H)，8.12(d，J＝8.4Hz，2H)。MS (APCI+) m/z 359 (M+H) +With m/z 376 (M+NH 4) +194F. 2-(4-fluorophenyl)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To 2-(4-fluorophenyl)-4-methyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (590mg; 1.65mmol) and the homogeneous reflux solution of tetracol phenixin (24ml) in add N-bromine succinimide (output: 308mg fast; 1.73mmol); add then benzoyl peroxide (12mg, 0.05mmol).After 1 hour, this reaction only finishes nearly 50%.(12mg 0.05mmol), checks reaction again after 1 hour to add extra benzoyl peroxide.Reaction remains unfulfilled, therefore add again benzoyl peroxide (4mg, 0.017mmol).After 30 minutes, reaction is finished.Mixture is cooled to 23 ℃, dilutes with ethyl acetate.Acetate solution saturated sodium bicarbonate solution, water and salt water washing.This solution filters and vacuum concentration through dried over mgso.Resistates obtains described product (output: 530mg, 74%) through chromatography purification (quick silica gel, ethyl acetate/hexane gradient 1: 1 to 4: 1). 1H?NMR(300MHz，CDCl 3)δ3.16(s，3H)，4.34(s，2H)，7.20(d，J＝8.8，8.8Hz，2H)，7.67-7.74(m，2H)，7.82(d，J＝8.7Hz，2H)，7.86(s，1H)，8.17(d，J＝8.7Hz，2H)。MS(APCI+)m/z?437(M+H) +。194G. 2-(4-fluorophenyl)-4-(4-fluorophenoxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(4-fluorophenyl)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl in the acetone (4ml) of being dissolved in to above preparation]-3 (2H)-pyridazinone (107mg; 0.246mmol) and 4-fluorophenol (30.3mg; 0.270mmol) add in the solution potassium carbonate powder (37.3mg, 0.270mmol).Mixture in 23 ℃ of stirrings 2 hours, is passed through Celite Pad filters and vacuum concentration.Resistates obtains described product (output: 83mg, 72%) through chromatography purification (quick silica gel, ethyl acetate/hexane 3: 2).M.p.65-80℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，4.94(s，2H)，6.78-6.86(m，2H)，6.91-7.00(m，2H)，7.15-7.24(m，2H)，7.65-7.72(m，2H)，7.74(d，J＝8.7Hz，2H)，7.93(s，1H)，8.08(d，J＝8.7Hz，2H)。MS(APCI+)m/z?469(M+H) +。C 24H 18F 2N 2O 4The analytical calculation value of S: C, 61.53; H, 3.87; N, 5.97.Measured value: C, 61.22; H, 3.63; N, 5.64.
Embodiment 1952-(4-fluorophenyl)-4-(3-fluorophenoxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 194G, replace the 4-fluorophenol with the 3-fluorophenol, preparation title compound (output: 94mg, 88%).M.p.142-144℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，4.98(s，2H)，6.49-6.56(m，1H)，6.60-6.73(m，2H)，7.15-7.25(m，3H)，7.65-7.75(m，4H)，7.93(s，1H)，8.07(d，J＝8.7Hz，2H)。MS(APCI+)m/z?469(M+H) +。C 24H 18F 2N 2O 4The analytical calculation value of S: C, 61.53; H, 3.87; N, 5.97.Measured value: C, 61.20; H, 3.92; N, 5.86.
Embodiment 1962-(4-fluorophenyl)-4-phenoxymethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 294G, replace the 4-fluorophenol with phenol, preparation title compound (output: 67g, 93%).M.p.42-75℃。 1H?NMR(300MHz，DMSO-d 6)δ3.28(s，3H)，4.92(s，2H)，6.83-6.90(m，2H)，6.91-6.99(m，1H)，7.22-7.30(m，2H)，7.35-7.44(m，2H)，7.66-7.73(m，2H)，7.81-7.88(m，2H)，8.02-8.08(m，2H)，8.21(s，1H)。MS(APCI+)m/z?451(M+H) +。
Embodiment 1972-(4-fluorophenyl)-4-(uncle's butylthio methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With NaI (35mg; 0.233mmol) 2-(4-fluorophenyl)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl of preparing among the Processing Example 194F]-3 (2H)-pyridazinone (92.5mg; 0.212mmol) 0 ℃ of solution in acetone (2.5ml); after 5 minutes; remove cooling bath, with reactant temperature to 23 ℃.After 30 minutes, finish to 2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methyl sulphonyl) phenyl] conversion of-3 (2H)-pyridazinones (thin-layer chromatography, ethyl acetate/hexane 4: 1).Pass through Celite Pad leaches NaBr and residual NaI.Add extra acetone (2ml) and 2-methyl-2-propylmercaptan (20.5mg 0.227mmol), is cooled to 0 ℃ with solution, add then silver carbonate (63mg, 0.227mmol).After 5 minutes, remove cooling bath, with solution temperature to 23 ℃ 5 hours.Pass through Celite Filter reaction mixture and vacuum concentration.Resistates obtains described product (output: 57mg, 60%) through chromatographic separation (quick silica gel, ethyl acetate/hexane gradient 1: 1 to 3: 2).M.p.50-70℃。 1H?NMR(300MHz，CDCl 3)δ1.34(s，9H)，3.14(s，3H)，3.65(s，2H)，7.13-7.21(m，2H)，7.63-7.70(m，2H)，7.79(s，1H)，7.84(d，J＝8.7Hz，2H)，8.13(d，J＝8.7Hz，2H)。MS(APCI+)m/z447(M+H) +。C 22H 23FN 2O 3S 2The analytical calculation value: C, 59.17; H, 5.19; N, 6.27.Measured value: C, 59.48; H, 5.36; N, 5.90.
Embodiment 1982-(4-fluorophenyl)-4-(methyl-prop sulfenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 197, replace 2-methyl alcohol-2-propylmercaptan with 2-methyl isophthalic acid-propylmercaptan, preparation title compound (output: 66mg, 70%).M.p.45-60℃。 1H?NMR(300MHz，CDCl 3)δ0.95(d，J＝6.6Hz，2H)，1.67-1.82(m，1H)，2.62(d，J＝6.6Hz，2H)，3.15(s，3H)，3.61(s，2H)，7.19(dd，J＝8.2，8.2Hz，2H)，7.62-7.71(m，2H)，7.75(d，J＝8.4Hz，2H)，7.79(s，1H)，8.13(d，J＝8.4Hz，2H)。MS(APCI+)m/z?447(M+H) +。C 22H 23FN 2O 3S 2The analytical calculation value: C, 59.17; H, 5.19; N, 6.27.Measured value: C, 59.35; H, 5.25; N, 6.05.
Embodiment 1992-(4-fluorophenyl)-4-(2-propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Prepare title compound by following reaction sequence.According to the method for embodiment 194A, make Mucobromic acid and 4-fluorobenzene hydrazine reaction, obtain 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones.Method according to described in the embodiment 194B replaces methyl alcohol with Virahol, makes described two bromo-intermediates reaction, optionally in 4 reactions, obtains 2-(4-fluorophenyl)-4-(2-propoxy-)-5-bromo-3 (2H)-pyridazinone.
According to the method for embodiment 6, described 5-bromine compounds is coupled to 4-(methylthio group) phenylo boric acid, obtain title compound (output: 435mg, 53.9%).M.p.135-137℃。 1HNMR (300MHz, CDCl 3) δ 1.21 (d, J=6Hz, 6H), 2.55 (s, 3H), 5.26 (septet, J=6Hz, 1H), 7.17 (t, J=9Hz, 2H), 7.34 (d, J=9Hz, 2H), 7.57 (d, J=9Hz, 2H), 7.58-7.66 (m, 2H), 7.95 (s, 1H).MS(DCI-NH 3)m/z?371(M+H) +。
Embodiment 2002-(4-fluorophenyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, the methyl sulfide compound oxidation with preparation among the embodiment 199 obtains title compound (output: 240mg, 92%).M.p.160-162℃。 1HNMR(300MHz，DMSO-d 6)δ1.30(d，J＝6Hz，6H)，3.41(s，3H)，5.41(m，1H)，7.48(t，J＝9Hz，2H)，7.77(dd，J＝9Hz，6Hz，2H)，8.05(d，J＝9Hz，2H)，8.19(d，J＝9Hz，2H)，8.31(s，1H)。MS(DCI-NH 3)m/z?403(M+H) +，420(M+NH 4) +。C 20H 19FN 2O 4The analytical calculation value of S: C, 59.70; H, 4.73; N, 6.97.Measured value: C, 59.40; H, 4.86; N, 6.69.
Embodiment 2012-(3-chloro-phenyl-)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 199, in the first step, replace the 4-fluorophenyl hydrazine hydrochloride, preparation 2-(3-chloro-phenyl-)-4-(2-propoxy-)-5-[4-(methylthio group) phenyl with 3-chlorophenyl hydrazine hydrochloride]-3 (2H)-pyridazinones.According to the method for embodiment 10,, obtain title compound (output: 260mg, 80%) with the oxidation of gained methyl sulfide.M.p.134-136℃。 1H NMR (300MHz, CDCl 3) δ 1.24 (d, J=6Hz, 6H), 3.13 (s, 3H), 5.48 (septet, J=6Hz, 1H), 7.37-7.48 (m, 2H), 7.59 (dt, J=7Hz, 1.5Hz, 1H), 7.70 (br s, 1H), 7.84 (d, J=9Hz, 2H), 7.93 (s, 1H), 8.06 (d, J=9Hz, 2H).MS(DCI-NH 3)m/z?419(M+H) +，436(M+NH 4) +。C 20H 19ClN 2O 4The analytical calculation value of S: C, 57.42; H, 4.55; N, 6.70.Measured value: C, 57.08; H, 4.59; N, 6.44.
Embodiment 2022-(3-fluorophenyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 199, in the first step, replace the 4-fluorophenyl hydrazine hydrochloride with the 3-fluorophenyl hydrazine hydrochloride, prepare described methyl sulfide intermediate.According to the method for embodiment 10,, obtain title compound (output: 290mg, 72%) with gained methyl sulfide compound oxidation.M.p.110-112℃。 1H NMR (300MHz, CDCl 3) δ 1.31 (d, J=6Hz, 6H), 3.11 (s, 3H), 5.47 (septet, J=6Hz, 1H), 7.09-7.18 (m, 1H), 7.41-7.52 (m, 3H), 7.83 (d, J=9Hz, 2H), 7.93 (s, 1H), 8.08 (d, J=9Hz, 2H).MS(DCI-NH 3)m/z?403(M+H) +，447(M+NH 4) +。C 20H 19FN 2O 4The analytical calculation value of S: C, 59.70; H, 4.73; N, 6.97.Measured value: C, 59.54; H, 4.87; N, 6.70.
Embodiment 2032-(3-bromophenyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Replace the 4-fluorophenyl hydrazine hydrochloride with 3-bromophenyl-hydrazine hydrochloride,, prepare described methyl sulfide intermediate according to the method for embodiment 199.According to the method for embodiment 10,, obtain title compound (output: 75mg, 77.6%) with gained methyl sulfide compound oxidation.M.p.130-132℃。 1H NMR (300MHz, CDCl 3) δ 1.23 (d, J=6Hz, 6H), 3.15 (s, 3H), 5.48 (septet, J=6Hz, 1H), 7.38 (t, J=9Hz, 1H), 7.55 (br d, J=7Hz, 1H), 7.65 (br d, J=7Hz, 1H), 7.79-7.87 (m, 1H), 7.83 (d, J=9Hz, 2H), 8.13 (s, 1H), 8.06 (d, J=9Hz, 2H).MS(DCI-NH 3)m/z?465(M+H) +，480(M+NH 4) +。C 20H 19BrN 2O 4The analytical calculation value of S: C, 51.84; H, 4.10; N, 6.05.Measured value: C, 51.95; H, 4.18; N, 5.74.
Embodiment 2042-(2, the 5-difluorophenyl)-4-(2-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2,5-difluorophenyl hydrazine hydrochloride replaces the 4-fluorophenyl hydrazine hydrochloride, according to the method for embodiment 199, and preparation 2-(2, the 5-difluorophenyl)-4-(2-propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.
According to the method for embodiment 10,, obtain title compound (output: 390mg, 90%) with gained methyl sulfide compound oxidation.M.p.161-164℃。 1H NMR (300MHz, CDCl 3) δ 1.23 (d, J=6Hz, 6H), 3.12 (s, 3H), 5.55 (septet, J=6Hz, 1H), 7.12-7.29 (m, 3H), 7.82 (d, J=9Hz, 2H), 7.92 (s, 1H), 8.07 (d, J=9Hz, 2H).MS(DCI-NH 3)m/z?421(M+H) +，438(M+NH 4) +。C 20H 18F 2N 2O 4S0.5H 2The analytical calculation value of O: C, 55.94; H, 4.31; N, 6.53.Measured value: C, 55.86; H, 4.19; N, 6.38.
Embodiment 2052-(3-chloro-4-fluorophenyl)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Prepare title compound by following reaction sequence.According to the method for embodiment 194A, make the reaction of Mucobromic acid and 3-chlorine 4-fluorophenyl hydrazine hydrochloride, obtain 2-(3-chloro-4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones.According to the method described in the embodiment 194B, make described intermediate in 4 optionally with isopropylcarbinol and alkali reaction, obtain 2-(4-fluorophenyl)-4-[1-(2-methyl propoxy-)]-5-bromo-3 (2H)-pyridazinone.According to the method for embodiment 6, described 5-bromine compounds is coupled to 3-fluoro-4-(methylthio group) phenylo boric acid that embodiment 194C prepares, produce the intermediate methyl sulfide.According to the method for embodiment 10, described sulfide compound is oxidized to target sulfone (output: 810mg, 83.8%).M.p.142-144℃。 1H NMR (300MHz, CDCl 3) δ 0.90 (d, J=6Hz, 6H), 1.95 (septet, J=6Hz, 1H), 3.30 (s, 3H), 4.37 (d, J=6Hz, 2H), 7.26 (t, J=9Hz, 1H), 7.52-7.61 (m, 3H), 7.75 (dd, J=9Hz, 3Hz, 1H), 7.89 (s, 1H), 8.10 (t, J=9Hz, 1H).MS(DCI-NH 3)m/z?469(M+H) +，486(M+NH 4) +。
Embodiment 2062-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 206A. 2-methyl sulfo-phenylmethylethers
Preparation 2-bromine sulfo-phenylmethylether (10.53g, the 52mmol) solution in tetrahydrofuran (THF) (173ml), and be cooled to-78 ℃.Inwall along reaction vessel adds n-Butyl Lithium (21.8ml, 54.5mmol, the solution in the 2.5M hexane) lentamente.The yellow solution of gained was stirred 30 minutes, then along the reaction vessel inwall slowly add methyl-iodide with tetrahydrofuran (THF) (6ml) dilution (8.10g, 57.1mmol).Again mixture was stirred 30 minutes in-78 ℃.Remove cooling bath, mixture was stirred 1 hour.Solution is cooled to 0 ℃, adds saturated aqueous ammonium chloride.The solution of gained with ethyl acetate extraction for several times, the acetic ester layer salt water washing of merging through dried over mgso, filtered also vacuum concentration.Resistates obtains described product (output: 6.74g, 94%) through chromatographic separation (quick silica gel, ethyl acetate/hexane 1: 19). 1H?NMR(300MHz，CDCl 3)δ2.34(s，3H)，2.46(s，3H)，7.02-7.09(m，1H)，7.12-7.22(m，3H)。206B. 4-bromo-2-methyl sulfo-phenylmethylether
To 2-bromine sulfo-phenylmethylether (0.50g, 3.57mmol) add in 0 ℃ of solution in methylene dichloride (40ml) powdery Fe (20mg, 0.36mmol), then dripping bromine (0.58g, 3.54mmol).After 30 minutes, raw material exhausts (thin-layer chromatography, hexane).Add NaHSO 3Solution is with excessive bromine quenching and stirred for several minute.The separate dichloromethane layer, water is with extra dichloromethane extraction.The dichloromethane solution that merges filters and vacuum concentration through dried over mgso.The oily matter of gained obtains described product (output: 0.74g, 96%) through chromatographic separation (quick silica gel, ethyl acetate/hexane 1: 49). 1H?NMR(300MHz，CDCl 3)δ2.30(s，3H)，2.45(s，3H)，7.00(d，J＝8.4Hz，1H)，7.27-7.33(m，2H)。206C. 3-methyl-4-(methylthio group) phenylo boric acid
According to the method for embodiment 1, replace 4-bromine sulfo-phenylmethylether, preparation 3-methyl-4-(methylthio group) phenylo boric acid (output: 5.3g, 67%) with 4-bromo-2-(methylthio group) phenylmethylether.M.p.208-210。 1H?NMR?2.28(s，3H)，2.46(s，3H)，7.20(d，J＝8.4Hz，1H)，7.62(s，1H)，7.70(d，J＝8.4Hz，1H)。206D. 2-(3, the 4-difluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones
According to the method for embodiment 194A, with 3,4-difluorophenyl hydrazine hydrochloride replaces the 4-fluorophenyl hydrazine hydrochloride, preparation title compound (output: 39g, 78%). 1H?NMR(300MHz，DMSO-d 6)δ7.45(m，1H)，7.61(m，1H)，7.75(m，1H)，8.30(s，1H)。MS(DCI-NH 3)m/z?382(M+NH 4) +。206E. 2-(3, the 4-difluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone
According to the method for embodiment 194B, with 2-(3, the 4-difluorophenyl)-4,5-two bromo-3 (2H)-pyridazinone replaces 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones, preparation title compound (output: 15mg, 88%). 1H?NMR(300MHz，DMSO-d 6)δ4.14(s，3H)，7.45(m，1H)，7.60(m，1H)，7.74(m，1H)，8.24(s，1H)。MS(DCI-NH 3)m/z317(M+H) +，334(M+NH 4) +。206F. 2-(3, the 4-difluorophenyl)-4-methoxyl group-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 6, with 2-(3, the 4-difluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone replacement 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone, and replace the 4-fluorobenzoic boric acid with 3-methyl-4-(methylthio group) phenylo boric acid, preparation title compound (output: 2.0g, 85%). 1HNMR(300MHz，CDCl 3)δ2.39(s，3H)，2.53(s，3H)，4.11(s，3H)，7.22-7.32(m，2H)，7.34(s，1H)，7.42-7.50(m，2H)，755-7.64(m，1H)，7.92(s，1H)。MS(APCI+)m/z?375(M+H) +。206G. 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, with 2-(3, the 4-difluorophenyl)-and 4-methoxyl group-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, and with 4-fluorophenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(3, the 4-difluorophenyl)-and 4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones (output: 330mg, 56%). 1H?NMR(300MHz，CDCl 3)δ2.24(s，3H)，2.47(s，3H)，6.90-7.03(m，6H)，7.22-7.31(m，2H)，7.49-7.54(m，1H)，7.60-7.68(m，1H)，8.02(s，1H)。MS(APCI+)m/z?439(M+H) +。206H. 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(3, the 4-difluorophenyl)-and 4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 251mg, 82%).M.p.80-100℃。 1H?NMR(300MHz，DMSO-d 6)δ2.59(s，3H)，3.25(s，3H)，7.13-7.34(m，5H)，7.45(s，1H)，7.52-7.69(m，2H)，7.81(d，J＝8.4Hz，1H)，7.81-7.90(m，1H)，8.27(s，1H)。MS (APCI+) m/z 471 (M+H) +With m/z 488 (M+NH 4) +C 24H 17F 3N 2O 3The analytical calculation value of S: C, 6 1.27; H, 3.64; N, 5.95.Measured value: C, 61.53; H, 3.92; N, 5.67.
Embodiment 2072-(3-chloro-phenyl-)-4-(4-fluorophenoxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 207A. 2-(3-chloro-phenyl-)-4,5-two bromo-3 (2H)-pyridazinones
According to the method for embodiment 194A, replace the 4-fluorophenyl hydrazine hydrochloride with 3-chlorophenyl hydrazine hydrochloride, preparation title compound (output: 24.8g, 88%). 1H?NMR(300MHz，DMSO-d 6)δ7.53-7.57(m，3H)，7.67-7.70(m，1H)，8.29(s，1H)。MS (DCI-NH 3) m/z 365 (M+H) +With m/z 382 (M+NH 4) +207B. 2-(3-chloro-phenyl-)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone
According to the method for embodiment 194B, with 2-(3-chloro-phenyl-)-4,5-two bromo-3 (2H)-pyridazinone replaces 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones, preparation title compound (output: 12.4g, 95%). 1H?NMR(300MHz，DMSO-d 6)δ4.21(s，3H)，7.58-7.62(m，3H)，7.73-7.76(m，1H)，8.28(s，1H)。MS (DCI-NH 3) m/z 317 (M+H) +With m/z 334 (M+NH 4) +207C. 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 6, replace 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone with 2-(3-chloro-phenyl-)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone, and replace the 4-fluorobenzoic boric acid with 4-(methylthio group)-phenylo boric acid, preparation title compound (output: 3.3g, 68%). 1H?NMR(300MHz，DMSO-d 6)δ2.54(s，3H)，4.03(s，3H)，7.40(d，J＝9.0Hz，2H)，7.50-7.64(m，5H)，7.73-7.77(m，1H)，8.18(s，1H)。MS(DCI-NH 3)m/z?359(M+H) +。207D. 2-(3-chloro-phenyl-)-4-methyl-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, with 2-(3-chloro-phenyl-)-4-methoxyl group-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, and with 4-fluorophenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-phenyl-)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio group) phenyl]-3 (2H)-pyridazinones (output: 180mg, 94%). 1H?NMR(300MHz，CDCl 3)δ2.25(s，3H)，2.56(s，3H)，7.28-7.45(m，6H)，7.58-7.63(m，1H)，7.71-7.74(m，1H)，7.82(s，1H)。MS (APCI+) m/z 343 (M+H) +With m/z 360 (M+NH 4) +207E. 2-(3-chloro-phenyl-)-4-methyl-5-[4-(the methyl sulphonyl phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(3-chloro-phenyl-)-4-methyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 125mg, 67%).M.P.164-168℃。 1HNMR(300MHz，CDCl 3)δ2.23(s，3H)，3.13(s，3H)，7.37-7.46(m，2H)，7.61(m，3H)，7.71-7.74(m，1H)，7.81(s，1H)，8.13(d，J＝8.7Hz，2H)。MS (APCI+) m/z 343 (M+H) +With m/z 360 (M+NH 4) +207F. 2-(3-chloro-phenyl-)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 194F; with 2-(3-chloro-phenyl-)-4-methyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-methyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation 2-(3-chloro-phenyl-)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (output: 90mg, 99%). 1H?NMR(300MHz，CDCl 3)δ3.13(s，3H)，4.33(s，2H)，7.40-7.47(m，2H)，7.66(ddd，J＝2.4，2.4，7.2Hz，1H)，7.76-7.78(m，1H)，7.81(d，J＝8.7Hz，2H)，7.86(s，1H)，8.17(d，J＝8.7Hz，2H)。MS (APCI+) m/z 453 (M+H) +With m/z 470 (M+NH 4) +207G. 2-(3-chloro-phenyl-)-4-(4-fluorophenoxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 194G; with 2-(3-chloro-phenyl-)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-brooethyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 30mg, 31%).M.p.50-80℃。 1H?NMR(300MHz，CDCl 3)δ3.11(s，3H)，4.94(s，2H)，6.78-6.85(m，2H)，6.91-6.99(m，2H)，7.39-7.48(m，2H)，7.64(ddd，J＝7.5，1.9，1.9Hz，1H)，7.71-7.77(m，3H)，7.93(s，1H)，8.08(d，J＝8.7Hz，2H)。MS(APCI+)m/z?485(M+H) +。
Embodiment 2082-(3-chloro-phenyl-)-4-(benzoyloxy methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 207, replace the 4-fluorophenol with phenylformic acid, preparation title compound (output: 33mg, 34%).M.p.50-70℃。 1H?NMR(300MHz，CDCl 3)δ3.00(s，3H)，5.36(s，2H)，7.36-7.48(m，4H)，7.52-7.59(m，1H)，7.61-7.68(m，3H)，7.75-7.78(m，1H)，7.83-7.88(m，2H)，7.89(s，1H)，8.02(d，J＝8.7Hz，2H)。MS(APCI+)m/z?495(M+H) +。
Embodiment 2092-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 193, replace the 4-fluoro benzyl bromide with 1-bromo-4-methylpentane, preparation title compound (output: 80mg, 19%). 1H?NMR(300MHz，CDCl 3)δ0.81(d，J＝7.5Hz，6H)，1.3-1.6(m，3H)，2.52(m，2H)，3.14(3H，s)，4.85(q，J＝9Hz，2H)，7.55(d，J＝9Hz，2H)，7.67(s，1H)，8.1(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?403(M+H) +。C 18H 21F 3N 2O 3S0.25H 2The analytical calculation value of O: C, 53.12; H, 5.32; N, 6.88.Measured value: C, 52.90; H, 5.14; N, 6.43.
Embodiment 2102-(2,2, the 2-trifluoroethyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl] preparation of-3 (2H)-pyridazinone 210A. boric acid:
(6g 31.7mmol) is dissolved among the exsiccant THF (50ml), and is cooled to-78 ℃ under nitrogen with 2-toluene fluoride-5-bromine.Slowly add n-Butyl Lithium (14ml, the THF solution of 2.5M) with the exsiccant syringe.Occur muddy.Reactant was stirred 40 minutes in-78 ℃.Under agitation slowly add triisopropyl borate ester (22ml, 95mmol).Allow the reactant temperature to room temperature.Continue again to stir 2 hours.Form faint yellow turbid solution.(TLC (1: 2 ethyl acetate/hexane)) shows that raw material disappears.Add the 10% NaOH aqueous solution (200ml) with the reactant quenching.Stir after 45 minutes, add 10% citric acid solution (300ml) and be about 5.0 to pH.Product extracts with ethyl acetate (500ml).Organic phase salt water washing is through dried over mgso and filtration.Concentrating under reduced pressure filtrate obtains white solid (output: 4.1g, 84%).210B. Suzuki coupling:
Under nitrogen; with the boric acid (231mg for preparing among the embodiment 210A; 1.5mmol), 2-(2; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (500mg; 1.36mmol), four-(triphenylphosphine)-palladium (O) (47mg, 0.041mmol) and CsF (413mg, 2.72mmol) stirring down 5 hours that in DMF (20ml), refluxes.TLC (1: 1 hexane/ethyl acetate) shows that all raw materials exhaust.Vacuum is removed volatile matter.Resistates is allocated between water and the ethyl acetate.Organic layer salt water washing is through dried over mgso and filtration.Concentrating under reduced pressure filtrate.Obtain pale powder (output: 275mg, 46%).M.p.88-91℃。 1H NMR (300MHz, CDCl 3, the rotational isomer mixture) δ 2.2,2.25 (2d, J=1.5Hz, 3H), 3.05,3.09 (2 s, 3H), 4.78-4.92 (m, 2H), 6.61-6.8 (m, 1H), 6.82-6.98 (m, 1H), 7.35 (d, J=9Hz, 1H), 7.78 (d, J=9Hz, 1H), 7.86-8.09 (m, 4H).MS(DCI-NH 3)m/z?441(M+H) +。C 20H 16F 4N 2O 3S0.5H 2The analytical calculation value of O: C, 53.45; H, 3.81; N, 6.23.Measured value: C, 53.17; H, 3.65; N, 5.88.
Embodiment 2112-(2,2, the 2-trifluoroethyl)-4-(3, the 5-dichlorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2-(2; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (150mg; 0.409mmol) (embodiment 193E) be dissolved among the anhydrous DME (8ml); CsF (150mg, 0.98mmol) and four (triphenylphosphine)-palladiums (O) (17.38mg 0.015mmol) exists down; with 3,5-dimethyl benzene boric acid is heated to backflow together.After being cooled to room temperature, the reaction mixture dilute with water is with ethyl acetate (100ml) extraction.Organic layer salt water washing is through dried over mgso and vacuum-evaporation.Compound is chromatography on silicagel column, with the pentane solution wash-out of 30% ethyl acetate, obtains title compound (output: 110mg, 58%). 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，4.88(q，J＝9Hz，2H)，7.06(d，J＝1.5Hz，9Hz，2H)，7.31(t，J＝1.5Hz，1H)，7.36(d，J＝9Hz，2H)，7.94(s，1H)，7.96(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?496(M+NH 4) +。C 19H 13Cl 2F 3N 2O 3The analytical calculation value of S: C, 47.81; H, 2.75; N, 5.87.Measured value: C, 47.77; H, 2.75; N, 5.65.
Embodiment 2122-(2,2, the 2-trifluoroethyl)-4-(3-ethoxyl phenenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 3-phenetole boric acid, 5-dimethyl benzene boric acid, preparation title compound (output: 155mg, 86%). 1H?NMR(300MHz，CDCl 3)δ1.42(t，J＝7.5Hz，3H)，3.06(s，3H)，3.90(q，J＝7.5Hz，2H)，4.88(q，J＝9Hz，2H)，6.65(d，J＝7.5Hz，1H)，6.75(t，J＝1.5Hz，1H)，6.85(dd，J＝1.5Hz，9Hz，1H)，7.15(t，J＝9Hz，1H)，7.38(d，J＝9Hz，2H)，7.88(d，J＝9Hz，2H)，7.90(s，1H)。MS(DCI-NH 3)m/z?470(M+NH 4) +。C 21H 19Cl 2F 3N 2O 4The analytical calculation value of S: C, 55.75; H, 4.23; N, 6.19.Measured value: C, 55.62; H, 4.30; N, 5.99.
Embodiment 2132-(2,2, the 2-trifluoroethyl)-4-(4-trifluoromethyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 4-(trifluoromethyl) phenylo boric acid, 4-dimethyl benzene boric acid, preparation title compound (output: 85mg, 44%). 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，4.90(q，J＝9Hz，2H)，7.35(t，J＝9Hz，4H)，7.58(d，J＝9Hz，2H)，7.90(d，J＝9Hz，3H)。MS(DCI-NH 3)m/z?494(M+NH 4) +。C 20H 14F 6N 2O 3The analytical calculation value of S: C, 50.42; H, 2.96; N, 5.88.Measured value: C, 50.20; H, 3.02; N, 5.70.
Embodiment 2142-(2,2, the 2-trifluoroethyl)-4-(3-nitrophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 3-oil of mirbane boric acid, 4-dimethyl benzene boric acid, preparation title compound (output: 40mg, 22%). 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，4.92(q，J＝9Hz，2H)，7.36(d，J＝9Hz，4H)，7.45-7.60(m，2H)，7.91(d，J＝9Hz，2H)，7.95(s，1H)，8.05(m，1H)，8.15-8.21(m，1H)。MS(DCI-NH 3)m/z?471(M+NH 4) +。C 19H 14Cl 2F 3N 3O 5The analytical calculation value of S0.5EtOAc: C, 50.70; H, 3.64; N, 8.44.Measured value: C, 50.61; H, 3.58; N, 8.53.
Embodiment 2152-(2,2, the 2-trifluoroethyl)-4-(2-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with the 2-methylphenylboronic acid, 4-dimethyl benzene boric acid, preparation title compound (output: 45mg, 27%). 1H?NMR(300MHz，CDCl 3)δ2.05，2.12(2s，3H)，3.01(s，3H)，4.75-5.05(m，2H)，6.88(d，J＝9Hz，1H)，7.03-7.25(m，3H)，7.31(d，J＝9Hz，4H)，7.85(d，J＝9Hz，2H)，7.95(s，1H)。MS(DCI-NH 3)m/z?440(M+NH 4) +。C 20H 17F 3N 2O 3The analytical calculation value of S: C, 55.10; H, 4.27; N, 6.42.Measured value: C, 55.17; H, 4.18N, 6.10.
Embodiment 2162-(2,2, the 2-trifluoroethyl)-4-(4-ethenylphenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with the 4-vinylphenylboronic acid, 4-dimethyl benzene boric acid, preparation title compound (output: 56mg, 32%). 1H?NMR(300MHz，CDCl 3)δ3.06，3.08(2s，3H)，4.78-4.95(m，2H)，5.30(t，J＝6Hz，1H)，5.65，5.75(2d，J＝18Hz，1H)，6.58-6.92(m，1H)，7.1-7.4(m，6H)，7.75-8.08(m，3H)。MS(DCI-NH 3)m/z?452(M+NH 4) +。C 21H 17F 3N 2O 3The analytical calculation value of S: C, 58.06; H, 3.94; N, 6.45.Measured value: C, 57.82; H, 4.01; N, 6.09.
Embodiment 2172-(2,2, the 2-trifluoroethyl)-4-[3-(trifluoromethyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 3-trifluoromethyl phenylo boric acid, 4-dimethyl benzene boric acid, preparation title compound (output: 120mg, 63%). 1H?NMR(300MHz，CDCl 3)δ3.03，3.08(2s，3H)，4.75-4.98(m，2H)，7.30-7.60(m，6H)，7.75-8.10(m，3H)。MS(DCI-NH 3)m/z?494(M+NH 4) +。C 20H 14F 6N 2O 3The analytical calculation value of S: C, 50.42; H, 2.96; N, 5.88.Measured value: C, 50.38; H, 2.97; N, 5.74.
Embodiment 2182-(2,2, the 2-trifluoroethyl)-4-(3-fluoro-4-p-methoxy-phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 3-fluoro-4-methoxyphenylboronic acid, 4-dimethyl benzene boric acid, preparation title compound (output: 32mg, 18%). 1H?NMR(300MHz，CDCl 3)δ3.05，3.09(2s，3H)，3.85，3.87(2s，3H)，4.78-4.90(m，2H)，6.60-7.10(m，3H)，7.30-8.15(m，5H)。MS(DCI-NH 3)m/z?474(M+NH 4) +。C 20H 16F 4N 2O 4S0.5H 2The analytical calculation value of O: C, 51.61; H, 3.68; N, 6.01.Measured value: C, 51.52; H, 3.65; N, 5.93.
Embodiment 2192-(2,2, the 2-trifluoroethyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, replace 3 with 3-fluoro-4-methylphenylboronic acid, 4-dimethyl benzene boric acid, preparation title compound (output: 58mg, 33%). 1H?NMR(300MHz，CDCl 3)δ2.21，2.25(2d，J＝1.5Hz，3H)，3.50，3.55(2s，3H)，4.75-4.95(m，2H)，6.56-7.15(m，3H)，7.30-8.10(m，5H)。MS(DCI-NH 3)m/z?458(M+NH 4) +。C 20H 16F 4N 2O 3S0.5H 2The analytical calculation value of O: C, 53.45; H, 3.81; N, 6.23.Measured value: C, 53.14; H, 3.80; N, 5.97.
Embodiment 2202-(2,2, the 2-trifluoroethyl)-4-(3,5-two fluoro-4-p-methoxy-phenyls)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 211, with 3,5-two fluoro-4-methoxyphenylboronic acids replace 3,4-dimethyl benzene boric acid, preparation title compound. 1H?NMR(300MHz，CDCl 3)δ2.9，3.1(2s，3H)，3.92，4.01(2s，3H)，4.78-4.95(m，2H)，6.25-6.80(m，1H)，7.30-7.5(m，2H)，7.7-8.15(m，4H)。MS(DCI-NH 3)m/z?492(M+NH 4) +。C 20H 15F 5N 2O 4The analytical calculation value of S: C, 50.64; H, 3.19; N, 5.90.Measured value: C, 50.542; H, 3,41; N, 5.67.
Embodiment 2212-(2,2, the 2-trifluoroethyl)-4-(1,3-dihydro-1-oxo-5-isobenzofuran-base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
(326 μ l 1.55mmol) are dissolved in the toluene (5ml), with the nitrogen gas stream degassing 5 minutes, with (Ph with 6-bromine (2-benzo [c] furanone) (300mg, 1.40mmol, Recl.Trav.Chim.Pays-Bays such as Teppema, 1923,42,47) and hexa methyl ditin 3P) 4Pd (79mg) handles, and the heating down 1 hour that refluxes.With the reactant cooling, directly go up chromatography purification, with 4: 1 hexane-eluent ethyl acetates at Biotage 40S post (, washing with hexane then) with hexane-TEA pre-treatment in 400: 1.The product flow point is mixed and evaporation, obtain intermediate 6-(tin trimethyl) (2-benzo [c] furanone) (output: 362mg, 87%).
Tin reagent (180mg with above preparation; 0.61mmol) and embodiment 193E in the 2-(2 for preparing; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (223mg; 0.61mmol) be dissolved in the exsiccant toluene (10ml); with the nitrogen gas stream degassing 5 minutes, with (Ph 3P) 4Pd (34mg) handles, and the heating down 1 day that refluxes.With reactant cooling, direct chromatography purification on Biotage 40S post was with 4: 1 hexane-eluent ethyl acetates.The product flow point is merged and evaporation, obtain the title compound and 4-(1,3-dihydro-1-oxo-6 the isobenzofuran-base)-isomer of 9: 1 ratios.With further operation (being chromatography, recrystallize from the ethyl acetate/hexane) failure (output: 176mg, 62%) of attempting to remove accessory isomer.M.p.237-239℃。 1H NMR (300MHz, CDCl 3) δ 3.07 (s, 3H), 4.91 (q, J=8Hz, 2H), (5.30 s, 2H, main isomer), 5.33 (s, 2H, less important isomer), 7.20 (dd, J=1H, 7Hz, 1H), 7.36 (d, J=8Hz, 2H), 7.52 (s, 1H), 7.79 (d, J=7Hz, 1H), 7.92 (d, J=8Hz, 2H), 7.96 (s, 1H).MS(DCI-NH 3)m/z?482(M+NH 4) +。C 21H 15F 3N 2O 5The analytical calculation value of S: C, 54.31; H, 3.26; N, 6.03.Measured value: C, 54.15; H, 3.12; N, 5.76.
Embodiment 2222-(2,2, the 2-trifluoroethyl)-4-(2-propenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl that will prepare according to the method for embodiment 193E] (200mg, 0.546mmol) suspension in THF (27ml) is cooled to-78 ℃ to-3 (2H)-pyridazinones.Add pseudoallyl magnesium bromide (2.8ml, 0.5M THF solution, Aldrich) solution.The reactant temperature to room temperature, and was stirred 30 minutes.By adding saturated ammonium chloride solution in 0 ℃ of quenching reactant, and with reactant distribution between ethyl acetate and other ammonium chloride solution.Organic layer salt water washing through dried over sodium sulfate, is filtered and concentrating under reduced pressure the brown solid that is slightly taken on a red color.Described crude material is dissolved in the methylene dichloride, and is adsorbed on the silica gel (2g).Solvent is removed in decompression, and the silica gel that adsorbs is layered on Extract-CleanCartridge (Alltech, the dress post: 5g silica gel), with this post of hexane/acetone stepwise gradient (step) wash-out, described stepwise gradient is made up of the following mixture of 40ml: hexane, 8: 1 hexane/acetone, 4: 1,2: 1 and 1: 1.The flow point that will contain required product merges, concentrates, and with HPLC (Technikrom Kromasil 60-5sil post, 20mm * 25cm) be further purified.This post is used by the linear gradient of 30% ethyl acetate/hexane to 100% ethyl acetate with 10ml/min wash-out 50 minutes.The flow point that will contain title product merges and concentrating under reduced pressure, obtains faint yellow solid (output: 99.3mg, 49%).M.p.192-195℃。 1H?NMR(300MHz，CDCl 3)δ8.03(d，J＝17.4Hz，2H)，7.76(s，1H)，755(d，2H，J＝17.4Hz)，5.23(br?s，1H)，4.84(m，3H)，3.11(s，3H)，1.98(s，3H)。MS(DCI-NH 3)m/z?373(M+H) +，m/z?390(M+NH 4) +。C 16H 15F 3N 2O 3The analytical calculation value of S: C, 51.61; H, 4.06; N, 7.52.Measured value: C, 51.72; H, 4.24; N, 7.35.
Embodiment 2232-(2,2, the 2-trifluoroethyl)-4-(2-butylene-2-yl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 222, replace the pseudoallyl magnesium bromide with 1-methyl isophthalic acid-propenyl magnesium bromide, prepare described product, obtain the mixture (about 3: 1 ratio) of geometrical isomer, be pale solid (output: 44.8mg, 21%).M.p.175-180℃。 1H?NMR(300MHz，CDCl 3)δ8.03(d，J＝18.0Hz，1.5H)，8.01(d，J＝18.0Hz，0.5H)，7.29(s，0.75H)，7.28(s，0.25H)，7.56(d，J＝17.4Hz，1.5H)，7.51(d，J＝17.4Hz，0.5H)，5.55(m，0.75H)，5.33(m，0.25H)，5.86(q，J＝17.4Hz，2H)，3.12(s，2.25H)，3.11(s，0.75H)，2.88(m，2H)，2.85(m，1H)，1.27(m，3H)。MS(DCI-NH 3)m/z?387(M+H) +，m/z?404(M+NH 4) +，m/z?421(M+2NH 4-H) +。C 17H 17F 3N 2O 3The analytical calculation value of S: C, 52.85; H, 4.43; N, 7.25.Measured value: C, 53.16; H, 4.68; N, 6.92.
Embodiment 2242-(2,2, the 2-trifluoroethyl)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 224A.3-luorobenzyl bromination magnesium
With the 3-fluoro benzyl bromide (613 μ l, 5mmol) and ethylene dibromide (10 μ l) order drop in the flask of oven drying, contain in the flask small pieces magnesium rod (134mg, 5.5mmol) and ether (12ml).Notice and emit gas, then the described ether of gentle reflux.Reactant is stirred to gas emits and stop, and the dissolving of most of magnesium rod.In next step reaction, directly use the 3-luorobenzyl bromination magnesium yellow solution of gained.224B. 2-(2,2, the 2-trifluoroethyl)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl that will prepare according to the method for embodiment 193E] (200mg, 0.546mmol) suspension in THF (10ml) is cooled to 0 ℃ to-3 (2H)-pyridazinones.The 3-luorobenzyl bromination magnesium (4.0ml, about 0.42M diethyl ether solution) that adds above preparation.Reactant was stirred 3 hours in 0 ℃, by adding saturated ammonium chloride solution, it is allocated between ethyl acetate and the other ammonium chloride solution its quenching.Organic layer salt water washing through dried over sodium sulfate, filtration and concentrating under reduced pressure, obtains yellow oil.Described crude material is dissolved in the methylene dichloride, and is adsorbed on the silica gel (2g).Solvent is removed in decompression, and the silica gel that adsorbs is layered on Extract-Clean Cartridge (Alltech, the dress post: 10g silica gel), with this post of hexane/acetone stepwise gradient wash-out, described stepwise gradient is made up of the following mixture of 60ml: hexane, 8: 1 hexane/acetone, 4: 1,2: 1 and 1: 1.The flow point that will contain required product merges, concentrates, and with HPLC (Technikrom Kromasil 60-5 sil silica column, 20mm * 25cm) be further purified.This post is used by the linear gradient of 30% ethyl acetate/hexane to 100% ethyl acetate with 10ml/min wash-out 50 minutes.The flow point that will contain title product merges and concentrating under reduced pressure, obtains faint yellow solid (output: 130.9mg, 54%).M.p.58-62℃。 1H?NMR(300MHz，CDCl 3)δ8.07(d，J＝18.0Hz，2H)，7.73(s，1H)，7.47(d，J＝17.4Hz，2H)，7.18(m，1H)，6.88(m，1H)，6.76(br?d，J＝15.6Hz，1H)，6.68(br?d，J＝18.6Hz，1H)，4.86(q，J＝17.4Hz，2H)，3.93(s，2H)，3.12(s，3H)。MS(DCI-NH 3)m/z?441(M+H) +，m/z?458(M+NH 4) +，m/z?475(M+2NH 4-H) +。C 20H 16F 4N 2O 3The analytical calculation value of S: C, 54.54; H, 3.66; N, 6.36.Measured value: C, 54.52; H, 3,81; N, 6.17.
Embodiment 2252-(2,2, the 2-trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 225A. trifluoromethanesulfonic acid 1-tetrahydrobenzene esters
((0.77ml is in THF 5.50mmol) (20ml) solution 5.50mmol) to add to Diisopropylamine in-78 ℃ for 2.5M hexane solution, 2.20ml with n-Butyl Lithium.With the yellow solution temperature to 0 of gained ℃ 30 minutes, be cooled to-78 ℃ then.Add pimelinketone (0.52ml, 5.0mmol), with almost colourless solution temperature to 0 ℃ 1 hour.Adding solid N-phenyl trifluoromethanesulfonate methylsulfonyl imines (1.79g, 5.5mmol).Solution was stirred under room temperature 12 hours.Then reaction mixture is allocated between ether and the saturated sodium bicarbonate solution.Ether layer water and salt solution wash in proper order, through dried over sodium sulfate, filter and concentrating under reduced pressure.Crude material obtains the faint yellow oily thing of described triflate (output: 0.73g, 64%) through flash chromatography purifying (20: 1 hexane/ethyl acetate).225B. 1-cyclohexenyl tin trimethyl
By making nitrogen pass through solution, will according to the 1-trifluoromethanesulfonic acid 1-tetrahydrobenzene ester of the method preparation of embodiment 225A (412mg, 1.79mmol) and LiCl (390mg, THF 8.95mmol) (9ml) solution deoxidation.(414mg 0.36mmol), heats reactant 12 hours down in refluxing to add hexa methyl ditin (339 μ l.1.61mmol) and tetrakis triphenylphosphine palladium (O).Reactant is cooled to room temperature, it is allocated between ether and the saturated sodium bicarbonate solution.Ether layer water and salt solution wash in proper order, through dried over sodium sulfate, filter and concentrating under reduced pressure.Described crude material is dissolved in the hexane (1ml), and last sample is to the wetting Extract-Clean Cartridge of hexane solution that uses 10% triethylamine (Alltech, dress post: 10g silica gel).With this post of hexane wash-out, the flow point that will contain described triflate merges, concentrating under reduced pressure, obtains the transparent oily matter of 1-cyclohexenyl tin trimethyl (output: 150mg, 34%).225C. 2-(2,2, the 2-trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The 1-cyclohexenyl tin trimethyl (150mg that will prepare according to the method for embodiment 225B; 0.61mmol) and according to the 2-(2 of the method for embodiment 193E preparation; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (172mg, 0.47mmol) the solution nitrogen deoxidation in anhydrous N-Methyl pyrrolidone (1ml).(6.6mg, 0.009mmol) (7.7mg 0.009mmol), heats reactant 16 hours in 80 ℃ with [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) to add two (triphenylphosphine) palladiums (II) of dichloro.Reaction mixture is cooled to room temperature, and is allocated between ether and the water.Ether washs in proper order with other two parts of water and salt solution, through dried over sodium sulfate, filters and concentrating under reduced pressure.Described crude material is dissolved in the acetone, and is adsorbed on the silica gel (1g).Solvent is removed in decompression, and the silica gel that adsorbs is layered on Extract-CleanCartridge (Alltech, the dress post: 10g silica gel), with this post of hexane/acetone stepwise gradient wash-out, described stepwise gradient is made up of following mixture: hexane (60ml), 8: 1 hexane/acetone (80ml), 4: 1 hexane/acetone (150ml).The flow point that will contain required product merges, concentrates, and with HPLC (Technikrom Kromasil 60-5 sil silica column, 20mm * 25cm) be further purified.This post is used by the linear gradient of 30% ethyl acetate/hexane to 100% ethyl acetate with 10ml/min wash-out 50 minutes.The flow point that will contain title product merges and concentrating under reduced pressure, obtains weak yellow foam shape thing (output: 95.0mg, 49%).M.p.75-81℃。 1H?NMR(300MHz，CDCl 3)δ8.02(d，J＝17.4Hz，2H)，7.76(s，1H)，7.55(d，J＝17.4Hz，2H)，5.51(br?s，1H)，4.83(br?q，J＝16.2Hz，3H)，3.11(s，3H)，2.18(br，2H)，1.96?br，2H)，1.70-1.50(m，4H)。MS(DCI-NH 3)m/z?413(M+H) +，m/z?430(M+NH 4) +，m/z?447(M+2NH 4-H) +。C 19H 19F 3N 2O 3The analytical calculation value of S: C, 55.33; H, 4.64; N, 6.79.Measured value: C, 55.53; N, 4.71; N, 6.55.
Embodiment 2262-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinone 226A. 3-fluoro-4-(methylthio group) phenylo boric acids
According to the method for embodiment 1, replace 4-bromine sulfo-phenylmethylether, preparation 3-fluoro-4-(methylthio group) phenylo boric acid with 4-bromo-3-fluorine sulfo-phenylmethylether.226B. 2-benzyl-4-methoxyl group-5-bromo-3 (2H)-pyridazinone
According to the method for embodiment 83B, with 2-benzyl-4,5-two bromo-3 (2H)-pyridazinone replaces 2-(2,2, the 2-trifluoroethyl)-4,5-two bromo-3 (2H)-pyridazinones, and replace Virahol, preparation 2-benzyl-4-methoxyl group-5-bromo-3 (2H)-pyridazinone with methyl alcohol.226C. 2-benzyl-4-methoxyl group-5-[4-(3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 83C, with 3-fluoro-4-(methylthio group) phenylo boric acid and 2-benzyl-4-methoxyl group-5-bromo-3 (2H)-pyridazinone coupling, obtain 2-benzyl-4-methoxyl group-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinone yellow solids (output: 4.98g, 91%). 1H?NMR(300MHz，CDCl 3)δ7.76(s，1H)，7.47(m，2H)，7.39-7.21(m，7H)，5.34(s，2H)，4.13(s，3H)，2.51(s，3H)。MS(DCI-NH 3)m/z?357(M+H) +，m/z374(M+NH 4) +。226D. 3-methyl butyl magnesium bromide
(134mg adds ether (12ml) in the flask of oven drying 5.5mmol) to containing the small pieces magnesium rod.(600 μ l 5mmol), drip ethylene dibromide (10 μ l) then to drip 1-bromo-3-methylbutane.Reaction needed heats under gentle reflux, observes gas then and emits.Reactant was refluxed 3 hours, and be cooled to room temperature.In next step reaction, use the light grey solution of 3-methyl butyl magnesium bromide.226E. 2-benzyl-4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
2-benzyl-4-methoxyl group-5-[3-fluoro-4-(methylthio group) phenyl that will prepare according to the method for embodiment 226C] (500mg, 1.40mmol) solution in THF (20ml) is cooled to-78 ℃ to-3 (2H)-pyridazinones.The 3-methyl butyl magnesium bromide that dropping prepares in embodiment 226D (5ml, 1.96mmol).Add when finishing, reaction mixture is placed ice bath.2.5 after hour, by adding saturated ammonium chloride solution with the reactant quenching.Crude reaction mixture is allocated between ethyl acetate and the other ammonium chloride solution.Organic layer salt water washing through dried over sodium sulfate, is filtered and concentrating under reduced pressure, obtains yellow oil (output: 550mg, 99%). 1H?NMR(300MHz，CDCl 3)δ7.67(s，1H)，7.49(m，2H)，7.39-7.25(m，4H)，7.02(m，2H)，5.35(s，2H)，2.57-2.49(m，2H)，2.52(s，3H)，1.62-1.36(m，3H)，0.83(d，6H，J＝12.0Hz)。MS(DCI-NH 3)m/z?397(M+H) +，m/z?414(M+NH 4) +，MS(DCI-NH 3)m/z?397(M+H) +，m/z?414(M+NH 4) +。226F. 4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 11,2-benzyl-4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl that will prepare according to the method for embodiment 226E]-3 (2H)-pyridazinone (550mg, 1.39mmol) go benzylization, obtain 4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones, be faint yellow solid (output: 375mg, 88%). 1H?NMR(300MHz，CDCl 3)δ7.65(s，1H)，7.34(dd，1H，J＝16.2，16.2Hz)，7.11-6.98(m，2H)，2.60-2.50(m，2H)，2.54(s，3H)，1.65-1.37(m，3H)，0.83(d，6H，J＝12.0Hz)。MS(DCI-NH 3)m/z?307(M+H) +，m/z?324(M+NH 4) +，MS(DCI-NH 3)m/z?307(M+H) +，m/z?324(M+NH 4) +。226G. 2-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 20,4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl that will prepare according to the method for embodiment 226F]-3 (2H)-pyridazinone (375mg, 1.23mmol) alkylation, obtain 2-(2,2, the 2-trifluoroethyl)-and 4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones, be clarification oily matter (output: 331mg, 69%). 1H?NMR(300MHz，CDCl 3)δ7.67(s，1H)，7.34(dd，1H，J＝16.8，16.8Hz)，7.11-6.98(m，2H)，4.82(dd，2H，J＝17.4，17.4Hz)，2.60-2.51(m，2H)，2.53(s，3H)，1.61-1.32(m，3H)，0.85(d，6H，J＝12.0Hz)。MS(DCI-NH 3)m/z?389(M+H) +，m/z?406(M+NH 4) +。MS(DCI-NH 3)m/z?389(M+H) +，m/z?406(M+NH 4) +。226H. 2-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 5; only use the MCPBA of a a great deal of; the 2-that will in embodiment 226G, prepare (2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinone (331mg; 0.85mmol) oxidation; obtain 2-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones; be pale solid (output: 240mg, 69%). 1H?NMR(300MHz，CDCl 3)δ8.02(dd，1H，J＝15.0，15.0Hz)，7.67(s，1H)，7.37(dd，1H，J＝17.4，3.0Hz)，7.11(dd，1H，J＝18.6，3.0Hz)，4.84(dd，2H，J＝17.4，17.4Hz)，2.91(s，3H)，2.53(m，2H)，1.60-1.35(m，3H)，0.57(d，6H，J＝12.0Hz)。MS(DCI-NH 3)m/z?405(M+H) +，m/z?422(M+NH 4) +。MS(DCI-NH 3)m/z405(M+H) +，m/z?422(M+NH 4) +。226I. 2-(2,2, the 2-trifluoroethyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 68; the 2-(2 that will in embodiment 226H, prepare; 2; the 2-trifluoroethyl)-and 4-(3-methyl butyl)-5-[3-fluoro-4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinone (240mg; 0.594mmol) be converted into sulphonamide; obtain title compound white solid (output: 109mg, 44%).M.p.153-156℃。 1H?NMR(300MHz，CDCl 3)δ8.07(dd，1H，J＝15.0，15.0Hz)，7.74(s，1H)，7.27-7.19(m，2H)，5.14(br?s，2H，4.83(q，J＝18.0Hz，2H)，2.52(m，2H)，1.55(m，1H)，1.41(m，2H)，0.85(d，J＝12.6?Hz，6H)。MS(ESI(-))m/z?420(M-H) -。C 17H 19F 4N 3O 3The analytical calculation value of S: C, 48.45; H, 4.54; N, 9.97.Measured value: C, 48.24; H, 4.56; N, 9.80.
Embodiment 2272-(2,2, the 2-trifluoroethyl)-4-benzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
By in 0 ℃ of diethyl ether solution (0.53ml with the 1.0M benzylmagnesium chloride; 0.53mmol) add to 2-(2 according to the preparation of the method for example 193E; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (150mg; 0.41mmol) THF (20ml) solution in, in 2 hours, allow the mixture temperature to room temperature then, the preparation title compound.After the aqueous solution was handled, through column chromatography purification (silica gel, 65: 35 hexane/ethyl acetate), crystallization from ethyl acetate/hexane obtained white crystallized product (output: 74mg, 43%) with rough material.M.p.112-114℃。 1H?NMR(300MHz，CDCl 3)δ3.12(s，3H)，3.94(s，2H)，4.85(q，J＝12Hz，2H)，6.99(dd，J＝7.5Hz，3Hz，2H)，7.2(m，3H)，7.48(d，J＝9Hz，2H)，7.72(s，1H)，8.06(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?423(M+H) +。C 20H 17F 3N 2O 3The analytical calculation value of S: C, 56.86; H, 4.05; N, 6.63.Measured value: C, 56.60; H, 4.13; N, 6.57.
Embodiment 2282-(4-fluorophenyl)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl for preparing among the embodiment 194C]-3 (2H)-pyridazinone (200mg, 0.51mmol) THF (8ml) solution be cooled to-78 ℃, diethyl ether solution (0.31ml, 0.7mmol) processing with 2M cyclohexyl chlorination magnesium.Reaction mixture in-78 ℃ of stirrings 2 hours, is passed through to remove the cooling bath temperature to room temperature then.Stirred 2 hours under room temperature, (50ml) adds in the reaction mixture with water, with ethyl acetate (50ml) extraction.Organic layer is through dried over mgso and vacuum concentration.The methyl sulfide compound of gained is through flash chromatography purifying (SiO 2, with 9: 1 hexanes: eluent ethyl acetate), obtain required product (output: 128mg, 69%).MS(DCI-NH 3)m/z?395(M+H) +，412(M+NH 4) +。
(122mg, methylene dichloride 0.3mmol) (10ml) solution is used CH in 0 ℃ with the methyl sulfide compound of above preparation 3CO 3(0.3ml 1mmol) handles H.Be reflected in 2 hours and finish.Reaction mixture dilutes with methylene dichloride, uses saturated sodium bicarbonate and salt water washing respectively.The rough resistates of gained is through flash chromatography purifying (SiO 2, with 1: 1 hexane: eluent ethyl acetate), obtain required product (output: 110mg, 93%).M.p.231-233℃。 1H?NMR(300MHz，DMSO-d 6)δ1.1(m，3H)，1.6(m，6H)，2.15(m，2H)，7.35(t，2H)，7.65(m，2H)，7.73(dd，2H)，7.93(s，1H)，8.1(d，2H)。MS(DCI-NH 3)m/z?427(M+H) +，444(M+NH 4) +。C 23H 23FN 2O 3S0.75H 2The analytical calculation value of O: C, 64.77; H, 5.44; N, 6.57.Measured value: C, 62.86; H, 5.53; N, 5.78.
Embodiment 2292-(4-fluorophenyl)-4-(aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with p-methylphenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 90mg, 39%).M.p.242-244℃。 1H?NMR(300MHz，DMSO-d 6)δ2.25(s，2H)，δ3.25(s，3H)，7.1(t，4H)，7.35(t，2H)，7.5(d，J＝9Hz，2H)，7.7(dd，2H)，7.9(d，J＝9Hz，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?435(M+H) +，452(M+NH 4) +。C 24H 19FN 2O 3S0.5H 2The analytical calculation value of O: C, 66.34; H, 4.41; N, 6.45.Measured value: C, 64.61; H, 4.57; N, 6.10.
Embodiment 2302-(4-fluorophenyl)-4-benzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with benzyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 179mg, 81%).M.p.180-182℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，7.0(d，2H)，7.2(m，3H)，7.35(t，2H)，7.65(m，2H)，7.72(d，2H)，8.05(m，3H)。MS(DCI-NH 3)m/z?435(M+H) +，452(M+NH 4) +。C 24H 19FN 2O 3S0.5H 2The analytical calculation value of O: C, 66.34; H, 4.41; N, 6.45.Measured value: C, 64.48; H, 4.17; N, 6.36.
Embodiment 2312-(4-fluorophenyl)-4-(phenylacetylene base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with phenylacetylene magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 150mg, 55.5%).M.p.203-204℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，7.4(d，8H)，7.7(m，2H)，8.16(m，4H)，8.35(s，1H)。MS(DCI-NH 3)m/z?435(M+H) +，452(M+NH 4) +。C 25H 17FN 2O 3The analytical calculation value of S: C, 67.56; H, 3.86; N, 6.30.Measured value: C, 67.63; N, 3.86; N, 6.30.
Embodiment 2322-(3, the 4-difluorophenyl)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones begin; preparation title compound (output: 245mg, 80%).M.p.80-83℃。 1H?NMR(300MHz，DMSO-d 6)δ1.1(m，3H)，1.6(m，6H)，2.15(m，2H)，7.5(m，1H)，7.6(m，2H)，7.7(d，2H)，7.78(m，2H)，7.93(s，1H)，8.1(d，2H)。MS(DCI-NH 3)m/z?445(M+H) +，462(M+NH 4) +。C 23H 22F 2N 2O 3The analytical calculation value of S: C, 62.15; H, 4.99; N, 6.30.Measured value: C, 62.65; H, 5.25; N, 5.97.
Embodiment 2332-(3, the 4-difluorophenyl)-4-benzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with benzyl magnesium bromide substituted cyclohexyl magnesium chloride; preparation title compound (output: 206mg, 66%).M.p.166-168℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，3.9(s，2H)，7.0(d，2H)，7.2(m，3H)，7.6(m，2H)，7.72(d，2H)，7.8(d，1H)，8.05(d，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?453(M+H) +，470(M+NH 4) +。C 24H 19F 2N 2O 3The analytical calculation value of S: C, 63.71; H, 4.01; N, 6.19.Measured value: C, 63.53; H, 4.33; N, 5.76.
Embodiment 2342-(3, the 4-difluorophenyl)-4-(aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and replace the p-methylphenyl magnesium bromide with cyclohexyl chlorination magnesium; preparation title compound (output: 140mg, 56%).M.p.190-192℃。 1HNMR(300MHz，DMSO-d 6)δ2.28(s，2H)，δ3.25(s，3H)，7.1(s，4H)，7.5(m，4H)，7.89(m，3H)，8.05(d，2H)，8.23(s，1H)。MS(DCI-NH 3)m/z453(M+H) +，470(M+NH 4) +。C 24F 2H 18N 2O 3The analytical calculation value of S: C, 63.71; H, 4.01; N, 6.19.Measured value: C, 63.69; H, 4.29; N, 5.96.
Embodiment 2352-(3, the 4-difluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with 4-fluoro-3-methylbenzene magnesium bromide substituted cyclohexyl magnesium chloride; preparation title compound (output: 180mg, 72.5%).M.p.166-168℃。 1HNMR(300MHz，DMSO-d 6)δ2.15(s，3H)，δ3.25(s，3H)，7.01(m，H)，7.25(d，1H)，7.6(m，4H)，7.9(m，3H)，8.26(s，2H)。MS(DCI-NH 3)m/z471(M+H) +，488(M+NH 4) +。C 24F 3H 17N 2O 3The analytical calculation value of S: C, 61.27; H, 3.64; N, 5.95.Measured value: C, 61.47; H, 3,84; N, 5.67.
Embodiment 2362-(3, the 4-difluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-4-vinyl-3 (2H)-pyridazinone
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with vinyl bromination magnesium substituted cyclohexyl magnesium chloride; preparation title compound (output: 85mg, 31.8%). 1H?NMR(300MHz，DMSO-d 6)δ2.15(s，3H)，δ3.3(s，3H)，5.7(dd，1H)，6.4(dd，1H)，6.7(dd，1H)，7.01(m，2H)，7.5(m，1H)，7.65(m，1H)，7.8(m，3H)，8.1(s，3H)。MS(DCI-NH 3)m/z?389(M+H) +，406(M+NH 4) +。
Embodiment 2372-(3, the 4-difluorophenyl)-4-(2-thienyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with 2-thienyl magnesium bromide substituted cyclohexyl magnesium chloride; preparation title compound (output: 66mg, 28%).M.p.189-191℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，6.95(m，2H)，7.55(m，1H)，7.7(m，5H)，7.85(m，1H)，8.03(d，J＝9Hz，2H)，8.13(s，1H)。MS(DCI-NH 3)m/z445(M+H) +，462(M+NH 4) +。C 21H 14F 2N 2O 3S 2The analytical calculation value: C, 56.75; H, 3.17; N, 6.30.Measured value: C, 56.92, H, 3.92, N, 5.79.
Embodiment 2382-(3, the 4-difluorophenyl)-4-(1-proyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with methylacetylene magnesium bromide substituted cyclohexyl magnesium chloride; preparation title compound (output: 65mg, 24%).M.p.149-150℃。 1H?NMR(300MHz，DMSO-d 6)δ2.1(s，3H)，3.3(s，3H)，7.51(m，1H)，7.65(m，1H)，7.8(m，1H)，8.1(m，4H)，8.3(s，1H)。MS(DCI-NH 3)m/z?463(M+H) +，480(M+NH 4) +。C 20H 14F 2N 2O 3S0.25H 2The analytical calculation value of O: C, 59.94; H, 3.52; N, 7.00.Measured value: C, 59.49; H, 3.63; N, 6.34.
Embodiment 2392-(3, the 4-the difluorophenyl)-4-tertiary butyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and with tertiary butyl bromination magnesium substituted cyclohexyl magnesium chloride; preparation title compound (output: 60mg, 24%).M.p.158-161℃。 1H?NMR(300MHz，DMSO-d 6)δ1.21(s，9H)，3.3(s，3H)，7.51(m，1H)，7.45(m，1H)，7.75(m，4H)，8.02(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?419(M+H) +，436(M+NH 4) +。C 21H 20F 2N 2O 3The analytical calculation value of S: C, 60.27 H, 4.82; N, 6.69.Measured value: C, 60.15; H, 5.10; N, 6.39.
Embodiment 2402-(2,2, the 2-trifluoroethyl)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228; with the 2-(2 for preparing among the embodiment 193E; 2; the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; preparation title compound (output: 120mg, 53%).M.p.215-218℃。 1H?NMR(300MHz，CDCl 3)δ1.1(tt，J＝9Hz，J＝4.5Hz，2H)，1.25(tt，J＝9Hz，4.5Hz，1H)，1.49(d，J＝12Hz，2H)，1.63(d，J＝12Hz，1H)，1.75(dt，J＝12Hz，3Hz，2H)，2.21(qd，J＝9Hz，4.5Hz，2H)，2.51(tt，J＝12Hz，3Hz，1H)，3.17(s，3H)，4.83(q，J＝12Hz，2H)，7.49(d，J＝9Hz，2H)，7.6(s，1H)，8.09(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?415(M+H) +。C 19H 21F 3N 2O 3The analytical calculation value of S: C, 55.06; H, 5.1; N, 6.75.Measured value: C, 55.08; H, 5.10; H, 6.70.
Embodiment 2412-(3-chloro-phenyl-)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228,2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl by preparation among the embodiment 331]-3 (2H)-pyridazinones begin, and with 3-luorobenzyl chlorination magnesium substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-phenyl-)-4-(3-luorobenzyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 180mg, 55%) with described methyl sulfide compound oxidation.M.p.142-143℃。 1H?NMR(300MHz，CDCl 3)δ3.14(s，3H)，3.98(s，2H)，6.75(br?d，J＝9Hz，1H)，6.82(br?d，J＝9Hz，1H)，6.88(br?t，J＝9Hz，1H)，7.15-7.23(m，1H)，7.37-7.47(m，2H)，7.54(d，J＝9Hz，2H)，7.63(dt，J＝9Hz，2Hz，1H)，7.75(t，J＝2Hz，1H)，7.82(s，1H)，8.10(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z469(M+H) +，486(M+NH 4) +。C 24H 18ClF 2N 2O 3SO.5H 2The analytical calculation value of O: C, 60.38; H, 3.88; N, 5.87.Measured value: C, 60.62; H, 3.89; N, 5.82.
Embodiment 2422-(4-fluorophenyl)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 194C (4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 3-luorobenzyl chlorination magnesium substituted cyclohexyl magnesium chloride, preparation 2-(4-fluorophenyl)-4-(3-luorobenzyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 1O,, obtain title compound (output: 450mg, 66.8%) with described methyl sulfide compound oxidation.M.p.176-178℃。 1H?NMR(300MHz，CDCl 3)δ3.14(s，3H)，3.95(s，2H)，6.75(br?d，J＝9Hz，1H)，6.82(br?d，J＝9Hz，1H)，6.88(br?t，J＝9Hz，1H)，7.14-7.23(m，3H)，7.54(d，J＝9Hz，2H)，7.67(dt，J＝9Hz，6Hz，2H)，7.81(s，1H)，8.1O(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?516(M+NH 4) +。C 24H 19F 2N 2O 5SH 2The analytical calculation value of O: C, 61.28; H, 4.04; N, 5.96.Measured value: C, 61.24; H, 4.09; N, 5.77.
Embodiment 2432-(3, the 4-difluorophenyl)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, with the 2-(3 for preparing among the embodiment 206E, the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, with 3-luorobenzyl chlorination magnesium substituted cyclohexyl magnesium chloride, preparation 2-(3, the 4-difluorophenyl)-and 4-(3-luorobenzyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for example 10, with described methyl sulfide compound oxidation, preparation title compound (output: 390mg, 68%).M.p.161-163℃。 1H?NMR(300MHz，CDCl 3)δ3.14(s，3H)，3.95(s，2H)，6.74(br?d，J＝9Hz，1H)，6.82(br?d，J＝9Hz，1H)，6.89(br?t，J＝9Hz，1H)，7.15-7.33(m，2H)，7.48-7.57(m，1H)，7.53(d，J＝9Hz，2H)，7.59-7.67(m，1H)，7.83(s，1H)，8.10(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?471(M+H) +，488(M+NH 4) +。C 24H 17F 3N 2O 3S0.5H 2The analytical calculation value of O: C, 60.13; H, 3.65; N, 5.85.Measured value: C, 60.08; H, 3.81; N, 5.54.
Embodiment 2442-(3-chloro-phenyl-)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 207B (3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 4-fluoro-3-aminomethyl phenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-phenyl-)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 620mg, 57%) with described methyl sulfide compound oxidation.M.p.228-230℃。 1H?NMR(300MHz，CDCl 3)δ2.20(s，3H)，3.06(s，3H)，6.83-6.93(m，2H)，7.19(br?d，J＝9Hz，1H)，7.37-7.47(m，2H)，7.40(d，J＝9Hz，2H)，7.65(dt，J＝7Hz，3Hz，1H)，7.68(t，J＝3Hz，1H)，7.91(d，J＝9Hz，2H)，7.98(s，1H)。MS(DCI-NH 3)m/z?469(M+H) +，486(M+NH 4) +。C 24H 18ClFN 2O 3The analytical calculation value of S: C, 61.54; H, 3,85; N, 5.99.Measured value: C, 61.39; H, 3.84; N, 5.82.
Embodiment 2452-(4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 194C (4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 4-fluoro-3-aminomethyl phenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 590mg, 74.4%) with described methyl sulfide compound oxidation.M.p.245-247℃。 1H?NMR(300MHz，CDCl 3)δ2.01(s，3H)，3.07(s，3H)，6.87(m，2H)，7.21(m，3H)，7.41(d，J＝9Hz，2H)，7.68(m，2H)，7.92(d，J＝9Hz，2H)，7.97(s，1H)。MS(DCI-NH 3)m/z?453(M+H) +，470(M+NH 4) +。C 24H 18F 2N 2O 3S0.5H 2The analytical calculation value of O: C, 62.47; H, 3.90; N, 6.08.Measured value: C, 62.11; H, 4.11; N, 5.81.
Embodiment 2462-(3-chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 246A.2-(3-chloro-4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones
According to the method for embodiment 194A, HCl replaces 4-fluorobenzene hydrazine HCl, preparation title compound (output: 9.1g, 9%) with 3-chloro-4-fluorobenzene hydrazine. 1H?NMR(300MHz，CDCl 3)7.22(d，J＝9Hz，1H)，7.53-7.58(m，1H)，7.73(dd，J＝9Hz，3Hz，1H)，7.94(s，1H)。MS(DCI-NH 3)m/z?383(M+H) +，400(M+NH 4) +。(246B.2-3-chloro-4-fluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone
According to the method for embodiment 194B, with 2-(3-chloro-4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinone replaces 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones, preparation title compound (output: 5.6g, 84%). 1H?NMR(300MHz，CDCl 3)4.32(s，3H)，7.22-7.30(m，1H)，7.45-7.55(m，1H)，7.64-7.74(m，1H)，7.94(d，J＝9Hz，1H)。MS(DCI-NH 3)m/z?335(M+H) +，352(M+NH 4) +。246C. 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 6, replacing 2-benzyl-5-methoxyl group-4-bromo-3 (2H)-pyridazinone with 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone begins, and replace the 4-fluorobenzoic boric acid with 3-methyl-4-(methylthio group) phenylo boric acid, preparation title compound (output: 3.2g, 63%). 1H?NMR(300MHz，CDCl 3)δ2.53(s，3H)，4.13(s，3H)，7.25(t，J＝9Hz，1H)，7.35(d，J＝9Hz，2H)，7.52(d，J＝9Hz，2H)，7.55-7.64(m，1H)，7.78(dd，J＝9Hz，3Hz，1H)，7.93(s，2H)。MS(DCI-NH 3)m/z?377(M+H) +，394(M+NH 4) +。246D. 2-(3-chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, with 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, handle described methoxyl group-sulfide compound with cyclohexyl chlorination magnesium, the preparation title compound obtains described cyclohexyl sulfide compound.246E. 2-(3-chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10,, obtain title compound (output: 150mg, 53%) with described methyl sulfide compound oxidation.M.p.180-181℃。 1H?NMR(300MHz，CDCl 3)δ1.02-1.36(m，2H)，1.49-1.68(m，4H)，1.75(br?d，J＝12Hz，2H)，2.28(dq，J＝12Hz，3Hz，2H)，2.57(tt，J＝12Hz，3Hz，1H)，3.17(s，3H)，7.25(t，J＝9Hz，1H)，7.53(d，J＝9Hz，1H)，7.53-7.61(m，2H)，7.69(s，1H)，7.78(dd，J＝9Hz，3Hz，1H)，8.12(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?461(M+H) +，478(M+NH 4) +。C 23H 22ClFN 2O 3The analytical calculation value of S: C, 60.01; H, 4.78; N, 6.09.Measured value: C, 59.85; H, 4.97; N, 5.79.
Embodiment 2472-(3-chloro-4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl according to embodiment 246D preparation]-3 (2H)-pyridazinones begin, and with 4-fluoro-3-aminomethyl phenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 118mg, 53.7%) with described methyl sulfide compound oxidation.M.p.207-208℃。 1H?NMR(300MHz，CDCl 3)δ2.21(br?s，3H)，3.08(s，3H)，6.81-6.93(m，2H)，7.15-7.30(m，2H)，7.41(d，J＝9Hz，2H)，7.60-7.68(m，1H)，7.85(dd，J＝9Hz，3Hz，1H)，7.93(d，J＝9Hz，2H)，7.99(s，1H)。MS(DCI-NH 3)m/z?487(M+H) +，504(M+NH 4) +。C 24H 17ClF 2N 2O 3S0.25H 2The analytical calculation value of O: C, 58.75; H, 3,52; N, 5.72.Measured value: C, 58.74; H, 3.60; N, 5.32.
Embodiment 2482-(3-chloro-4-fluorophenyl)-4-benzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 246D (3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with benzylmagnesium chloride substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 110mg, 38.4%) with described methyl sulfide compound oxidation.M.p.164-165℃。 1H?NMR(300MHz，CDCl 3)δ3.11(s，3H)，3.99(s，2H)，7.01-7.06(m，2H)，7.17-7.28(m，4H)，7.53(d，J＝9Hz，2H)，7.59-7.66(m，1H)，7.81(s，1H)，7.82(dd，J＝6Hz，3Hz，1H)，8.09(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 24H 18ClFN 2O 3The analytical calculation value of S: C, 61.54; H, 3.85; N, 5.99.Measured value: C, 61.40; H, 3.82; N, 5.54.
Embodiment 2492-(3-chloro-4-fluorophenyl)-4-(3-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 246D (3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 3-luorobenzyl chlorination magnesium substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-4-fluorophenyl)-4-(3-luorobenzyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 33mg, 15%) with described methyl sulfide compound oxidation.M.p.101-103℃。 1H?NMR(300MHz，CDCl 3)δ3.15(s，3H)，3.95(s，2H)，6.73(br?d，J＝9Hz，1H)，6.81(br?d，J＝9Hz，1H)，6.88(br?t，J＝9Hz，1H)，7.15-7.28(m，2H)，7.51(d，J＝9Hz，2H)，7.53(ddd，J＝9Hz，3Hz，1.5Hz，1H)，7.83(dd，J＝6Hz，3Hz，1H)，7.83(s，1H)，8.10(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?487(M+H) +，504(M+NH 4) +。C 24H 17ClF 2N 2O 3The analytical calculation value of S: C, 58.75; H, 3.52.N.5.62.Measured value: C, 58.50; H, 3.65; N, 5.29.
Embodiment 2502-(4-fluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 194C (4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 3-fluoro-4-methyl-phenyl-magnesium-bromide substituted cyclohexyl magnesium chloride, preparation 2-(4-fluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 540mg, 73%) with described methyl sulfide compound oxidation.M.p.245-248℃。 1H?NMR(300MHz，CDCl 3)δ2.22(br?s，3H)，3.05(s，3H)，6.83(dd，J＝9Hz，1.5Hz，1H)，6.96(dd，J＝9Hz，1.5Hz，1H).7.06(t，J＝9Hz，1H)7.18(t，J9Hz，2H)，7.41(d，J＝9Hz，2H)，7.65-7.72(m，2H)，7.91(d，J＝9Hz，2H)，7.95(s，1H)。MS(DCI-NH 3)m/z?452(M+H) +，470(M+NH 4) +。C 24H 18F 2N 2O 3The analytical calculation value of S: C, 63.86; H, 3.99; N, 6.21.Measured value: C, 63.49; H, 4.13; N, 5.98.
Embodiment 2512-(3-chloro-4-fluorophenyl)-4-(3,5-two fluoro-4-p-methoxy-phenyls)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 246D (3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 3,5-two fluoro-4-p-methoxy-phenyl magnesium bromide substituted cyclohexyl magnesium chlorides, preparation 2-(3-chloro-4-fluorophenyl)-4-(3,5-two fluoro-4-p-methoxy-phenyls)-and 5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 590mg, 65.7%) with described methyl sulfide compound oxidation.M.p.195-197℃。 1H?NMR(300MHz，CDCl 3)δ3.10(s，3H)，4.12(s，3H)，6.81(br?d，J＝9Hz，2H)，7.27(t，J＝9Hz，2H)，7.43(d，J＝9Hz，2H)，7.60-7.67(m，1H)，7.83(br?d，J＝9Hz，1H)，7.98(d，J＝9Hz，2H)，7.98(s，1H)。MS(DCI-NH 3)m/z?487(M+H) +，504(M+NH 4) +。C 24H 16ClF 3N 2O 3S0.5H 2The analytical calculation value of O: C, 54.44; H, 3.12; N, 5.30.Measured value: C, 54.50; H, 3.12; N, 5.15.
Embodiment 2522-(3-chloro-4-fluorophenyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, by the 2-for preparing among the embodiment 246D (3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and with 1-(3-methyl butyl) magnesium bromide substituted cyclohexyl magnesium chloride, preparation 2-(3-chloro-4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, obtain described methyl sulfide compound.
According to the method for embodiment 10,, obtain title compound (output: 425mg, 54.4%) with described methyl sulfide compound oxidation.M.p.102-104℃。 1H?NMR(300MHz，CDCl 3)δ0.85(d，J＝9Hz，6H)，1.41-1.62(m，1H)，2.50-2.63(m，2H)，3.30(s，3H)，7.22-7.38(m，3H)，7.57-7.64(m，1H)，7.72(br?s，1H)，7.80(br?d，J＝6Hz，1H)，8.15(t，J＝9Hz，1H)。MS(DCI-NH 3)m/z?467(M+H) +，484(M+NH 4) +。C 22H 21ClF 2N 2O 3The analytical calculation value of S: C, 56.65; H, 4.51; N, 6.01.Measured value: C, 56.25; H, 4.49; N, 6.06.
Embodiment 2532-(4-fluorophenyl)-4-(3-luorobenzyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 69B, will be oxidized to described methyl sulfoxide from the methyl sulfide intermediate of embodiment 242 with the metachloroperbenzoic acid of a a great deal of, obtain described sulfinyl compound.
According to the method for embodiment 68, described sulfoxide is converted into title sulphonamide (output: 120mg, 31%).M.p.199-202℃。 1H?NMR(300MHz，DMSO-d 6)δ3.92(s，2H)，6.85(br?t，J＝9Hz，2H)，6.99(br?t，J＝9Hz，1H)，7.26(q，J＝7Hz，1H)，7.35(t，J＝9Hz，2H)，7.50(s，2H)，7.62-7.71(m，4H)，7.95(d，J＝9Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z?454(M+H) +，471(M+NH 4) +。C 23H 17F 2N 3O 3The analytical calculation value of S: C, 60.86; H, 3.75; N, 9.27.Measured value: C, 60.99; H, 3.76; N, 9.02.
Embodiment 2542-(3, the 4-difluorophenyl)-4-(phenylacetylene base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 232, replace muriate with phenylacetylene base magnesium bromide, preparation title compound (output: 195mg, 61%).M.p.211-213℃。 1H?NMR(300MHz，DMSO-d 6)δ7.46(m，5H)，7.65(m，2H)，8.18(t，4H)，8.4(s，1H)。MS(DCI-NH 3)m/z?463M+H) +，480(M+NH 4) +。C 25H 16F 2N 2O 3The analytical calculation value of S: C, 64.56; H, 3.49; N, 6.06.Measured value: C, 64.49; H, 3.68; N, 5.86.
Embodiment 2552-(3, the 4-difluorophenyl)-4-(3, the 4-difluorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With magnesium chips (19.4mg 0.81mmol) handles 3 in the ether (10ml), the 4-difluoro benzyl bromide (0.1ml, 0.8mmol), with reaction mixture refluxed 1 hour.Reaction mixture being cooled off, and adds to 2-(3, the 4-difluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl in-78 ℃] (0.25g is in THF 0.7mmol) (10ml) solution for-3 (2H)-pyridazinones.Under room temperature, reaction mixture was stirred 18 hours.(50ml) adds in the reaction mixture with water, with ethyl acetate (50ml) extraction.Organic layer is through dried over mgso and vacuum concentration.The rough resistates of gained is through flash chromatography purifying (SiO 2, with 9: 1 hexanes: eluent ethyl acetate), obtain the required product of 120mg and some raw materials.
In 0 ℃, use CH 3CO 3H (0.3ml, 1mmol) handle above-mentioned methylthiolation compound in the methylene dichloride (10ml) (120mg, 0.3mmol).Be reflected in 2 hours and finish.Use the methylene dichloride diluted reaction mixture, use saturated sodium bicarbonate and salt water washing respectively.The rough resistates of gained is through flash chromatography purifying (SiO 2, with 1: 1 hexane: eluent ethyl acetate), obtain required product (output: 44mg, 13%).M.p.177-179℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，3.9(s，2H)，6.85(m，1H)，7.15(m，1H)，7.25(m，2H)，7.6(m，7H)，8.15(m，3H)。MS(DCI-NH 3)m/z?489(M+H) +，506(M+NH 4) +。C 24H 16F 4N 2O 3S0.25H 2The analytical calculation value of O: C, 59.01; H, 3.30; N, 5.74.Measured value: C, 58.16; H, 3.56; N, 4.51.
Embodiment 2562-(3, the 4-difluorophenyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 233; with 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones; and replace 3 with 1-bromo-3-methylbutane; the 4-difluoro benzyl bromide, preparation title compound (output: 198mg, 48%).M.p.55-58℃。 1H?NMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.4，(m，3H)，2.48(m，2H)，3.3(s，3H)，7.51(m，1H)，7.65(m，1H)，7.75(d，J＝9Hz，2H)，7.81(m，1H)，8.05(s，1H)，8.12(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?433(M+H) +，450(M+NH 4) +。C 22H 22F 2N 2O 3S0.25H 2The analytical calculation value of O: C, 61.10; H, 5.13; N, 6.48.Measured value: C, 61.09; H, 5.23; N, 6.36.
Embodiment 2572-(3-chloro-4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 233; by 2-(3; the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replace 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin; and replace 3 with 1-bromo-3-methylbutane; the 4-difluoro benzyl bromide; preparation title compound (output: 256mg, 88%).M.p.55-58℃。 1HNMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.4，(m，3H)，2.48(m，2H)，3.3(s，3H)，7.62(m，2H)，7.75(d，2H)，7.93(dd，1H)，8.05(s，1H)，8.12(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 22H 22FN 2O 3SCl0.25H 2The analytical calculation value of O: C, 58.86; H, 4.94; N, 6.24.Measured value: C, 59.23; H, 5.12; N, 6.00.
Embodiment 2582-(3, the 4-difluorophenyl)-4-(3-methyl butyl)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 233; with 2-(3; the 4-difluorophenyl)-and 4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-4-fluorophenyl)-4-methoxyl group-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones; and replace 3 with 1-bromo-3-methylbutane; the 4-difluoro benzyl bromide; preparation title compound (output: 100mg, 20%).M.p.119-121℃。 1HNMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.4，(m，3H)，2.48(m，2H)，3.4(s，3H)，7.51(m，1H)，7.8(m，2H)，7.81(m，2H)。MS(DCI-NH 3)m/z451(M+H) +，468(M+NH 4) +。C 22H 21F 3N 2O 3The analytical calculation value of S: C, 58.66; H, 4.7; N, 6.22.
Embodiment 2592-[4-fluoro-3-(methylthio group) phenyl]-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under room temperature, and usefulness sulfo-sodium methylate (51mg 0.7mmol) handles 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (315mg, the stirred solution of DMF 0.69mmol) (10ml).Reaction mixture was stirred under room temperature 3.15 hours.Reactant is inclined to water (75ml), it is extracted in the ethyl acetate.Organic layer is with salt water washing 2 times, through dried over mgso and vacuum concentration.The rough resistates of gained flash chromatography purifying (SiO 2, with 15: 1 methylene dichloride: the ether wash-out), obtain required product (output: 30mg, 8%).M.p.105-107℃。 1H?NMR(300MHz，DMSO-d 6)δ2.55(s，3H)，3.23(s，3H)，δ7.15(m，2H)，7.3(m，2H)，7.55(m，5H)，7.9(d，2H)，8.25(s，1H)。MS(DCI-NH 3)m/z?485(M+H) +，502(M+NH 4) +。C 24H 18F 2N 2O 3S 2The analytical calculation value: C, 59.49; H, 3.74; N, 5.78.
Embodiment 2602-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethyl sulfonyl) phenyl]-3 (2H)-pyridazinones: 260A.2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones
By 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones begin, and according to the step among the embodiment 69B with described sulfide oxidation, the preparation title compound.260B. two (4-(5-(2-benzyl-4-(4-fluorophenyl)-3 (2H)-pyridazinones) phenyl) disulphide
With 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl] (1.0g, 2.39mmol) (10ml stirred 2 hours under 70.8mmol) multi-phase solution in refluxes-3 (2H)-pyridazinones fast, and its bath temperature is 40-43 ℃ at trifluoroacetic anhydride.Reaction soln is cooled to 23 ℃, vacuum concentration and with toluene (2 * 5-7ml) azeotropic.Huang/the orange of gained is cooled to 0 ℃, under stirring fast, along the inwall of reaction vessel slowly add methyl alcohol/triethylamine (1: 1,6ml).Shiny red-orange solution was stirred 10 minutes in 0 ℃, remove cooling bath, with reaction mixture restir 1.5 hours, simultaneously with its temperature to 23 ℃.Mixture is cooled back 0 ℃, slowly add saturated ammonium chloride solution (200ml), add the enough 1M HCl aqueous solution then solution is transferred to pH1-2.Remove cooling bath, solution stirring is spent the night.The mixture ethyl acetate extraction.Ethyl acetate solution water and salt water washing, vacuum concentration.The yellow/brown oily matter (0.89g) of gained is mainly the mixture of described monosulphide and required disulphide.Subsequently in the 23 ℃ of described crude reaction mixture of a part (360mg) and I that stir fast in the benzene (100ml) 2(648mg 2.55mmol) 30 minutes, finishes the conversion of monosulphide to disulphide.(Chem.Pharm.Bull，1992，40，2842)。Use 0.1M Na 2S 2O 3The solution-treated mixture is to consume excessive iodine.This solution ethyl acetate extraction, ethyl acetate layer filter and vacuum concentration through dried over mgso.Be dissolved in the dichloromethane/hexane resistates and vacuum concentration, obtain described product (output: 347mg, 90% part transforms). 1H?NMR(300MHz，CDCl 3)δ5.38(s，4H)，6.91(dd，J＝8.8，8.8Hz，4H)，7.02(d，J＝8.7Hz，4H)，7.11-7.20(m，4H)，7.28-7.39(m，10H)，7.54(dd，J＝6.9，1.5Hz，4H)，7.83(s，2H)。260C.2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio) phenyl]-3 (2H)-pyridazinones:
With two [4-{5-[2-benzyl-4-(4-fluorophenyl)-3 (2H)-pyridazinones] } phenyl]-disulphide (140mg, 0.181mmol), (55mg is 0.361mmol) and in the pre-warmed oil bath of immersing 180 ℃ that stirs the mixture fast of tetramethylene sulfone (1.5ml) for trifluoroacetic acid potassium.The oil bath heating temperature is risen to 210 ℃, after immersing 10 minutes first, is taken out reaction flask rapidly from oil bath.During reaction, mixture is by the colourless heterogeneous dark blood red homogeneous phase that becomes.After being cooled to 23 ℃, the mixture ethyl acetate extraction is with 1M HCl, water and salt water washing.Ethyl acetate solution filters and vacuum concentration through dried over mgso.Resistates obtains described product (output: 17mg, 41%) through chromatographic separation (quick silica gel, ethyl acetate/hexane 1: 4).(Tetrahedron?Lett..，1996，37，9057)。 1H?NMR(300MHz，CDCl 3)δ5.41(s，2H)，6.94(dd，J＝8.2，8.2Hz，2H)，7.11-7.20(m，4H)，7.31-7.42(m，3H)，7.52-7.61(m，4H)，7.86(s，1H)。MS (APCI+) m/z 457 (M+H) +With m/z 474 (M+NH 4) +260D.2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethyl sulfonyl) phenyl]-3 (2H)-pyridazinones:
Make 2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio) phenyl]-3 (2H)-pyridazinones (100mg, 0.219mmol), 3-chlorine peroxybenzoic acid (380mg, 1.3mmol, 57-86%) and the solution of methylene dichloride (5ml) reflux in 55 ℃ bath temperature.1.75 hour, after 3.5 hours, 5 hours and 6 hours, the reaction do not finish as yet, add at every turn extra 3-chlorine peroxybenzoic acid (380mg, 1.3mmol, 57-86%).7.75 a hour afterreaction is finished, and mixture is cooled to 23 ℃ and vacuum concentration.Resistates dilutes with ethyl acetate, carefully with sodium sulfite solution jolting number minute, and 3 times, to consume excessive 3-chlorine peroxybenzoic acid.Use saturated sodium carbonate solution (3 *), water and salt water washing ethyl acetate solution subsequently,, filter and vacuum concentration through dried over mgso.Resistates obtains product (output: 93mg, 87%) through chromatographic separation (quick silica gel, ethyl acetate/dichloromethane/hexane 1: 2: 7).(J.Med.Chem.，1990，33，2569)。M.p.80-115℃。 1H?NMR(300MHz，DMSO-d 6)δ5.36(s，2H)，7.11(dd，J＝9.0，9.0Hz，2H)，7.18-7.26(m，2H)，7.29-7.46(m，5H)，7.66(d，J＝8.7Hz，2H)，8.10(d，J＝8.7Hz，2H)，8.18(s，1H)。MS (APCI+) m/z 489 (M+H) +With m/z 506 (M+NH 4) +C 24H 16F 4N 2O 3The analytical calculation value of S: C, 59.02; H, 3.30; N, 5.74.Measured value: C, 59.30; H, 3.48; N, 5.59.
Embodiment 2612-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The 2-(2 that will prepare according to the method for embodiment 193E; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (150mg; 0.41mmol) and neopentyl alcohol (43mg; 0.49mmol) be dissolved among the DMF (2ml), under jolting, add NaH (25mg, 0.62mmol; 60% mineral oil solution), standing over night.With reaction mixture quenching carefully, with the ethyl acetate dilution, with 1N HCl extracting twice, the water extraction is 3 times then, through dried over mgso with saturated ammonium chloride solution.Behind filtration drying agent and the vacuum concentrated filtrate, resistates is through silica gel (Biotage40S) chromatography purification, with 2: 1 hexane-eluent ethyl acetates.The product flow point is merged and evaporation, obtain title compound (output: 137mg, 76%).M.p.145-146℃。 1H?NMR(300MHz，DMSO-d 6)δ0.76(s，9H)，3.28(s，3H)，4.06(s，2H)，5.02(q，J＝9Hz，2H)，7.88(d，J＝8Hz，2H)，8.04(d，J＝8Hz，2H)，8.13(s，1H)。MS(DCI-NH 3)m/z?419(M+H) +，436(M+NH 4) +。C 18H 21F 3N 2O 4The analytical calculation value of S: C, 51.67; H, 5.06; N, 6.69.Measured value: C, 51.47; H, 5.12; N, 6.48.
Embodiment 2622-(2,2, the 2-trifluoroethyl)-4-(4-methoxyl group phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 4-methoxyphenol, preparation title compound (output: 130mg, 54%).M.p.194-195℃。 1H?NMR(300MHz，DMSO-d 6)δ2.24(s，3H)，3.26(s，3H)，5.00(q，J＝9Hz，2H)，6.88(d，J＝8Hz，2H)，7.09(d，J＝8Hz，2H)，7.37(d，J＝8Hz，2H)，8.03(d，J＝8Hz，2H)，8.33(s，1H)。MS(ESI-)m/z?439(M-H) -。C 19H 17F 3N 2O 4The analytical calculation value of S: C, 54.79; H, 3.91; N, 6.39.Measured value: C, 55.04; H, 4.00; N, 6.11.
Embodiment 2632-(2,2, the 2-trifluoroethyl)-4-(2-fluoro-5-4-trifluoromethylphenopendant)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 2-fluoro-5-trifloro methyl phenol, preparation title compound (output: 155mg, 89%).M.p.133-135℃。 1H?NMR(300MHz，DMSO-d 6)δ3.28(s，3H)，5.03(q，J＝9Hz，2H)，7.10-7.53(m，2H)，7.72(dd，J＝1Hz，7Hz?1H)，7.92(d，J＝8Hz，2H)，8.07(d，J＝8Hz，2H，8.38(s，1H)。MS(DCI-NH 3)m/z?528(M+NH 4) +。C 20H 13F 7N 2O 4The analytical calculation value of S: C, 47.66; H, 3.09; N, 5.05.Measured value: C, 47.68; H, 2.95; N, 5.16.
Embodiment 2642-(2,2, the 2-trifluoroethyl)-4-(4-cyano-benzene oxygen)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 4-cyanophenol, preparation title compound (output: 109mg, 71%).M.p.179-181℃。 1H?NMR(300MHz，DMSO-d 6)δ3.26(s，3H)，5.02(q，J＝9Hz，2H)，7.25(d，J＝9Hz，2H)，7.81(d，J＝9Hz，2H)，7.86(d，J＝8Hz，2H)，8.03(d，J＝8HZ，2H)，8.37(s，1H)。MS(DCI-NH 3)m/z?467(M+NH 4) +。C 20H 14F 3N 3O 4The analytical calculation value of S: C, 53.45; H, 3.14; N, 9.35.Measured value: C, 53.19; H, 3.01; N, 9.09.
Embodiment 2652-(2,2, the 2-trifluoroethyl)-4-(3-pyridyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 3-pyridone, preparation title compound (output: 120mg, 69%).M.p.191-193℃。 1H?NMR(300MHz，DMSO-d 6)δ3.26(s，3H)，5.01(q，J＝9Hz，2H)，7.36(dd，J＝3Hz，8Hz，1H)，7.55(ddd，J＝1Hz，3Hz，8Hz，1H)，7.88(d，J＝8Hz，2H)，8.04(d，J＝8Hz，2H)，8.31(dd，J＝1Hz，5Hz，1H)，8.36(s，1H)，8.38(d，J＝3Hz，1H)。MS(DCI-NH 3)m/z?426(M+H) +，443(M+NH 4) +。C 18H 14F 3N 3O 4The analytical calculation value of S: C, 50.82; H, 3.32; N, 9.88.Measured value: C, 50.95; H, 3.57; N, 9.71.
Embodiment 2662-(2,2, the 2-trifluoroethyl)-4-(4-n-propyl phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 4-(n-propyl) phenol, preparation title compound (output: 147mg, 77%).M.p.152-153℃。 1H?NMR(300MHz，DMSO-d 6)δ0.87(t，J＝7Hz，3H)，1.54(h，J＝7Hz，2H)，3.25(s，3H)，5.00(q，J＝9Hz，2H)，6.88(d，J＝9Hz，2H)，7.09(d，J＝9Hz，2H)，7.87(d，J＝8Hz，2H)，8.02(d，J＝8Hz，2H)，8.32(s，1H)。MS(DCI-NH 3)m/z?484(M+H) +。C 22H 21F 3N 2O 4The analytical calculation value of S: C, 56.33; H, 4.54; N, 6.01.Measured value: C, 56.23; H, 4.75; N, 5.79.
Embodiment 2672-(2,2, the 2-trifluoroethyl)-4-[(4-(methyl sulphonyl) phenoxy group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 4-(methyl sulphonyl) phenol, preparation title compound (output: 115mg, 56%).M.p.212-213℃。 1H?NMR(300MHz，DMSO-d 6)δ3.21(s，3H)，3.27(s，3H)，5.03(q，J＝9Hz，2H)，7.31(d，J＝9Hz，2H)，7.83-7.89(m，4H)，8.04(d，J＝8Hz，2H)，8.40(s，1H)。MS(DCI-NH 3)m/z?520(M+NH 4) +。C 20H 17F 3N 2O 6S 2The analytical calculation value: C, 47.81; H, 3.41; N, 5.58.Measured value: C, 47.92; H, 3.18; N, 5.52.
Embodiment 2682-(2,2, the 2-trifluoroethyl)-4-(4-phenyl phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 4-phenylphenol, preparation title compound (output: 105mg, 51%).M.p.163-165℃。 1H?NMR(300MHz，DMSO-d 6)δ3.26(s，3H)，5.02(q，J＝9Hz，2H)，7.10(d，J＝8Hz，2H)，7.33(br?t，J＝7Hz，1H)，7.44(t，J＝7Hz，2H)，7.57-7.63(m，4H)，7.92(d，J＝8Hz，2H)，8.04(d，J＝8Hz，2H)，8.37(s，1H)。MS(DCI-NH 3)m/z518(M+NH 4) +。C 25H 19F 3N 2O 4The analytical calculation value of S: C, 60.00; H, 3.83; N, 5.60.Measured value: C, 60.18; H, 3.66; N, 5.52.
Embodiment 2692-(2,2, the 2-trifluoroethyl)-4-[2-(methylthio group) oxyethyl group)-and 5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 2-(methylthio group) ethanol, preparation title compound (output: 105mg, 61%).M.p.103-105℃。 1H?NMR(300MHz，DMSO-d 6)δ2.01(s，3H)，2.72(t，J＝7Hz，2H)，3.29(s，3H)，4.59(t，J＝7Hz，2H)，5.03(q，J＝9Hz，2H)，7.91(d，J＝8Hz，2H)，8.04(d，J＝8Hz，2H)，8.15(s，1H)。MS(DCI-NH 3)m/z?423(M+H) +，440(M+NH 4) +。C 16H 17F 3N 2O 4S 2The analytical calculation value: C, 45.49; H, 4.06; N, 6.33.Measured value: C, 45.83:H, 4.11; N, 6.42.
Embodiment 2702-(2,2, the 2-trifluoroethyl)-4-(phenyl methoxyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with phenylcarbinol phenol, preparation title compound (output: 137mg, 76%).M.p.121-123℃。 1H?NMR(300MHz，DMSO-d 6)δ3.28(s，3H)，5.06(q，J＝9Hz，2H)，5.48(s，2H)，7.20-7.25(m，2H)，7.27-7.81(m，3H)，7.76(d，J＝8Hz，2H)，7.98(d，J＝8Hz，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?456(M+H) +。C 20H 17F 3N 2O 4The analytical calculation value of S: C, 54.79; H, 3.91; N, 6.39.Measured value: C, 55.10; H, 3.91; N, 6.13.
Embodiment 2712-(2,2, the 2-trifluoroethyl)-4-(2-furyl methoxyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 2-(methylol) furans, preparation title compound (output: 101mg, 58%).M.p.113-115℃。 1H?NMR(300MHz，DMSO-d 6)δ3.28(s，3H)，5.07(q，J＝9Hz，2H)，5.52(s，2H)，6.41(dd，J＝2Hz，3Hz，1H)，6.45(d，J＝4Hz，1H)，7.62(d，J＝2Hz，1H)，7.69(d，J＝8Hz，2H)，7.97(d，J＝8Hz，2H)，8.13(s，1H)。MS(DCI-NH 3)m/z?446(M+NH 4) +。C 18H 15F 3N 2O 5The analytical calculation value of S: C, 50.66; H, 3.80; N, 6.21.Measured value: C, 51.02; H, 3.71; N, 6.23.
Embodiment 2722-(2,2, the 2-trifluoroethyl)-4-[2-(3, the 4-Dimethoxyphenyl) oxyethyl group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 2-(3, the 4-Dimethoxyphenyl) ethanol, preparation title compound (output: 118mg, 56%).M.p.133-134℃。 1HNMR(300MHz，DMSO-d 6)δ2.82(t，J＝7Hz，2H)，3.28(s，3H)，3.63(s，3H)，3.70(s，3H)，4.68(t，J＝7Hz，2H)，5.01(q，J＝9Hz，2H)，6.61(dd，J＝2Hz，8Hz，1H)，6.74(d，J＝2Hz，1H)，6.77(d，J＝8Hz，1H)，7.74(d，J＝8Hz，2H)，7.93(d，J＝8Hz，2H)，8.11(s，1H)。MS(DCI-NH 3)m/z530(M+NH 4) +。C 23H 23F 3N 2O 6The analytical calculation value of S: C, 53.90; H, 4.52; N, 5.47.Measured value: C, 53.87; H, 4.48; N, 5.45.
Embodiment 2732-(2,2, the 2-trifluoroethyl)-4-[2-(4-morpholino) oxyethyl group)]-and 5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 4-(2-hydroxyethyl) morpholine, preparation title compound (output: 111mg, 59%).M.p.147-148℃。 1H?NMR(300MHz，DMSO-d 6)δ2.23(m，4H)，2.46(t，J＝5Hz，2H)，3.28(s，3H)，3.40(m，4H)，4.60(t，J＝5Hz，2H)，5.02(q，J＝8Hz，2H)，7.96(d，J＝8Hz，2H)，8.03(d，J＝8Hz，2H)，8.17(s，1H)。MS(DCI-NH 3)m/z?462(M+H) +。C 19H 22F 3N 3O 5The analytical calculation value of S: C, 49.45; H, 4.81; N, 9.11.Measured value: C, 49.59; H, 4.80; N, 8.88.
Embodiment 2742-(2,2, the 2-trifluoroethyl)-4-[2-(piperidino) oxyethyl group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 1-(2-hydroxyethyl) piperidines, preparation title compound (output: 103mg, 55%).M.p.117-118℃。 1H?NMR(300MHz，DMSO-d 6)δ1.30(br?s，6H)，2.20(br?s，4H)，2.41(t，J＝4Hz，2H)，3.28(s，3H)，4.60(t，J＝5Hz，2H)，5.02(q，J＝9Hz，2H)，7.97(d，J＝8Hz，2H)，8.03(d，J＝8Hz，2H)，8.15(s，1H)。MS(DCI-NH 3)m/z?460(M+H) +。C 20H 24F 3N 3O 4The analytical calculation value of S: C, 52.28; H, 5.26; N, 9.15.Measured value: C, 52.22; H, 5.08; N, 8.94.
Embodiment 2752-(2,2, the 2-trifluoroethyl)-4-[4-(formamido group) phenoxy group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 4-hydroxybenzamide, preparation title compound (output: 50mg, 26%).M.p.＞250℃。 1H?NMR(300MHz，DMSO-d 6)δ3.26(s，3H)，5.02(q，J＝8Hz，2H)，7.08(d，J＝9Hz，2H)，7.30(s，1H)，7.82(d，J＝9Hz，2H)，7.88(d，J＝8Hz，2H)，7.92(s，1H)，8.03(d，J＝8Hz，2H)，8.47(s，1H)。MS(DCI-NH 3)m/z?468(M+H) +，485(M+NH 4) +。C 20H 16F 3N 3O 5The analytical calculation value of S: C, 51.39; H, 3.45; N, 8.99.Measured value: C, 51.31; H, 3.28; N, 8.77.
Embodiment 2762-(2,2, the 2-trifluoroethyl)-4-(1-indane oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 1-indanol, preparation title compound (output: 84mg, 44%).M.p.113-114℃。 1H?NMR(300MHz，DMSO-d 6)δ2.07-2.14(m，1H)，2.22-2.35(m，1H)，2.73(dd，J＝5Hz，7Hz，2H)，3.24(s，3H)，5.00-5.22(m，2H)，6.48(dd，J＝2Hz，6Hz，1H)，7.12-7.24(m，2H)，7.21-7.28(m，2H)，7.44(d，J＝8Hz，2H)，7.87(d，J＝8Hz，2H)，8.09(s，1H)。MS(DCI-NH 3)m/z?482(M+NH 4) +。C 22H 19F 3N 2O 4The analytical calculation value of S: C, 57.19; H, 4.48; N, 5.80.Measured value: C, 57.36; N, 4.30; N, 5.78.
Embodiment 2772-(2,2, the 2-trifluoroethyl)-4-[2-(kharophen) phenoxy group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 4-acetoamidophenol, preparation title compound (output: 45mg, 23%).M.p.215-216℃。 1H?NMR(300MHz，DMSO-d 6)δ2.02(s，3H)，3.26(s，3H)，5.02(q，J＝8Hz，2H)，6.61-6.65(m，1H)，7.17-7.20(m，2H)，7.34(br?s，1H)，7.88(d，J＝9Hz，2H)，8.03(d，J＝8Hz，2H)，8.36(s，1H)，9.97(s，1H)。MS(DCI-NH 3)m/z?499(M+NH 4) +。C 21H 18F 3N 3O 5The analytical calculation value of S: C, 52.39; H, 3.77; N, 8.73.Measured value: C, 52.57; N, 4.02; N, 8.37.
Embodiment 2782-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with the 2-methylpropanol, preparation title compound (output: 111mg, 50%).M.p.108-110℃。 1H NMR (300MHz, DMSO-d 6) δ 0.77 (d, J=6.4Hz, 6H), 1.52 (septet, J=6.4Hz, 1H), 3.28 (s, 3H), 4.17 (d, J=6Hz, 2H), 5.02 (q, J=9Hz, 2H), 7.88 (d, J=9Hz, 2H), 8.04 (d, J=9Hz, 2H), 8.14 (s, 1H).MS(DCI-NH 3)m/z?405(M+H) +，422(M+NH 4) +。C 17H 19F 3N 2O 4The analytical calculation value of S: C, 50.49; H, 4.74; N, 6.93.Measured value: C, 50.69; H, 4.89; N, 6.75.
Embodiment 2792-(2,2, the 2-trifluoroethyl)-4-(1-methyl cyclo propyl methoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, replace neopentyl alcohol with 1-methyl cyclopropyl-carbinol, preparation title compound (output: 360mg, 75.5%).M.p.98-99℃。 1H?NMR(300MHz，CDCl 3)δ0.35(dt，J＝40Hz，5Hz，4H)，0.91(s，3H)，3.11(s，3H)，4.32(s，2H)，4.82(q，J＝8.5Hz，2H)，7.80(d，J＝8.5Hz，2H)，7.84(s，1H)，8.06(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?417(M+H) +，434(M+NH 4) +。C 18H 19F 3N 2O 4The analytical calculation value of S: C, 51.92; H, 4.60; H, 6.73.Measured value: C, 51.87; H, 4.72; N, 6.69.
Embodiment 2802-(2,2, the 2-trifluoroethyl)-4-(3,3-dimethyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 261, with 3,3-dimethyl-1-butanols replaces neopentyl alcohol, preparation title compound (output: 270mg, 67.4%).M.p.83-85℃。 1H?NMR(300MHz，CDCl 3)δ0.88(s，9H)，1.56(t，J＝8Hz，2H)，4.60(t，J＝8Hz，2H)，4.83(q，J＝8.5Hz，2H)，7.73(d，J＝8.5Hz，2H)，7.81(s，1H)，8.05(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?433(M+H) +，450(M+NH 4) +。C 19H 23F 3N 2O 4The analytical calculation value of S: C, 52.77; H, 5.36; N, 6.48.Measured value: C, 52.95; H, 5.29; N, 6.35.
Embodiment 2812-(324-difluorophenyl)-4-(4-chlorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl with preparation among the embodiment 78]-3 (2H)-pyridazinone (187mg; 0.5mmol), para-chlorophenol (129mg; 0.5mmol) and NaH (60% oil suspension) (40mg; 1mmol) mixture in THF (25ml) is in 50 ℃ of backflows 3 hours, vacuum concentration then.Resistates is allocated between water and the ethyl acetate.The salt water washing of acetic ester layer is through dried over mgso and vacuum concentration.Resistates obtains 2-benzyl-4-(4-chlorophenoxy)-5-[4-(methyl sulphonyl) phenyl through chromatography purification (silica gel, 1: 1 hexane-ethyl acetate)]-3 (2H)-pyridazinones (output: 200mg, 82%).
Above derivative is dissolved in the toluene (25ml), uses AlBr 3(400mg 1.5mmol) handled 20 minutes in 80 ℃.Mixture is cooled to room temperature, inclines to ice-10% citric acid-ethyl acetate.Separate organic layer,, obtain the rough benzyl derivative that goes through dried over mgso and vacuum concentration.This compound is dissolved in the pyridine (50ml) immediately, with 3, the 4-difluoro bromobenzene (0.17ml, 1.5mmol), (100mg 1.5mmol) refluxes and handled 16 hours down for Cu (20mg) and salt of wormwood.Behind the mixture vacuum concentration, resistates is dissolved in the ethyl acetate water, 10% citric acid and salt water washing.Through column chromatography purification (silica gel, 1: 1 hexane-ethyl acetate), obtain title compound (output: 73mg, 30%).M.p.192-194℃。 1H?NMR(300MHz，DMSO-d 6)δ3.22(s，3H)，7.13(m，2H)，7.35(m，2H)，7.50(m，1H)，7.60(m，1H)，7.75(m，1H)，7.87(d，J＝9Hz，2H)，8.05(d，J＝9Hz，2H)，8.41(s，1H)。MS (APCI+) m/z 488 (M+H) +(APCI-) m/z 523 (M+Cl) -
Embodiment 2822-(3, the 4-difluorophenyl)-4-(4-bromine phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 281 replaces para-chlorophenol with p bromophenol, preparation title compound (output: 54mg, 20%).M.p.196-199℃。 1H?NMR(300MHz，DMSO-d 6)δ3.25(s，3H)，7.09(d，J＝9Hz，2H)，7.47(d，J＝9Hz，2H)，7.52(m，1H)，7.62(m，1H)，7.78(m，1H)，7.89(d，J＝9Hz，2H)，8.05(d，J＝9Hz，2H).8.41(s，1H)。MS (APCI+) m/z 533 (M+H) +(APCI-) m/z 569 (M+Cl) -
Embodiment 2832-(2,2, the 2-trifluoroethyl)-4-(encircling penta sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under nitrogen, by syringe to NaH (26mg, drip in acetonitrile 1.1mmol) (3.0ml) solution cyclopentyl mercaptan (120 μ l, 1.1mmol).The solution of gained nitrogen wash 20 minutes, the 2-(trifluoroethyl) for preparing among the after this disposable adding embodiment 193E-4-chloro-5-[4-(methyl sulphonyl) phenyl] and-3 (2H)-pyridazinones (200mg, 0.52mmol).With solution restir 20 minutes, this moment, all 4-bromine pyridazinones exhausted then.Analyze this solution through TLC (1: 1, ethyl acetate-hexane).。Add entry (5ml) carefully, with reactant distribution between ethyl acetate (125ml) and saturated brine (50ml).Organic layer is with saturated brine (50ml) washing, through dried over mgso and vacuum concentration.Through silica gel column chromatography (20% ethyl acetate-80% hexane), obtain faint yellow solid (output: 202mg, 83.1%).M.p.149-151℃。 1H?NMR(300MHz，CDCl 3)δ1.40-1.34(m，2H)，1.62-1.54(m，4H)，1.93-1.88(m，2H)，3.13(s，3H)，4.40-4.35(m，1H)，4.85(q，J＝8.2Hz，2H)，7.58(d，J＝8.5Hz，2H)，7.66(s，1H)，8.06(d，J＝8.4Hz，2H)。MS(DCI-NH 3)m/z?432(M+H) +，(M+NH 4) +。C 18H 19F 3N 2O 3S 2The analytical calculation value: C, 49.99; H, 4.43; N, 6.48.Measured value: C, 50.15; H, 4.39; N, 6.45.
Embodiment 2842-(2,2, the 2-trifluoroethyl)-4-(1H-1,2,4-triazole-3-base sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, use 1H-1,2,4-triazole-3-mercaptan substituted ring pentan-thiol, preparation title compound (output: 164mg, 93%).M.p.197-200℃。 1H?NMR(300MHz，CDCl 3))δ3.14(s，3H)，4.84(q，J＝8.1Hz，2H).7.41(s，1H)，7.68(d，J＝6.8Hz，2H)，7.83(s，1H)，8.00(d，J＝7.1Hz，2H)，8.05(s，1H)。MS(DCI-NH 3)m/z?431(M+H) +，(M+NH 4) +。C 15H 12F 3N 2O 3S 2The analytical calculation value: C, 41.76; H, 2.80; N, 16.23.Measured value: C, 41.68; H, 2.85; N, 15.99.
Embodiment 2852-(2,2, the 2-trifluoroethyl)-4-phenyl methylthio group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with beneze methane thiol substituted ring pentan-thiol, preparation title compound (output: 141mg, 76%).M.p.108-111℃。 1H?NMR(300MHz，CDCl 3)δ3.01(s，3H)，4.38(s，2H)，4.87(q，J＝Hz，2H)，7.10-7.06(m，2H)，7.22-7.20(m，5H)，7.59(s，1H)，7.95(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?454(M+H) +，(M+NH 4) +。C 20H 17F 3N 2O 3S 2, the analytical calculation value of 0.75EtOAc: C, 53.06; H, 4.45; N, 5.38.Measured value: C, 53.55; H, 4.16; N, 5.84.
Embodiment 2862-(2,2, the 2-trifluoroethyl)-4-(4-fluorobenzene sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with 4-fluorophenyl thiomethyl alcohol substituted ring pentan-thiol, preparation title compound (output: 184mg, 73.5%).M.p.182-185℃。 1H?NMR(300MHz，CDCl 3)δ3.08(s，3H)，4.82(q，J＝8.5Hz，2H)，6.87-6.81(m，2H)，7.19-7.11(m，2H)，7.48(d，J＝9.0Hz，2H).7.68(s，1H)，7.93(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?458(M+H) +，(M+MH 4) +。C 19H 14F 4N 2O 3S 2The analytical calculation value: C, 49.78; H, 3.08; N, 6.11.Measured value: C, 49.89; H, 3.18; N, 5.86.
Embodiment 2872-(2,2, the 2-trifluoroethyl)-4-(hexamethylene sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with cyclohexylmercaptan substituted ring pentan-thiol, preparation title compound (output: 189mg, 78%).M.p.165-167℃。 1H?NMR(300MHz，CDCl 3)δ1.28-1.17(m，5H)，1.64-1.56(m，3H)，1.82-1.79(m，2H)，3.13(s，3H)，4.08-4.05(m，1H)，4.86(q，J＝8.5Hz，2H)，7.58(d，J＝8.4Hz，2H)，7.67(s，1H)，8.06(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?446(M+H) +，(M+NH 4) +。C 19H 21F 3N 2O 3S 2The analytical calculation value: C, 51.11; H, 4.74; N, 6.27.Measured value: C, 51.39; H, 4.72; N, 5.91.
Embodiment 2882-(2,2, the 2-trifluoroethyl)-4-(3-chloro-4-fluorobenzene sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with 3-chloro-4-fluoro thiophenol substituted ring pentan-thiol, preparation title compound (output: 190mg, 65%).M.p.142-145℃。 1H?NMR(300MHz，CDCl 3)δ3.18(s，3H)，4.85(q，J＝8.4Hz，2H)，6.96(ov.t，J＝8.5Hz，1H)，7.14-7.10(m，1H)，7.18(dd，J＝2.1，6.5Hz，1H，)，7.53(d，J＝8.4Hz，2H)，7.77(s，1H)，7.96(d，J＝8.0Hz，2H)。MS(CI)m/z?493(M+1) +，(M+NH 4) +。C 19H 13ClF 4N 2O 3S 20.25C 6H 6H 2The analytical calculation value of O: C, 47.36; H, 2.92; N, 5.41.Measured value: C, 47.88; H, 2.95; N, 5.24.
Embodiment 2892-(2,2, the 2-trifluoroethyl)-4-(2,2,2-trifluoro ethylmercapto group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with 2,2,2-trifluoro sulfur alcohol substituted ring pentan-thiol, preparation title compound (output: 175mg, 66%).M.p.155-158℃。 1H?NMR(300MHz，CDCl 3)δ3.14(s，3H)，3.98(q，J＝9.8Hz，2H)，4.86(q，J＝8.1Hz，2H)，7.58(d，J＝8.4Hz，2H)，7.75(s，1H)，8.10(d，J＝8.4Hz，2H)。MS(DCI-NH 3)m/z?446(M+H) +，(M+NH 4) +。C 15H 12F 6N 2O 3S 2The analytical calculation value: C, 40.36; H, 2.71; N, 6.28.Measured value: C, 40.50; H, 2.72; N, 6.01.
Embodiment 2902-(2,2, the 2-trifluoroethyl)-4-(uncle's butylthio)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with tert.-butyl mercaptan substituted ring pentan-thiol, preparation title compound (output: 212mg, 85%).M.p.186-189℃。 1H?NMR(300MHz，CDCl 3)δ1.25(s，9H)，3.13(s，3H)，4.87(q，J＝8.1Hz，2H)，7.62(d，J＝8.5Hz，2H).7.67(s，1H)，8.05(d，J＝8.1Hz，2H)。MS(ESI)m/z?420(M+H) +，(M+Na) +。C 17H 19F 3N 2O 3S 2The analytical calculation value: C, 48.56; H, 4.55; N, 6.66.Measured value: C, 50.15; H, 4.39; N, 6.45.
Embodiment 2912-(2,2, the 2-trifluoroethyl)-4-(2-kharophen thiophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with 4-kharophen thiophenol substituted ring pentan-thiol, preparation title compound (output: 100mg, 37%).M.p.191-193℃。 1H?NMR(300MHz，CDCl 3)δ2.16(s，3H)，3.08(s，3H)，4.83(q，J＝8.2Hz，2H)，7.00(d，J＝8.8Hz，2H)，7.19(d，J＝8.8Hz，2H)，7.31(d，J＝8.1Hz，2H)，7.58(s，1H)，7.78(d，J＝8.1Hz，2H)。MS(Cl)m/z?497(M+H) +，(M+NH 4) +。C 21H 18F 3N 3O 4S 20.25H 2O, 0.25C 6H 6The analytical calculation value: C, 52.83; H, 4.06; N, 7.70.Measured value: C, 52.97; H, 3.85; N, 7.65.
Embodiment 2922-(2,2, the 2-trifluoroethyl)-4-(2-rosickyite base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with isopropyl mercaptan substituted ring pentan-thiol, preparation title compound (output: 180mg, 81%).M.p.165-167℃。 1H?NMR(300MHz，CDCl 3)δ1.17(d，J＝6.8Hz，6H)，3.13(s，3H)，4.33(p，J＝6.8Hz，1H)，4.86(q，J＝8.5Hz，2H)，6.59(d，J＝8.5Hz，2H)，7.68(s，1H)，8.07(d，J＝8.1Hz，2H)。MS(DCI-NH 3)m/z?406(M+H) +，(M+NH 4) +。C 16H 17F 3N 2O 4S 2, 0.75H 2The analytical calculation value of O: C, 45.76; H, 4.4; N, 6.67.Measured value: C, 45.91; H, 3.98; N, 6.46.
Embodiment 2932-(2,2, the 2-trifluoroethyl)-4-(2-methyl-prop-1-base sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 283, with 2-methyl isophthalic acid-propylmercaptan substituted ring pentan-thiol, preparation title compound (output: 100mg, 83%).M.p.135-138℃。 1H?NMR(300MHz，CDCl 3)δ0.87(d，J＝6.4Hz，6H)，1.67-1.60(m，1H)，3.00(d，J＝6.7Hz，2H)，3.14(s，3H)，4.84(q，J＝8.5Hz，2H)，7.61(d，J＝8.4Hz，2H).7.67(s，1H)，8.08(d，J＝8.5Hz，2H)。MS(DCI-NH 3)m/z?420(M+H) +，(M+NH 4) +。C 17H 19F 3N 2O 3S 2The analytical calculation value: C, 48.56; H, 4.55; N, 6.66.Measured value: C, 47.86; N, 4.57; N, 6.51.
Embodiment 2942-(2,2, the 2-trifluoroethyl)-4-amino-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Will be according to 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methylthio group) phenyl of embodiment 193E preparation] (500mg 1.36mmol) is dissolved among the DMF (10ml)-3 (2H)-pyridazinones, uses NaN 3(100mg 1.5mmol) handles.After following 2 hours, reactant dilutes with ethyl acetate and washes with water 4 times, through dried over mgso in room temperature.Behind filtration drying agent and the vacuum concentrated filtrate, with resistates through silica gel (Biotage 40S) chromatography purification, with 2: 1 hexane-eluent ethyl acetates.The product flow point is merged and evaporation, obtains azido-intermediate 2-(2,2, the 2-trifluoroethyl)-4-azido--5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones (output: 481mg, 95%).
(39mg 0.105mmol) is dissolved among THF (3ml) and the MeOH (2ml), uses excessive N aBH with above 4-azido cpd 4Handle.After 15 minutes, reactant saturated ammonium chloride solution quenching is extracted into product in the ethyl acetate.Organic layer washes with water 3 times and through dried over mgso.Behind filtration drying agent and the evaporating solvent, obtain title compound (output: 26mg, 71%).M.p.＞260℃。 1H?NMR(300MHz，DMSO-d 6)δ3.26(s，3H)，4.93(q，J＝9Hz，2H)，6.71(s，2H)，7.72(s，1H)，7.76(d，J＝8Hz，2H)，8.02(d，J＝8Hz，2H)。MS(ESI-)m/z?346(M-H) -。C 13H 12F 3N 3O 3The analytical calculation value of S: C, 44.96; H, 3.48; N, 12.10.Measured value: C, 44.59; H, 3.52; N, 11.93.
Embodiment 2952-(2, the 22-trifluoroethyl)-4-(3-methoxy propyl amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The 2-(2 that will prepare according to the method for embodiment 193E; 2; the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (200mg, 0.546mmol) and 3 methoxypropyl amine (145mg, pyridine 1.64mmol) (4ml) solution in 100 ℃ the heating 16 hours.Reaction mixture is cooled to room temperature, and (2g) mixes with silica gel, and solvent is removed in decompression.The silica gel of absorption is layered on Extract-Clean Cartridge (Alltech, the dress post: 10g silica gel), with this post of hexane/acetone stepwise gradient wash-out, described stepwise gradient is made up of each 60ml of following mixture: hexane, 8: 1 hexane/acetone, 4: 1,2: 1 and 1: 1.The flow point that will contain required product merges, concentrates, and with HPLC (Technikrom Kromasil 60-5 sil silica column, 20mm * 25cm) be further purified.This post is used by the linear gradient of 30% ethyl acetate/hexane to 100% ethyl acetate with 10ml/min wash-out 50 minutes.The flow point that will contain product merges and concentrating under reduced pressure, obtains described product, is canescence crystal (output: 215mg, 95%).M.p.110-113℃。 1H?NMR(300MHz，CDCl 3)δ8.02(d，J＝18.0Hz，2H)，7.55(d，2H，J＝18.0Hz)，7.48(s，1H)，6.57(br?t，1H，J＝9.0Hz)，4.81(q，J＝17.4Hz，2H)，3.33(t，J＝12.0Hz，2H)，3.28(s，3H)，3.12(s，3H)，2.76(dt，J＝12.0，12.0Hz，2H)，1.65(tt，J＝12.0，12.0Hz，2H)。MS(DCI-NH 3)m/z?420(M+H) +，m/z?437[M+NH 4] +。C 17H 20F 3N 3O 4The analytical calculation value of S: C, 48.68; H, 4.81; N, 10.02.Measured value: C, 48.74; N, 4.69; N, 9.84.
Embodiment 2962-(2,2, the 2-trifluoroethyl)-4-(cyclopentyl amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 295 replaces 3 methoxypropyl amine with cyclopentamine, prepares described product, obtains brown crystal (output: 195mg, 86%).M.p.134-139℃。 1HNMR(300MHz，CDCl 3)δ8.03(d，J＝18.0Hz，2H)，7.56(d，J＝18.0Hz，2H)，7.45(s，1H)，6.12(br?d，J＝16.8Hz，1H)，4.79(q，J＝17.4Hz，2H)，3.33(br?m，1H)，3.12(s，3H)，1.64-1.23(br?m，8H)。MS(DCI-NH 3)m/z416(M+H) +，m/z?433(M+NH 4) +。C 18H 20F 3N 3O 3The analytical calculation value of S: C, 52.04; H, 4.85; N, 10.11.Measured value: C, 52.40; N, 4.93; N, 10.03.
Embodiment 2972-(2,2, the 2-trifluoroethyl)-4-(cyclobutyl amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with ring fourth amylamine, prepare described product, obtain pale solid (output: 206mg, 94%).M.p.169-172℃。 1HNMR(300MHz，CDCl 3)δ8.03(d，J＝17.4Hz，2H)，7.54(d，J＝17.4Hz，2H)，7.45(s，1H)，6.28(br?d，J＝16.2Hz，1H)，4.81(q，J＝17.4Hz，2H)，3.42(m，1H)，3.13(s，3H)，1.79(m，4H)，1.64(m，1H)，1.39(m，1H)。MS(DCI-NH 3)m/z?402(M+H) +，m/z?419(M+NH 4) +。C 17H 18F 3N 3O 3S0.25CH 3COCH 3The analytical calculation value: C, 51.25; H, 4.72; N, 10.10.Measured value: C, 51.38; N, 4.68; N, 10.25.
Embodiment 2982-(2,2, the 2-trifluoroethyl)-4-(3,4-dimethoxy benzene ethylamino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, with 3, the 4-dimethoxy-phenylethylamine replaces 3 methoxypropyl amine, prepares described product, obtains pale solid (output: 206mg, 94%).M.p.163-165℃。 1H?NMR(300MHz，CDCl 3)δ8.02(d，J＝18.0Hz，2H)，7.52(d，J＝18.0Hz，2H)，7.45(s，1H)，6.75(d，J＝16.2Hz，1H)，6.50(m，2H)，6.16(br?d，J＝11.4Hz，1H)，4.79(q，J＝17.4Hz，2H)，3.84(s，3H)，3.83(s，3H)，3.11(s，3H)，2.91(dt，J＝12.6，12.6Hz，2H)，2.60(t，J＝13.8Hz，2H)。MS(DCI-NH 3)m/z?529(M+NH 4) +。C 23H 24F 3N 3O 5The analytical calculation value of S: C, 54.01; H, 4.73; N, 8.21.Measured value: C, 54.30; H, 4.69; N, 8.16.
Embodiment 2992-(2,2, the 2-trifluoroethyl)-4-(hexamethylene amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 295 replaces 3 methoxypropyl amine with hexahydroaniline, prepares described product, obtains pale solid (output: 103mg, 42%). 1H?NMR(300MHz，CDCl 3)δ8.04(d，J＝18.0Hz，2H)，7.58(d，J＝18.0Hz，2H)，7.44(s，1H)，6.06(br?d，J＝18.6Hz，1H)，4.81(q，J＝18.0Hz，2H)，3.11(s，3H)，2.70(m，1H)，1.66-1.48(m，4H)，1.42(m，1H)，1.07(m，3H)，0.76(m，2H)。MS(DCI-NH 3)m/z?430(M+H) +，m/z?447(M+NH 4) +。C 19H 22F 3N 3O 3The analytical calculation value of S: C, 53.14; H, 5.16; N, 9.78.Measured value: C, 52.86; H, 5.06; N, 9.52.
Embodiment 3002-(2,2, the 2-trifluoroethyl)-4-[2-(piperidino) ethylamino]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 295 replaces 3 methoxypropyl amine with cyclopentamine, prepares described product, obtains pale solid (output: 210mg, 84%). 1H?NMR(300MHz，CDCl 3)δ8.02(d，J＝18.0Hz，2H)，7.56(d，J＝18.0Hz，2H)，7.49(s，1H)，6.91(br，1H)，4.82(q，J＝18.0Hz，2H)，3.13(s，3H)，2.64(br，2H)，2.32(br，4H)，1.58(br，6H)，1.42(br，2H)。MS(DCI-NH 3)m/z?459(M+H) +。C 19H 22F 3N 3O 3The analytical calculation value of S: C, 52.39; H, 5.50; N, 12.22.Measured value: C, 52.64; H, 5.59; N, 12.00.
Embodiment 3012-(2,2, the 2-trifluoroethyl)-4-(2-tetrahydrofurfuryl amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with tetrahydrofurfuryl amine, prepare described product, obtain pale solid (output: 150mg, 64%).M.p.128-129℃。 1HNMR(300MHz，CDCl 3)δ8.03(d，J＝18.0Hz，2H)，7.56(d，J＝18.0Hz，2H)，7.47(s，1H)，6.48(br?t，J＝9.0Hz，1H)，4.81(q，J＝18.0Hz，2H)，3.84(m，2H)，3.72(m，1H)，3.12(s，3H)，2.83(m，1H)，2.64(m，1H)，1.84(m，3H)，1.34(m，1H)。MS(DCI-NH 3)m/z?432(M+H) +，m/z?449(M+NH 4) +。C 18H 20F 3N 3O 3The analytical calculation value of S: C, 50.11; H, 4.67; N, 9.74.Measured value: C, 50.25; H, 4.68; N, 9.68.
Embodiment 3022-(2,2, the 2-trifluoroethyl)-4-(cyclopropylamino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 295 replaces 3 methoxypropyl amine with cyclopropyl-methylamine, prepares described product, obtains pale solid (output: 130mg, 59%).M.p.145-146℃。 1H?NMR(300MHz，CDCl 3)δ8.01(d，J＝18.0Hz，2H)，7.53(d，J＝18.0Hz，2H)，7.48(s，1H)，6.20(br，1H)，4.82(q，J＝18.0Hz，2H)，3.12(s，3H)，2.45(br?d，J＝13.2Hz，2H)，0.88(m，1H)，0.51(m，2H)，0.10(m，2H)。MS(DCI-NH 3)m/z?402(M+H) +，m/z?419(M+NH 4) +。C 17H 18F 3N 3O 3The analytical calculation value of S: C, 50.87; H, 4.52; N, 10.47.Measured value: C, 51.00; H, 4.52; N, 10.44.
Embodiment 3032-(2,2, the 2-trifluoroethyl)-4-(2,3-dihydro-1H-indenes-1-base is amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with 1-indanyl amine, prepare described product, obtain pale solid (output: 82mg, 32%).M.p.155-158℃。 1H?NMR(300MHz，CDCl 3)δ8.04(d，J＝18.0Hz，2H)，7.68(d，J＝18.0Hz，2H)，7.49(s，1H)，7.27-7.14(m，4H)，6.30(br?d，J＝18.0Hz，1H)，4.81(q，J＝18.0Hz，2H)，4.57(m，1H)，3.09(s，3H)，2.89(m，1H)，2.60(m，1H)，1.85(m，1H)，1.68(m，1H)。MS(ESI(-))m/z?462(M-H) -。C 22H 20F 3N 3O 3The analytical calculation value of S: C, 57.01; H, 4.35; N, 9.07.Measured value: C, 57.30; H, 4.45; N, 8.86.
Embodiment 3042-(2,2, the 2-trifluoroethyl)-4-(piperidino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 295 replaces 3 methoxypropyl amine with piperidines, prepares described product, obtains pale solid (output: 180mg, 79%).M.p.160-161℃。 1HNMR(300MHz，CDCl 3)δ8.04(d，J＝18.0Hz，2H)，7.58(s，1H)，7.46(d，J＝18.0Hz，2H)，4.80(q，J＝18.0Hz，2H)，3.13(s，3H)，2.96(m，4H)，1.65-1.52(m，6H)。MS(DCI-NH 3)m/z?416(M+H) +。C 18H 20F 3N 3O 3SH 2The analytical calculation value of O: C, 52.04; H, 4.85; N, 10.11.Measured value: C, 52.21; H, 5.02; N, 9.75.
Embodiment 3052-(2,2, the 2-trifluoroethyl)-4-(3-hydroxyl third amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with 3-hydroxyl propylamine, prepare described product, obtain white solid (output: 109.6mg, 50%).M.p.152-154℃。 1H?NMR(300MHz，CDCl 3)δ8.02(d，J＝18.0Hz，2H)，7.56(d，J＝18.0Hz，2H)，7.48(s，1H)，6.48(br，1H)，4.79(q，J＝17.4Hz，2H)，3.63(t，J＝12.0Hz，2H)，3.12(s，3H)，2.81(dt，J＝12.0，12.0Hz，2H)，1.65(tt，J＝12.0，12.0Hz，2H)。MS(DCI-NH 3)m/z?406(M+H) +，m/z?423(M+NH 4) +。C 16H 18F 3N 3O 4The analytical calculation value of S: C, 47.41; H, 4.48; N, 10.37.Measured value: C, 47.53; H, 4.33; N, 10.27.
Embodiment 3062-(2,2, the 2-trifluoroethyl)-4-[3-(1H-imidazoles-1-yl) third amino]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with (3-aminopropyl) imidazoles, prepare described product.Reaction mixture is concentrated into dried, with RP-HPLC (Rainin DynamaxC-18 post, 60 apertures, 21.4mm i.d.) purifying resistates.This post with 20% acetonitrile (containing 0.1%TFA)/80% water (containing 0.1%TFA) to the linear gradient of 100% acetonitrile (containing 1%TFA) with 15ml/min wash-out 70 minutes.Collection obtains brown moisture absorption foam (output: 70.2mg, 28%) corresponding to the peak of title product and with its freeze-drying. 1H?NMR(300MHz，DMSO)δ8.95(br?s，1H)，7.97(d，J＝16.8Hz，2H)，7.66(d，J＝16.2Hz，2H)，7.61(s，1H)，7.58(d，J＝15.0Hz，2H)，6.99(br?t，1H，J＝13.2Hz)，4.97(dt，J＝18.0，18.0Hz，2H)，3.97(t，J＝13.2Hz，2H)，3.28(s，3H)，2.69(m，2H)，1.81(tt，J＝13.2，13.2Hz，2H)。MS(DCI-NH 3)m/z?456(M+H) +。C 19H 20F 3N 5O 3S1.4CF 3The analytical calculation value of COOH: C, 42.57; H, 3.51; N, 11.39.Measured value: C, 42.78; H, 3.58; N, 11.24.
Embodiment 3072-(2,2, the 2-trifluoroethyl)-4-(2R-hydroxyl third amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with (R)-(-)-2-Propanolamine, prepare described product, obtain pale solid (output: 109.6mg, 50%).M.p.＝140-142℃。 1H?NMR(300MHz，CDCl 3)δ8.04(d，J＝18.0Hz，2H)，7.56(d，J＝18.0Hz，2H)，7.49(s，1H)，6.42(br，1H)，4.79(m，2H)，3.80(m，1H)，3.12(s，3H)，2.68(m，2H)，1.02(d，J＝12.0Hz，3H)。MS(DCI-NH 3)m/z?406(M+H) +，m/z?423(M+NH 4) +。C 16H 18F 3N 3O 4The analytical calculation value of S: C, 47.41; H, 4.48; N, 10.37.Measured value: C, 47.56; H, 4.41; N, 10.25.
Embodiment 3082-(2,2, the 2-trifluoroethyl)-4-(2-cyano group ethylamino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 295, replace 3 methoxypropyl amine with 1-cyano group ethamine, prepare described product, obtain pale solid (output: 27mg, 12%).M.p.172-174℃。 1H?NMR(300MHz，CDCl 3)δ8.09(d，J＝18.0Hz，2H)，7.63(d，J＝18.0Hz，2H)，7.51(s，1H)，6.08(br?t，1H)，4.87(q，J＝18.0Hz，2H)，3.17(dt，J＝13.2，13.2Hz，2H)，3.13(s，3H)，2.39(t，J＝13.2Hz，2H)。MS(DCI-NH 3)m/z?418(M+NH 4) +。C 16H 15F 3N 4O 3The analytical calculation value of S: C, 48.00; H, 3.78; N, 13.99.Measured value: C, 48.28; H, 3.77; N, 13.80.
Embodiment 3092-(2,2, the 2-trifluoroethyl)-4-(4-cyano-aniline base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
The 2-(2 that will prepare according to the method for embodiment 193E; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (300mg; 0.820mmol), 4-anthranilo nitrile (290mg; 2.46mmol) and silver suboxide (760mg, 3.28mmol) suspension in pyridine stirred 24 hours in 80 ℃.Reaction mixture is cooled to room temperature, is adsorbed on the silica gel (2g), and solvent is removed in decompression.The silica gel of absorption is layered on Extract-Clean Cartridge (Alltech, the dress post: 10g silica gel), with this post of hexane/acetone stepwise gradient wash-out, described stepwise gradient is made up of each 60ml of following mixture: hexane, 8: 1 hexane/acetone, 4: 1,2: 1 and 1: 1.The flow point that will contain required product merges, concentrates, and with HPLC (TechnikromKromasil 60-5 sil silica column, 20mm * 25cm) be further purified.This post with the linear gradient of 30% ethyl acetate/hexane to 100% ethyl acetate with 10ml/min wash-out 50 minutes.The flow point that will contain product merges and concentrating under reduced pressure, obtains described product, is brown solid (output: 149.9mg, 41%).M.p.＞230℃。 1H?NMR(300MHz，DMSO)δ9.49(s，1H)，8.00(s，1H)，7.69(d，J＝17.4Hz，2H)，7.43(d，J＝16.8Hz，2H)，7.32(d，J＝18.0Hz，2H)，6.78(d，J＝18.0Hz，2H)，5.06(q，J＝18.0Hz，2H)，3.13(s，3H)，2.68(m，2H)，1.02(d，J＝12.0Hz，3H)。MS(DCI-NH 3)m/z?466(M+NH 4) +。C 20H 15F 3N 4O 3The analytical calculation value of S: C, 53.57; H, 3.37; N, 12.49.Measured value: C, 53.47; H, 3.49; N, 12.35.
Embodiment 3102-(2,2, the 2-trifluoroethyl)-4-[3-methoxyl group-5-(trifluoromethyl) anilino]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, replace the 4-anthranilo nitrile with 3-methoxyl group-5-(trifluoromethyl) aniline, prepare described product, obtain brown solid (output: 226.5mg, 80%).M.p.206-208℃。 1H?NMR(300MHz，CDCl 3)δ7.90(s，1H)，7.77(s，1H)，7.71(d，J＝18.0Hz，2H)，7.28(d，J＝17.4Hz，2H)，6.61(br?s，1H)，6.46(br?s，1H)，6.31(br?s，1H)，4.90(q，J＝17.4Hz，2H)，3.72(s，3H)，2.94(s，3H)。MS(DCI-NH 3)m/z?539(M+NH 4) +。C 21H 17F 6N 3O 4The analytical calculation value of S: C, 48.37; H, 3.29; N, 8.06.Measured value: C, 48.60; H, 3.33; H, 7.94.
Embodiment 3112-(2,2, the 2-trifluoroethyl)-4-anilino-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, replace the 4-anthranilo nitrile with aniline, prepare described product, obtain brown solid (output: 90mg, 53%).M.p.154-156℃。 1H?NMR(300MHz，CDCl 3)δ7.89(br?s，1H)，7.72(s，1H)，7.62(d，J＝18.0Hz，2H)，7.19(d，J＝18.0Hz，2H)，7.96-7.82(m，3H)，6.61(d，J＝14.4Hz，2H)，4.90(q，J＝18.0Hz，2H)，2.94(s，3H)。MS(DCI-NH 3)m/z?424(M+H) +，m/z?441(M+NH 4) +。C 19H 16F 3N 3O 3The analytical calculation value of S: C, 53.90; H, 3.81; N, 9.92.Measured value: C, 53.87; H, 3.73; N.9.89.
Embodiment 3122-(2,2, the 2-trifluoroethyl)-4-(2,5-dimethoxy phenylamino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, with 2, the 5-dimethoxyaniline replaces the 4-anthranilo nitrile, prepares described product, obtains brown solid (output: 140mg, 53%).M.p.95-96℃。 1H?NMR(300MHz，CDCl 3)δ7.78(br?s，1H)，7.72(s，1H)，7.63(d，J＝18.0Hz，2H)，7.18(d，J＝18.0Hz，2H)，6.54(d，J＝18.0Hz，1H)，6.38(dd，J＝6.0，18.0Hz，1H)，4.89(q，J＝18.0Hz，2H)，3.73(s，3H)，3.47(s，3H)，2.96(s，3H)。MS(DCI-NH 3)m/z?484(M+H) +，m/z?501(M+NH 4) +。C 21H 20F 3N 3O 5The analytical calculation value of S: C, 52.17; H, 4.17; N, 8.69.Measured value: C, 52.47; H, 4.17; N, 8.43.
Embodiment 3132-(2,2, the 2-trifluoroethyl)-4-(3-fluoroanilino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, replace the 4-anthranilo nitrile with the 3-fluoroaniline, prepare described product, obtain brown solid (output: 151.3mg, 42%).M.p.156-158℃。 1HNMR(300MHz，CDCl 3)δ9.18(s，1H)，7.91(s，1H)，7.62(d，J＝17.4Hz，2H)，7.36(d，J＝17.4Hz，2H)，6.88(dd，J＝15.0，15.0Hz，1H)，6.56(m，1H)，6.49(m，2H)，5.04(q，J＝18.0Hz，2H)，3.08(s，3H)。MS(DCI-NH 3)m/z?442(M+H) +，m/z?459(M+NH 4) +，m/z?476(M+2NH 4-H) +。C 19H 15F 4N 3O 3S0.5CH 3COCH 3The analytical calculation value: C, 52.33; H, 3.85; N, 8.93.Measured value: C, 52.51; H, 3.58; N, 8.81.
Embodiment 3142-(2,2, the 2-trifluoroethyl)-4-(2,4 difluorobenzene amido)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, replace the 4-anthranilo nitrile with 2,4 difluorobenzene amine, prepare described product, obtain brown solid (output: 63.1mg, 17%).M.p.170-175℃。 1H?NMR(300MHz，DMSO)δ9.00(s，1H)，7.80(s，1H)，7.57(d，J＝17.4Hz，2H)，7.26(d，J＝17.4Hz，2H)，7.05(m，1H)，6.75(m，2H)，5.05(q，J＝18.0Hz，2H)，3.09(s，3H)。MS(DCI-NH 3)m/z?460(M+H) +，m/z?477(M+NH 4) +。C 19H 14F 5N 3O 3The analytical calculation value of S: C, 49.68; H, 3.07; N, 9.15.Measured value: C, 50.00; H, 2.95; N, 9.10.
Embodiment 3152-(2,2, the 2-trifluoroethyl)-4-(2,3,5-trifluoro-benzene amido)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, with 2,3, the 5-trifluoromethyl aniline replaces the 4-anthranilo nitrile, prepares described product, obtains lavender solid (output: 85.3mg, 22%).M.p.190-194℃。 1H?NMR(300MHz，DMSO)δ9.27(s，1H)，7.90(s，1H)，7.70(d，J＝17.4Hz，2H)，7.39(d，J＝17.4Hz，2H)，7.03(m，1H)，6.76(m，1H)，5.06(q，J＝18.0Hz，2H)，3.14(s，3H)。MS(DCI-NH 3)m/z?495(M+NH 4) +。C 19H 13F 6N 3O 3The analytical calculation value of S: C, 47.80; H, 2.74; N, 8.80.Measured value: C, 47.51; H, 2.55; N, 8.63.
Embodiment 3162-(2,2, the 2-trifluoroethyl)-4-(4-fluoroanilino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 309, replace the 4-anthranilo nitrile with the 4-fluoroaniline, prepare described product, obtain brown solid (output: 15.8mg, 4%).M.p.158-160℃。 1HNMR(300MHz，CDCl 3)δ7.80(br?s，1H)，7.69(s，1H)，7.65(d，J＝18.0Hz，2H)，7.18(d，J＝18.0Hz，2H)，6.63(d，J＝3.6Hz，2H)，6.61(s，2H)，4.89(q，J＝17.4Hz，2H)，2.96(s，3H)。MS(DCI-NH 3)m/z?459(M+NH 4) +。C 19H 15F 4N 3O 3S1.25H 2The analytical calculation value of O: C, 49.19; H, 3.80; N, 9.05.Measured value: C, 59.57; H, 3.53; N, 8.70.
Embodiment 3172-benzyl-4-(3-thienyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl with preparation among the embodiment 78]-3 (2H)-pyridazinone (150mg; 0.4mmol), thiophene-3-boric acid (66.5mg; 0.52mmol), CsF (145.8mg; 0.96mmol) and four (triphenylphosphine)-palladiums (O) (13.9mg, the following stirring of DME 0.012mmol) (25ml) solution backflow 6 hours.TLC (1 methylene dichloride: 1 hexane: 1.5 ethyl acetate) show that all raw materials exhaust.Reaction mixture is cooled to room temperature and concentrating under reduced pressure.Resistates is allocated between water and the ethyl acetate.Organic layer salt water washing is through dried over mgso and filtration.Concentrating under reduced pressure filtrate.Resistates silicagel column purifying (0.5: 2.5: 0.5 dichloromethane/hexane/ethyl acetate).Obtain yellow powder (output: 50mg, 31%). 1H?NMR(300MHz，CDCl 3)δ3.09(s，3H)，5.41(s，2H)，6.72(dd，J＝1.5Hz，9Hz，1H)，7.13(dd，J＝3Hz，3Hz，1H)，7.3-7.45(m，5H)，7.5-7.6(m，3H)，7.78(s，1H)，7.92(d，9Hz，2H)。MS(DCI-NH 3)m/z?423(M+H) +。C 22H 18N 2O 3S 20.5H 2The analytical calculation value of O: C, 6.23; H, 4.43; N, 6.49.Measured value: C, 61.29; H, 4.40; N, 6.16.
Embodiment 3182-benzyl-4-(2-benzofuryl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with 2-cumarone boric acid, preparation title compound (output: 46mg, 25%). 1H?NMR(300MHz，CDCl 3)δ3.13(s，3H)，5.5(s，2H，)，6.85-6.92(m，1H)，7.15-7.25(m，3H)，7.3-7.42(m，3H)，7.45-7.7(m，5H)，7.79(s，1H)，8.0(d，J＝9Hz，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?457(M+H) +。C 26H 20N 2O 4SH 2The analytical calculation value of O: C, 65.80; H, 4.67; N, 5.90.Measured value: C, 65.44; H, 4.42; N, 6.14.
Embodiment 3192-benzyl-4-(1,3-dihydro-1-oxo-5-isobenzofuran-base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 221; 2-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl with preparation among the embodiment 78]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 112mg, 44%).M.p.＞250℃。 1H?NMR(300MHz，DMSO-d 6)δ3.20(s，3H)，5.34(s，2H)，5.36(s，2H)，7.30-7.44(m，6H)，7.48(d，J＝8Hz，2H)，7.57(s，1H)，7.73(d，J＝8Hz，1H)，7.85(d，J＝8Hz，2H)，8.17(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+H) +。C 26H 20N 2O 5The analytical calculation value of S: C, 65.46; H, 4.33; N, 5.87.Measured value: C, 65.56; H, 4.48; N, 5.75.
Embodiment 3202-benzyl-4-(5-chloro-2-thienyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with 4-chloro-2-thienyl boric acid, preparation title compound (output: 21mg, 17%). 1H?NMR(300MHz，CDCl 3)δ3.15(s，3H)，5.45(s，2H)，6.51(d，J＝4.5Hz，1H)，6.7(d，J＝4.5Hz，1H)，7.3-7.4(m，3H)，7.5-7.6(m，4H)，7.6(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?457(M+H) +。C 18H 15ClN 2O 3The analytical calculation value of S: C, 57.68; H, 4.03; N, 7.47.Measured value: C, 57.61; H, 3.84; N, 7.14.
Embodiment 3212-benzyl-4-(3-nitrophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with 3-oil of mirbane boric acid, preparation title compound (output: 20mg, 11%). 1H?NMR(300MHz，CDCl 3)δ3.0(s，3H)，5.93(s，2H)，7.6-7.8(m，9H)，7.8(t，J＝4.5Hz，3H)，8.04(s，1H)，8.15(m，1H)。MS(DCI-NH 3)m/z?462(M+H) +。C 24H 19N 3O 5S0.75H 2The analytical calculation value of O: C, 60.68; H, 4.35; N, 8.84.Measured value: C, 60.99; H, 3.97; N, 8.35.
Embodiment 3222-benzyl-4-(4-ethenylphenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with the 4-vinylphenylboronic acid, preparation title compound (output: 40mg, 23%). 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.28(d，J＝12Hz，1H)，5.41(s，2H)，5.74(d，J＝18Hz，1H)，6.65(dd，J＝12Hz，18Hz，1H)，7.1-7.6(m，11H)，7.83(d，J＝3Hz，2H)，7.85(s，1H)。MS(DCI-NH 3)m/z?443(M+H) +。C 26H 22N 2O 3The analytical calculation value of S: C, 70.57; H, 5.01; N, 6.33.Measured value: C, 70.34; H, 4.67; N.5.97.
Embodiment 3232-benzyl-4-(4-trifluoromethyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with 4-(trifluoromethyl) phenylo boric acid, preparation title compound (output: 101mg, 52%). 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，5.42(s，2H)，7.3-7.5(m，8H)，7.55-7.6(m，3H)，7.85(s，2H)，7.9(s，1H)。MS(DCI-NH 3)m/z?485(M+H) +。C 25H 19F 3N 2O 3S0.25H 2The analytical calculation value of O: C, 61.40; H, 4.01; N, 5.72.Measured value: C, 61.26; H, 4.01; N, 5.35.
Embodiment 3242-benzyl-4-(2-p-methoxy-phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 317, replace 3 thienylboronic acid with the 2-methoxyphenylboronic acid, preparation title compound (output: 75mg, 42%). 1H?NMR(300MHz，CDCl 3)δ3.01(s，3H)，3.5(s，3H)，5.40(dd，J＝12Hz，18Hz，2H)，6.76(d，J＝9Hz，1H)，6.85-6.95(m，1H)，7.09(dd，J＝1.5Hz，9Hz，1H)，7.26-7.41(m，6H)，7.55(dd，J＝1.5Hz，9Hz，2H)，7.82(d，J＝9Hz，3H)。MS(DCI-NH 3)m/z?447(M+H) +。C 25H 22N 2O 4S0.5H 2The analytical calculation value of O: C, 65.91; H, 5.08; N, 6.14.Measured value: C, 65.86; H, 5.08; N, 5.58.
Embodiment 3252-benzyl-4-(3, the 4-3,5-dimethylphenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-benzyl-4-chloro-5-[4-(methyl sulphonyl) phenyl with preparation among the embodiment 78]-3 (2H)-pyridazinone (150mg; 0.4mmol) be dissolved among the anhydrous DME (10ml); and at CsF (146mg; 0.96mmol) and four (triphenylphosphine)-palladium (O) (14mg; 0.012mmol) existence is down with 3,4-dimethyl benzene boric acid is heated to together and refluxed 6 hours.After reaction mixture is cooled to room temperature, this reaction mixture dilute with water and with ethyl acetate (100ml) extraction.Organic layer salt water washing is through dried over mgso and vacuum-evaporation.This compound purifying on silicagel column with the pentane solution wash-out of 30% ethyl acetate, obtains required compound (output: 100mg, 56%). 1H?NMR(300?MHz，CDCl 3)δ2.15，2.20(2s，3H)，2.25，2.30(2s，3H)，3.05，3.08(2s，3H)，5.35，5.40(2s，2H)，6.60-7.1(m，3H)，7.30-7.40(m，4H)，7.42-7.60(m，2H)，7.70-8.02(m，4H)。MS(DCI-NH 3)m/z?445(M+H) +。C 26H 24N 2O 3SH 2The analytical calculation value of O: C, 67.51; H, 5.66; N, 6.05.Measured value: C, 67.45; H, 5.56; N, 5.85.
Embodiment 3262-benzyl-4-(3-fluoro-4-p-methoxy-phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 325, replace 3 with 3-fluoro-4-methoxyphenylboronic acid, 4-dimethyl benzene boric acid, preparation title compound (output: 35mg, 19%). 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，3.85(s，3H)，5.3，5.4(2s，2H)，6.75-7.03(m，3H)，7.3-7.40(m，5H)，7.4-7.55(dd，J＝1.5Hz，7.5Hz，2H)，7.8-7.95(m，3H)。MS(DCI-NH 3)m/z?465(M+H) +。C 25H 21N 2O 4S0.25H 2The analytical calculation value of O: C, 64.02; H, 4.62; N, 5.97.Measured value: C, 63.93; H, 4.54; N, 5.43.
Embodiment 3272-benzyl-4-[3-(2-methoxypyridine base)]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 325, replace 3 with 2-methoxyl group-3-pyridyl boric acid, 4-dimethyl benzene boric acid, preparation title compound (output: 35mg, 19%). 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，3.58(s，3H)，5.4(dd，J＝15Hz，18Hz；2H)，6.88(m，1H)，7.28-7.40(m，5H)，7.5-7.6(dd，J＝1.5Hz；7.5Hz，3H)，7.82(s，1H)，7.85(d，J＝18Hz，2H)，8.15(br?s，1H)。MS(DCI-NH 3)m/z?448(M+H) +。C 24H 21N 3O 4The analytical calculation value of S: C, 64.42; H, 4.73; N, 9.39.Measured value: C, 64.17; H, 5.11; N, 9.04.
Embodiment 3282-benzyl-4-(3-ethoxyl phenenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 325, replace 3 with 3-phenetole boric acid, 4-dimethyl benzene boric acid, preparation title compound (output: 115mg, 67%). 1H?NMR(300MHz，CDCl 3)δ1.31(t，J＝7.5Hz，3H)，3.05(s，3H)，3.89(q，J＝7.5Hz，2H)，5.14(s，2H)，6.65(d，J＝9Hz，1H)，6.72(t，J＝1.5Hz，1H)，6.8(dd，J＝1.5Hz，9Hz，1H)，7.15(t，J＝9Hz，1H)，7.3-7.4(m，5H)，7.5-7.6(m，2H)，7.85(d，J＝9Hz，3H)。MS(DCI-NH 3)m/z?461(M+H) +。C 26H 24N 2O 4S0.5H 2The analytical calculation value of O: C, 66.50; H, 5.36; N, 5.96.Measured value: C, 66.39; H, 5.02; N, 5.77.
Embodiment 3292-benzyl-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 329A.2-benzyls-4,5-two bromo-3 (2H)-pyridazinones
According to the method for embodiment 194A, replace the 4-fluorophenyl hydrazine hydrochloride with benzyl hydrazonium salt hydrochlorate, preparation title compound (output: 7.86g, 60%). 1H?NMR(300MHz，DMSO?d 6)δ5.27(s，2H).7.26-7.41(m，5H)，8.19(s，1H)。MS(DCI-NH 3)m/z?345(M+H) +，362(M+NH 4) +。329B.2-benzyl-5-bromo-4-methoxyl group-3 (2H)-pyridazinone
According to the method for describing among the embodiment 194B, with 2-benzyl-4,5-two bromo-3 (2H)-pyridazinone replaces 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones, preparation title compound (output: 2.877g, 85%). 1H?NMR(300MHz，DMSO-d 6)δ4.14(s，3H)，5.23(s，2H)，7.26-7.38(m，5H)，8.11(s，1H)。MS(DCI-NH 3)m/z?295(M+H) +，312(M+NH 4) +。329C.2-benzyl-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
According to the method for describing among the embodiment 6, replace 2-benzyl-4-methoxyl group-5-bromo-3 (2H)-pyridazinone with 2-benzyl-4-methoxyl group-5-bromo-3 (2H)-pyridazinone, preparation title compound (output: 3.705g). 1H?NMR(300MHz，DMSO-d 6)δ2.52(s，3H)，3.99(s，3H)，5.28(s，2H)，7.26-7.41(m，7H)，7.55(m，2H)，8.02(s，1H)。MS(DCI-NH 3)m/z?339(M+H) +，356(M+NH 4) +。329D.2-benzyl-4-(4-luorobenzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 233, with 4-luorobenzyl chlorination magnesium substituted cyclohexyl magnesium bromide, and with 2-benzyl-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replace 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, the preparation title compound.329C.2-benzyl-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10, (embodiment 329D) is oxidized to described sulfonyloxy methyl based compound with described sulfide compound.M.p.186-189℃。 1H?NMR(300MHz，DMSO?d 6)δ3.27(s，3H)，3.83(s，2H)，5.31(s，2H)，6.94-7.05(m，4H)，7.27-7.40(m，5H)，7.67(m，2H)，7.94(s，1H)，8.03(m，2H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+H) +。C 25H 21FN 2O 3The analytical calculation value of S: C, 66.95; H, 4.72; N, 6.25.Measured value: C, 66.68; H, 4.75; N, 6.14.
Embodiment 3302-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 330A.2-(tertiary butyl)-4,5-two chloro-3 (2H)-pyridazinones
(33.8g, 200mmol) (24.9g, methyl alcohol 200mmol) (400ml) solution reflux to stir down and spend the night with uncle's fourth hydrazonium salt hydrochlorate with mucochloric acid.Vacuum is removed methyl alcohol, and resistates is allocated between ether and the water.Organic layer is through dried over mgso and filtration.Vacuum concentrated filtrate, resistates is through column chromatography purification (silica gel, 100% hexane).Merge the flow point that contains product, crystallization title compound from ether/hexane (output: 10.0g, 22.6%).M.p.63-64℃。 1H?NMR(300MHz，CDCl 3)δ1.65(s，9H)，7.73(s，1H)。MS(DCI-NH 3)m/z?221(M+H) +，238(M+NH 4) +。(330B.2-the tertiary butyl)-4-(3-methyl butoxy)-5-chloro-3 (2H)-pyridazinone
(0.24g, oil suspension 5.88mmol) handle 3-methyl isophthalic acid-butanols (0.5ml, tetrahydrofuran (THF) 4.52mmol) (10ml) solution that stirs under room temperature with 60% sodium hydride.Therefore after 5 minutes, emitting of hydrogen calmed down, and (1.0g, 4.52mmol), reaction mixture stirred under room temperature 20 hours to add two chloromethylated intermediates of embodiment 330A.With 10% aqueous citric acid solution quenching reactant, use ethyl acetate extraction.Organic layer salt water washing is through dried over mgso and filtration.Vacuum concentrated filtrate, resistates is through column chromatography purification (silica gel, 100% hexane).Obtain title compound, be faint yellow oily thing (output: 0.7g, 56.7%). 1H NMR (300MHz, CDCl 3) δ 0.95 (d, J=6Hz, 6H), 1.63 (s, 9H), 1.64 (q, J=6Hz, 2H), 1.85 (nine heavy peaks, J=6Hz, 1H), 4.49 (t, J=6Hz, 2H), 7.64 (s, 1H).MS(DCI-NH 3)m/z273(M+H) +，290(M+NH 4) +。(330C.2-the tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Intermediate (700mg with embodiment 330B, 2.57mmol), 4-(methylthio group) phenylo boric acid (560mg, 3.34mmol), cesium carbonate (2.17g, 6.67mmol) and tetrakis triphenylphosphine palladium (O) (210mg, glycol dimethyl ether 0.18mmol) (40ml) the solution heating down 5 hours that refluxes.Remove thermal source then, reaction mixture was stirred under room temperature 64 hours.Reaction mixture is filtered, and vacuum concentrated filtrate obtains brown oil.This oily matter obtains semi-solid product (output: 270mg, 29.2%) through column chromatography purification 2 times (silica gel, 97: 3 hexane/ethyl acetate, 96: 4 hexane/ethyl acetate then). 1H NMR (300MHz, CDCl 3) δ 0.81 (d, J=6Hz, 6H), 1.49 (q, J=6Hz, 2H), 1.63 (nine heavy peaks, J=6Hz, 1H), 1.69 (s, 9H), 2.52 (s, 3H), 7.32 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.73 (s, 1H).MS(DCI-NH 3)m/z?361(M+H) +。(330D.2-the tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 188mg, 63.9%).M.p.138-139℃。 1H?NMR(300MHz，CDCl 3)δ0.81(d，J＝6Hz，2H)，1.48(q，J＝6Hz，2H)，1.48-1.68(m，1H)，1.69(s，9H)，3.10(s，3H)，4.38(t，J＝6Hz，2H)，7.71(s，1H)，7.74(d，J＝9Hz，2H)，8.03(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?393(M+H) +。C 20H 28N 2O 4The analytical calculation value of S: C, 61.20; H, 7.19; N, 7.14.Measured value: C, 61.13; H, 7.23; N, 6.89.
Embodiment 3312-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 10, with 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones (embodiment 207C) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 3.31g, 96%).M.p.112-114℃。 1H?NMR(300MHz，DMSO?d 6)δ3.31(m，3H)，4.10(m，3H)，7.52-7.65(m，3H)，7.75(m，1H)，7.90(m，2H)，8.07(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?391(M+H) +，408(M+NH 4) +。C 18H 15ClN 2O 4S0.25H 2The analytical calculation value of O: C, 54.68; H, 3.95; N, 7.08.Measured value: C, 54.59; N, 3.65; N, 6.98.
Embodiment 3322-(3-chloro-phenyl-)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl] (6.26g, 16mmol) (heating is 1.5 hours under the suspension returning in 54ml) De diox (39.4ml) solution at 5%NaOH for-3 (2H)-pyridazinones.After reaction was carried out, solution became orange and homogeneous phase.Under constant agitation with mixture cooling and incline to 1N HCl.Leach the white solid of gained, and water flushing, allow its dried overnight.Most of exsiccant product is absorbed in the methylene dichloride,,, obtains required product, be white solid (output: 6.79g,＞100%) to remove residual water with methylbenzene azeotropic. 1H?NMR(300MHz，DMSO?d 6)δ2.27(s，3H)，7.51-7.62(m，2H)，7.68(m，1H)，7.79(m，1H)，8.03(m，4H)，8.24(s，1H)。MS(DCI-NH 3)m/z?377(M+H) +，396(M+NH 4) +。
Embodiment 3332-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
In embodiment 332 preparation 2-(3-chloro-phenyl-)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (and 6.79g, add in 0 ℃ of pyridine (160ml) solution 16mmol) Tosyl chloride (3.06g, 16mmol).At nitrogen, stir under with the slow ground temperature of solution left standstill to room temperature.2.5 after hour, under constant agitation, this mixture is inclined to water.Leach the pale solid of gained, wash with water and drying, obtain required product (output: 6.26g, 79%).M.p.198-200℃。 1H?NMR(300MHz，DMSO?d 6)δ2.35(s，3H)，3.28(s，3H)，7.20(m，2H)，7.52-7.64(m，5H)，7.70(m，3H)，7.89(m，2H)，8.32(s，1H)。MS?APCI +531(M+H) +，548(M+H 2O) +，APCI -493(M+35) -。C 24H 19ClN 2O 6S 2The analytical calculation value: C, 54.29; H, 3.61; N, 5.28.Measured value: C, 54.55; H, 3.46; N, 5.57.
Embodiment 3342-(3-chloro-phenyl-)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
At nitrogen, stir under, with 2-(3-chloro-phenyl-)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl of preparation among the embodiment 332] POCl of-3 (2H)-pyridazinones 3Solution is heated to and refluxed 3 hours.Mixture is cooled to room temperature, and has a down dip to ice in constant rotation.The white solid ethyl acetate extraction that is produced.The organism that merges washes with water, through dried over mgso and simmer down to solid.Raw product flash chromatography purifying (SiO 2, with 1: 1 ethyl acetate/hexane wash-out), obtain required product (output: 0.151g, 29%).M.p.203-204℃。 1H NMR (300MHz, DMSO d 6) δ 3.29-3.36 (3H is disturbed by water), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s, 1H).MS(DCI-NH 3)m/z?395(M+H) +，412(M+NH 4) +。C 17H 12Cl 2N 2O 3The analytical calculation value of S: C, 51.66; H, 3.06; N, 7.09.Measured value: C, 51.67; H, 3.03; N, 6.93.
Embodiment 3352-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl of preparation in embodiment 333]-3 (2H)-pyridazinone (0.175g; 0.33mmol) add isopropylcarbinol (0.03ml in the stirred suspension in THF (3.3ml); 0.33mmol) and NaH (0.0132g, 0.33mmol).Under nitrogen, stir the solution 1 hour of gained.Reactant is inclined to water, use ethyl acetate extraction.The organism that merges is through dried over mgso and vacuum concentration.Rough solid flash chromatography purifying (SiO 2, with 2: 1 hexane/ethyl acetate wash-outs), obtain required product (output: 0.1088g, 76%).M.p.166-169℃。 1H?NMR(300MHz，DMSO?d 6)δ0.78(d?J＝6Hz，6H)，1.84(m，1H)，3.29(s，3H)4.20(d，J＝6Hz，2H)，7.51-7.63(m，3H)，7.76(m，1H)，7.92(m，2H)，8.07(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?433(M+H) +，450(M+NH 4) +。C 21H 21ClN 2O 4The analytical calculation value of S: C, 57.07; H, 5.01; N, 6.33.Measured value: C, 57.06; H, 4.78; N, 6.13.
Embodiment 3362-(3-chloro-phenyl-)-4-(tert.-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335 replaces isopropylcarbinol with the trimethyl carbinol, preparation title compound (output: 0.093g, 66%).M.p.232-235℃。 1H?NMR(300MHz，DMSOd 6)δ1.18(s，9H)，3.30(s，3H)，7.52-7.64(m，3H)，7.74(m，1H)，7.92(m，2H)，8.08(m，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?433(M+H) +，450(M+NH 4) +。C 21H 21ClN 2O 4The analytical calculation value of S: C, 58.26; H, 4.89 N, 6.47.Measured value: C, 58.21; N, 4.88; N, 6.28.
Embodiment 3372-(3-chloro-phenyl-)-4-(cyclohexyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335 replaces isopropylcarbinol with hexalin, preparation title compound (output: 0.139g, 92%).Semi-solid; 1H NMR (300MHz, CDCl 3) δ 1.09-1.50 (m, 6H), 1.57 (m, 2H), 1.88 (m, 2H), 3.13 (s, 3H), 5.19 (m, 1H), 7.38-7.48 (m, 2H), 7.59 (m, 1H), 7.70 (m, 1H), 7.83 (m, 2H), 7.92 (s, 1H), 8.07 (m, 2H).MS?APCI +459(M+H) +，476(M+H 2O) +，APCI-458(M) -，493(M+35) -。C 23H 23ClN 2O 4S0.25H 2The analytical calculation value of O: C, 59.60; H, 5.11; N, 6.04.Measured value: C, 59.48; H, 4.86; N, 5.88.
Embodiment 3382-(3-chloro-phenyl-)-4-(2,2-dimethyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335 replaces isopropylcarbinol with neopentyl alcohol, preparation title compound (output: 0.109g, 74%).M.p.151-153℃。 1H?NMR(300MHz，DMSOd 6)δ0.78(s，9H)，3.29(s，3H)，4.10(s，2H)，7.52-7.64(m，3H)，7.76(m，1H)，7.92(m，2H)，8.07(m，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?447(M+H) +，464(M+NH 4) +。C 22H 23ClN 2O 4The analytical calculation value of S: C, 59.12; H, 5.19; N, 6.27.Measured value: C, 59.40; H, 5.31; N, 5.99.
Embodiment 3392-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 3-methyl isophthalic acid-butanols, preparation title compound (output: 0.229g, 80.5%).M.p.134-135℃。 1H?NMR(300MHz，DMSO?d 6)δ0.79(d，J＝6Hz，6H)，1.42-1.64(m，3H)，3.30(s，3H)，4.43(t，J＝6Hz，2H)，7.52-7.65(m，3H)，7.76(m，1H)，7.90(m，2H)，8.07(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?447(M+H) +，464(M+NH 4) +。C 22H 23ClN 2O 4The analytical calculation value of S: C, 59.12; H, 5.19; N, 6.27.Measured value: C, 58.91; H, 5.12; N, 6.01.
Embodiment 3402-(3-chloro-phenyl-)-4-(3-octyne-1-base oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 3-octyne-1-alcohol, preparation title compound (output: 0.128g, 77%).Oily matter. 1H?NMR(300MHz，CDCl 3)δ0.88(m，3H)，1.25-1.44(m，4H)，2.05(m，2H)，2.52(m，2H)，4.68(t，J＝6Hz，2H)，7.43(m，2H)，7.59(m，1H)，7.70(m，1H)，7.86(m，2H)，7.92(s，1H)。MS(DCI-NH 3)m/z?485(M+H) +。C 25H 25ClN 2O 4The analytical calculation value of S: C, 61.94; H, 5.20; N, 5.78.Measured value: C, 61.82; H, 4.99; N, 5.57.
Embodiment 3412-(3-chloro-phenyl-)-4-[2-(dimethylamino) oxyethyl group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, use N, N-(dimethyl) thanomin replaces isopropylcarbinol, preparation title compound (output: 0.111g, 75%).M.p.110-113℃。 1H?NMR(300MHz，DMSO?d 6)δ2.29(bs，6H)，2.68(bs，2H)，4.68(t，J＝5Hz，2H)，7.38-7.48(m，2H)，7.57(m，1H)，7.68(m，1H)，7.89(m，2H)，8.07(m，2H)。MS(DCI-NH 3)m/z?448(M+H) +。C 21H 22ClN 3O 4S0.50H 2The analytical calculation value of O: C, 55.19; H, 5.07; N, 9.19.Measured value: C, 55.24; H, 4.97; N, 9.07.
Embodiment 3422-(3-chloro-phenyl-)-4-[2-methyl isophthalic acid-(1-methylethyl) propoxy-]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, with 2,4-dimethyl-3-amylalcohol replaces isopropylcarbinol, preparation title compound (output: 0.075g, 48%).Semi-solid; 1H NMR (300MHz, DMSO d 6) δ 0.79 (m, 12H), 1.78-1.92 (m, J=6Hz, 2H), 3.29 (s, 3H), 5.40 (t, J=6Hz, 1H), 7.57 (m, 3H), 7.72 (m, 1H), 7.91 (m, 2H), 8.07 (m, 2H), 8.17 (m, 1H).MS(DCI-NH 3)m/z?475(M+H) +，492(M+NH 4) +。C 24H 27ClN 2O 4S (0.75H 2O) analytical calculation value: C, 59.00; H, 5.88; N, 5.78.Measured value: C, 58.83; N, 5.74; N, 5.52.
Embodiment 3432-(3-chloro-phenyl-)-4-(phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335 replaces isopropylcarbinol with phenol, preparation title compound (output: 0.053g, 35%).M.p.205-207℃。 1H?NMR(300MHz，DMSO?d 6)δ3.28(s，3H)，7.08(m，3H)，7.31(m，2H)，7.50-7.64(m，3H)，7.73(m，1H)，7.90(m，2H)，8.05(m，2H)，8.40(s，1H)。MS(DCI-NH 3)m/z?453(M+H) +，470(M+NH 4) +。C 23H 17ClN 2O 4The analytical calculation value of S: C, 60.99; H, 3.78; N, 6.19.Measured value: C, 60.79; H, 3.65; N, 5.87.
Embodiment 3442-(3-chloro-phenyl-)-4-[3-(dimethylamino) phenyl]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 3-(dimethylamino) phenol, preparation title compound (output: 0.057g, 60%).M.p.191-193℃。 1H?NMR(300MHz，DMSO?d 6)δ2.85(s，6H)，3.27(s，3H)，6.36(m，3H)，7.05(m，1H)，7.51-7.63(m，3H)，7.72(m，1H)，7.90(m，2H)，8.05(m，2H)，8.39(s，1H)。MS?APCI +495(M+H) +，APCI-495(M) -，590(M+35) -。C 25H 22ClN 3O 4The analytical calculation value of S: C, 60.54; H, 4.47; N, 8.47.Measured value: C, 60.04; N, 4.49; N, 8.26.
Embodiment 3452-(3-chloro-phenyl-)-4-(4-methoxyl group phenoxy group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with the 4-methoxyphenol, preparation title compound (output: 0.080g, 69%).M.p.182-184℃。 1H?NMR(300MHz，DMSO?d 6)δ3.27(s，3H)，3.70(s，3H)，6.84(m，2H)，7.00(m，2H)，7.56(m，3H)，7.72(m，1H)，7.90(m，2H)，8.04(m，2H)，8.38(s，1H)。MS(DCI-NH 3)m/z?483(M+H) +，500(M+NH 4) +。C 24H 19ClN 2O 5The analytical calculation value of S: C, 59.64; H, 3.97; N, 5.80.Measured value: C, 59.86; H, 3.94; N, 5.62.
Embodiment 3462-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 150mg, 61%).M.p.116-117℃。 1H?NMR(300MHz，DMSO-d 6)δ0.78(d，6H)，1.84(m，1H)，3.3(s，3H)，4.2(d，2H)，7.54(m，1H)，7.6(m，1H)，7.82(m，1H)，7.91(d，2H)，8.07(d，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?435(M+H) +，452(M+NH 4) +。C 21F 2H 20N 2O 4The analytical calculation value of S: C, 58.06; H, 4.64; N, 6.45.
Embodiment 3472-(3, the 4-difluorophenyl)-4-(3-methyl isophthalic acid-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 346, replace isopropylcarbinol with 3-methyl isophthalic acid-butanols, preparation title compound (output: 63mg, 23%).M.p.121-123℃。 1H?NMR(300MHz，DMSO-d 6)δ0.78(d，6H)，1.48(m，3H)，3.3(s，3H)，4.43(t，2H)，7.54(m，1H)，7.6(m，1H)，7.82(m，1H)，7.91(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 22H 22F 2N 2O 4The analytical calculation value of S: C, 58.92; H, 4.94; N, 6.25.Measured value: C, 59.22; H, 4.97; N, 6.07.
Embodiment 3482-(3.4-difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 346; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-difluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and, prepare title compound with 4-fluorophenol replacement isopropylcarbinol.M.p.168-170℃。 1H?NMR(300MHz，DMSO-d 6)δ3.39(s，3H)，7.15(d，4H)，7.51(m，1H)，7.6(m，1H)，7.75(m，3H)，7.97(t，1H)，8.4(s，1H)。MS(DCI-NH 3)m/z?491(M+H) +，508(M+NH 4) +。C 23H 14F 4N 2O 4The analytical calculation value of S: C, 56.33; H, 2.88; N, 5.71.Measured value: C, 56.07; H, 2.94; N, 5.33.
Embodiment 3492-(3, the 4-difluorophenyl)-4-(2,2-dimethyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 346 replaces isopropylcarbinol with neopentyl alcohol, preparation title compound (output: 1.18g, 94%).M.p.126-128℃。 1H?NMR(300MHz，DMSO-d 6)δ0.78(s，9H)，3.3(s，3H)，4.1(s，2H)，7.51(m，1H)，7.6(m，1H)，7.82(m，1H)，7.91(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 22H 22F 4N 2O 4The analytical calculation value of S: C, 58.92; N, 4.94; N, 6.25.Measured value: C, 59.03; H, 5.03; N, 6.18.
Embodiment 3502-(3, the 4-difluorophenyl)-4-[2-(isopropoxy) oxyethyl group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 346, replace isopropylcarbinol with 2-(isopropoxy) ethanol, preparation title compound (output: 432mg, 72%).M.p.105-107℃。 1H?NMR(300MHz，DMSO-d 6)δ0.95(d，6H)，3.3(s，3H)，3.43(m，1H)，3.54(m，2H)，4.63(m，2H)，7.54(m，1H)，7.6(m，1H)，7.8(m，1H).8.01(m，4H)，8.2(s，1H)。MS(DCI-NH 3)m/z?465(M+H) +，482(M+NH 4) +。C 22H 22F 2N 2O 5The analytical calculation value of S: C, 56.89; N, 4.77; N, 6.03.Measured value: C, 57.03; H, 4.65; N, 5.83.
Embodiment 3512-(3, the 4-difluorophenyl)-4-(3-methyl pentyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 346, replace isopropylcarbinol with 3-methyl amyl-1-alcohol, preparation title compound (output: 400mg, 80%).M.p.100-102℃。 1H?NMR(300MHz，DMSO-d 6)δ0.75(m，6H)，1.05(m，1H)，1.28(m，3H)，1.6(m，1H)，3.3(s，3H)，4.45(m，2H)，7.5(m，1H)，7.6(m，1H)，7.8(m，1H)，7.9(d，J＝9Hz，2H)，8.05(d，J＝9Hz，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?463(M+H) +，480(M+MH 4) +。C 23H 24F 2N 2O 4The analytical calculation value of S: C, 59.73; H, 5.23; N, 6.06.Measured value: C, 59.78; H, 5.31; N, 6.00.
Embodiment 3522-(3, the 4-difluorophenyl)-4-(4-methyl-3-amylene-1-base oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 346, replace isopropylcarbinol with 4-methyl-3-amylene-1-ol, preparation title compound (output: 405mg, 67.8%).M.p.88-90℃。 1H?NMR(300MHz，DMSO-d 6)δ1.5(d，6H)，2.27(m，2H)，3.3(s，3H)，4.43(t，2H)，4.95(m，1H)，7.5(m，1H).7.6(m，1H)，7.8(m，1H)，7.9(d，2H)，8.06(d，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?461(M+H) +，478(M+NH 4) +。C 23H 22F 2N 2O 4The analytical calculation value of S: C, 59.99; H, 4.82; N, 6.08.Measured value: C, 59.88; H, 4.76; N, 5.84.
Embodiment 3532-(3, the 4-difluorophenyl)-4-[3-(methoxyl group) butoxy]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 346, replace isopropylcarbinol with 3-methoxyl group butyl-1-alcohol, preparation title compound (output: 350mg, 68%).M.p.99-101℃。 1H?NMR(300MHz，DMSO-d 6)δ0.97(d，3H)，1.7(m，2H)，3.05(s，3H)，3.2(m，1H)，3.3(s，3H)，4.45(m，2H)，7.54(m，1H)，7.6(m，1H)，7.8(m，1H)，7.9(d，J＝9Hz，2H)，8.01(d，J＝9Hz，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?465(M+H) +，482(M+NH 4) +。C 22H 22F 2N 2O 5The analytical calculation value of S: C, 56.89; H, 4.77; N, 6.03.Measured value: C, 56.60; H, 4.83; N, 5.96.
Embodiment 3542-(3-chloro-phenyl-)-4-(N-methyl-benzyl amino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To the N-methylbenzylamine (67.5mg, 0.56mmol) and drip n-butyllithium solution (0.235ml, 0.59mmol, 2.5M hexane solution) in 0 ℃ of quick stirred mixture of tetrahydrofuran (THF) (3.7ml).Reaction mixture in 0 ℃ of stirring 10 minutes, was stirred 1 hour in 23 ℃.Solution is cooled to-78 ℃, adds 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl along the reaction vessel inwall lentamente] and-3 (2H)-pyridazinones (200mg, 0.56mmol).Reaction mixture stirred spend the night, slowly ground temperature to 23 ℃ carries out the cooling bath evaporation simultaneously.The quenching of reactant water is with a large amount of excessive ethyl acetate dilutions.Separate each layer, ethyl acetate layer is water and salt water washing again, through dried over mgso, filters and vacuum concentration.Resistates obtains 2-(3-chloro-phenyl-)-4-(N-methyl-benzyl amino)-5-[4-(methylthio group) phenyl through chromatographic separation (quick silica gel, ethyl acetate/hexane 1: 9)]-3 (2H)-pyridazinones (output: 145mg, 58%).
Method according to embodiment 10, with 2-(3-chloro-phenyl-)-4-(N-methyl-benzyl amino)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 143mg, 95%).M.p.60-85℃。 1H?NMR(300MHz，CDCl 2)δ2.46(s，3H)，3.09(s，3H)，4.63(s，2H)，7.19(d，J＝8.7Hz，2H)，7.24-7.29(m，2H)，7.32-7.48(m，5H)，7.60(ddd，J＝7.2，1.8，1.8Hz，1H)，7.67(s，1H)，7.70(dd，J＝1.8，1.8Hz，1H)，7.91(d，J＝8.7Hz，2H)。MS(APCI+)m/z?480(M+H) +。
Embodiment 3552-(4-fluorophenyl)-4-(piperidino)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To piperidines (99.7mg, 1.17mmol) and toluene (8ml) be cooled in-78 ℃ the uneven slightly solution and drip n-butyllithium solution (0.235ml, 0.59mmol, 2.5M hexane solution).After 10 minutes, remove cooling bath in-78 ℃ of stirrings, mixture was stirred 1 hour in 23 ℃ again.With heat gun (heat gun) with 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinone (400mg, 1.17mmol) gradation is dissolved in toluene (3 * 6-7ml equal portions), and be cooled to 0 ℃, be transferred to lithamide solution (being cooled to-78 ℃) by syringe then.Slowly add along the reaction vessel inwall.The reaction mixture stirring is spent the night, be slowly to warm to 23 ℃, carry out the cooling bath evaporation simultaneously.The quenching of reactant water is with a large amount of excessive ethyl acetate dilutions.Separate each layer, ethyl acetate layer is water and salt water washing again, through dried over mgso, filters and vacuum concentration.Resistates obtains 2-(4-fluorophenyl)-5-[4-(methylthio group) phenyl of 440mg (95%) through chromatographic separation (quick silica gel, ethyl acetate/hexane 1: 2)]-4-piperidino-(1-position only)-3 (2H)-pyridazinone.
Method according to embodiment 10, with 2-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-4-piperidino-(1-position only)-3 (2H)-pyridazinone replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 165mg, 98%).M.p.80-100℃。 1H?NMR(300MHz，CDCl 2)δ1.59(br?s，6H)，2.59(br?s，4H)，3.14(s，3H)，7.17(dd，J＝8.7，8.7Hz，2H)，7.51(d，J＝8.7Hz，2H)，7.55-7.62(m，2H)，7.68(s，1H)，8.06(d，J＝8.7Hz，2H)。MS(APCI+)m/z?428(M+H) +。From CH 2Cl 2/ C 6H 14In separate out powder.C 22H 22FN 3O 3S0.25C 6H 14The analytical calculation value: C, 62.85; H, 5.72; N, 9.35.Measured value: C, 62.46; H, 5.77; N, 9.13.
Embodiment 3562-(4-fluorophenyl)-4-(1-pyrrolidyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 355, use the tetramethyleneimine substituted piperidine, preparation title compound (output: 107mg, 82%).M.p.192-195℃。 1H?NMR(300MHz，CDCl 3)δ1.71-1.80(m，4H)，3.13(s，3H)，3.40-3.49(m，4H)，7.16(dd，J＝8.7，8.7Hz，2H)，7.47-7.60(m，5H)，7.99(d，J＝8.7Hz，2H)。MS(APCI+)m/z414(M+H) +。C 21H 20FN 3O 3The analytical calculation value of S: C, 61.00; H, 4.87; N, 10.16.Measured value: C, 60.95; H, 4.94; N, 10.07.
Embodiment 3572-(3-chloro-phenyl-)-4-(4-methylbenzene sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl of preparation in embodiment 333]-3 (2H)-pyridazinone (0.0802g; 0.15mmol) EtOH (1.5ml) stirred suspension in add thiocresol (0.019g; 0.15mmol) and salt of wormwood (0.0203g, 0.15mmol).With suspension under agitation be heated to 50 ℃ 2.5 hours.Under constant agitation, mixture is inclined to water.Filter the precipitation of gained, the water flushing is also dry, obtains required product (output: 0.060g, 83%).M.p.178-178℃。 1H?NMR(300MHz，DMSO?d 6)δ2.19(s，3H)，3.23(s，3H)，6.95(m，2H)，7.08(m，2H)，7.52-7.66(m，3H)，7.72(m，1H)，7.88(m，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?483(M+H) +，500(M+NH 4) +。C 24H 19ClN 2O 3S 20.75H 2The analytical calculation value of O: C, 58.05; H, 4.16; N, 5.64.Measured value: C, 57.99; H, 3.69; N, 5.76.
Embodiment 3582-(3-chloro-phenyl-)-4-(2-pyridine sulfenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 357, replace thiocresol with the 2-mercaptopyridine, preparation title compound (output: 0.061g, 39%).M.p.110-114℃。 1H?NMR(300MHz，DMSO?d 6)δ3.28(s，3H)，7.16(m，1H)，7.37(m，1H).7.51-7.71(m，5H)，7.81(m，2H)，8.03(m，2H)，8.27(s，1H)，8.34(m，1H)。MS(DCI-NH 3)m/z?470(M+H) +。C 22H 16ClN 3O 3S 20.50H 2The analytical calculation value of O: C, 55.16; H, 3.57; N, 8.77.Measured value: C, 54.88; H, 3.19; N, 8.59.
Embodiment 3592-(3-chloro-phenyl-)-4-(phenyl methylthio group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl of preparation in embodiment 333]-3 (2H)-pyridazinone (0.175g; 0.33mmol) THF (3.3ml) stirred suspension in add benzyl sulfhydrate (0.04ml; 0.33mmol) and TEA (0.046ml, 0.33mmol).Gained solution was stirred 1 hour down in room temperature, nitrogen.Mixture is inclined to water, use ethyl acetate extraction.The organism that merges is through dried over mgso and vacuum concentration.The raw product of gained separates (SiO through flash chromatography 2, 2: 1 hexanes: ethyl acetate), obtain required product (output: 0.136g, 85%).M.p.142-145℃。 1H?NMR(300MHz，DMSO?d 6)δ3.31(s，3H)，4.36(s，2H)，7.17(m，2H)，7.21-7.33(m，3H)，7.51(m，2H)，7.57-7.64(m，3H)，7.74(m，1H)，8.01(m，2H)。MS(DCI-NH 3)m/z?483(M+H) +，500(M+NH 4) +。C 24H 19ClN 2O 3S 2The analytical calculation value: C, 59.68; H, 3.96; N, 5.80.Measured value: C, 59.40; H, 4.11; N, 5.71.
Embodiment 3602-(3-chloro-phenyl-)-4-(2-furyl methylthio group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 359 replaces benzyl sulfhydrate with furfurylmercaptan, preparation title compound (output: 0.162g, 100%).M.p.140-149℃。 1H?NMR(300MHz，DMSOd 6)δ3.31(s，3H)，4.46(s，2H)，6.20(m，1H)，6.37(m?1H)，7.50-7.67(m，6H)，7.77(m，1H)，8.03(m，2H)，8.08(s，1H)。MS(DCI-NH 3)m/z?473(M+H) +，490(M+NH 4) +。C 22H 17ClN 2O 4S 2The analytical calculation value: C, 55.87; , 3.62; N, 5.92.Measured value: C, 55.84; H, 3.61; N, 5.82.
Embodiment 3612-(3-chloro-phenyl-)-4-[2-(methyl-propyl) sulfenyl]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 359, replace benzyl sulfhydrate with 2-methyl isophthalic acid-propylmercaptan, preparation title compound (output: 0.134g, 91%).Oily matter. 1H?NMR(300MHz，DMSOd 6)δ0.61(d，J＝6z，6H)，1.54-1.69(m，1H)，2.91(d，J＝6Hz，2H)，3.33(s，3H)，7.52-7.64(m，3H)，7.74(m，1H)，7.79(m，2H)，8.04(m，3H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 21H 21ClN 2O 3S 2(0.50H 2O) analytical calculation value: C, 55.07; H, 4.84; N, 6.11.Measured value: C, 54.70; H, 4.64; N, 5.85.
Embodiment 3622-(3-chloro-phenyl-)-4-(cyclopentyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl of preparation in embodiment 333]-3 (2H)-pyridazinone (0.175g; 0.33mmol)-78 ℃ of stirred solutions of THF (3.3ml) in add cyclopentyl magnesium chloride (0.17ml, 1.0M diethyl ether solution).With gained solution undermixing 1 hour under nitrogen, temperature is to room temperature simultaneously.Mixture is inclined to water, use ethyl acetate extraction.The organism that merges is through dried over mgso and vacuum concentration.The raw product of gained flash chromatography purifying (SiO 2, 2: 1 ethyl acetate: hexane), obtain required product (output: 0.1328g, 94%).M.p.155-157℃。 1H NMR (300MHz, DMSO d 6) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09 (m, 2H), 2.90 (m, J=8Hz, 1H), 3.26-3.37 (3H is disturbed by water), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H).MS(DCI-NH 3)m/z?429(M+H) +，446(M+NH 4) +。C 22H 21ClN 2O 3The analytical calculation value of S: C, 61.60; H, 4.93; N, 6.53.Measured value: C, 61.48; H, 4.81; N, 6.22.
Embodiment 3632-(3-chloro-phenyl-)-4-(3-methyl-propyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362,, be prepared as the title compound (output: 0.132g, 96%) of oily matter with isobutyl-chlorination magnesium substituted cyclohexyl magnesium chloride. 1H?NMR(300MHz，CDCl 3)δ0.77(d，J＝6Hz，6H)，2.08(m，1H)，2.54(d，J＝7Hz，2H)，7.36-7.46(m，2H)，7.56(m，2H)，7.62(m，1H)，7.73(m，2H)，8.11(m，2H)。MS(DCI-NH 3)m/z?417(M+H) +，434(M+NH 4) +。C 21H 21ClN 2O 3S0.50 H 2The analytical calculation value of O: C, 59.21; H, 5.20; N, 6.57.Measured value: C, 59.27; H, 5.40; H, 6.12.
Embodiment 3642-(3-chloro-phenyl-)-4-(cyclohexyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362,, be prepared as the title compound (output: 0.0579g, 38%) of oily matter with cyclohexyl methyl magnesium bromide substituted ring amyl group magnesium chloride. 1H NMR (300MHz, DMSO d 6) δ 0.66 (m, 2H), 1.03 (m 3H), 1.50 (m, 6H), 1.61 (m, 1H), 2.46 (m, 1H), 3.27-3.42 (3H is disturbed by water), 7.50-7.66 (m, 3H), 7.75 (m, 3H), 7.99 (s, 1H), 8.10 (m, 2H).MS(DCI-NH 3)m/z?457(M+H) +，474(M+NH 4) +。C 24H 25ClN 2O 3The analytical calculation value of S: C, 63.08; H, 5.51; N, 6.13.Measured value: C, 63.08; H, 5.47; N, 6.04.
Embodiment 3652-(3-chloro-phenyl-)-4-(2-cyclohexyl ethyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with cyclohexyl ethylmagnesium bromide substituted ring amyl group magnesium chloride, preparation title compound (output: 0.165g, 94%). 1H NMR (300MHz, DMSO d 6) δ 0.76 (m, 3H), 0.99-1.21 (m, 5H), 1.31-1.62 (m, 8H), 2.42-2.56 (1H, disturbed by DMSO), 3.25-3.34 (2H is disturbed by water), 7.48-7.65 (m, 3H), 7.48-7.65 (m, 3H), 7.76 (m, 3H), 8.01 (s, 1H), 8.10 (m, 2H).MS(DCI-NH 3)m/z?471(M+H) +，488(M+NH 4) +。C 25H 27ClN 2O 3The analytical calculation value of S: C, 63.75; H, 5.78; N, 5.95.Measured value: C, 63.48; H, 5.70; N, 5.67.
Embodiment 3662-(3-chloro-phenyl-)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with 3-methyl butyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 0.0221g, 16%).M.p.60-65℃。 1H?NMR(300MHz，DMSO?d 6)δ0.75(d，J＝7Hz，6H)，1.32-1.52(m，3H)，3.31(s，3H)，7.50-7.65(m，3H)，7.77(m，3H)，8.03(s，1H)，8.11(m，2H)。MS(DCI-NH 3)m/z?431(M+H) +，448(M+NH 4) +。C 22H 23ClN 2O 3S0.25 H 2The analytical calculation value of O: C, 60.68; H, 5.43; N, 6.43.Measured value: C, 60.29; H, 5.60; N, 6.17.
Embodiment 3672-(3-chloro-phenyl-)-4-benzyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with benzylmagnesium chloride substituted cyclohexyl magnesium chloride, the preparation title compound.M.p.174-177 ℃ (output: 25.9g, 57%). 1H?NMR(300MHz，DMSO?d 6)δ3.30(s，3H)，3.91(bs，2H)，7.02(m，2H)，7.12-7.25(m，3H)，7.51-7.64(m，3H)，7.72(m，3H)，8.07(m，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?451(M+H) +，468(M+NH 4) +。C 24H 19ClN 2O 3The analytical calculation value of S: C, 63.92; H, 4.25; N, 6.21.Measured value: C, 63.69; H, 4.28; N, 6.02.
Embodiment 3682-(3-chloro-phenyl-)-4-cyclohexyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with cyclohexyl chlorination magnesium substituted ring amyl group magnesium chloride, preparation title compound (output: 0.099g, 68%).M.p.85-90℃。 1H?NMR(300MHz，CDCl 3)δ1.01-1.30(m，3H)，1.48-1.69(m，3H)，1.75(m，2H)，2.28(m，2H)，2.57(m，1H)，3.16(s，3H)，7.35-7.46(m，2H)，7.50-7.62(m，3H)，7.68(m，2H)，8.11(m，2H)。MS(DCI-NH 3)m/z?443(M+H) +，460(M+NH 4) +。C 23H 23ClN 2O 3S (1.25H 2O) analytical calculation value: C, 59.34; H, 5.52; N, 6.01.Measured value: C, 59.02; H, 5.24; N, 5.65.
Embodiment 3692-(3-chloro-phenyl-)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with 4-luorobenzyl chlorination magnesium substituted ring amyl group magnesium chloride, preparation title compound (output: 0.1895g, 41%).M.p.183-185℃。 1H NMR (300MHz, DMSO d 6) δ 3.25-3.36 (3H is disturbed by water), 3.89 (bs, 2H), 6.97-7.09 (m, 4H), 7.50-7.64 (m, 3H), 7.71 (m, 3H), 8.06 (m, 2H), 8.11 (s, 1H).MS(DCI-NH 3)m/z?469(M+H) +，486(M+NH 4) +。C 24H 18ClFN 2O 3The analytical calculation value of S: C, 61.47; H, 3.87; N, 5.97.Measured value: C, 61.23; H, 3.84; N, 5.77.
Embodiment 3702-(3-chloro-phenyl-)-4-(4-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with right-tolyl bromination magnesium substituted ring amyl group magnesium chloride, preparation title compound (output: 65mg, 40.9%).M.p.222-224℃。 1H?NMR(300MHz，DMSO?d 6)δ2.28(s，3H)，3.25(s，3H)，7.12(t，4H)，7.6(m，5H)，7.79(t，1H)，7.9(d，J＝9Hz，2H)，8.22(s，1H)。MS(DCI-NH 3)m/z451(M+H) +，468(M+NH 4) +。C 24H 19ClN 2O 3S0.25H 2The analytical calculation value of O: C, 63.92; H, 4.25; N, 6.21.Measured value: C, 62.99; H, 4.28; N, 5.85.
Embodiment 3712-(3, the 4-difluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 362; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones begin; and with 3-fluoro-4-aminomethyl phenyl magnesium bromide substituted cyclohexyl magnesium chloride; obtain described methyl sulfide compound; preparation 2-(3, the 4-difluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.
According to the method for embodiment 10,, obtain title compound (output: 265mg, 85.4%) with described methyl sulfide oxidation.M.p.204-206℃。 1H?NMR(300MHz，CDCl 3)δ2.25(br?s，3H)，3.08(s，3H)，6.83(dd，J＝9Hz，1.5Hz，1H)，6.96(dd，J＝9Hz，1.5Hz，1H)，7.08(t，J＝9Hz，1H)，7.23-7.33(m，1H)，7.41(d，J＝9Hz，2H)，7.49-7.56(m，1H)，7.61-7.69(m，1H)，7.93(d，J＝9Hz，2H)，7.99(s，1H)。MS(DCI-NH 3)m/z?471(M+H) +，488(M+NH 4) +。C 24H 17F 3N 2O 3The analytical calculation value of S: C, 61.28; H, 3.62; N, 5.96.Measured value: C, 61.07; H, 3.95; N, 5.56.
Embodiment 3722-(3-chloro-phenyl-)-4-(styroyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 228, with 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, and with styroyl magnesium chloride substituted cyclohexyl magnesium chloride, the method of using embodiment 10 then is with its oxidation, preparation title compound (output: 0.100g, 39%).M.p.142-145℃。 1H?NMR(300MHz，DMSO?d 6)δ2.80(m，4H)，3.30(s，3H)，7.01(m，2H)，7.21(m，3H)，7.51-7.60(m，4H)，7.63(m，1H)，7.78(m，1H)，8.03(m，3H)。MS(DCI-NH 3)m/z?465(M+H) +，482(M+NH 4) +。C 25H 21ClN 2O 3The analytical calculation value of S: C, 64.58; H, 4.55; N, 6.02.Measured value: C, 64.24; H, 4.50; N, 5.90.
Embodiment 3732-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 373A.2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-bromo-3 (2H)-pyridazinones
According to the method for embodiment 194B, with 2-(3-chloro-phenyl-)-4,5-two bromo-3 (2H)-pyridazinones (embodiment 207A) replace 2-(4-fluorophenyl)-4,5-two bromo-3 (2H)-pyridazinones, and, prepare title compound with 2-methyl isophthalic acid-propyl alcohol replacement methyl alcohol.(373B.2-3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 6, replace 2-benzyl-4-bromo-5-methoxyl group-3 (2H)-pyridazinone with 2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-bromo-3 (2H)-pyridazinone, and, prepare title compound with 3-fluoro-4-(methylthio group) phenylo boric acid (embodiment 72C) replacement 4-fluorobenzoic boric acid.(373C.2-3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 10,, obtain title compound (output: 0.73g, 100%) with described methyl sulfide compound oxidation.M.p.180-183℃。 1H NMR (300MHz, DMSO d 6) (2H), (3H is by H for 3.30-3.39 for d, J=6Hz for δ 0.82 2O disturbs), 4.25 (d, J=6Hz, 2H), 7.57 (m, 3H), 7.75 (m, 1H), 7.85 (m, 1H), 8.00 (m, 1H), 8.23 (s, 1H).MS(DCI-NH 3)m/z?451(M+H) +，468(M+NH 4) +。C 21H 20ClFN 2O 4The analytical calculation value of S: C, 55.94; H, 4.47; N, 6.21.Measured value: C, 55.73; H, 4.58; N, 6.01.
Embodiment 3742-(3-chloro-phenyl-)-4-(benzyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To 2-(3-chloro-phenyl-)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 332) (0.100g, 0.28mmol) stirred solution in DMF (2.8ml) add benzyl chloride (0.32ml, 0.28mmol).Being heated under 60 ℃, the gained solution stirring is spent the night.Vacuum is removed solvent, and the resistates of gained is allocated between ethyl acetate and 10% citric acid.Behind ethyl acetate extraction, the organism of merging is through dried over mgso and vacuum concentration.Raw product flash chromatography purifying (SiO 2, 1: 1 ethyl acetate: hexane), obtain required product (output: 0.096g, 76%).M.p.110-113℃。 1H?NMR(300MHz，DMSO?d 6)δ3.39(s，3H)，5.48(s，2H)，7.29(m，4H)，7.59-7.71(m，3H)，7.76(m，3H)，8.00(m，2H)，8.21(s，2H)。MS(DCI-NH 3)m/z?467(M+H) +，484(M+NH 4) +。C 24H 19ClN 2O 4The analytical calculation value of S: C, 61.73; H, 4.10; N, 6.00.Measured value: C, 62.00; H, 4.18; N, 5.93.
Embodiment 3752-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 194C; 2-(4-fluorophenyl)-4-methoxyl group-5-bromo-3 (2H)-pyridazinone (embodiment 194B) is converted into 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones, follow method oxidation according to embodiment 10.According to the method for embodiment 332,, described methoxylation compound is converted into 2-(3-chloro-phenyl-)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl by handling with NaOH]-3 (2H)-pyridazinones.Method according to embodiment 333 is handled described oxy-compound with p-toluenesulfonyl chloride, obtains 2-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-4-tosyloxy-3 (2H)-pyridazinone.
Method according to embodiment 335; with 2-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-4-tosyloxy-3 (2H)-pyridazinone replacement 2-(3-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-4-tosyloxy-3 (2H)-pyridazinone; and replace isopropylcarbinol with 3-methyl isophthalic acid-butanols; preparation title compound (output: 0.3932g, 94%).M.p.117-120℃。 1HNMR(300MHz，CDCl 3)δ0.79(d，J＝6Hz，6H)，1.41-1.59(m，3H)，3.30(s，3H)，4.42(d，J＝5Hz，2H)，7.36(m，2H)，7.65(m，2H)，7.90(m，2H)，8.06(m，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?431(M+H) +，448(M+NH 4) +。C 22H 23FN 2O 4The analytical calculation value of S: C, 61.38; H, 5.39; N, 6.51.Measured value: C, 61.42; H, 5.30; N, 6.40.
Embodiment 3762-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-4-tosyloxy-3 (2H)-pyridazinone (as the intermediate preparation of embodiment 375) replacement 2-(3-chloro-phenyl-)-5-[4-(methyl sulphonyl) phenyl]-4-tosyloxy-3 (2H)-pyridazinone; preparation title compound (output: 0.486g, 100%).M.p.121-128℃。 1H?NMR(300MHz，DMSO?d 6)δ0.78(d，J＝7Hz，6H)，1.84(m，1H)，3.30(s，3H)，4.20(d，J＝6Hz，2H)，7.37(m，2H)，7.66(m，2H)，7.92(m，2H)，8.07(m，2H)，8.19(s，1H)。MS(DCI-NH 3)m/z?417(M+H) +，434(M+NH 4) +。C 21H 21FN 2O 4S0.50H 2The analytical calculation value of O: C, 59.28; H, 5.21; N, 6.58.Measured value: C, 59.49; H, 4.97; N, 6.34.
Embodiment 3772-(4-fluorophenyl)-4-(4-luorobenzyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 62, by 4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones begin, and with the reaction of 1-iodo-4-fluorobenzene, preparation title compound (output: 0.0881g, 78%).M.p.175-177℃。 1H NMR (300MHz, DMSO d 6) (3H is by H for δ 3.27-3.36 2O disturbs), 3.88 (bs, 2H), 6.98-7.09 (m, 4H), 7.34 (m, 2H), 7.65 (m, 2H), 7.71 (m, 2H), 8.06 (m, 3H).MS(DCI-NH 3)m/z?453(M+H) +，470(M+NH 4) +。C 24H 18F 2N 2O 3The analytical calculation value of S: C, 63.71; H, 4.01; N, 6.19.Measured value: C, 63.61; H, 4.26; N, 6.03.
Embodiment 3782-(4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 228, with 3-methyl butyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 0.325g, 69%).M.p.151-154℃。 1HNMR(300MHz，DMSO?d 6)δ0.75(d，J＝7Hz，6H)，1.32-1.51(m，3H)，3.31(s，3H)，7.37(m，2H)，7.66(m，2H)，7.77(m，2H)，8.00(s，1H)，8.10(m，2H)。MS(DCI-NH 3)m/z?415(M+H) +，432(M+NH 4) +。C 22H 23FN 2O 3S0.50H 2The analytical calculation value of O: C, 62.39; H, 5.71; N, 6.61.Measured value: C, 62.04; H, 5.78; N, 6.46.
Embodiment 3792-(tetrahydrochysene-2H-pyrans-2-yl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl according to embodiment 11 preparations]-3 (2H)-pyridazinone (172mg; 0.5mmol) and right-toluenesulphonic acids hydrate (19mg; 0.1mmol add 2 in) De diox (10ml) solution, 3-dihydropyrane (2ml).Mixture was stirred under room temperature 6 hours.Then mixture is inclined to saturated sodium bicarbonate solution, use ethyl acetate extraction.The vacuum concentration ethyl acetate, resistates obtains title compound (output: 25mg, 11%) through chromatographic separation (silica gel, 1: 1 hexane-ethyl acetate). 1H?NMR(DMSO-d 6，300MHz)δ1.54(m，2H)，1.74(m，2H)，2.00(m，1H)，2.17(m，1H)，3.23(s，1H)，3.62(m，1H)，4.00(m，1H)，5.98(m，1H)，7.13(7，J＝9Hz，2H)，7.23(m，2H)，7.47(d，J＝9Hz，2H)，7.86(d，J＝9Hz，2H)，8.12(s，1H)。MS(DCI-NH 3)m/z?429(M+H) +。
Embodiment 3802-(3-(4-fluorophenyl) phenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 4; with 2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 166) replacement 2-benzyl-4-bromo-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones; and replace yellow soda ash with cesium fluoride; preparation title compound (output: 0.62g, 62%).M.p.222-225℃。 1H?NMR(300MHz，DMSO?d 6)δ3.24(s，3H)，7.16(m，2H)，7.36(m，3H)，7.53(m，2H)，7.64(m，2H)，7.73-7.81(m，3H)，7.93(m，3H)，8.27(s，1H)。MS(DCI-NH 3)m/z?515(M+H) +，532(M+NH 4) +。C 29H 20F 2N 2O 3S0.25H 2The analytical calculation value of O: C, 67.10; H, 3.98; N, 5.35.Measured value: C, 66.93; H, 3.99; N, 5.17.
Embodiment 3812-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 261; with 2-(2; 2; the 2-trifluoroethyl)-and 4-chloro-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones replacement 2-(2,2, the 2-trifluoroethyl)-4-chloro-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation 2-(2; 2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[3-fluoro-4-(methylthio group) phenyl]-3 (2H)-pyridazinones.
The described methyl sulfide of metachloroperbenzoic acid oxidation with 1 part of a great deal of obtains described methyl sulfoxide.According to the method for embodiment 68, described sulfoxide is converted into title compound (output: 196mg, 28%).M.p.144-145℃。 1H?NMR(300MHz，CDCl 3)δ0.86(s，9H)，4.23(s，2H)，4.82(q，J＝8Hz，2H)，5.10(s，2H)，7.46(s，1H)，7.48(br?s，1H)，7.79(s，1H)，8.03(t，J＝8Hz，1H)。MS(DCI-NH 3)m/z?438(M+H) +。C 17H 19F 3N 3O 4The analytical calculation value of S: C, 46.68; H, 4.38; N, 9.61.Measured value: C, 46.76; H, 4.30; N, 9.52.
Embodiment 3822-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 68; with 2-(2; 2; the 2-trifluoroethyl)-and 4-(2-methyl propoxy-)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones, preparation title compound (output: 260mg, 26%).M.p.163-164℃。 1H NMR (300MHz, CDCl 3) δ 0.86 (d, J=6.6Hz, 6H), 1.91 (septet, J=6.6Hz, 1H), 4.34 (d, J=6.6Hz, 2H), 5.11 (br s, 2H), 7.43-7.52 (m, 2H), 7.80 (s, 1H), 8.02 (t, J=8Hz, 2H).MS(DCI-NH 3)m/z?424(M+H) +，441(M+NH 4) +。C 16H 17F 4N 3O 4The analytical calculation value of S: C, 45.39; H, 4.05; N, 9.92.Measured value: C, 59.89; H, 3.83; N, 8.61.
Embodiment 3832-benzyl-4-(4-luorobenzyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-benzyl-4-(4-fluorophenyl methyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3; the 4-difluorophenyl)-and 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.5723g, 34%).M.p.120-123℃。 1H?NMR(300MHz，DMSO?d 6)δ3.83(bs，2H)，5.30(bs，2H)，6.95-7.06(m，4H)，7.28-7.40(m，5H)，7.47(m，2H)，7.60(m，2H)，7.91(m，2H)，7.95(s，1H)。MS(DCI-NH 3)m/z?450(M+H) +，467(M+NH 4) +。C 24H 20FN 3O 3The analytical calculation value of S: C, 64.13; H, 4.48; N, 9.35.Measured value: C, 63.76; N, 4.71; N, 9.02.
Embodiment 3842-benzyl-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
To 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (130mg; 0.3mmol) and azo-2-carboxylic acid's di tert butyl carbonate (DBAD) (69mg; 0.3mmol) drip 1N 1 in-78 ℃ of solution in THF (30ml); 1; 1,3,3; 3-hexamethyl two silicon nitrogenize (silazide) lithium (0.9ml, THF solution 0.9mmol).After the adding, with reactant in-78 ℃ of restir 45 minutes (or show that until TLC raw material disappears).Ethyl acetate extraction is used in reactant saturated aqueous ammonium chloride quenching.Acetic acid ethyl ester extract obtains the rough affixture of 220mg through dried over mgso and vacuum concentration.
Above-mentioned affixture is dissolved among the THF (30ml), under room temperature, handled 5 hours with 1N NaOH (3ml).Add sodium acetate (NaOAc3H 2O, 1.38g, 10mmol), add then hydroxylamine-o-sulfonic acid (1.13g, 10mmol) and water (30ml).The gained mixture stirred under room temperature 18 hours, used ethyl acetate extraction then.Extract water, salt water washing are through dried over mgso and vacuum concentration.Resistates obtains required product (output: 70mg, 54%) through chromatography purification (silica gel, 1: 1 hexane-ethyl acetate).M.p.185-189℃。 1H?NMR(DMSO-d 6，300MHz)δ5.33(s，2H)，7.11(m，2H)，7.22(m，2H)，7.40(m，7H)，7.83(d，J＝9Hz，2H)，8.10(s，1H)。MS(DCI-NH 3)m/z?436(M+H) +。C 23H 18FN 3O 3S0.75H 2The analytical calculation value of O: C, 61.65; H, 4.26; N, 9.04.Measured value: C, 61.67; H, 4.61; N, 8.66.
Embodiment 3852-(4-fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the product of embodiment 108 is converted into title sulphonamide (output: 65mg, 28.8%).M.p.227-229℃。 1H?NMR(300MHz，??DMSO-d 6)δ7.08-7.17(m，4H)，7.36(t，J＝3Hz，2H)，7.47(br?s，2H)，7.61-7.69(m，2H)，7.83(d，J＝9Hz，2H)，7.93(d，J＝9Hz，2H)，8.40(s，1H)。MS(DCI-NH 3)m/z?469(M+H) +，486(M+NH 4) +。C 24H 15F 2N 3O 4The analytical calculation value of S: C, 58.02; H, 3.30; N, 9.24.Measured value: C, 57.84; H, 3.34; N, 9.01.
Embodiment 3862-(3, the 4-difluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the product of embodiment 371 is converted into title sulphonamide (output: 45mg, 28%).M.p.198-200℃。 1H?NMR(300MHz，DMSO-d 6)δ6.87(dd，J＝9Hz，3Hz，1H)，7.13(dt，J＝9Hz，3Hz，1H)，7.19(t，J＝7Hz，1H)，7.46(d，J＝9Hz，2H)，7.47(br?s，2H)，7.52-7.69(m，2H)，7.79(d，J＝9Hz，2H)，7.82-7.89(m，1H)，8.25(s，1H)。MS(DCI-NH 3)m/z?472(M+H) +，489(M+NH 4) +。
Embodiment 3872-(4-fluorophenyl)-4-(3-fluoro-4-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the product of embodiment 250 is converted into title sulphonamide (output: 185mg, 46%).M.p.187-188℃。 1H?NMR(300MHz，DMSO-d 6)δ2.22(br?s，3H)，6.87(dd，J＝9Hz，3Hz，1H)，7.16(q，J＝9Hz，2H)，7.38(t，J＝9Hz，2H)，7.46(br?s，2H)，7.47(d，J＝9Hz，2H)，7.67-7.73(m，2H)，7.77(d，J＝9Hz，2H)，8.22(s，1H)。MS(DCI-NH 3)m/z?454(M+H) +，471(M+NH 4) +。C 23H 17F 2N 3O 3S0.25H 2The analytical calculation value of O: C, 60.36; H, 3.87; N, 9.19.Measured value: C, 60.30; H, 4.26; N, 8.83.
Embodiment 3882-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl 1-3 (2H)-pyridazinone
According to the method for embodiment 384, the product of embodiment 109 is converted into title sulphonamide (output: 110mg, 45.7%).M.p.224-226℃。 1H?NMR(300MHz，CDCl 3)δ4.86(br?s，2H)，6.89-7.03(m，4H)，7.19-7.30(m，1H)，7.45-7.52(m，1H)，7.56-7.66(m，1H)，7.79(d，J＝9Hz，2H)，8.04(d，J＝9Hz，1H)，8.08(s，1H)。MS(DCI-NH 3)m/z?474(M+H) +，491(M+NH 4) +。C 22H 14F 3N 3O 4S0.25H 2The analytical calculation value of O: C, 55.32; H, 2.93; N, 8.80.Measured value: C, 55.26; H, 3.11; N, 8.58.
Embodiment 3892-(3-chloro-4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the product of embodiment 247 is converted into title sulphonamide (output: 230mg, 38%).M.p.243-245℃。 1H?NMR(300MHz，DMSO-d 6)δ2.17(br?s，3H)，6.94-7.09(m，2H)，7.25(dd，J＝9Hz，3Hz，1H)，7.41-7.48(m，4H)，7.60(t，J＝9Hz，1H)，7.68-7.75(m，1H)，7.77(d，J＝9Hz，2H)，7.95(dd，J＝6Hz，3Hz，1H)，8.25(s，1H)。MS(DCI-NH 3)m/z?469(M+H) +，486(M+NH 4) +。C 23H 16ClF 2N 3O 3The analytical calculation value of S: C, 56.67; H, 3.29; N, 8.63.Measured value: C, 56.81; H, 3.35; N, 8.95.
Embodiment 3902-(4-fluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the methyl sulfone product of embodiment 245 is converted into title sulphonamide (output: 78mg, 28.3%).M.p.202-204℃。 1H?NMR(300MHz，CDCl 3)δ2.22(s，3H)，4.86(s，2H)，6.83-6.91(m，2H)，7.14-7.25(m，3H)，7.36(d，J＝9Hz，2H)，7.65-7.72(m，2H)，7.91(d，J＝9Hz，2H)，8.0(s，1H)。MS(DCI-NH 3)m/z?454(M+H) +，471(M+NH 4) +。C 23H 17F 2N 3O 3S0.25H 2The analytical calculation value of O: C, 60.36; N, 3.77; N, 9.19.Measured value: C, 60.24; H, 3.93; N, 9.25.
Embodiment 3912-(3-chloro-phenyl-)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, the methyl sulfone product of embodiment 224 is converted into title sulphonamide (output: 125mg, 39%).M.p.187-188℃。 1H?NMR(300MHz，CDCl 3)δ2.21(s，3H)，4.71(s，2H)，6.85-6.92(m，2H)，7.21(d，J＝9Hz，1H)，7.32-7.47(m，2H)，7.37(d，J＝9Hz，2H)，7.64(dt，J＝7Hz，3Hz，1H)，7.77(br?s，1H)，7.91(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?470(M+H) +，487(M.+NH 4) +。C 23H 17ClFN 3O 3S0.25H 2The analytical calculation value of O: C, 58.32; 1H, 3.65; N, 8.88.Measured value: C, 58.27; H, 3.91; N, 8.62.
Embodiment 3922-(3-chloro-phenyl-)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-phenyl-)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 366) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.0756g, 16%).M.p.167-170℃。 1H NMR (300MHz, DMSO d 6) δ 0.78 (d, J=6Hz, 6H), 1.47 (5H is disturbed by hexane), 7.51-7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H).MS(DCI-NH 3)m/z?432(M+H) +，449(M+NH 4) +。C 21H 22ClN 3O 3S (0.25H 2O) analytical calculation value: C, 57.79; H, 5.19; N, 9.62.Measured value: C, 57.78; H, 5.02; N, 9.40.
Embodiment 3932-(3-chloro-phenyl-)-4-(styroyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-phenyl-)-4-(styroyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 372) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.075g, 17%).Semi-solid. 1H NMR (300MHz, DMSO d 6) δ 2.80 (m, 4H), 3.29-3.42 (3H is disturbed by water), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H).MS(DCI-NH 3)m/z?466(M+H) +，483(M+NH 4) +。C 24H 20ClN 2O 3S0.25H 2The analytical calculation value of O: C, 61.27; H, 4.39; N, 8.93.Measured value: C, 61.18; H, 4.68; N, 8.58.
Embodiment 3942-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 339) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.575g, 18%).M.p.137-139℃。 1H?NMR(300MHz，DMSO?d 6)δ0.81(d，J＝7Hz，6H)，1.49(m，2H)，1.57(m，1H)，4.42(t，J＝7Hz，2H)，7.44-7.65(m，5H)，7.76(m，1H)，7.84(m，2H)，7.94(m，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?448(M+H) +，465(M+NH 4) +。C 21H 22ClN 3O 4The analytical calculation value of S: C, 56.31; H, 4.95; N, 9.38.Measured value: C, 56.02; H, 4.82; N, 9.31.
Embodiment 3952-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 335) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.0458g, 25%).M.p.80-85℃。 1H?NMR(300MHz，DMSO?d 6)δ0.80(d，J＝6Hz，6H)，1.74-1.92(m，3H)，4.20(d，J＝6Hz，2H)，7.49-7.64(m，5H)，7.76(m，1H)，7.85(m，2H)，7.95(m，2H)，8.21(m，1H)。MS(DCI-NH 3)m/z?434(M+H) +，451(M+NH 4) +。C 20H 20ClN 3O 4The analytical calculation value of S: C, 55.36; H, 4.65; N, 9.68.Measured value: C, 55.12; H, 4.58; N, 9.42.
Embodiment 3962-(4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 378) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.090g, 21%).M.p.180-183℃。 1H?NMR(300MHz，DMSO?d 6)δ0.78(d，J＝6Hz，6H)，1.49(m，5H)，7.36(m，2H)，7.53(m，2H)，7.62-7.73(m，4H)，7.98(m，3H)。MS(DCI-NH 3)m/z?416(M+H) +，433(M+NH 4) +。C 21H 22FN 3O 3The analytical calculation value of S: C, 60.71; H, 5.34; N, 10.11.Measured value: C, 60.37; H, 5.36; N, 9.84.
Embodiment 3972-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 376) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.024g, 6%).M.p.132-136℃。 1H?NMR(300MHz，DMSO?d 6)δ0.79(d，J＝6Hz，6H)，1.83(m，1H)，4.19(d，J＝6Hz，2H)，7.36(m，2H)，7.50(m，2H)，7.66(m，2H)，7.84(m，2H)，7.95(m，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?418(M+H) +，435(M+NH 4) +。C 20H 20FN 3O 4The analytical calculation value of S: C, 57.54; H, 4.83; N, 10.07.Measured value: C, 57.26; N, 5.00; N, 9.78.
Embodiment 3982-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 375) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.051g, 18%).Yellow oil. 1H?NMR(300MHz，DMSO?d 6)δ0.80(d，J＝5Hz，6H)，1.47(m，3H)，4.42(t，J＝6Hz，2H)，7.37(m，2H)，7.50(m，1H)，7.65(m，2H)，7.83(m，2H)，7.93(m，2H)，8.18(s，1H)，8.60(bs，1H)。MS(DCI-NH 3)m/z?432(M+H) +，449(M+NH 4) +。C 21H 22FN 3O 4The analytical calculation value of S: C, 58.46; H, 5.14; N, 9.74.Measured value: C, 58.16; H, 5.21; N, 9.57.
Embodiment 3992-(tertiary butyl)-4-(3-methyl isophthalic acid-butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
With the metachloroperbenzoic acid of 1 part of a great deal of with 2-(tertiary butyl)-4-(3-methyl isophthalic acid-butoxy)-5-[4-(methylthio group) phenyl for preparing among the embodiment 330C]-3 (2H)-pyridazinones are oxidized to corresponding methyl sulfoxide.According to the method for embodiment 68, described sulfoxide is transformed title sulphonamide (output: 1.25g, 54%).M.p.153-155℃。 1H?NMR(300MHz，CDCl 3)δ0.82(d，J＝6Hz，2H)，1.48(q，J＝6Hz，2H)，1.49-1.69(m，1H)，1.70(s，9H)，4.37(t，J＝6Hz，2H)，4.32(s，2H)，7.70(d，J＝9Hz，2H)，7.72(s，1H)，8.01(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?394(M+H) +。C 19H 27N 3O 4The analytical calculation value of S: C, 57.99; H, 6.91; N, 10.67.Measured value: C, 58.11; H, 6.71; N, 10.58.
Embodiment 4002-(3, the 4-difluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-4-(4-fluorophenyl)-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 182) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 950mg, 54%).M.p.177-181℃。 1H?NMR(300MHz，DMSO-d 6)δ7.15(t，2H)，7.29(m，2H)，7.43(s，1H)，7.45(bs，2H)，7.59(m，2H)，7.76(d，J＝9Hz，2H)，7.85(m，1H)，8.27(s，1H)。MS(DCI-NH 3)m/z?458(M+H) +，475(M+NH 4) +。C 22H 14F 3N 3O 3The analytical calculation value of S: C, 57.77; H, 3.08; N, 9.19.Measured value: C, 57.22; H, 3.28; N, 8.99.
Embodiment 4012-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 380mg, 47%).M.p.208-210℃。 1H?NMR(300MHz，DMSO-d 6)δ7.15(t，2H)，7.27(m，2H)，7.43(s，1H)，7.45(bs，2H)，7.51(d，J＝9Hz，4H)，7.6(t，1H)，7.7(m，1H)，7.75(d，J＝9Hz，2H)，7.94(dd，1H)，8.25(s，1H)。MS(DCI-NH 3)m/z?474(M+H) +，491(M+NH 4) +。C 22H 14F 2Cl 2N 3O 3S0.5H 2The analytical calculation value of O: C, 55.76; H, 2.98; N, 8.87.Measured value: C, 56.05; H, 3.42; N, 8.65.
Embodiment 4022-(3, the 4-difluorophenyl)-4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(4-fluoro-3-aminomethyl phenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 105mg, 27%).M.p.243-245℃。 1H?NMR(300MHz，DMSO-d 6)δ2.2(s，3H)，7.01(m，2H)，7.25(m，1H)，7.45(s，1H)，7.47(bs，2H)，7.6(m，2H)，7.77(d，J＝9Hz，2H)，7.85(m，1H)，8.26(s，2H)。MS(DCI-NH 3)m/z?472(M+H) +，489(M+NH 4) +。C 24H 17F 3N 2O 3S0.5H 2The analytical calculation value of O: C, 58.59; H, 3.42; N, 8.91.Measured value: C, 57; H, 4.23; N, 8.89.
Embodiment 4032-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 35mg, 42%).M.p.169-171℃。 1H?NMR(300MHz，DMSO-d 6)δ0.78(d，6H)，1.84(m，1H)，4.2(d，2H)，7.54(m，3H)，7.6(m，1H)，7.82(m，3H)，7.91(d，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?436(M+H) +，453(M+NH 4) +。C 20H 19F 2N 3O 4S0.25 H 2The analytical calculation value of O: C, 55.17; H, 4.40; N, 9.65.Measured value: C, 54.19; H, 4.25; N, 9.35.
Embodiment 4042-(3, the 4-difluorophenyl)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 58mg, 52%).M.p.171-173℃。 1H?NMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.4，(m，3H)，2.48(m，2H)，3.3(s，3H)，7.51(m，1H)，7.65(m，1H)，7.75(d，J＝9Hz，2H)，7.81(m，1H)，8.05(s，1H)，8.12(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?434(M+H) +，451(M+NH 4) +。C 21H 21F 2N 3O 3S0.25H 2The analytical calculation value of O: C, 58.19; H, 4.88; N, 9.69.Measured value: C, 57.69; N, 5.01; N, 9.18.
Embodiment 4052-(3-chloro-4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 102mg, 61.8%).M.p.154-156℃。 1H?NMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.4(m，3H)，2.48(m，2H)，7.54(s，2H)，7.6(m，1H)，7.69(m，2H)，7.93(dd，1H)，8.05(m，2H)。MS(DCI-NH 3)m/z?450(M+H) +，468(M+NH 4) +。C 22H 22FN 2O 3SCl0.25H 2The analytical calculation value of O: C, 58.86; H, 4.94; N, 6.24.Measured value: C, 59.23; H, 5.12; N, 6.00.
Embodiment 4062-(3, the 4-difluorophenyl)-4-(2,2-dimethyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-4-(2; 2-dimethyl propoxy-)-and 5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 310mg, 38%).M.p.173-175℃。 1H?NMR(300MHz，DMSO-d 6)δ0.8(s，9H)，3.3(s，3H)，4.1(s，2H)，7.51(m，3H)，7.6(m，1H)，7.85(m，3H)，7.95(d，J＝9Hz，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?450(M+H) +，467(M+NH 4) +。C 21H 21F 2N 3O 4The analytical calculation value of S: C, 56.12; H, 4.71; N, 9.35.Measured value: C, 55.83; , 4.73; N, 9.08.
Embodiment 4072-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 400; with 2-(3; the 4-difluorophenyl)-and 4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 125mg, 31%).M.p.224-226℃。 1H?NMR(300MHz，DMSO-d 6)δ7.15(d，4H)，7.51(m，1H)，7.6(m，2H)，7.75(m，4H)，7.9(t，1H)；8.4(s，1H)。MS(DCI-NH 3)m/z?492(M+H) +，509(M+NH 4) +。C 22H 13F 4N 3O 4The analytical calculation value of S: C, 53.77; H, 2.67; N, 8.55.Measured value: C, 53.33; H, 2.84; N, 8.22.
Embodiment 4082-(3,3-two fluoro-2-propenyl)-4-(4-fluorophenyl)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
With the metachloroperbenzoic acid oxidation of 1 part of a great deal of intermediate 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methylthio group) phenyl according to the method preparation of embodiment 72]-3 (2H)-pyridazinones, obtain methyl sulfoxide, method according to embodiment 68 is translated into sulphonamide.According to the method for embodiment 11, described sulphonamide material is gone benzylization, according to the method N-alkylation of embodiment 127, and with 1,3-two bromo-1, the 1-difluoropropane replaces 3,4-difluoro benzyl bromide and with the salt of wormwood of 4 parts of a great deal oves obtains title compound (output: 120mg, 27%).M.p.180-183℃。 1H?NMR(300MHz，CDCl 3)δ4.71(dt，J＝15Hz，7.5Hz，2H)，4.75(d，J＝7.5Hz，2H)，5.06(s，2H)，7.02(m，2H)，7.19(dd，J＝9Hz，6Hz，2H)，7.81(s，1H)，7.87(t，J＝7.5Hz，2H)。MS(DCI-NH 3)m/z?440(M+H) +。C 19H 13F 4N 3O 3The analytical calculation value of S: C, 51.93; H, 2.98; N, 9.56.Measured value: C, 51.71; H, 3.15; N, 9.28.
Embodiment 4092-(3, the 4-difluorophenyl)-4-[2-(2-propoxy-) oxyethyl group]-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-4-[2-(2-propoxy-) oxyethyl group]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 110mg, 34%).M.p.54-56℃。 1H?NMR(300MHz，DMSO-d 6)δ1.0(d，6H)，3.43(m，1H)，3.54(m，2H)，4.63(m，2H)，7.5(m，3H)，7.6(m，1H)，7.8(m，1H)，7.95(m，4H)，8.2(s，1H)。MS(DCI-NH 3)m/z?466(M+H) +，483(M+NH 4) +。C 21H 21F 2N 3O 5The analytical calculation value of S: C, 54.19; H, 4.55; N, 9.03.Measured value: C, 54.29; H, 4.67; N, 8.95.
Embodiment 4102-(3, the 4-difluorophenyl)-4-(4-methyl-3-amylene oxygen base)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(4-methyl-3-amylene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones, the preparation title compound.M.p.70-73℃。 1H?NMR(300MHz，DMSO-d 6)δ1.5(d，6H)，2.27(m，2H)，4.43(t，2H)，4.5(m，1H)，7.5(m，2H)，7.6(m，1H)，7.8(m，2H)，7.92(d，J＝2H，2H)，8.2(s，1H)。MS(DCI-NH 3)m/z?462(M+H) +，479(M+NH 4) +。C 22H 21F 2N 3O 4The analytical calculation value of S: C, 57.26; H, 4.59; N, 9.11.Measured value: C, 56.96; H, 4.70; N, 9.01.
Embodiment 4112-(3-chloro-phenyl-)-4-(3-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with the 3-fluorophenol, preparation title compound (output: 0.034g, 22%).M.p.178-180℃。 1H?NMR(300MHz，DMSO?d 6)δ3.27(s，3H)，6.88-7.00(m，2H)，7.10(m，1H)，7.36(m，1H)，7.59(m，3H)，7.74(m，1H)，7.90(m，2H)，8.06(m，2H)，8.43(s，1H)。MS(DCI-NH 3)m/z?488(M+H) +。C 23H 16ClFN 2O 4S0.25H 2The analytical calculation value of O: C, 58.10; H, 3.49; N, 5.89.Measured value: C, 58.04; H, 3.59; N, 5.80.
Embodiment 4122-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 384; with 2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 0.019g, 10%).M.p.157-159℃。 1H?NMR(300MHz，DMSO?d 6)δ0.81(d，J＝6Hz，6H)，1.86(m，1H)，4.24(d，J＝6Hz，2H)，7.75(m，3H)，7.66(m，1H)，7.73(m，2H)，7.83m，2H)，7.91(m，1H)，8.23(s，1H)。C 21H 19ClFN 3O 4The analytical calculation value of S: C, 53.16; H, 4.24; N, 9.30.Measured value: C, 53.02; H, 4.43; N, 9.10.
Embodiment 4132-(3-chloro-phenyl-)-4-(4-methyl pentyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 4-methyl-1-pentene alcohol, preparation title compound (output: 0.137g, 90%).M.p.139-140℃。 1H?NMR(300MHz，DMSO?d 6)δ0.74(d，J＝6Hz，6H)，1.03(m，2H)，1.39(m，1H)，1.54(m，2H)，3.29(s，3H)，4.40(t，J＝5Hz，2H)，7.51-7.60(m，3H)，7.75(m，1H)，7.90(m，2H)，8.07(m，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?461(M+H) +，478(M+NH 4) +。C 23H 25ClN 2O 4The analytical calculation value of S: C, 59.95; H, 5.97; N, 6.08.Measured value: C, 59.62; H, 5.63; N, 5.86.
Embodiment 4142-(4-fluorophenyl)-4-(4-methyl pentyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with 4-methyl-1-pentene alcohol; preparation title compound (output: 0.128g, 85%).M.p.123-125℃。 1H?NMR(300MHz，DMSO?d 6)δ0.74(d，J＝6Hz，6H)，1.03(m，2H)，1.39(m，1H)，1.54(m，2H)，3.28(s，3H)，4.39(t，J＝6Hz，2H)，7.37(m，2H)，7.66(m，2H)，7.91(m，2H)，8.07(m，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?445(M+H) +。C 23H 25FN 2O 4The analytical calculation value of S: C, 62.14; H, 5.67; N, 6.30.Measured value: C, 62.28; H, 5.59; N, 6.25.
Embodiment 4152-(4-fluorophenyl)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 332; with 2-(4-fluorophenyl)-4-methoxyl group 5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 2.022g, 97%). 1H?NMR(300MHz，DMSO?d 6)δ3.28(s，3H)，7.38(m，2H)，7.70(m，2H)，8.03(m，4H)，8.22(s，1H)。MS(APCI-+Q1MS)361(M+H) +，(-Q1MS)359(M-H) -。
Embodiment 4162-(4-fluorophenyl)-4-cyclo propyl methoxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with cyclopropyl-carbinol; preparation title compound (output: 0.117g, 83%).M.p.166-167℃。 1H?NMR(300MHz，DMSO?d 6)δ0.22(m，2H)，0.46(m，2H)，1.10(m，1H)，3.31(s，3H)，4.30(d，J＝7Hz，2H)，7.36(m，2H)，7.66(m，2H)，7.96(m，2H)，8.07(m，2H)，8.20(s，1H)。MS(DCI-NH 3)m/z?415(M+H) +，432(M+NH 4) +。C 23H 25ClN 2O 4The analytical calculation value of S: C, 60.86; H, 4.62; N, 6.76.Measured value: C, 60.76; , 4.72; N, 6.61.
Embodiment 4172-(4-fluorophenyl)-4-(2-cyclopropyl-1-oxyethyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with 2-cyclopropane ethanol; preparation title compound (output: 0.1472g, 100%).M.p.111-117℃。 1H?NMR(300MHz，DMSO?d 6)δ-0.01(m，2H)，0.31(m，2H)，0.60(m，1H)，1.49(q，J＝6Hz，2H)，3.29(s，3H)，4.48(t，J＝6Hz，2H)，7.37(m，2H)，7.65(m，2H)，7.91(m，2H)，8.06(m，2H)，8.17(s，1H)。MS(DCI-NH 3)m/z429(M+H) +，446(M+NH 4) +。C 22H 21FN 2O 4The analytical calculation value of S: C, 61.67; H, 4.94; N, 6.54.Measured value: C, 61.59; H, 5.02; N, 6.45.
Embodiment 4182-(3-chloro-phenyl-)-4-cyclopropane methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with cyclopropane methyl alcohol, preparation title compound (output: 0.0917g, 64%).M.p.158-161℃。 1H?NMR(300MHz，DMSO?d 6)δ0.22(m，2H)，0.46(m，2H)，1.13(m，1H)，3.31(s，3H)，4.31(d，J＝7Hz，2H)，7.57(m，3H)7.75(m，1H)，7.96(m，2H)，8.08(m，2H)，8.23(s，1H)。MS(DCI-NH 3)m/z?431(M+H) +，448(M+NH 4) +。C 21H 19ClN 2O 4S0.25H 2The analytical calculation value of O: C, 57.92; H, 4.51; N, 6.43.Measured value: C, 57.86; H, 4.35; N, 6.27.
Embodiment 4192-(3-chloro-phenyl-)-4-(2-cyclopropane-1-oxyethyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 2-cyclopropane ethanol, preparation title compound (output: 0.114g, 78%).M.p.124-128℃。 1H?NMR(300MHz，DMSO?d 6)δ0.00(m，2H)，0.32(m，2H)，0.61(m，1H)，1.49(q，J＝6Hz，2H)，3.30(s，3H)，4.50(t，J＝6Hz，2H)，7.58(m，3H)，7.76(m，1H)，7.91(m，2H)，8.07(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?445(M+H) +，462(M+NH 4) +。C 22H 21ClN 2O 4The analytical calculation value of S: C, 59.39; H, 4.76; N, 6.30.Measured value: C, 58.92; H, 4.94; N, 6.15
Embodiment 4202-(4-fluorophenyl)-4-(4-methyl amyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 362; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and with 4-methylpentane-1-magnesium bromide substituted ring propyl group magnesium chloride; preparation title compound (output: 0.165g, 99%).M.p.112-115℃。 1H?NMR(300MHz，DMSO?d 6)δ0.75(d，J＝7Hz，6H，1.07(q，J＝7Hz，2H)，1.32-1.53(m，3H)，2.45(t，2H)，3.31(s，3H)，7.37(m，2H)，7.66(m，2)，7.76(m，2H)，8.00(s，1H)，8.10(m，2H)。MS(DCI-NH 3)m/z?429(M+H) +，446(M+NH 4) +。C 23H 25FN 2O 3The analytical calculation value of S: C, 64.47; H, 5.88; N, 6.54.Measured value: C, 64.44; H, 5.90; N, 6.49.
Embodiment 4212-(3-chloro-phenyl-)-4-(4-methyl amyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 362, with 4-methylpentane-1-magnesium bromide substituted ring propyl group magnesium chloride, preparation title compound (output: 165mg, 98%).Oily matter. 1H?NMR(300MHz，DMSO?d 6)δ0.76(d，J＝6Hz，6H)，1.07(m，2H)，1.33-1.55(m，3H)，2.45(m，2H)，3.32(s，3H)，7.51-7.65(m，4H)，7.76(m，2H)，8.03(s，1H)，8.11(m，2H)。MS(DCI-NH 3)m/z?445(M+H) +，462(M+NH 4) +。C 23H 25ClN 2O 3The analytical calculation value of S: C, 62.06; H, 5.66; N, 6.30.Measured value: C, 61.86; H, 5.64; N, 6.18.
Embodiment 4222-(4-fluorophenyl)-4-(3-methyl-2-butene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with 3-methyl-2-butene-1-alcohol; preparation title compound (output: 0.1284g, 88%).M.p.128-132℃。 1HNMR(300MHz，DMSO?d 6)δ1.58(s，3H)，1.67(s，3H)，3.30(s，3H)，4.95(d，J＝7Hz，2H)，5.31(m，1H)，7.38(m，2H)，7.65(m，2H)，7.89(m，2H)，8.06(m，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?429(M+H) +，446(M+NH 4) +。C 22H 21FN 2O 4The analytical calculation value of S: C, 61.67; H, 4.94; N, 6.54.Measured value: C, 61.41; H, 4.95; N, 6.47.
Embodiment 4232-(3-chloro-phenyl-)-4-(3-methyl-2-butene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 3-methyl-2-butene-1-alcohol, preparation title compound (output: 0.119g, 81%).M.p.113-115℃。 1H?NMR(300MHz，DMSO?d 6)δ1.58(s，3H)，1.67(s，3H)，3.31(s，3H)，4.96(m，2H)，5.32(m，1H)，7.58(m，3H)，7.75(m，1H)，7.89(m，2H)，8.07(m，2H)。MS(APCI+QlMS)445(M+H) +，(APCI-QlMS)479(M+35) -。C 22H 21ClN 2O 4The analytical calculation value of S: C, 59.39; H, 4.76; N, 6.30.Measured value: C, 59.14; H, 4.66; N, 6.16.
Embodiment 4242-(4-fluorophenyl)-4-(4-methyl-3-amylene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with 4-methyl-2-amylene-1-ol; preparation title compound (output: 0.1165g, 77%).M.p.111-114℃。 1HNMR(300MHz，DMSO?d 6)δ1.46(s，3H)，1.56(s，3H)，2.26(m，2H)，3.30(s，1H)，4.43(t，J＝7Hz，2H)，4.96(m，1H)，7.37(m，2H)，7.65(m，2H)，7.91(m，2H)，8.06(m，2H)，8.18(s，1H)。MS(DCI-NH 3)m/z?443(M+H) +，460(M+NH 4) +。C 23H 23FN 2O 4The analytical calculation value of S: C, 62.43; H, 5.24; N, 6.33.Measured value: C, 62.32; H, 5.30; N, 6.25.
Embodiment 4252-(4-fluorophenyl)-4-(3-methyl-3-butenyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 335; with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3-chloro-phenyl-)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace isopropylcarbinol with 3-methyl-3-butene-1-alcohol; preparation title compound (output: 0.1327g, 91%).M.p.109-111℃。 1HNMR(300MHz，DMSO?d 6)δ1.61(s，3H)，2.32(t，J＝7Hz，2H)，3.30(s，3H)，4.56(t，J＝7Hz，2H)，4.63(bs，1H)，4.68(bs，1H)，7.37(m，2H)，7.66m，2H)，7.90(m，2H)，8.05(m，2H)，8.19(s，1H)。MS(DCI-NH 3)m/z?429(M+H) +，446(M+NH 4) +。C 22H 21FN 2O 4The analytical calculation value of S: C, 61.67; H, 4.94; N, 6.54.Measured value: C, 61.50; H, 5.00; N, 6.45.
Embodiment 4262-(3-chloro-phenyl-)-4-(4-methyl-3-amylene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 4-methyl-3-amylene-1-ol, preparation title compound (output: 0.1149g, 76%).M.p.110-111℃。 1H?NMR(300MHz，DMSO?d 6)δ1.47(s，3H)，1.55(s，3H)，2.27(m，2H)，3.30(s，3H)，4.44(t，J＝6Hz，2H)，4.96(m，1H)，7.52-7.64(m，3H)，7.75(m，1H)，7.91(M，2H)，8.06(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?459(M+H) +，476(M+NH 4) +。C 23H 23ClN 2O 4The analytical calculation value of S: C, 60.19; H, 5.05; N, 6.10.Measured value: C, 60.06; H, 4.90; N, 5.96.
Embodiment 4272-(3-chloro-phenyl-)-4-(3-methyl-3-butenyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 335, replace isopropylcarbinol with 3-methyl-3-butene-1-alcohol, preparation title compound (output: 0.1159g, 79%).M.p.110-112℃。 1H?NMR(300MHz，DMSO?d 6)δ1.62(s，3H)，2.32(t，J＝7Hz，2H)，3.30(s，3H)，4.57(t，J＝6Hz，2H)，4.63(bs，1H)，4.68(bs，1H)，7.51-7.64(m，3H)，7.76(m，1H)，7.90(m，2H)，8.05(m，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?445(M+H) +，462(M+NH 4) +。C 22H 21ClN 2O 4The analytical calculation value of S: C, 59.39; H, 4.76; N, 6.30.Measured value: C, 59.27; H, 4.68; N, 6.18.
Embodiment 4282-(4-fluorophenyl)-4-(1,5-hexadienyl-3-oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, with 1,5-hexadiene-3-alcohol replaces 2-ethyl-1-hexanol, preparation title compound (output: 150mg, 85%).M.p.104-105℃。 1H?NMR(300MHz，DMSO-d 6)δ2.42(m，2H)，3.30(s，3H)，5.00(m，2H)，5.17(m，2H)，5.64(m，2H)，7.36(t，J＝9Hz，2H)，7.64(m，2H)，7.92(d，J＝9Hz，2H)，8.06(d，J＝9Hz，2H)，8.19(s，1H)。MS(APCI+)m/z?441(M+H) +；(APCI-)m/z?475(M+Cl) -。C 23H 21FN 2O 4The analytical calculation value of S: C, 62.71; H, 4.80; N, 6.35.Measured value: C, 62.96; H, 4.93; N, 5.85.
Embodiment 4292-(4-fluorophenyl)-4-(5-methyl-2-hexyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, replace 2-ethyl-1-hexanol with 5-methyl-2-hexanol, preparation title compound (output: 150mg, 82%).M.p.102-103℃。 1H?NMR(300MHz，DMSO-d 6)δ0.73(d，J＝7Hz，6H)，1.04(m，2H)，1.14(d，J＝7Hz，3H)，1.40(m，3H)，3.29(s，3H)，5.12(m，1H)，7.36(t，J＝9Hz，2H)，7.66(m，2H)，7.92(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.19(s，1H)。MS(APCI+)m/z?459(M+H) +；(APCI-)m/z?493(M+C1) -。C 24H 27FN 2O 4The analytical calculation value of S: C, 62.86; H, 5.93; N, 6.10.Measured value: C, 62.83; H, 5.99; N, 6.07.
Embodiment 4302-(4-fluorophenyl)-4-(2-ethyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, replace 2-ethyl-1-hexanol with 2-ethyl-1-butanols, preparation title compound (output: 140mg, 80%).M.p.107-108℃。 1H NMR (300MHz, DMSO-d 6) δ 0.73 (t, J=7Hz, 6H), 1.20 (septet, J=7Hz, 4H), 1.40 (m, 1H), 3.29 (s, 3H), 4.29 (d, J=7Hz, 2H), 7.37 (t, J=9Hz, 2H), 7.66 (m, 2H), 7.90 (d, J=9Hz, 2H), 8.07 (d, J=9Hz, 2H), 8.19 (s, 1H).MS(APCI+)m/z?445(M+H) +；(APCI-)m/z?479(M+Cl) -。C 23H 25FN 2O 4The analytical calculation value of S: C, 62.14; H, 5.66; N, 6.30.Measured value: C, 62.05; H, 5.86; N, 6.30.
Embodiment 4322-(4-fluorophenyl)-4-(2-sulfo-sec.-propyl-1-oxyethyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, replace 2-ethyl-1-hexanol with 2-(iprotiazem base) ethanol, preparation title compound (output: 138mg, 74%).M.p.137-139℃。 1HNMR (300MHz, DMSO-d 6) δ 1.13 (d, J=7Hz, 6H), 2.77 (t, J=7Hz, 2H), 2.88 (septet, J=7Hz, 1H), 3.29 (s, 3H), 4.58 (t, J=7Hz, 2H), 7.37 (t, J=9Hz, 2H), 7.66 (m, 2H), 7.92 (d, J=9Hz, 2H), 8.06 (d, J=9Hz, 2H), 8.18 (s, 1H).MS(APCI+)m/z?463(M+H) +。C 22H 23FN 2O 4S 2The analytical calculation value: C, 57.12; H, 5.01; N, 6.05.Measured value: C, 56.82; N, 4.91; N, 5.99.
Embodiment 4332-(4-fluorophenyl)-4-(3-methylthio group-1-hexyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, replace 2-ethyl-1-hexanol with 3-(methylthio group)-1-hexanol, preparation title compound (output: 155mg, 79%).M.p.90-92℃。 1H?NMR(300MHz，DMSO-d 6)δ0.78(t，J＝7Hz，3H)，1.30(m，4H)，1.76(m，2H)，2.82(s，3H)，2.38(m，1H)，3.29(s，3H)，4.55(m，2H)，7.37(t，J＝9Hz，2H)，7.66(m，2H)，7.92(d，J＝9Hz，2H)，8.06(d，J＝9Hz，2H)，8.18(s，1H)。MS(APCI+)m/z?491(M+H) +；(APCI-)m/z?525(M+Cl) -。C 24H 27FN 2O 4S 2The analytical calculation value: C, 58.75; H, 5.54; N, 5.70.Measured value: C, 58.66; H, 5.54; N, 5.66.
Embodiment 4342-(4-fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, replace 2-ethyl-1-hexanol with 2-methyl-4-amylene-1-ol, preparation title compound (output: 135mg, 76%).M.p.106-107℃。 1HNMR(300MHz，DMSO-d 6)δ0.76(d，J＝7Hz，3H)，1.78(m，2H)，2.00(m，1H)，3.29(s，3H)，4.25(m，2H)，4.90(m，2H)，5.67(m，1H)，7.37(t，J＝9Hz，2H)，7.66(m，2H)，7.92(d，J＝9Hz，2H)，8.06(d，J＝9Hz，2H)，8.18(s，1H)。MS(APCI+)m/z?443(M+H) +；(APCI-)m/z?477(M+Cl) -。C 23H 23FN 2O 4The analytical calculation value of S: C, 62.42; H, 5.23; N, 6.33.Measured value: C, 62.13; H, 5.12; N, 6.22.
Embodiment 4352-(3.4-difluorophenyl)-4-(3-Trifluoromethyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
To 2-(3, the 4-difluorophenyl)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl] and-3 (2H)-pyridazinones (189mg, 0.5mmol), Ph 3(262mg, 1mmol) (66mg, (0.2m1, THF 1mmol) (5ml) solution stirred the gained mixture 8 hours P under room temperature to drip DIAD in THF 0.5mmol) (25ml) solution with 3-Trifluoromethyl-1-butanols.With the mixture vacuum concentration, resistates obtains required product (output: 180mg, 71%) through chromatographic separation (silica gel, 1: 1 hexane-ethyl acetate).M.p.126-128℃。 1H?NMR(300MHz，DMSO-d 6)δ0.96(d，J＝7Hz，3H)，1.55(m，1H)，1.97(m，1H)，2.30(m，1H)，3.29(s，3H)，4.46(m，2H)，7.52(m，1H)，7.62(m，1H)，7.81(m，1H)，7.90(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)，8.22(s，1H)。MS(APCI+)m/z?503(M+H) +；(APCI-)m/z?537(M+Cl) -。C 22H 19F 5N 2O 4The analytical calculation value of S: C, 52.59; H, 3.81; N, 5.57.Measured value: C, 52.70; H, 3.73; N, 5.63.
Embodiment 4362-(3, the 4-difluorophenyl)-4-oxyethyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 2-ethyl-1-hexanol with ethanol; preparation title compound (output: 25mg, 12%).M.p.121-123℃。 1H?NMR(300MHz，DMSO-d 6)δ1.23(t，J＝7Hz，3H)，3.30(s，3H)，4.51(q，J＝7Hz，2H)，7.52(m，1H)，7.62(m，1H)，7.81(m，1H)，7.90(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)，8.22(s，1H)。MS(APCI+)m/z?407(M+H) +；(APCI-)m/z?441(M+Cl) -。C 19H 16F 2N 2O 4S0.25H 2The analytical calculation value of O: C, 55.53; H, 4.04; N, 6.81.Measured value: C, 55.58; H, 4.21; N, 6.61.
Embodiment 4372-(3, the 4-difluorophenyl)-4-(4-methyl-1-pentene oxygen base)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 2-ethyl-1-hexanol with 4-methyl-1-pentene alcohol; preparation title compound (output: 120mg, 52%).M.p.98-99℃。 1HNMR(300MHz，DMSO-d 6)δ0.73(d，J＝7Hz，6H)，1.02(m，2H)，1.29(m，1H)，1.54(m，2H)，3.30(s，3H)，4.40(t，J＝7Hz，2H)，7.52(m，1H)，7.62(m，1H)，7.81(m，1H)，7.90(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)，8.22(s，1H)。MS(APCI+)m/z?463(M+H) +；(APCI-)m/z?497(M+C]) -。C 23H 24F 2N 2O 4The analytical calculation value of S: C, 59.72; H, 5.23; N, 6.05.Measured value: C, 59.57; H, 5.28; N, 6.01.
Embodiment 4382-(3, the 4-difluorophenyl)-4-(4-methyl-2-pentyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 2-ethyl-1-hexanol with 4-methyl-2-amylalcohol; preparation title compound (output: 115mg, 50%).M.p.132-133℃。 1H?NMR(300MHz，DMSO-d 6)δ0.80(d，J＝7Hz，3H)，0.87(d，J＝7Hz，3H)，1.10(d，J＝7Hz，3H)，1.26(m，1H)，1.50(m，1H)，1.63(m，1H)，3.30(s，3H)，5.31(m，1H)，7.52(m，1H)，7.62(m，1H)，7.8?1(m，1H)，7.90(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)，8.22(s，1H)。MS(APCI+)m/z463(M+H) +；(APCI-)m/z?497(M+Cl) -。C 23H 24F 2N 2O 4The analytical calculation value of S: C, 59.72; H, 5.23; N, 6.05.Measured value: C, 59.44; H, 5.26; N, 5.99.
Embodiment 4392-(3, the 4-difluorophenyl)-4-(2-cyclopentyl-1-oxyethyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 2-ethyl-1-hexanol with 2-cyclopentyl-1-ethanol; preparation title compound (output: 115mg, 60%).M.p.100-101℃。 1H?NMR(300MHz，DMSO-d 6)δ1.00(m，2H)，1.38(m，2H)，1.57(m，7H)，3.30(s，3H)，4.42(t，J＝7Hz，2H)，7.52(m，1H)，7.62(m，1H)，7.81(m，1H)，7.90(d，J＝9Hz，2H)，8.08(d，J＝9Hz，2H)，8.22(s，1H)。MS(APCI+)m/z?475(M+H) +；(APCI-)m/z?509(M+Cl) -。C 24H 24F 2N 2O 4S0.25H 2The analytical calculation value of O: C, 60.17; H, 5.15; N, 5.84.Measured value: C, 60.12; H, 5.14; N, 5.76.
Embodiment 4402-(3, the 4-difluorophenyl)-4-(2-ring penta-2-thiazolinyl-1-oxyethyl group)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace 2-ethyl-1-hexanol with 2-ring penta-2-thiazolinyl-1-ethanol; preparation title compound (output: 95mg, 48%).M.p.126-127℃。 1H NMR (300MHz, DMSO-d 6) δ 1.30 (m, 1H), 1.57 (sextet, J=7Hz, 1H), 1.69 (sextets, J=7Hz, 1H), 1.87 (m, 2H), 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60 (m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9Hz, 2H), 8.08 (d, J=9Hz, 2H), 8.22 (s, 1H).MS(APCI+)m/z?473(M+H) +；(APCI-)m/z?507(M+Cl) -。C 24H 22F 2N 2O 4The analytical calculation value of S: C, 61.00; H, 4.69; N, 5.92.Measured value: C, 60.76; H, 4.65; N, 5.80.
Embodiment 4412-(2-hydroxyl-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Product 2-(phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl with embodiment 46]-3 (2H)-pyridazinone (700mg; 1.5mmol) and sodium borohydride (69mg, 1.8mmol) mixture in ethanol (200ml) stirred 2 hours in 40 ℃.The vacuum concentration reaction mixture is allocated in resistates between ethyl acetate and the 2N aqueous hydrochloric acid then.Organic layer salt water washing is through dried over mgso and filtration.With the filtrate vacuum concentration, obtain faint yellow solid, with its crystallization from ethyl acetate/hexane, obtain title compound, be white crystal (output: 540mg, 78%).M.p.205-207℃。 1H?NMR(300MHz，CDCl 3)δ3.07(s，3H)，3.75(br?s，1H)，4.63-4.47(m，2H)，5.33(dd，J＝9Hz，3Hz，1H)，7.00(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，3Hz，2H)，7.30-7.45(m，5H)，7.52(d，J＝9Hz，2H)，7.91(s，1H)，7.91(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?465(M+H) +。C 25H 21FN 2O 4The analytical calculation value of S: C, 64.64; H, 4.55; N, 6.03.Measured value: C, 64.34; H, 4.66; N, 5.93.
Embodiment 4422-(2-methoxyl group-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Product 2-(2-hydroxyl-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl with embodiment 441]-3 (2H)-pyridazinone (210mg; 0.45mmol), methyl iodide (56 μ l; 0.90mmol) and 80% sodium hydride (18mg, 0.59mmol) mixture of oil dispersion in dry DMF (16ml) was in stirring at room 18 hours.Reaction mixture is allocated between ethyl acetate and the 2N aqueous hydrochloric acid.Organic layer salt water washing is through dried over mgso and filtration.With the filtrate vacuum concentration, obtain yellow oil, with it through column chromatography purification (silica gel, 70: 30 hexane/ethyl acetate).The flow point that will contain product merges and vacuum concentration, and resistates is ground with hexane, obtains title compound (output: 75mg, 34.7%).M.p.135-137℃。 1H?NMR(300MHz，CDCl 3)δ3.07(s，3H)，3.26(s，3H)，4.33-4.52(m，2H)，4.91(dd，J＝9Hz，3Hz，1H)，6.99(t，J＝9Hz，2H)，7.20(dd，J＝9Hz，3Hz，2H)，7.31-7.50(m，7H)，7.87(s，1H)，7.89(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?479(M+H) +。C 26H 23FN 2O 4The analytical calculation value of S: C, 65.25; H, 4.84; N, 5.85.Measured value: C, 64.98; H, 4.83; N, 5.81.
Embodiment 4432-(2-methoxyimino-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Product 2-(phenacyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl with embodiment 46]-3 (2H)-pyridazinone (220mg; 0.476mmol), methoxamine hydrochloride (318mg; 3.8mmoL) and sodium acetate (518mg, the 3.8mmol) stirring down 48 hours that refluxes of the mixture in methyl alcohol (100ml).The vacuum concentration reaction mixture is allocated in resistates between ethyl acetate and the saturated aqueous ammonium chloride.Organic layer salt water washing is through dried over mgso and filtration.With the filtrate vacuum concentration, obtain brown oil, with it through column chromatography purification (silica gel, 70: 30 hexane/ethyl acetate).The flow point that will contain product merges and vacuum concentration.With resistates crystallization from methanol, obtain title compound, be the mixture (output: 82mg, 35%) of E and Z oxime.M.p.95-99℃。 1H?NMR(300MHz，CDCl 3)δ3.03(s，3H)，4.07(s，3H)，5.57(s，2H)，6.94(t，J＝9Hz，2H)，7.07(dd，J＝9Hz，3Hz，2H)，7.24(d，J＝9Hz，2H)，7.31-7.37(m，3H)，7.60-7.67(m，2H)，7.74(s，1H)，7.83(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?492(M+H) +。C 26H 22FN 3O 4The analytical calculation value of S: C, 63.53; H, 4.51; N, 8.54.Measured value: C, 63.40; H, 4.51; N, 8.31.
Embodiment 4442-(3, the 4-difluorophenyl)-4-(4-methyl amyl)-5-[3-fluoro-4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 255, replace 3 with 1-bromo-4-methylpentane, 4-difluoro benzyl bromide, preparation title compound (output: 145mg, 58%).M.p.111-113℃。 1HNMR(300MHz，DMSO-d 6)δ0.75(d，6H)，1.09(m，2H)，1.4(m，3H)，2.48(m，2H)，3.4(s，3H)，7.61(m，2H)，7.75(d，2H)，7.81(m，1H)，8.02(s，1H)，8.1(d，2H)。MS(DCI-NH 3)m/z?447(M+H) +，464(M+NH 4) +。C 23H 24F 2N 2O 3The analytical calculation value of S: C, 61.87; H, 5.42; N, 6.27.Measured value: C, 61.76; H, 5.55; N, 6.11.
Embodiment 4452-(3, the 4-difluorophenyl)-4-(3-methyl isophthalic acid-butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Described according to embodiment 384; with 2-(3; the 4-difluorophenyl)-and 4-(3-methyl isophthalic acid-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 347) replacement 2-benzyl-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 248mg, 42%).M.p.149-151℃。 1H?NMR(300MHz，DMSO-d 6)δ0.8(d，J＝6Hz，6H)，1.48(m，2H)，1.54(m，1H)，4.4(t，2H)，7.51(m，3H)，7.6(m，1H)，7.85(m，3H)，7.95(d，J＝9Hz，2H)，8.21(s，1H)。MS(DCI-NH 3)m/z?450(M+H) +，467(M+NH 4) +。C 21H 21F 2N 3O 4The analytical calculation value of S: C, 56.12; H, 4.71; N, 9.35.Measured value: C, 56.12; H, 4.67; N, 9.15.
Embodiment 4462-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 90D, make the intermediate 2-(2 for preparing among the embodiment 90C, 2, the 2-trifluoroethyl)-and 4-hydroxyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones and 2,2-dimethyl-propyl alcohol reaction obtains 2-(2,2, the 2-trifluoroethyl)-and 4-(2,2-dimethyl propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.With of the metachloroperbenzoic acid oxidation of this product, obtain described methyl sulfoxide with 1 part of a great deal of.Method according to embodiment 68; with 2-(2; 2; the 2-trifluoroethyl)-4-(2; 2-dimethyl propoxy-)-and 5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones replacement 2-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones; described sulfoxide is converted into title compound (output: 125mg, 53%).M.p.123-124℃。 1H?NMR(300MHz，CDCl 3)δ0.82(s，9H)，4.18(s，2H)，4.82(q，J＝9Hz，2H)，4.84(s，2H)，7.70(d，J＝9Hz，2H)，7.81(s，1H)，8.04(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?420(M+H) +。C 17H 20F 3N 3O 4The analytical calculation value of S: C, 48.68; H, 4.80; N, 10.01.Measured value: C, 48.76; H, 4.77; N, 9.94.
Embodiment 4472-(2,2, the 2-trifluoroethyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 83, replace Virahol with 3-methyl isophthalic acid-butanols, preparation title compound (output: 65mg, 85%).M.p.111-113℃。 1H?NMR(300MHz，CDCl 3)δ0.84(d，J＝6Hz，6H)，1.51(m，2H)，1.63(m，1H)，3.11(s，3H)，4.54(t，J＝6Hz，2H)，4.83(q，J＝9Hz，2H)，7.73(d，J＝9Hz，2H)，7.82(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?419(M+H) +。C 18H 21F 3N 2O 4The analytical calculation value of S: C, 51.66; H, 5.05; N, 6.69.Measured value: C, 51.91; H, 5.06; N, 6.56.
Embodiment 4482-(2,2, the 2-trifluoroethyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 90D, with the intermediate 2-(2 for preparing among the embodiment 90C, 2, the 2-trifluoroethyl)-and 4-hydroxyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones and 3-methyl isophthalic acid-butanols reaction, obtain 2-(2,2, the 2-trifluoroethyl)-4-(3-methyl butoxy)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.This product obtains described methyl sulfoxide with the metachloroperbenzoic acid oxidation of 1 part of a great deal of.Method according to embodiment 68; with 2-(2; 2; the 2-trifluoroethyl)-and 4-(3-methyl butoxy)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones, described sulfoxide is converted into title compound (output: 65mg, 50%).M.p.123-124℃。 1H?NMR(300MHz，CDCl 3)δ0.84(d，J＝6Hz，6H)，1.52(q，J＝6Hz，2H)，1.60(h，J＝7.5Hz，1H)，4.52(t，J＝6Hz，2H)，4.83(q，J＝9Hz，2H)，4.90(s，2H)，7.69(d，J＝9Hz，2H)，7.82(s，1H)，8.04(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?420(M+H) +。C 17H 20F 3N 3O 4The analytical calculation value of S: C, 48.68; H, 4.80; N, 10.01.Measured value: C, 48.86; H, 4.83; N, 9.92.
Embodiment 4492-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 90D, with the intermediate 2-(2 for preparing among the embodiment 90C, 2, the 2-trifluoroethyl)-and 4-hydroxyl-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones and 2-methyl isophthalic acid-propyl alcohol reaction, obtain 2-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.This product obtains described methyl sulfoxide with the metachloroperbenzoic acid oxidation of 1 part of a great deal of.Method according to embodiment 68; with 2-(2; 2; the 2-trifluoroethyl)-and 4-(2-methyl propoxy-)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones, described sulfoxide is converted into title compound (output: 120mg, 40%).M.p.170-172℃。 1H?NMR(300MHz，CDCl 3)δ0.83(d，J＝6Hz，6H)，1.9(m，1H)，4.3(m，2H)，4.82(s，2H)，4.88(m，2H)，7.70(d，J＝9Hz，2H)，7.79(s，1H)，8.03(d，J＝9Hz，2H)；MS(DCI-NH 3)m/z?406(M+H) +。C 16H 18F 3N 3O 4The analytical calculation value of S: C, 47.4; H, 4.47; N, 10.36.Measured value: C, 47.48; H, 4.36; N.10.25.
Embodiment 4502-(2,3, the 3-trifluoro-propenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
With the method for embodiment 11, with product 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl of embodiment 4]-3 (2H)-pyridazinones go benzylization, obtain 4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones.With the 1-methyl sulphonyl oxygen base-2,3 of this intermediate and 1 part of a great deal of, the acetic acid ethyl fluid of 3-three fluoro-2-propylene (embodiment 88A) mixes, and the cesium carbonate with 1 part of a great deal of mixes then.With reaction mixture be heated to 50 ℃ 5 hours.Through water treatment, after chromatographic separation, obtain 2-(2,3, the 3-trifluoro-propenyl)-4-(4-fluorophenyl)-5-[4-(methylthio group) phenyl then]-3 (2H)-pyridazinones (650mg, 63%).This product is with the metachloroperbenzoic acid oxidation of 1 part of a great deal of; obtain described methyl sulfoxide; method according to embodiment 68; with 2-(2,3, the 3-trifluoro-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones replacement 2-(2; 2; the 2-trifluoroethyl)-and 4-(4-fluorophenyl)-5-[4-(methylsulfinyl) phenyl]-3 (2H)-pyridazinones, described methyl sulfoxide is converted into title compound (output: 65mg, 35%).M.p.190-193℃。 1H?NMR(300MHz，CDCl 3)δ5.07(s，2H)，5.10(dt，J＝21Hz，J＝3Hz，2H)，7.05(m，4H)，7.19(dd，J＝9Hz，J＝6Hz，2H)，7.84(s，1H)，7.87(t，J＝7.5Hz，1H)。MS(ESI-NH 3)m/z?456(M-H) +。C 19H 12F 5N 3O 3The analytical calculation value of S: C, 49.89; H, 2.64; N, 9.18.Measured value: C, 49.89; H, 2.73; N, 9.03.
Embodiment 4512-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, use the 3-methyl isophthalic acid, the 3-butyleneglycol replaces 2-ethyl-1-hexanol, preparation title compound (output: 110mg, 61%).M.p.133-134℃。 1HNMR(300MHz，DMSO-d 6)δ1.04(s，6H)，1.72(t，J＝7Hz，2H)，3.29(s，3H)，4.32(s，1H)，4.53(t，J＝7Hz，2H)，7.37(t，J＝9Hz，2H)，7.66(m，2H)，7.90(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2H)，8.19(s，1H)。MS(APCI+)m/z?447(M+H) +；(APCI-)m/z?481(M+Cl) -。C 22H 23FN 2O 4S0.25H 2The analytical calculation value of O: C, 58.59; H, 5.25; N, 6.21.Measured value: C, 58.42; H, 5.00; N, 6.02.
Embodiment 4522-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 178; with 2-(3; the 4-difluorophenyl)-and 4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and use the 2-methyl isophthalic acid; the 2-propylene glycol replaces 2-ethyl-1-hexanol; preparation title compound (output: 55mg, 31%). 1H?NMR(300MHz，DMSO-d 6)δ0.97(s，6H)，3.30(s，3H)，4.20(s，2H)，4.54(s，1H)，7.52(m，1H)，7.62(m，1H)，7.81(m，1H)，7.98(d，J＝9Hz，2H)，8.05(d，J＝9Hz，2H)，8.21(s，1H)。MS(APCI+)m/z?451(M+H) +；(APCI-)m/z485(M+Cl) -。C 21H 20F 2N 2O 5The analytical calculation value of S: C, 55.99; H, 4.47; N, 6.21.Measured value: C, 56.00; H, 4.48; N, 5.87.
Embodiment 4532-(3, the 4-difluorophenyl)-4-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
From the reaction mixture of embodiment 233, separate title compound (output: 22mg, 8%) as the unreacting material oxidation products.M.p.113-115℃。 1H?NMR(300MHz，DMSO-d 6)δ3.3(s，3H)，4.1(s，3H)，7.53(m，1H)，7.63(m，1H)，7.8(m，1H)，8.15(d，2H)，8.2(s，2H)。MS(DCI-NH 3)m/z?393(M+H) +，410(M+NH 4) +。C 18H 14F 2N 2O 4The analytical calculation value of S: C, 55.10; H, 3.60; N, 7.14.
Embodiment 4542-(2,3,4,5, the 6-PFBBR)-4-(4-fluorophenyl)-5-[4-[(dimethylamino)-and methylene radical] the amino-sulfonyl phenyl]-3 (2H)-pyridazinones
In the reaction mixture from embodiment 125, separate conduct and solvent N, the title compound (output: 53mg, 16%) of dinethylformamide reaction products therefrom.M.p.194-196℃。 1H?NMR(300MHz，CDCl 3)δ3.05(s，3H)，3.17(s，3H)，5.49(s，2H)，6.97(t，J＝9Hz，2H)，7.18(dd，J＝9Hz，6Hz，2H)，7.20(d，J＝9Hz，2H)，7.81(s，1H)，7.82(d，J＝9Hz，2H)，8.14(s，1H)。MS(DCI-NH 3)m/z?581(M+H) +。C 26H 18F 6N 4O 3The analytical calculation value of S: C, 53.79; H, 3.12; N, 9.65.Measured value: C, 53.50; H, 3.24; N, 9.56.
Embodiment 4552-(2, the 4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-[(dimethylamino) methylene radical]-the amino-sulfonyl phenyl]-3 (2H)-pyridazinones
In the reaction mixture from embodiment 124, separate conduct and solvent N, the title compound (output: 55mg, 18%) of dinethylformamide reaction products therefrom.M.p.193-195℃。 1H?NMR(300MHz，CDCl 3)δ3.03(s，3H)，3.16(s，3H)，5.43(s，2H)，6.88(m，2H)，6.95(t，J＝9Hz，2H)，7,18(dd，J＝9Hz，6Hz，2H)，7.20(d，J＝9Hz，2H)，7.52(m，1H)，7.81(d，J＝9Hz，2H)，7.84(s，1H)，8.13(s，1H)。MS(DCI-NH 3)m/z?527(M+H) +。C 26H 21F 3N 4O 3The analytical calculation value of S: C, 59.30; H, 4.02; N, 10.64.Measured value: C, 59.08; H, 3.97; N, 10.48.
Embodiment 4562-(4-fluorophenyl)-5-[4-(methyl selenonyl) phenyl]-3 (2H)-pyridazinone 446A.4-bromine seleno (seleno) phenylmethylethers
Under vigorous stirring, with newly the crushing magnesium chips (6.1g 0.25mol) is suspended in ether (360ml) and 1, and (10g is in solution 0.04mol) for the 4-dibromobenzene.Make solution reflux not initiation reaction 30 minutes.Add several iodine crystal, the initiation reaction thing is refluxed to controlling oneself.When slow adding residue 1, (49g in the time of 0.21mol), keeps backflow to the 4-dibromobenzene.Finish 1, after the adding of 4-dibromobenzene, reactant was refluxed 2 hours again.When nearly all magnesium chips exhausts, yellow/grey multi-phase solution is cooled to 23 ℃, by spatula with aliquot add selenium (19g, 0.24mol), to keep gentle reflux.Be adhered to the selenium of flask walls with extra ether washing.After the adding, solution in 23 ℃ of stirrings 20 minutes, is cooled to 0 ℃ then.(35.5g, ether 0.25mol) (20ml) solution slowly drops in this reaction mixture with methyl-iodide.Finish and add fashionablely, remove cooling bath, solution was stirred 3 hours in 23 ℃.Reaction soln is slowly inclined to frozen water/1M HCl, then this biphasic solution is filtered by the glass tampon.Separate the ether layer, water extracts 2 times with ether again.The ether extract that merges filters and vacuum concentration through dried over mgso, obtains half viscosity orange.When-20 ℃ of standing over night, form a large amount of yellow spicules.By the residual oily matter of transfer pipet sucking-off, obtain 17g (27%) crystalline product.(J.Org.Chem.，1983，48，4169)。 1H?NMR(300MHz，CDCl 3)δ2.46(s，3H)，7.12(d，J＝8.7Hz，2H)，7.39(d，J＝8.7Hz，2H)。MS (APCI+) m/z 248 (Se 76M+H) +, m/z250 (Se 78M+H) +, m/z 252 (Se 80M+H) +With m/z 254 (Se 82M+H) +446B.2, two (4-fluorophenyl)-5-[4-(methyl seleno) phenyl of 4-] and-3 (2H)-pyridazinones
Method according to embodiment 228, using 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methyl seleno) phenyl] [method according to embodiment 194C prepares-3 (2H)-pyridazinones, (method according to embodiment 1 prepares with 4-(methyl seleno) phenylo boric acid, replace 4-bromine sulfo-phenylmethylether with 4-bromine seleno phenylmethylether) replacement 4-(methylthio group) phenylo boric acid] replacement 2-(4-fluorophenyl)-4-methoxyl group-5-[4-(methylthio group) phenyl]-3 (2H)-pyridazinones, and with 4-fluorophenyl magnesium bromide substituted cyclohexyl magnesium chloride, preparation title compound (output: 44mg, 69%). 1H?NMR(300MHz，CDCl 3)δ2.37(s，3H)，6.98(dd，J＝8.8，8.8Hz，2H)，7.05(d，J＝8.7Hz，2H)，7.17(dd，J＝8.7，8.7Hz，2H)，7.23-7.31(m，2H)，7.32(d，J＝8.7Hz，2H)，7.65-7.72(m，2H)，8.00(s，1H)。MS(APCI+)m/z?455(M+H) +。446C.2, two (4-fluorophenyl)-5-[4-(methyl selenonyl) phenyl of 4-] and-3 (2H)-pyridazinones
In 23 ℃, (100mg, 342mmol 57-86%) handle 2 with 3-chlorine peroxybenzoic acid, two (4-the fluorophenyl)-4-(4-fluorophenyl) of 4--5-[4-(methyl seleno) phenyl]-3 (2H)-pyridazinones (40mg, 88.1mmol) stirred solution in methylene dichloride (2ml).After 2 hours, reactant be it seems only to finish slightly and is surpassed 50%.Add again 3-chlorine peroxybenzoic acid (80mg, 274mmol, 57-86%).Reaction is that 23 ℃ of restir finish in 16 hours.Solution dilutes with ethyl acetate, and and NaHSO 3Solution is jolting number minute (twice) carefully together, to consume excessive 3-chlorine peroxybenzoic acid.Ethyl acetate solution saturated sodium carbonate solution (twice), water and salt water washing subsequently, and through dried over mgso, filter and vacuum concentration.Resistates obtains described product (output: 40mg, 93%) through chromatographic separation (quick silica gel, acetone/dichloromethane/hexane 2: 2: 1).(J.Chem.Soc.，Chem.Commun.，1985，569)。M.p.110-150℃。 1H?NMR(300MHz，CDCl 3)δ3.32(s，3H)，6.91(dd，J＝8.7，8.7Hz，2H)，7.14-7.27(m，4H)，7.48(d，J＝8.4Hz，2H)，7.65-7.73(m，2H)，7.97(s，1H).8.00(d，J＝8.4Hz，2H)。MS (APCI+) m/z 487 (M+H) +With m/z 504 (M+NH 4) +C 23H 16F 2N 2O 3Se0.5H 2The analytical calculation value of O: C, 55.88; H, 3.46; N, 5.66.Measured value: C, 55.60; H, 3.61; N, 5.29.
Embodiment 4572-(3, the 4-difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Described in embodiment 62; with 4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and with 3; the 4-difluoro bromobenzene replaces 1-bromo-4-fluorobenzene; preparation title compound (output: 185mg, 46.5%).M.p.182-185℃。 1H?NMR(300MHz，DMSO-d 6)δ3.23(s，3H)，6.98(d，J＝9Hz，1H)，7.18(m?2H)，7.32(m，1H)，7.52(d，J＝9Hz，2H)，7.6(m，2H)，7.85(m，1H)，7.9(d，J＝9Hz，2H)，8.3(s，1H)。MS(DCI-NH 3)m/z?457(M+H) +，474(M+NH 4) +。
Embodiment 4582-(4-fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Described in embodiment 62; with 4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 135mg, 34%).M.p.199-201℃。 1HNMR(300MHz，DMSO-d 6)δ3.24(s，3H)，6.98(d，J＝9Hz，1H)，7.18(m，2H)，7.32(m，1H)，7.39(t，1H)，7.54(d，J＝9Hz，2?H)，7.71(m，2H)，7.91(d，J＝9Hz，2H)，8.27(s，1H)。MS(DCI-NH 3)m/z?439(M+H) +，456(M+NH 4) +。
Embodiment 4592-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 384, with 2-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (embodiment 452) are converted into the title sulphonamide.
Embodiment 4602-(3, the 4-difluorophenyl)-4-(2-oxo-1-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under room temperature, drip DIAD (0.4ml, THF 1mmol) (5ml) solution-treated 2-(3, the 4-difluorophenyl)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones (378mg, 1mmol), Ph 3P (524mg, 2mmol) and hydroxyacetone (74mg, 1mmol) solution in THF (25ml).This mixture was stirred under room temperature 6 hours, and vacuum concentration.Resistates obtains described product (output: 205mg, 48%) through chromatographic separation (silica gel, 1: 1 hexane-ethyl acetate).M.p.169-170℃。 1H?NMR(300MHz，DMSO-d 6)δ2.08(s，3H)，3.30(s，3H)，5.30(s，2H)，7.48(m，1H)，7.62(q，J＝10Hz，1H)，7.75(m，1H)，7.94(d，J＝9Hz，2H)，8.05(d，J＝9Hz，2H)，8.21(s，1H)。MS(APCI+)m/z?435(M+H) +，(APCI-)m/z?469(M+Cl) -。C 20H 16F 2N 2O 5S0.75H 2The analytical calculation value of O: C, 53.62; H, 3.93; N.6.25.Measured value: C, 53.26; H, 3.61; N, 6.08.
Embodiment 4612-(3, the 4-difluorophenyl)-4-[2-(methoxyimino) propoxy-]-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With methoxy amine hydrochlorate (84mg; 1mmol) and sodium acetate trihydrate (138mg; 1mmol) the 2-(3 of Processing Example 460; the 4-difluorophenyl)-and 4-(2-oxo-1-propoxy-)-5-[4-(methyl sulphonyl) phenyl] (150mg, 0.3mmol) (10ml) is with the mixture in the diox (20ml) at water for-3 (2H)-pyridazinones.Mixture was stirred under room temperature 6 hours.This reaction mixture ethyl acetate extraction, and, obtain title compound (output: 20mg, 15%) through column chromatography purification (silica gel, 1: 1 hexane-ethyl acetate).M.p.143-145℃。 1H?NMR(300MHz，DMSO-d 6)δ1.63(s，3H)，3.30(s，3H)，3.74(s，3H)，4.93(s，2H)，7.54(m，1H)，7.65(q，J＝10Hz，1H)，7.82(m，1H)，7.92(d，J＝9Hz，2H)，8.07(d，J＝9Hz，2)，8.24(s，1H)。MS(APCI+)m/z?464(M+H) +；(APCI-)m/z?498(M+Cl) -。C 21H 19F 2N 3O 5The analytical calculation value of S: C, 54.42; H, 4.13 N, 9.06.Measured value: C, 54.33; H, 393; N, 8.92.
Embodiment 462 (S)-2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone 462A (R)-3-tert.-butoxy-2-methyl isophthalic acid-propyl alcohol
Use 70%HClO 4(1.18g, the 10mmol) solution in tert.-butyl acetate (30ml) leave standstill reaction mixture 24 hours in the flask that is sealing under the room temperature (0.1ml) to handle 3-hydroxy-2-methyl propionic acid (S)-(+)-methyl esters.Mixture is inclined to saturated sodium bicarbonate solution, use extracted with diethyl ether.Vacuum is removed ether, and resistates is dissolved among the THF (50ml).(925mg 25mmol), and drips methyl alcohol (10ml) in 55 ℃ to add sodium borohydride in gained solution.Reactant is proceeded 1 hour in 55 ℃, be cooled to room temperature then, to pH5, and use ethyl acetate extraction with 10% citric acid acidifying.Acetic ester extract water, salt water washing are through dried over mgso and vacuum concentration.Resistates obtains (R)-3-tert.-butoxy-2-methyl isophthalic acid-propyl alcohol (output: 1g, 68%) through chromatographic separation (silica gel, 2: 1 hexane-ethyl acetate). 1H?NMR(300MHz，CDCl 3)δ0.85(d，J＝7Hz，3H)，1.20(s，9H)，2.03(m，1H)，3.30(t，J＝12Hz，1H)，3.53(dd，J＝12Hz，4.5Hz，1H)，3.70(m，2H)。MS(DCI-NH 3)m/z?164(M+NH 4) +。462B (S)-2-(3, the 4-difluorophenyl)-4-(3-tert.-butoxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Under room temperature, to 2-(3, the 4-difluorophenyl)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl] and-3 (2H)-pyridazinones (378mg, 1mmol), Ph 3(524mg, 2mmol) (146mg 1mmol) drips DIAD (0.4ml, THF 2mmol) (5ml) solution to P in the solution in THF (25ml) with above-mentioned alcohol (R)-3-tert.-butoxy-2-methyl isophthalic acid-propyl alcohol.Then mixture was stirred under room temperature 6 hours and vacuum concentration.Make resistates pass through silicagel pad (hexane-ethyl acetate is as eluent); obtain roughly (the S)-2-(3 of purifying of 550mg; the 4-difluorophenyl)-and 4-(3-tert.-butoxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones, this material still pollutes a spot of DIAD.MS(APCI+)m/z?507(M+H) +；(APCI-)m/z?541(M+Cl) -。462C (S)-2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
With above-mentioned product (100mg ,～0.2mmol) mixture in TFA (5ml) stirred 24 hours under room temperature, vacuum concentration then.Resistates is with the saturated sodium bicarbonate neutralization and use ethyl acetate extraction.Through column chromatography purification (silica gel, 1: 2 hexane-ethyl acetate), obtain title compound (output: 51mg, 56%). 1H NMR (300MHz, DMSO-d 6) δ 0.75 (d, J=7Hz, 3H), 1.81 (septet, J=7Hz, 1H), 3.21 (d, J=6Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J=12Hz, 6Hz, 1H), 4.40 (dd, J=12Hz, 6Hz, 1H), 4.48 (br s, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 7.91 (d, J=9Hz, 2H), 8.07 (d, J=9Hz, 2H), 8.20 (s, 1H).MS(APCI+)m/z?451(M+H) +；(APCI-)m/z?485(M+Cl) -。C 21H 20F 2N 2O 5The analytical calculation value of S: C, 55.99; H, 4.47; N, 6.21.Measured value: C, 55.65; H, 4.65; N, 5.92.
Embodiment 463 (R)-2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 462, replace 3-hydroxy-2-methyl propionic acid (s)-(-)-methyl esters by 3-hydroxy-2-methyl propionic acid (R)-(-)-methyl esters and begin, preparation desired substance (output: 65mg, 61%). 1H NMR (300MHz, DMSO-d 6) δ 0.75 (d, J=7Hz, 3H), 1.81 (septet, J=7Hz, 1H), 3.21 (t, J=6Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J=6Hz and 12Hz, 1H), 4.40 (dd, J=6Hz and 12Hz, 1H), 4.49 (t, J=6Hz, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 7.91 (d, J=9Hz, 2H), 8.07 (d, J=9Hz, 2H), 8.20 (s, 1H).MS(APCI+)m/z?451(M+H) +；(APCI-)m/z?485(M+Cl) -。C 21H 20F 2N 2O 5The analytical calculation value of S: C, 55.99; H, 4.47; N, 6.21.Measured value: C, 55.62; H, 4.52; N, 6.06.
Embodiment 464 (S)-2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
In-78 ℃ to (S)-2-(3 from embodiment 462; the 4-difluorophenyl)-and 4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinone (450mg;～0.9mmol) and DBAD (207mg; 0.9mmol) THF (25ml) solution in drip THF (3ml, 3mmol) solution of two (TMS) lithamides of 1M.The gained mixture was stirred 2 hours in-78 ℃.With the mixture temperature to room temperature, add 1N NaOH (5ml, 5mmol).After 12 hours, (2.76g, 20mmol) and water (10ml), (2g 15mmol), stirred mixture 5 hours under room temperature to add hydroxylamine-o-sulfonic acid then to add sodium acetate trihydrate under room temperature.Product obtains required intermediate (output: 160mg, 35%) with ethyl acetate extraction and through chromatography purification (silica gel, 1: 2 hexane-ethyl acetate).MS(APCI+)m/z?508(M+H) +；(APCI-)m/z?542(M+Cl) -。
TFA (5ml) is added to above-mentioned intermediate, gained solution was stirred under room temperature 24 hours.Vacuum is removed TFA, and resistates is with the saturated sodium bicarbonate neutralization and use ethyl acetate extraction.Organic extract is through dried over mgso and filtration.With the filtrate vacuum concentration, resistates obtains title compound (output: 50mg, 33%) through chromatographic separation (silica gel, 1: 2 hexane-ethyl acetate). 1H NMR (300MHz, DMSO-d 6) δ 0.76 (d, J=7Hz, 3H), 1.81 (sextet, J=7Hz, 1H), 3.22 (t, J=6Hz, 2H), 4.28 (dd, J=12Hz, 6Hz, 1H), 4.40 (dd, J=12Hz, 6Hz, 1H), 4.50 (t, J=6Hz, 1H), 7.51 (m, 3H), 7.61 (m, 1H), 7.80 (m, 1H), 7.84 (d, J=9Hz, 2H), 7.95 (d, J=9Hz, 2H), 8.20 (s, 1H).MS(APCI+)m/z?452(M+H) +；(APCI-)m/z?486(M+Cl) -。
Embodiment 465 (R)-2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 464; with (R)-2-(3; the 4-difluorophenyl)-and 4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement (S)-2-(3; the 4-difluorophenyl) 4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; preparation title compound (output: 30mg, 20%). 1H NMR (300MHz, DMSO-d 6) δ 0.76 (d, J=7Hz, 3H), 1.81 (sextet (J=7Hz, 1H), 3.22 (d, J=6Hz, 2H), 4.28 (dd, J=6Hz and 12Hz, 1H), 4.40 (dd, J=6Hz and 12Hz, 1H), 4.50 (t, J=6Hz, 1H), 7.51 (m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 7.84 (d, J=9Hz, 2H), 7.95 (d, J=9Hz, 2H), 8.20 (s, 1H).MS(APCI+)m/z?452(M+H) +；(APCI-)m/z?486(M+Cl) -。C 20H 19F 2N 3O 5The analytical calculation value of S: C, 53.21; H, 4.24; N, 9.30.Measured value: C, 53.45; HJ, 5.53; N, 9.50.
Embodiment 4662-(4-fluorophenyl)-4-(4-hydroxy-3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 178, use the 2-methyl isophthalic acid, the 4-butyleneglycol replaces 2-ethyl-1-hexanol, and through preparation property silica gel tlc, uses ethyl acetate: hexane (4/1) wash-out, separate described regional isomerism product, prepare title compound. 1H?NMR(300MHz，CDCl 3)δ0.87(d，J＝8.1Hz，3H)，1.48-1.87(m，4H)，3.13(s，3H)，3.41(dd，J＝6.3，13.5Hz，1H)，3.46(dd，J＝6.3，13.5Hz，1H)，4.48-4.63(m，2H)，7.15-7.24(m，2H)，7.58-7.66(m，2H)，7.79(d，J＝10.5Hz，2H)，7.91(s，1H)，8.07(d，J＝10.5Hz，2H)。MS(APCI+)m/z?447(M+H) +。
Embodiment 4672-(3, the 4-difluorophenyl)-4-(3-oxo butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
According to the method for embodiment 460, replace hydroxyacetone with 4-hydroxyl-2-butanone, preparation title compound (output: 95.0mg, 21%).M.p.134-135℃。 1H?NMR(300MHz，CDCl 3)δ2.06(s，3H)，2.81(t，J＝9Hz，2H)，3.13(s，3H)，4.75(t，J＝9Hz，2H)，7.30(m，1H)，7.45(m，1H)，7.58(m，1H)，7.73(d，J＝9Hz，2H)，7.89(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?449(M+H) +，466(M+NH 4) +。C 21H 18F 2N 2O 5The analytical calculation value of S: C, 56.25; H, 4.02; N, 6.25.Measured value: C, 55.97; H, 4.17; N, 6.11.
Embodiment 4682-(4-fluorophenyl)-4-(3-oxo butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones
Method according to embodiment 460; with 2-(4-fluorophenyl)-4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones replacement 2-(3; the 4-difluorophenyl)-and 4-hydroxyl-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; and replace hydroxyacetone with 4-hydroxyl-2-butanone; preparation title compound (output: 85.0mg, 20%).M.p.133-136℃。 1H?NMR(300MHz，CDCl 3)δ2.04(s，3H)，2.80(t，J＝9Hz，2H)，3.13(s，3H)，4.76(t，J＝9Hz，2H)，7.20(t，J＝9Hz，2H)，7.55(m，2H)，7.75(d，J＝9Hz，2H)，7.91(s，1H)，8.05(d，J＝9Hz，2H)。MS(DCI-NH 3)m/z?43?1(M+H) +，448(M+NH 4) +。C 21H 19FN 2O 5The analytical calculation value of S: C, 58.60; H, 4.42; N, 6.52.Measured value: C, 58.87; H, 4.55; N, 6.51.Prostaglandin(PG) suppresses to measure compound and administration
During oral administration, using the same day, (TRL-R Instrument, Jamaica NY), are suspended in test-compound in 100% polyoxyethylene glycol (PEG 400) with the electric homogenizer of being furnished with the pestle that scribbles Teflon.
For the average response of comparison process group, use variance analysis.By the mean value of relatively each processing and the mean value of control group, determine to suppress fraction values.In suitable mensuration, assess IC with linear regression 50Inhibition percentage/ED 50The inhibition percentage.The EIA of prostaglandin(PG) measures
Be used for EIA reagent that prostaglandin(PG) measures available from Perseptive Diagnostics (Cambridge, MA).Sample after drying under the nitrogen is also duplicated with the mensuration damping fluid, is measured PGE in the irrigating solution 2(PGE 2) level.With respect to the standard substance that prepare in the equivalent environment, measure the PGE in enzymatic determination or the cell culture medium 2Level.Immunoassay are carried out in suggestion by the manufacturer.Carry out EIA in 96 hole microtiter plates (Nunc Roskilde, Denmark), (Menlo Park CA) measures optical density(OD) for Vmax, Molecular Devices Corp. to read the plate instrument with small plate.Recombinant human PGHS-1 and PGHS-2 enzymatic determination
Suppress with recombinant human Cox-1 (r-hu Cox-1) and Cox-2 (r-hu Cox-2) enzymatic determination assessment prostaglandin(PG) external biological synthetic.To be dissolved in the microsome (Gierse that obtains among recombinant human PGHS-1 that the representative compounds of DMSO (3.3%v/v) and baculovirus/Sf9 cell system expresses or the PGHS-2, J.K., Hauser, S.D., Creely, D.P., Koboldt, C., Rangwala, S., H., Isakson, P.C. and Seibert, K. composition form and induce the expression and the selectivity of the cyclo-oxygenase of form to suppress, Biochem is J.1995,305:479.) and cofactor phenol (2mM) and protoferriheme (1 μ M) preincubate 60 minutes together, add 10 μ M arachidonic acids then.Allow react on and carried out under the room temperature 2.5 minutes, neutralize with the HCl quenching and with NaOH then.Analyze by EIA, measure and have and lack PGE under the situation of described medicine 2Produce.Carry out EIA in 96 hole microtiter plates (Nunc Roskilde, Denmark), (Menlo Park CA) measures optical density(OD) for Vmax, Molecular Devices Corp. to read the plate instrument with small plate.Be used for EIA reagent that prostaglandin(PG) measures available from Perseptive Diagnostics (Cambridge, MA).With respect to the standard substance that prepare in the equivalent environment, measure PGE 2Level.Immunoassay are carried out in suggestion by the manufacturer.
Table 1 data presented explanation The compounds of this invention suppresses prostaglandin(PG) external biological synthetic.Described compound is by embodiment number name.The 2nd hurdle shows the inhibition percentage of Cox-1 at micromole's dosage level, and the 3rd hurdle shows the inhibition percentage of Cox-2 at the nmole dosage level.The numeric representation IC that COx-2 suppresses in the bracket 50Value.Referring to subordinate list
Table 1
Embodiment number The inhibition % (μ M) of RHUCX1 under following dosage The inhibition % (μ M) of RHUCX2 under following dosage
????10 ??2@100 ??(0.014)
????12 ??0@100 ??97@10 ??77@1 [email protected]
????20 ??10@100 [email protected] [email protected]
????21 ??19@100 ??(0.92)
????22 ??25@100 [email protected] [email protected]
????23 ??0@100 [email protected] [email protected]
????24 ??60@100 ??0@10 ??99@1 [email protected] [email protected]
????25 ??1@100 ??93@1 [email protected]
????26 ??10@100 ??91@1 [email protected] [email protected]
????32 ??20@100 ??96@1 [email protected]
????34 ??16@100 ??(0.92)
????35 ??34@100 ????(0.017)
????36 ??21@10 ????(0.57)
????39 ??0@100 ????(0.44)
????40 ??76@10 ??69@1 ????97@1 [email protected]
????41 ??13@100 ????49@1 [email protected]
????42 ??0@100 ????99@1 [email protected]
????43 ??8@100 ????100@1 [email protected]
????45 ??5@100 ????85@1 [email protected]
????48 ??0@100 ????73@1 [email protected]
????50 ??23@100 ????99@1 [email protected]
????52 ??32@10 ????99@1 [email protected]
????53 ??10@100 ????95@1 [email protected]
????54 ??0@100 ????95@1 [email protected]
????58 ??0@100 ????(0.95)
????60 ??7@100 ??100@ ??1,000
????62 ??6@100 ??(0.624)
????64 ??68@1 ??34@1 [email protected]
????65 ??13@100 ??98@1 [email protected]
????68 ??32@100 ??(0.297)
????69 ??2@100 ??88@1 [email protected] [email protected]
????72 ??0@100 ??65@1 [email protected]
????73 ??9@100 ??(1.34)
????74 ??11@100 ??86@1 [email protected]
????77 ??35@100 ??82@10 ??39@1
????80 ??41@10 ??37@1 ??(0.064)
????81 ??6@100 ??97@1 [email protected]
????84 ??49@10 ??9@1 [email protected]
????88 ??0@100 ?97@1,000 [email protected]
????89 ??62@10 ??40@10 ?(0.35)
????97 ??35@100 ?(0.332)
????100 ??62@10 ??65@1 ?100@10 [email protected]
????105 ??85@1 ?98@1 [email protected]
????106 ??19@200 ?(0.135)
????107 ??88@10 ??50@1 ?86@1 [email protected]
????108 ??0@100 ?(0.279)
????109 ??6@100 ?(0.147)
????110 ??5@100 ?93@1 [email protected]
????111 ??13@100 ?(0.052)
????112 ??5@100 ?(0.136)
????118 ??31@100 [email protected] [email protected]
????119 ??(0.178) ?(0.027)
????120 ??15@100 ?97@1 [email protected]
????121 ??0@100 ?(0.005)
????122 ??1@100 ??(0.285)
????124 ??26@100 ??(0.044)
????127 ??50@10 ??30@1 ??74@1 [email protected]
????128 ??14@100 ??(0.477)
????132 ??93@1 ??88@1 [email protected]
????133 ??23@100 ??(0.358)
????134 ??54@100 ??35@10 ??(0.053)
????140 ??(3.06) ??(0.022)
????141 ??55@100 ??62@10 ??99@1 [email protected]
????142 ??80@10 ??53@1 ??96@1 [email protected] [email protected]
????143 ??62@100 ??43@10 ??(0.076)
????144 ??(0.058) ??88@1 [email protected] [email protected]
????145 ??(0.238) [email protected] [email protected]
????146 ??82@10 ??53@1 ??100@1 [email protected]
????147 ??(0.067) ??100@1 [email protected] [email protected]
????149 ??45@10 ??40@1 ??(0.003)
????150 ??56@100 ??39@10 [email protected]
????153 ??54@100 ??35@10 ??(0.062)
????154 ??(0.126) ??(0.018)
????165 ??0@100 ??(1.08)
????166 ??3@100 ??(0.199)
????168 ??0@100 ??85@1 [email protected]
????171 ??0@100 ??82@10 ??74@1 [email protected]
????178 ??6@100 ??92@1,000 ??34@10
????180 ??8@100 ??78@1 [email protected]
????182 ??(5.01) ??(0.07)
????183 ??25@100 ??97@1 [email protected]
????187 ??2@100 ??(0.094)
????188 ?18@100 ?(0.526)
????190 ?(1.88) ?(0.134)
????194 ?35@100 ?90@10 ?73@1 [email protected]
????198 ?10@100 ?68@1 [email protected]
????207 ?97@1 [email protected]
????209 ?0@100 ?79@1 [email protected] [email protected]
????213 ?0@100 ?(0.812)
????219 ?20@100 ?90@1 [email protected]
????220 ?51@100 ?38@1 ?96@1 [email protected]
????226 ?0@100 ?(1.09)
????228 ?7@100 ?(0.209)
????230 ?4@100 ?(0.215)
????231 ?7@100 ?90@1 [email protected]
????232 ?23@100 ?(0.024)
????234 ?0@100 ?(0.328)
????235 ??22@100 ??(0.21)
????237 ??54@10 ??44@1 [email protected]
????240 ??14@100 ??(0.297)
????241 ??0@100 ??(0.028)
????245 ??9@100 ??(1.38)
????246 ??0@100 ??(0.054)
????247 ??72@10 ??55@1 ??99@10 ??71@1 [email protected]
????248 ??13@100 ??(0.08)
????249 ??6@100 ??98@1 [email protected] [email protected]
????252 ??0@100 [email protected] [email protected]
????253 ??77@100 ??29@10 ??(0.272)
????254 ??7@100 ??84@1 [email protected]
????256 ??0@100 ??(0.134)
????257 ??0@100 ??(0.04)
????260 ??8@100 ??2@10
????261 ??0@200 ??(0.161)
????262 ??15@100 ??(0.432)
????263 ??1@100 ??85@10 ??76@1 [email protected]
????265 ??8@100 ??53@10 ??48@1 [email protected]
????272 ??0@100 ??70@1 [email protected]
????273 ??16@100 ??54@10 ??42@1
????278 ??36@100 ??96@1 [email protected]
????279 ??0@100 ??60@1 [email protected]
????281 ??7@100 ??71@1 [email protected] [email protected]
????283 ??0@100 ??90@10 ??71@1 [email protected]
????287 ??0@100 ??93@10 ??79@1 [email protected]
????314 ??7@100 ??51@10 ??4@1
????318 ??23@100 ??97@1 [email protected]
????321 ??4@100 ??(0.192)
????322 ??39@100 ??54@10 ??(0.058)
????323 ??1@100 ??(0.365)
????325 ??(0.199)
????330 ??15@100 ??85@1 [email protected] [email protected]
????335 ??5@100 ??(0.001)
????338 ??0@100 ??100@1 [email protected]
????339 ??2@100 ??(0.088)
????344 ??16@100 ??(0.897)
????345 ??0@100 ??(0.242)
????346 ??14@100 ??94@1 [email protected] [email protected]
????347 ??11@100 ??(0.075)
????349 ??0@100 ??(0.086)
????351 ??3@100 ??91@1 [email protected] [email protected]
????352 ??0@100 ??(0.154)
????353 ??6@100 ??(0.826)
????354 ??0@100 ??45@10 ??45@1 [email protected]
????355 ??0@100 ??79@10 ??66@1 [email protected]
????358 ??30@100 ??(2.45)
????361 ??3@100 ??(0.011)
????362 ??1@100 ??84@10 ??49@1
????364 ??0@100 ??86@1 [email protected]
????366 ??0@100 ??(0.03)
????367 ??0@100 ??(0.077)
????368 ??13@100 ??96@1 [email protected]
????369 ??0@100 ??70@1 [email protected]
????370 ??8@100 ??(0.048)
????371 ??8@100 ??(0.166)
????372 ??0@100 ??94@10 ??88@1 [email protected]
????374 ?2@100 ??(0.02)
????375 ?46@100 ?31@10 ??(0.18)
????376 ?12@100 ??(0.027)
????381 ?0@100 ??(0.188)
????384 ?82@100 ?49@10 ??99@1 [email protected]
????386 ?58@100 ?47@1 ??83@1 [email protected] [email protected]
????387 ?57@10 ?60@1 ??76@1 [email protected] [email protected]
????388 ?74@10 ?36@1 ??(0.049)
????390 ?88@10 ?45@1 ??99@10 ??72@1 [email protected]
????392 ?56@100 ?35@10 [email protected] [email protected]
????393 ?15@100 ??85@1 [email protected]
????394 ?86@100 ?38@10 ??94@1 [email protected] [email protected]
????395 ??91@100 ??35@10 ?93@1 [email protected] [email protected]
????396 ??22@100 ?(0.059)
????397 ??25@100 ?93@1 [email protected] [email protected]
????398 ??26@100 ?(0.202)
????400 ??27@100 ?(0.142)
????401 ??(0.753) ?96@1 [email protected] [email protected]
????402 ??89@1 ?(0.221)
????403 ??(150.76) ?92@1 [email protected] [email protected]
????404 ??77@100 ??47@10 [email protected] [email protected]
????405 ??90@100 ??61@10 ?(0.198)
????406 ??23@100 ?100@1 [email protected] [email protected]
????407 ??32@100 ?(0.17)
????408 ??0@100 ?(0.279)
????410 ??48@100 ??1@10 [email protected] [email protected]
????411 ??96@10 ??81@1 ??(0.009)
????412 ??31@100 ??(0.002)
????413 ??0@100 ??(0.11)
????414 ??0@100 ??87@1 [email protected]
????418 ??33@100 ??85@1 [email protected] [email protected]
????419 ??12@100 ??(0.1)
????420 ??29@100 ??(0.323)
????421 ??(0.269) ??92@1 [email protected] [email protected]
????422 ??53@100 ??82@10 ??76@1 ??52@1 [email protected]
????423 ??0@100 ??87@1 [email protected] [email protected]
????424 ??7@100 ??75@1 [email protected] [email protected]
????425 ??12@100 [email protected] [email protected]
????426 ?1@100 ??(0.057)
????434 ?0@100 ??(0.081)
????437 ?16@100 ??(0.124)
????438 ?0@100 ??(0.127)
????440 ?20@100 ??84@1 [email protected] [email protected]
????442 ?55@100 [email protected] [email protected]
????443 ?35@100 [email protected] [email protected]
????444 ?0@100 ??83@1 [email protected] ??14@10
????445 ?(56.62) ??(0.069)
????446 ?0@200 ??(0.373)
????447 ?0@100 ??90@1 [email protected] [email protected]
????449 ?5@200 ??(0.129)
????450 ?29@100 ??87@1 [email protected] [email protected]
????451 ?10@100 ??43@1 [email protected]
????452 ?14@100 ??15@1
The beta induced PGE of IL-1 in the WISH cell 2Generation
Making people's amnion WISH cell grow to 80% in 48 orifice plates converges.After removing growth medium and using the GeyShi balanced salt solution to wash 2 times, with 5ng IL-1 β/ml (UBI, LakePlacid, NY) add to the Neuman-Tytell serum free medium (GIBCO that contains or do not contain test-compound DMSO solution (0.01%v/v), Grand Island is NY) in the cell in.Hatched 18 hours so that after it induces PGHS-2 to greatest extent, remove conditioned medium, analyze by EIA as mentioned above, analyze PGE 2Content.
(MD) cell is grown in the mode similar to WISH cell for ATCC, Rockville to make monocyte U937.After hatching, remove conditioned medium, analyze by EIA as mentioned above, analyze Cox-1 content.
Table 2 data presented explanation The compounds of this invention suppresses prostaglandin(PG) external biological synthetic.The inhibition percentage of U937 value representation Cox-1 under specific micromole's dosage level, and value representation IC in the bracket 50Value.Inhibition percentage under the specific micromole's dosage level of WISH cell value representation, and the value representation IC in the bracket 50Value.People's whole blood platelet cyclo-oxygenase-1 is measured (HWCX)
Will be in the test tube that contains ACD (acid citrate dextrose) as antithrombotics from the volunteer's of normal health blood collecting.This blood is centrifugal with 175 * g, be rich in hematoblastic blood plasma with preparation.It is centrifugal with 100 * g to be rich in hematoblastic blood plasma then, with the precipitation white corpuscle, stays thrombocyte in supernatant liquor.Supernatant liquor is layered on the Tyrodes solution (Gibco of 0.7ml 10% bovine serum albumin; Grand Island is NY) on the bed course, centrifugal with 1000 * g then.Remove then from this centrifugal supernatant liquor that obtains, Tyrodes solution is added in the remaining thrombocyte precipitation.Then the equal portions of thrombocyte with 120 μ l are added in 96 orifice plates.Add experimental compound, allow its preincubate 10 minutes.When this preincubate finished, it was 8.8 μ M that calcium particle carrier A 23187 is added to final concentration, continues to hatch 10 minutes.Add cold 6mMEDTA termination reaction, mixtures incubated is centrifugal with 220 * g, use commercially available CaymanChemical (Ann Arbor, MI) the test kit thromboxane in the clear liquid analytically then.Referring to subordinate list
Table 2
Embodiment number The inhibition % (μ M) of U937 under following dosage The inhibition % (μ M) of HWPX under following dosage The inhibition % (μ M) of Wish under following dosage
????10 ????(4.1) ??(0.014)
????20 ???33@1 ??(0.001)
????24 ???(0.19) ??(0.007)
????43 ????86@10 ????9@1 ??(0.008)
????53 ????78@10 ????8@1 [email protected] [email protected]
????65 ??(0.02)
????69 ????(1.14) ??(0.02)
????72 ????(25) ??(0.072)
????75 ????84@10 ????0@3 ??(0.001)
????77 ????(8.8) ??(0.126)
????85 ??(0.47)
????86 ??52@1 [email protected]
????89 ???(3.8) ????(2.1) ??(0.05)
????100 ????(0.13) ??(0.02)
????102 ??(0.05)
????105 ????62@1 ??(0.018)
????106 ????(17.5) ??(0.03)
????108 ????(8) ??(0.097)
????109 ????(2.693) ??(0.018)
????119 ????(0.076) ??(0.001)
????120 ??74@3 ??58@1 ??(0.025)
????121 ??(0.041)
????123 ??90@1 [email protected] ??(0.001)
????126 ??(0.05)
????129 ??(0.04)
????132 [email protected] [email protected]
????140 ??(0.773) ??(0.01)
????141 [email protected] ??(0.004)
????142 ??(7.53) ??(0.088)
????143 ??(0.007)
????145 ??72@1 [email protected] ??(0.009)
????146 ??84@10 ??46@3 ??(0.044)
????147 [email protected] ??(0.029)
????148 [email protected] ??(0.042)
????149 ??89@10 ??34@3 ??(0.03)
????152 ??(0.029)
????153 ??(2.95) ??(0.046)
????154 [email protected] [email protected] [email protected] [email protected]
????160 ??(7.2) ??(0.03)
????162 ??(0.034)
????165 ??(1.9) ??(0.030)
????166 ??(9.4) ??(0.02)
????168 ??47@1 ??(0.009)
????171 ??90@1 [email protected]
????187 ??(12.6) ??(0.015)
????189 ?31@100 ????(0.041)
????190 ?(9.96) ????(0.03)
????191 ????(0.06)
????194 ?(28.09) ????(0.069)
????198 ????(0.184)
????203 ????77@1 [email protected]
????207 ????(0.068)
????228 ?(19.6) ????(0.086)
????241 ????(0.0474)
????243 ????(0.03)
????244 ?(3.67) ????(0.019)
????245 ????(0.046)
????246 ????(0.02)
????247 ?(7.76) ????(0.02)
????248 ?82@30 ?17@10 ????(0.005)
????252 ????(0.044)
????256 ?(4.7) ????(0.028)
????261 ?(34) ????(0.099)
????271 ????52@1 [email protected]
????278 ????(0.07)
????279 ????(0.391)
????287 ????(0.16)
????317 ????(0.027)
????320 ?29@3 [email protected] [email protected]
????321 [email protected]
????322 ????(0.026)
????323 [email protected]
????324 ????(0.047)
????325 ?????(2.3) ????(0.04)
????326 ????(0.05)
????330 ?????(16.7) ????(0.005)
????335 ????(0.023)
????338 ?????(14.93) ????(0.004)
????339 ?????(0.393) ????(0.026)
????343 ?????(0.191) ????(0.016)
????344 ????(0.1)
????345 ????(0.03)
????349 ?????34@100 ????(0.041)
????352 ????(5.5) ????(6.048)
????358 ????69@1 [email protected]
????366 ????(1.615) ????(0.002)
????367 ????50@1 [email protected] ????(0.018)
????368 ????(13.7) [email protected] [email protected]
????370 ????(8.4) ????(0.02)
????374 ????(0.03)
????381 ????31@30 ????91@100 ????(0.075)
????385 ????(2.18) ????(0.023)
????388 [email protected] ????(0.032)
????392 ????(1.95) ????(0.02)
????394 ????(0.019)
????396 ????(12.7) ????(0.02)
????397 ????(13.8) ????(0.04)
????399 [email protected] [email protected]
????400 ????(0.3) ????(0.026)
????401 ????(0.32) ????(0.017)
????403 ????(0.902) ??(0.018)
????404 ????(0.337) [email protected] [email protected]
????406 ????(1.61) ??(0.026)
????408 ??(0.029)
????410 ??(0.053)
????414 ??54@1 [email protected]
????418 ????(14.25) ??(0.25)
????430 ????34@10 ????89@100 ??(0.054)
????442 ??(0.42)
????445 ????100@100 ????22@10 ??(0.025)
????446 ????(24.4) ??(0.02)
????449 ????(40) ??(0.089)
????450 ??(0.05)
????451 ????(25.6) ??(0.15)
????452 ??56@1 [email protected]
Carrageenan inductive pawl oedema (CPE) in the rat
As Proc.Soc.Exp.Biol.Med. such as Winter, 1962,111, described in 544, in male rat, induce the rear solid end oedema.In brief, the male Sprague-Dawley rat oral test compound of giving heavy 170-190g is after 1 hour, with 0.1ml 1% carrageenan sodium (the λ carrageenan, Sigma Chemical Co., St Louis, MO) vola is injected into right back pawl.Behind the injection carrageenan, (Troy NY) measures right corpus unguis long-pending (ml), as measuring baseline volume for Buxco Electronics, Inc. to use the Buxco volume recorder immediately.Behind the injection carrageenan 3 hours, measure right pawl once more, by the reading when deducting zero in 3 hours readings, calculate the pawl oedema of every rat.Data with average inhibition percentage+/-SEM report.By many comparing checks of Dunnetts (multiple comparison test), the significance,statistical of analytical results is considered to have significance,statistical when p＜0.05.Rat carrageenan pleura inflammation (CIP) model
According to Fed.Proc.1976 such as Vinegar, 35, the method for 2447-2456 is induced the pleura inflammation in adrenalectomized Sprague-Dawley male rat.Give the oral experimental mixture of animal, intrapleural injection 2% λ carrageenan (Sigma Chemical Co., St.Louis MO) after 30 minutes.After 4 hours, with animal euthanasia, with ice-cold salt solution lavation pleural space.Then irrigating solution is added in the ice cold methanol of 2 times of volumes (final concentration of methyl alcohol is 66%), with lysing cell and precipitating proteins.Measure eicosanoid by EIA as mentioned above.
Table 3 data presented explanation The compounds of this invention is to biosynthetic inhibition in the prostaglandin(PG) body.Numerical value is with the report of the inhibition percentage under 10 milligrams of the pers kilogram of body weight.Carrageenan inductive air bag prostaglandin(PG) biosynthesizing model (CAP)
By in the back of the body of the 0th day injection 20ml sterile air, forming air bag at male Sprague-Dawley rat.After 3 days, again with 10ml sterile air this capsule that expands again.The 7th day, the 1ml saline injection that will contain 0.2% λ carrageenan (Sigma Chemical Co.) was gone in this capsule, it is characterized by the inflammatory reaction that discharges prostaglandin(PG) to induce.Before giving carrageenan 30 minutes, give 0.1-10mg/kg test-compound.Behind the injection carrageenan 4 hours, this capsule of lavation, and with the level of commercial reagent box by enzyme immunoassay mensuration prostaglandin(PG).Compare by reaction in the animal that will accept carrier and the reaction of having accepted in the animal of compound, calculate and suppress percentage.The numeric representation ED that Cox-2 suppresses in the bracket 50Value.
Table 3 data presented explanation The compounds of this invention is to biosynthetic inhibition in the prostaglandin(PG) body.The numerical value of CIP and CPE test is with 10 milligrams of inhibition percentage reports down of per kilogram of body weight, and the numerical value of CAP test is reported with the inhibition percentage under 3 milligrams of the pers kilogram of body weight.Referring to subordinate list
Table 3
Embodiment number CIP suppresses % @10mpk CPE suppresses % @10mpk CAP suppresses % @3mpk
????10 ???44
????12 ???42 ????25
????34 ???36 ????31
????54 ???31 ????30
????58 ???42 ????14 ????67
????62 ???57 ????21
????66 ???59 ????7 ????0
????67 ???40@3mpk
????68 ???64 ????40.3
????69 ???61 ????45.5 ????ED 30＝5.4 ????87
????72
????73 ????46 ????29
????74 ???46.5 ????18 ????34
????77 ???51 ????21
????80 ???60 ????28.5 ????91
????89 ???68.3 ???ED 50＝3.4 ????45.5 ????94
????106 ????47
????109 ????13 ????71
????112 ????21 ????42.5
????119 ???82 ????27 ????76
????120 ???5 ????11
????121 ???19 ????8
????123 ????23
????143 ????59
????153 ????51
????160 ????56 ????35
????166 ????40 ????59
????168 ????0 ????6
????180 ????34.5
????182 ????59 ????27 ????98
????185 ????59 ????20 ????53
????187 ????51 ????28 ????30
????190 ????60 ????28 ????71
????205 ????54
????226 ????21 ????40.5
????243 ????7
????245 ????47
????246 ????48
????248 ????49
????256 ????47
????257 ????60
????261 ????28 ????79
????330 ????4.5
????335 ????45
????339 ????43 ????90.5 ????ED 50＝0.58
????346 ????49.5
????347 ????27 ????66.5
????349 ????63
????351/64 ????0
????352 ????89 ????ED 50＝5.0
????353/63 ????0
????361 ????65
????366 ????63 ????ED 50＝1.5
????367 ????48
????375 ????47 ????91 ????ED 50＝0.30
????376 ????17 ????77.5
????378 ????59
????384/33 ????51 ????15 ????51
????385 ????65
????388 ????28 ????80
????390 ????60
????391 ????61
????392 ????60
????394 ????70
????395 ????71
????396 ????23 ????85
????397 ????70
????400 ????65 ????41 ????95
????403 ????43 ????68.5 ????ED 50＝0.35
????405 ????53
????406 ????23 ????66.5
????407 ????61
????419 ????48
????427 ????78
????445 ????15 ????73
????446 ????44 ????92 ????ED 50＝0.5
????449 ????23 ????76 ????ED 50＝1.8
????450 ????86
????451 ????80.5 ????ED 50＝1
????452 ????71
Medicinal compositions
The present invention also provides medicinal compositions, and this medicinal compositions comprises the compound of preparing with one or more nontoxic pharmaceutically acceptable carriers of the present invention.Medicinal compositions of the present invention comprises the compound of the present invention of the treatment significant quantity of preparing with one or more pharmaceutically acceptable carriers.That term used herein " pharmaceutically acceptable carrier " is meant is nontoxic, the preparation auxiliary of weighting agent, thinner, packing material or any kind of inert solid, semisolid or liquid.Some example that can be used as the material of pharmaceutically acceptable carrier is a sugar, such as lactose, dextrose plus saccharose; Starch is such as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are such as Xylo-Mucine, ethyl cellulose and rhodia; The powdery tragakanta; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle is such as theobroma oil and suppository wax; Oil is such as peanut oil, Oleum Gossypii semen; Thistle oil; Sesame oil; Sweet oil; Semen Maydis oil and soya-bean oil; Dibasic alcohol; Such as propylene glycol; Ester is such as ethyl oleate and Laurate ethyl; Agar; Buffer reagent is such as magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; RingerShi solution; Ethanol and phosphate buffer soln and other nontoxic compatible lubricant, such as sodium lauryl sulphate and Magnesium Stearate, according to method well known to those skilled in the art and judgement, also can exist toner, releasing agent, Drug coating, sweeting agent, correctives and spices, sanitas and antioxidant in the said composition.Can per os, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), cheek or as mouthful or nasal spray, give human and other animal with medicinal compositions of the present invention.
Compound of the present invention can be used for the treatment of several diseases or morbid state potentially, such as diseases associated with inflammation, dysmenorrhoea, asthma, premature labor, adhesion particularly pelvic adhesion, osteoporosis and ankylosing spondylitis.Current Drugs Ltd, ID Patent Fast Alert, AG16, on May 9th, 1997.
Compound of the present invention also can be used for the treatment of cancer, particularly colorectal carcinoma potentially.Proc.Natl.Acad.Sci., 94, the 3336-3340 pages or leaves, 1997.
Compound of the present invention also can use by medicinal compositions is provided, to suppress the biosynthesizing of prostaglandin(PG), described medicinal compositions comprises formula I compound or its pharmacy acceptable salt, ester or prodrug and a kind of pharmaceutically acceptable carrier for the treatment of significant quantity.
Compound of the present invention also can use by the biosynthetic medicinal compositions of inhibition prostaglandin(PG) is provided, and described medicinal compositions comprises formula II compound or its pharmacy acceptable salt, ester or prodrug and a kind of pharmaceutically acceptable carrier for the treatment of significant quantity.
Compound of the present invention also can suppress the biosynthetic medicinal compositions use of prostaglandin(PG) by providing, and described medicinal compositions comprises formula III compound or its pharmacy acceptable salt, ester or prodrug and a kind of pharmaceutically acceptable carrier for the treatment of significant quantity.
In addition, compound of the present invention also can use by the biosynthetic method of inhibition prostaglandin(PG) is provided, and described method comprises formula I compound or its pharmacy acceptable salt, ester or the prodrug of the Mammals treatment significant quantity that needs this treatment.
Compound of the present invention also can use by the biosynthetic method of inhibition prostaglandin(PG) is provided, and described method comprises formula II compound or its pharmacy acceptable salt, ester or the prodrug of the Mammals treatment significant quantity that needs this treatment.
Compound of the present invention also can use by the biosynthetic method of inhibition prostaglandin(PG) is provided, and described method comprises formula III compound or its pharmacy acceptable salt, ester or the prodrug of the Mammals treatment significant quantity that needs this treatment.
In addition, compound of the present invention also can use by treatment pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer are provided, and described method comprises the formula I compound of the Mammals treatment significant quantity that needs this treatment.
In addition, compound of the present invention also can use by treatment pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer are provided, and described method comprises the formula II compound of the Mammals treatment significant quantity that needs this treatment.
In addition, compound of the present invention also can use by treatment pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer are provided, and described method comprises the formula III compound of the Mammals treatment significant quantity that needs this treatment.
Be used for oral liquid dosage form and comprise pharmaceutically acceptable emulsion, microemulsion, solution, suspension agent, syrup and elixir.Remove described active ingredient beyond the region of objective existence, liquid dosage form also comprises this area inert diluent commonly used, such as water or other solvent; Solubilizing agent and emulsifying agent, such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (such as Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Semen Ricini oil, sesame wet goods), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of anhydro sorbitol and their mixture.Except that inert solvent, oral compositions also can comprise auxiliary, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Can adopt suitable dispersion agent or wetting agent and suspension agent according to known technique, the injection formulations of the formulation example such as the aseptic injection aqueous solution or oiliness suspension agent.Described aseptic injection preparation also can be aseptic parenteral solution, suspension agent or the emulsion of (for example in the 1,3 butylene glycol) in nontoxic parenteral acceptable diluent or the solvent.Operable acceptable carrier and solvent comprise water, RingerShi solution, isotonic sodium chlorrde solution etc.In addition, aseptic fixed oil is usually as solvent or suspension medium.For this reason, the fixed oil of any gentleness be can use, synthetic one or two glyceryl ester comprised.In addition, can be used for preparing injection formulations such as oleic lipid acid.
Injection formulations can be sterilized by methods known in the art, sterilising method is such as by holding back the membrane filtration of bacterium, or in the aseptic solid composite form, mixing disinfectant, described aseptic solid composite can be dissolved in or be scattered in before use in sterilized water or other aseptic injection medium.
For the effect of prolong drug, the absorption of the medicine of need slow down usually subcutaneous or intramuscularly.Can utilize the liquid suspension of the crystalline or amorphous substance of poorly water-soluble to finish this point.Then the uptake rate of medicine depends on its dissolution rate, and its dissolution rate may depend on crystalline size and crystal formation again.Perhaps, by medicine being dissolved in or being suspended in the oily carrier, finish the delay absorption that parenteral gives medicine.By being formed on such as the bag micro-capsule matrix in the biodegradable polymer of polylactide and poly-glycollide preparation injection storage form.According to the character of the ratio of medicine and polymkeric substance and used particular polymers, can control drug release speed.The example of other biodegradable polymer comprises poly-(ortho ester) and polyanhydride.By medicine is captured in can be compatible with body tissue liposome or microemulsion in, also can prepare the storage injection formulations.
The composition that is used for rectum or vagina administration is suppository preferably, can be by The compounds of this invention be mixed with suitable nonirritant excipient or carrier (such as theobroma oil, polyoxyethylene glycol or suppository wax), preparation suppository, described suppository is in be solid under the room temperature but down therefore melting also release of active compounds for liquid in rectum or vaginal canal in body temperature.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In this class solid dosage, described active compound usually mixes with the pharmaceutically acceptable vehicle of at least a inert or carrier (such as Trisodium Citrate or dicalcium phosphate) and/or following material: a) weighting agent or swelling agent, such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) Humectant, such as glycerine, d) disintegrating agent, such as agar-agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) solution retarding agent, such as paraffin, f) absorb accelerator, such as quaternary ammonium compound, g) wetting agent, such as hexadecanol and Zerol, h) sorbent material is such as white bole and POLARGEL NF, and) lubricant, such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their compound.Under the situation of capsule, tablet and pill, described formulation also can comprise buffer reagent.
The solids composition of similar type also can be as the weighting agent in soft or the hard-filled gelatin capsule, and described gelatine capsule adopts the vehicle such as lactose and high molecular weight polyethylene glycol etc.
The solids composition of similar type also can be as the weighting agent in soft or the hard-filled gelatin capsule, and described gelatine capsule adopts the vehicle such as lactose and high molecular weight polyethylene glycol etc.
Described active compound also can be for having the microencapsulation form of above-mentioned one or more vehicle.Can prepare tablet, drageeing, capsule, pill and granule with the dressing and the shell of other dressing thing of knowing such as casing, the controlled dressing thing of release and medicinal preparations field.In this class solid dosage, described active compound can mix with at least a inert diluent such as sucrose, lactose or starch.As common practice, this class formulation can comprise other the material beyond the inert diluent, and for example film-making lubricant and other film-making rib agent is such as Magnesium Stearate and Microcrystalline Cellulose.Under the situation of capsule, tablet and pill, described formulation also can comprise buffer reagent.They can randomly contain opacifying agent, only also can have or preferentially randomly discharge the composition of described active ingredient with delayed mode in certain part of enteron aisle.The example of operable embedding composition comprises polymeric material and wax.
The formulation that is used for The compounds of this invention part or percutaneous dosing comprises ointment, paste, emulsifiable paste, lotion, gelifying agent, powder, solution, sprays, inhalation or patch.Described active ingredient is mixed with any sanitas of pharmaceutically acceptable carrier and needs or the buffer reagent that needs under aseptic condition.Ophthalmic preparation, auristillae, eye ointment, powder and solution are also imagined and are belonged to scope of the present invention.
Remove active ingredient beyond the region of objective existence of the present invention, ointment, paste, emulsifiable paste and gelifying agent can also contain vehicle, such as animal and plant fat, oil, wax, paraffin, starch, tragakanta, derivatived cellulose, polyoxyethylene glycol, siloxanes, wilkinite, silicic acid, talcum powder and zinc oxide or their mixture.
Except that containing The compounds of this invention, powder and sprays also can contain vehicle, such as the mixture of lactose, talcum powder, silicic acid, aluminium hydroxide, Calucium Silicate powder and polyamide powder or these materials.Sprays can also contain conventional propellent, such as Chlorofluorocarbons (CFCs).
Having through the skin patch provides the extra advantage that compound control is passed to body.Can prepare this formulation by described compound is dissolved in or is scattered in the suitable media.Absorption enhancer also can be in order to increase the endermic flux of this compound.Rate controlling membranes perhaps is provided, perhaps this compound is scattered in polymeric matrix or the gel, control this speed.
According to methods of treatment of the present invention, by giving The compounds of this invention, treat described patient such as human or mammiferous patient treatment significant quantity, wherein dosage and time are that to reach required result necessary." the treatment significant quantity " of The compounds of this invention is meant with the rational benefit/risk that is applicable to any therapeutic treatment than the enough amounts of this compound that required alleviation is provided.Yet should be appreciated that, will determine The compounds of this invention and the total daily dosage portion of composition in the medical judgment scope reliably by the attending doctor.The concrete treatment effective dose level of any particular patient will depend on multiple factor, comprise the disease to be treated and the severity of this disease; The activity of used particular compound; Used concrete composition; This patient's age, body weight, general health situation, sex and diet; The discharge rate of administration time, route of administration and used particular compound; The time that treatment continues; With the medicine of used particular compound coupling or use simultaneously and the factor that medical field is known.
The total per daily dose that gives the mankind or other Mammals The compounds of this invention with single dose or divided dose can be following amount, be that every day 0.001 is to about 1000mg/kg body weight for example for oral administration, or more preferably about 0.1 to 100mg/kg body weight, or be that every day 0.01 is to about 10mg/kg for parenteral admin.Unit-dose composition can contain this amount or constitute a plurality of sub-doses of this per daily dose.
Can will change according to treated host and concrete route of administration with the amount of described carrier substance coupling with the active ingredient of generation one-pack type.
The reagent that synthetic The compounds of this invention is required or easily derive from multiple commercially available source, as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St.Louis, MO, USA); With Fluka Chemical Corp. (Ronkonkoma, NY, USA); A1fa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (JanssenChemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT.06708).The compound that can not obtain from market can adopt the currently known methods preparation the chemical literature.

Claims (35)

1. formula I compound or its pharmacy acceptable salt, ester or prodrug:
Figure A9880832200021
Wherein
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R is selected from hydrogen; alkyl; alkenyl; alkynyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; the alkyl sulphonyl aralkyl; alkoxyl group; alkoxyalkyl; carboxyl; carboxyalkyl; the cyano group alkyl; haloalkyl; halogenated alkenyl; the halo alkynyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl group; cycloalkenyl alkyl; aryl; aralkyl; aromatic yl alkenyl; aromatic yl polysulfide yl; alkoxy aryl; the aryl halide substituted alkyl; the aryl hydroxyalkyl; aryloxy; the aryloxy hydroxyalkyl; the aryloxy haloalkyl; aryl alkyl carbonyl; the halogenated alkoxy hydroxyalkyl; heterocyclic radical; the heterocyclic radical alkyl; the heterocyclic radical alkoxyl group; the heterocyclyloxy base;-C (O) R 5,-(CH 2) nC (O) R 5,-R 6-R 7,-(CH 2) nCH (OH) R 5,-(CH 2) nCH (OR d) R 5,-(CH 2) nC (NOR d) R 5,-(CH 2) nC (NR d) R 5,-(CH 2) nCH (NOR d) R 5,-(CH 2) nCH (NR dR e) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-CX ' 3,-(CH 2) n(CX ' 2) m-(CH 2) n-CX ' 3,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8,-(CH 2) n(CX ' 2) m-(CH 2) nR 8,-(CH 2) n(CHX ') m-(CH 2) n-CX ' 3,-(CH 2) n(CHX ') m-(CH 2) n-R 8With-(CH 2) n-R 20
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, halogenated alkenyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;
R wherein 6Be selected from alkylidene group or alkylene group or halo alkylidene group halo alkylene group;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
R dAnd R eBe independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5; R 1, R 2And R 3In at least one is
Figure A9880832200031
Or
X wherein 1Be selected from-SO 2-,-SO (NR 10)-,-SO-,-SeO 2-,-PO (OR 11) and-PO (NR 12R 13)-;
R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino ,-NHNH 2,-N=CH (NR 11R 12), dialkyl amido, alkoxyl group, thiol, alkyl sulfide hydroxyl, blocking group and be connected to X by an alkylidene group 1Blocking group;
X 2Be selected from hydrogen, halogen, alkyl, alkenyl and alkynyl;
R 10, R 11, R 12And R 13Be independently selected from hydrogen, alkyl and cycloalkyl, or R 12And R 13Can form the heterocycle of 3-6 atom with the nitrogen that they connect;
R 1, R 2And R 3Two of in the group all the other are independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, the alkylthio alkoxyl group, alkoxyl group, alkoxyalkyl, alkoxyalkyl amino, the alkoxyl group alkoxyl group, amido, amidoalkyl, haloalkyl, the halo alkenyloxy, halogenated alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, the cycloalkenyl group alkoxyl group, cycloalkyl alkoxy, cycloalkyl alkyl amino, cycloalkyl amino, cycloalkyloxy, the cycloalkylidene alkyl, amino, aminocarboxyl, aminoalkoxy, the aminocarboxyl alkyl, the alkylamino aryloxy, dialkyl amido, the dialkyl amido aryloxy, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aralkyl, alkylthio-aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, alkoxy aryl, aryloxy, heterocyclic radical, the heterocyclic radical alkyl, heterocyclic radical (alkyl) amino, the heterocyclic radical alkoxyl group, heterocyclic radical amino, the heterocyclyloxy base, the heterocyclic radical sulfenyl, hydroxyl, hydroxyalkyl, hydroxyalkyl amino, the hydroxy alkoxy base, the hydroxyl alkylthio, the sulfydryl alkoxyl group, the oxo alkoxyl group, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl);
R 16, R 17And R 19Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
2. formula II compound or its pharmacy acceptable salt, ester or prodrug:
Figure A9880832200041
Wherein Z is the group with following formula:
Figure A9880832200051
Or X wherein 1Be selected from-SO 2-,-SO-,-SeO 2-,-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino ,-NHNH 2, dialkyl amido, alkoxyl group, thiol base, alkyl sulfide hydroxyl, blocking group and be connected to X by an alkylidene group 1Blocking group;
R 10Be selected from hydrogen, alkyl and cycloalkyl;
X 2Be selected from hydrogen, halogen, alkyl, alkenyl and alkynyl;
R is selected from hydrogen; alkyl; alkenyl; alkynyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; the alkyl sulphonyl aralkyl; alkoxyl group; alkoxyalkyl; carboxyl; carboxyalkyl; the cyano group alkyl; haloalkyl; halogenated alkenyl; the halo alkynyl; hydroxyalkyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl group; cycloalkenyl alkyl; aryl; aralkyl; aromatic yl alkenyl; aromatic yl polysulfide yl; alkoxy aryl; the aryl halide substituted alkyl; the aryl hydroxyalkyl; aryloxy; the aryloxy hydroxyalkyl; the aryloxy haloalkyl; aryl alkyl carbonyl; the halogenated alkoxy hydroxyalkyl; heterocyclic radical; the heterocyclic radical alkyl; the heterocyclic radical alkoxyl group; the heterocyclyloxy base;-C (O) R 5,-(CH 2) nC (O) R 5,-R 6-R 7,-(CH 2) nCH (OH) R 5,-(CH 2) nCH (OR d) R 5,-(CH 2) nC (NOR d) R 5,-(CH 2) nC (NR d) R 5,-(CH 2) nCH (NOR d) R 5,-(CH 2) nCH (NR dR e) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-CX ' 3,-(CH 2) n(CX ' 2) m-(CH 2) n-CX ' 3,-(CH 2) n[CH (CX ' 3)] m-(CH 2) n-R 8,-(CH 2) n(CX ' 2) m-(CH 2) nR 8,-(CH 2) n(CHX ') m-(CH 2) n-CX ' 3,-(CH 2) n(CHX ') m-(CH 2) n-R 8With-(CH 2) n-R 20
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, halogenated alkenyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;
R wherein 6Be selected from alkylidene group or alkylene group or halo alkylidene group halo alkylene group;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
R dAnd R eBe independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, the alkylthio alkoxyl group, alkoxyl group, alkoxyalkyl, alkoxyalkyl amino, the alkoxyl group alkoxyl group, amido, amidoalkyl, haloalkyl, the halo alkenyloxy, halogenated alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, the cycloalkenyl group alkoxyl group, cycloalkyl alkoxy, cycloalkyl alkyl amino, cycloalkyl amino, cycloalkyloxy, amino, aminocarboxyl, aminoalkoxy, the aminocarboxyl alkyl, the alkylamino aryloxy, dialkyl amido, the dialkyl amido aryloxy, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aralkyl, alkylthio-aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, alkoxy aryl, aryloxy, heterocyclic radical, the heterocyclic radical alkyl, heterocyclic radical (alkyl) amino, the heterocyclic radical alkoxyl group, heterocyclic radical amino, the heterocyclyloxy base, the heterocyclic radical sulfenyl, hydroxyl, hydroxyalkyl, hydroxyalkyl amino, the hydroxy alkoxy base, the sulfydryl alkoxyl group, the oxo alkoxyl group, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl);
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
3. formula III compound or its pharmacy acceptable salt, ester or prodrug:
Figure A9880832200071
Wherein X, X 1, X 2, R, R 1, R 3And R 9Define as claim 1.
4. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl ,-(CH 2) nC (O) R 5,-(CH 2) nC ≡ C-R 7,-(CH 2) n[CH (CX ' 3)] m(CH 2) n-R 8With-(CH 2) n-R 20
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 7And R 8Be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
X ' is a halogen;
N is 0 to about 10, and m is 0 to about 5;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, aminocarboxyl alkyl, alkylamino, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, aryloxy, heterocyclic radical, heterocyclic radical alkyl, cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-,-N=CR 21R 22, N-R 21R 22With-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl);
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
5. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl ,-(CH 2) nC (O) R 5With-(CH 2) n-R 20
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
R 20Be selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heterocyclic radical alkyl;
N is 0 to about 10;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkoxyalkyl, alkylthio alkyl, aryloxy alkyl, arylthio alkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, the aminocarboxyl alkyl, alkylamino, the alkylamino alkyl, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, heterocyclic radical, heterocyclic radical (alkyl), cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl) and
R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group;
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
6. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from hydrogen, alkyl, alkenyl, alkynyl, alkyl-carbonyl alkyl, alkyl sulphonyl alkyl, alkyl sulphonyl aralkyl, carboxyalkyl, cyano group alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aromatic yl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, heterocyclic radical alkyl, aralkyl and-(CH 2) nC (O) R 5
R wherein 5Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl, aralkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;
N is 0 to about 10;
R 1And R 3Be independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxyl group, alkoxyalkyl, alkylthio alkyl, aryloxy alkyl, arylthio alkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, amino, aminocarboxyl, the aminocarboxyl alkyl, alkylamino, the alkylamino alkyl, dialkyl amido, arylamino, aryl-alkyl amino, ammonia diaryl base, aryl, heterocyclic radical, heterocyclic radical (alkyl), cyano group, nitro and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O) NR 21R 22-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkoxyalkyl, alkylthio alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl alkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical (alkyl);
R 15, R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group;
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
7. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-,-SO-,-SeO 2-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from alkyl, haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from alkoxyl group, alkenyloxy, hydroxy alkoxy base, aryloxy, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl and-Y-R 14, wherein Y be selected from-O-,-S-,-C (R 16) (R 17)-,-C (O)-,-C (O) O-,-NH-,-NC (O)-and-NR 19-, R 14Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, cycloalkenyl group, amino, cyano group, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R 3Be hydrogen;
R 15, R 16, R 17And R 19Be independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group; With
R 21And R 22Be independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl group, alkoxyl group, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl or cyano group.
8. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-,-SO-and-SO (NR 10)-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from alkyl, haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from alkoxyl group, alkenyloxy, hydroxy alkoxy base, aryloxy, aryl, aralkyl, heterocyclic radical and heterocyclic radical alkyl; With
R 3Be hydrogen.
9. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, alkylamino or dialkyl amido;
X 2Be selected from hydrogen and halogen;
X is selected from O, S, NR 4, N-OR aAnd N-NR bR c, R wherein 4Be selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, alkyl cycloalkenyl group, aryl, heterocyclic radical and aralkyl; And R a, R bAnd R cBe independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;
R be selected from haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl and-(CH 2) n-R 20, R wherein 20Be that replace or unsubstituted aryl, the aryl compound of wherein said replacement is for to replace with halogen;
N is 0 to about 10;
R 1Be selected from unsubstituted aryl and with being selected from the aryl that of fluorine or chlorine, two or three substituting groups replace, include but not limited to rubigan, to fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl etc.; With
R 3Be hydrogen.
10. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be selected from alkyl and amino;
X 2Be selected from hydrogen and halogen;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, halogenated alkoxy, aralkyl, alkyl and aryloxy; With
R 3Be hydrogen.
11. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be selected from alkyl and amino;
X 2Be selected from hydrogen and fluorine;
R is selected from haloalkyl, aryl and alkyl;
N is 0 to about 10;
R 1Being selected from isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, aryloxy comprises 4-fluorophenoxy, unsubstituted aryl and with being selected from the aryl that fluorine and chlorine, two or three substituting groups replace, comprises 4-fluorophenyl, 4-chloro-phenyl-, 3-chloro-4-fluoro-phenyl 4-chloro-3-fluoro-phenyl; With
R 3Be hydrogen.
12. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1Be selected from-SO 2-and-SO (NR 10)-, and R 9Be alkyl;
X 2Be selected from hydrogen and halogen;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, alkyl and aryloxy; With
R 3Be hydrogen.
13. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be amino;
X 2Be selected from hydrogen and fluorine;
X is O;
R is selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and aralkyl;
R 1Be selected from alkoxyl group, aryl, alkenyloxy, hydroxy alkoxy base, alkyl and aryloxy; With
R 3Be hydrogen.
14. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be methyl;
X 2Be selected from hydrogen;
X is O;
R is selected from the tertiary butyl, 3-chloro-phenyl-, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF 3CH 2-;
R 1Be selected from aryloxy, isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-chloro-3-fluoro-phenyl, 4-fluoro-phenoxy group; With
R 3Be hydrogen.
15. the compound of claim 3 or its pharmacy acceptable salt, ester or prodrug, wherein X 1For-SO 2-, and R 9Be amino;
X 2Be selected from hydrogen;
X is O;
R is selected from the tertiary butyl, 3-chloro-phenyl-, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF 3CH 2-;
R 1Be selected from aryloxy, isobutoxy, isopentyloxy, 1-(3-methyl-3-butenyl) oxygen base, 2-hydroxy-2-methyl-propoxy-, 3-hydroxy-3-methyl-butoxy, neopentyl oxygen, isopentyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-chloro-3-fluoro-phenyl, 4-fluoro-phenoxy group; With
R 3Be hydrogen.
16. the compound of claim 3 is selected from following compounds or its pharmacy acceptable salt, ester or prodrug: 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl-3-butenyloxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(tertiary butyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3-chloro-phenyl-)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(2,2-dimethyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2, two (4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (the 2H)-pyridazinones of 4-; 2-(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; And 2-(3, the 4-difluorophenyl)-4-(2-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-oxopropoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methoxyl group-imino--propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (R)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (S)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; (R)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; (S)-and 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(3-oxo-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-oxo-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2, two (4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl of 4-]-3 (2H)-pyridazinones.
17. the compound of claim 16 is selected from following compounds or its pharmacy acceptable salt, ester or prodrug: 2-phenyl-4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (2H)-pyridazinones; 2-(2,2, the 2-trifluoroethyl)-4-(4-chloro-phenyl-)-5-(4-methyl sulphonyl phenyl)-3 (2H)-pyridazinones; 2-(4-fluorophenyl)-4-(3-methyl butoxy)-5-[4-(methyl sulphonyl) phenyl]-3 (2H)-pyridazinones; 2-(3, the 4-difluorophenyl)-4-(2-methyl propoxy-)-5-[4-(amino-sulfonyl) phenyl]-3 (2H)-pyridazinones; 2, two (4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-3 (the 2H)-pyridazinones of 4-.
18. be used to suppress the biosynthetic medicinal compositions of prostaglandin(PG), comprise compound and a kind of pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
19. be used to suppress the biosynthetic medicinal compositions of prostaglandin(PG), comprise compound and a kind of pharmaceutically acceptable carrier of the claim 2 for the treatment of significant quantity.
20. be used to suppress the biosynthetic medicinal compositions of prostaglandin(PG), comprise compound and a kind of pharmaceutically acceptable carrier of the claim 3 for the treatment of significant quantity.
21. suppress the biosynthetic method of prostaglandin(PG), comprise the compound of the claim 1 of the Mammals treatment significant quantity that needs this treatment.
22. suppress the biosynthetic method of prostaglandin(PG), comprise the compound of the claim 2 of the Mammals treatment significant quantity that needs this treatment.
23. suppress the biosynthetic method of prostaglandin(PG), comprise the compound of the claim 3 of the Mammals treatment significant quantity that needs this treatment.
24. treat pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer, comprise the compound of the claim 1 for the treatment of significant quantity.
25. treat pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer, comprise the compound of the claim 2 for the treatment of significant quantity.
26. treat pain, heating, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and method for cancer, comprise the compound of the claim 3 for the treatment of significant quantity.
27. the compound with following formula of preparation claim 3 or the method for its pharmacy acceptable salt, ester or prodrug, Wherein X, X 1, X 2, R, R 1, R 3And R 9Define as claim 1;
Comprise make have formula III, step that wherein R is the compound of hydrogen and alkylating agent reaction.
28. according to the method for claim 27, wherein said alkylating agent has formula R 99-Q, wherein Q is a leavings group, and R 99Be selected from methyl, ethyl, 1,1, the 1-trifluoroethyl, the cyclopropyl methyl, 3-(2-methyl)-propenyl, 4-(2-methyl) but-2-ene base, 1,1-dichloropropylene-3-base, 2,2,-dimethyl-3-oxo-4-butyl, 2,3,3,4,4,4-hexafluoro-n-butene-1-base, propargyl, the phenyl propargyl, phenyl, styroyl, 1-phenyl propylene-3-base, benzyl, Alpha-Methyl-4-luorobenzyl, 2,3,4,5, the 6-PFBBR, 4-trifluoromethoxy benzoyl methyl, the 4-luorobenzyl, the 4-fluorophenyl, the 2-trifluoromethyl benzyl, 2, the 4-difluorobenzyl, 2,4 difluorobenzene formyl methyl, 4-trifluoromethyl benzoyl methyl, phenacyl, 4-carboxyl phenacyl, 4-chlorobenzoyl methyl, 4-cyano group phenacyl, 4-diethylin benzoyl methyl, the 3-thienyl methyl, 5-thiotolene-2-ylmethyl, 5-chlorothiophene-2-ylmethyl, 2-benzo [b] thienyl methyl, 3-thionaphthene formyl methyl (thienacyl), 5-diuril azoles-2-ylmethyl, 5-methylthiazol-2-ylmethyl, the 2-pyridylmethyl, the 3-pyridylmethyl, the 4-pyridylmethyl, quinoline-2-ylmethyl and fluoro quinoline-2-ylmethyl.
29. according to the method for claim 27, wherein said alkylating agent has formula R 99-Q, wherein Q is a leavings group, and R 99Be selected from methyl, ethyl, 1,1, the 1-trifluoroethyl, the cyclopropyl methyl, 3-(2-methyl)-propenyl, 4-(2-methyl) but-2-ene base, 1,1-dichloropropylene-3-base, 2,3,3,4,4,4-hexafluoro-n-butene-1-base, propargyl, the phenyl propargyl, phenyl, styroyl, 1-phenyl propylene-3-base, benzyl, Alpha-Methyl-4-luorobenzyl, 2,3,4,5, the 6-PFBBR, 4-trifluoromethoxy benzoyl methyl, the 4-luorobenzyl, the 4-fluorophenyl, 2, the 4-difluorobenzyl, 2,4 difluorobenzene formyl methyl, 4-trifluoromethyl benzoyl methyl, phenacyl, 4-carboxyl phenacyl, 4-chlorobenzoyl methyl, 4-cyano group phenacyl, 4-diethylin benzoyl methyl, the 3-thienyl methyl, 5-thiotolene-2-ylmethyl, 5-chlorothiophene-2-ylmethyl, 2-benzo [b] thienyl methyl and 3-thionaphthene formyl methyl.
30. according to the method for claim 27, wherein said alkylating agent has formula R 99-Q, wherein Q is a leavings group, and R 99Be selected from 1,1,1-trifluoroethyl, 3-(2-methyl)-propenyl, 4-(2-methyl) but-2-ene base, 1,1-dichloropropylene-3-base, 2,3,3,4,4,4-hexafluoro-n-butene-1-base, propargyl, phenyl propargyl, phenyl, benzyl, Alpha-Methyl-4-luorobenzyl, 2,3,4,5,6-PFBBR, 4-luorobenzyl, 4-fluorophenyl, 2,4-difluorobenzyl, 3-thienyl methyl, 5-thiotolene-2-ylmethyl, 5-chlorothiophene-2-ylmethyl and 2-benzo [b] thienyl methyl.
31. according to the method for claim 27, wherein said alkylating agent has formula R 99-Q, wherein Q is a leavings group, and R 99Be selected from 1,1,1-trifluoroethyl, phenyl, benzyl, Alpha-Methyl-4-luorobenzyl, 4-luorobenzyl, 4-fluorophenyl and 2,4-difluorobenzyl.
32. according to the method for claim 27, wherein said alkylating agent has formula R 99-Q, wherein Q is a leavings group, and R 99Be selected from 1,1,1-trifluoroethyl, benzyl and 4-fluorophenyl.
33. regioselectivity ground preparation 4, the pyridazone that 5-replaces or the method for its pharmacy acceptable salt, ester or prodrug may further comprise the steps:
A) make compound with following formula
Figure A9880832200201
Wherein R is an alkyl or aryl, and X is a leavings group, with the nucleophilic reagent reaction, to replace the X group;
B) general-OR 98Be converted into leavings group; With
C) make described compound and second kind of nucleophilic reagent reaction, to provide 4, the pyridazone that 5-replaces.
34. according to the method for claim 33, wherein said benzyl is removed with Lewis acid.
35. regioselectivity ground preparation 4, the pyridazone that 5-replaces or the method for its pharmacy acceptable salt, ester or its prodrug comprise making the compound with following formula
Figure A9880832200202
With having formula RNHNH 2Hydrazine handle, so that the pyridazone with following formula to be provided:
Figure A9880832200211
Wherein X, X 1, X 2, R, R 1, R 3And R 9Define as claim 1.
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CN110988375A (en) * 2018-10-03 2020-04-10 株式会社岛津制作所 Sample injection device and sample injection system
CN114560814A (en) * 2022-03-02 2022-05-31 天津理工大学 Synthesis method of substituted 2, 3-phthalazinone compound

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CN107334767A (en) * 2017-06-08 2017-11-10 中国医学科学院医药生物技术研究所 A kind of application of pyridazinone compound in oncotherapy
CN107334767B (en) * 2017-06-08 2019-03-05 中国医学科学院医药生物技术研究所 A kind of application of pyridazinone compound in oncotherapy
CN110988375A (en) * 2018-10-03 2020-04-10 株式会社岛津制作所 Sample injection device and sample injection system
CN114560814A (en) * 2022-03-02 2022-05-31 天津理工大学 Synthesis method of substituted 2, 3-phthalazinone compound
CN114560814B (en) * 2022-03-02 2023-10-20 天津理工大学 Synthesis method of substituted 2, 3-naphthyridine ketone compound

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