CN101062916B - Three-substituted 1H-pyrromonazole compound, preparation method, medicament composition and pharmacy use thereof - Google Patents

Three-substituted 1H-pyrromonazole compound, preparation method, medicament composition and pharmacy use thereof Download PDF

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CN101062916B
CN101062916B CN 200610078014 CN200610078014A CN101062916B CN 101062916 B CN101062916 B CN 101062916B CN 200610078014 CN200610078014 CN 200610078014 CN 200610078014 A CN200610078014 A CN 200610078014A CN 101062916 B CN101062916 B CN 101062916B
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phenyl
pyrazole
fluorophenyl
methylenedioxyphenyl
pyridine
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CN101062916A (en
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李松
李行舟
代现平
郑志兵
王莉莉
肖军海
刘洪英
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention discloses a general formula I compound to inhibit TGF-beta acceptor ALK5 to Smad protein phosphoric acid function and therapy salt or hydrate, which is characterized by the following: defining each substituent group as description; comprising preparing method of the general formula I compound; including the general formula I compound or therapy salt or medicinal compound of hydrate;including usages of the general formula I compound or therapy salt or hydrate in producing medicine; using the medicine to cure mammal ALK5 acceptor agent disease; inhibiting TGF-beta signal in mammal body; inhibiting formation of mammal body intercellular substance.

Description

Three replace 1H-pyrazole compound, its preparation method, pharmaceutical composition and pharmaceutical applications thereof
Technical field
The present invention relates to three and replace 1H-pyrazoles transforming growth factor-beta (transforming growthfactor β; TGF-β) suppressor factor of signal pathway; Specifically be TypeI acceptor or title activin appearance kinases-5 acceptor (activin-like kinase-5 receptor; Be called for short the ALK-5 acceptor) to the suppressor factor of Smad (mother against dpp) 2 or Smad3 phosphorylation; And their preparation method and in the purposes of medical field, particularly treat purposes with the unusual relevant various diseases of prevention and TGF-signal.
Background technology
Transforming growth factor-beta is a type cytokines superfamily; This superfamily member comprises transforming growth factor-beta s (TGF β s), activin (activines), statin (inhibins) and osteogenin [bone morphogenetic proteins (BMP)] and Miu Shi inhibition (Mullerian-inhibiting substance) etc.; Can regulate physiological process very widely, comprise cell propagation, break up, adhere to, move and downright bad.
The conduction of the signal of TGF-beta superfamily needs two types single span film serine/threonine acceptor, and these two kinds of acceptors are called Type I or ALK acceptor and Type II acceptor respectively.The difference of TypeI or ALK acceptor and Type II acceptor is following three aspects: (1) ALK acceptor lacks an interior fragment of cell that is rich in serine/threonine; (2) in various Type I acceptors, there is one to be different from Type II acceptor height homologous serine/threonine kinase functional zone; (3) at various Type I acceptors a common sequence fragment that is called the GS functional zone is arranged all; Comprise a zone of being rich in glycocoll and serine residue in these functional zone; Be positioned at the N end in cell kinase function district, this zone is most important by Type II receptor activation to it.
Many researchs show: the TGF-signal needs the acting in conjunction of ALK and Type II acceptor.Substantially; The dimer of TGF-β (part) combines with the dimer of a Type II acceptor earlier; Then raise two Type I acceptors; By the GS functional zone of TGF-β activated T ype II receptor phosphorylation ALKs, and therefore make it activation, the C end of the Smads (R-Smads) of the intracytoplasmic receptor activation of its downstream signaling molecule of activatory ALKs phosphorylation; The R-Smads of two phosphorylations can form trimer compositions with a Smad4-also claim general media Smad [commonmediator Smad (C-Smad)], and this mixture gets into nucleus and regulates transcribing of target gene.
Usually; In most of kinds; Type II acceptor is regulated the differentiation of cell, and Type I acceptor is regulated the generation of intercellular substance, and the compound of Formula I that therefore the present invention relates to is to be used to suppress Type I acceptor; And then regulate the synthetic of intercellular substance, rather than the cytodifferentiation that is used to regulate Type II institute media.
Seven kinds of Type I acceptors (ALK1-7) and five kinds of Type II acceptors in Mammals, have been found altogether; The combination of specific T ype I and Type II acceptor has determined specificity (the Piek and Roberts of part signal; 2001); Activin (Activins) or TGF β s activated T ypeI acceptor ALK4 and ALK5 be phosphorylation Smad2 and Smad3 respectively, and BMP activatory ALK1, ALK2, ALK3 and ALK6 pSmad1, Smad5 and Smad8 (Heldin etal., 1997).It must be noted that, evidence show, but in endotheliocyte TGF β s also activation ALK1 and Smad1 and Smad5 (Oh et al., 2000; Goumans et al., 2002).Recently the ALK7 that finds is considered to another kind of member Nodal (Reissmann et al., 2001, Watanabe et al., 1999 through activation Smad2 mediation TGF β Superfamily; Jornvall et al., 2001), although the Smad approach is studied in large quantities, the signal of TGF 'beta ' family part also can other signal pathways of activation.Comprise MAKP approach and phosphatidyl-inositol 3-kinase, infer and also can pass through TypeI acceptor (de Caestecker et al., 2000).
Unusual and the disease of TGF signal
Early stage research shows, abnormal TGF β 1 (first comes to light and studies the most thorough TGF β Superfamily member) signal with such as many pathologic processes such as fibrosis and canceration relevant (Border and Noble, 1994; Wakefield and Roberts, 2002).TGF β 1 also plays an important role in wound healing, its abnormal signal maybe with formation relevant (Bettinger et al., 1996 of the scar and the keloid of excessive growth; O ' Kane and Ferguson, 1997).
In recent years more continuous report relevant for TGF signal relative disease.For example the activation of report TGF-β 1 signal such as Border W.A and the expansion of extracellular matrix are early stage performance and lasting inducement (Border W.A., Noble N.A., N.Engl.J.Med., Nov.10,1994 of chronic nephritis and vascular property disease; 331 (19): 1286-92).In addition, TGF-β 1 plays a role in the formation of fibronectin and plasminogen activator suppressor factor-1 to the phosphorylation of Smad3 through its acceptor ALK5, and these all are the sedimental moity of sclera (Zhang Y.; FengX.H., Derynck R., Nature; Aug.27,1998; 394 (6696): 909-13; UsuiT., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., MiyataK., Kawabata M., Yamashita H., Invest.Ophthalmol.Vis.Sci., October 1998; 39 (11): 1981-9).
Kidney and cardiovascular systems to carry out fibrosis be human underlying cause of death and be the main consumer of health resources.TGF-β 1 be proved fibrosis lesion with a lot of kidneys relevant (Border W.A., Noble N.A., N.Engl.J.Med., Nov 10,1994; 331 (19): 1286-92).Acute or chronic glomerulonephritis (Yoshioka K., Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., MakiS., Lab.Invest., Februa ry 1993 are taking place; 68 (2): 154-63), dn-(Yamamoto, T., Nakamura, T.; Noble, N.A., Ruoslahti, E.; Border, W.A., (1993) PNAS 90:1814-1818), (Border W.A., Noble N.A. when heteroplastic transplantation repulsion, HIV ephrosis, II Angiotensin II inductive ephrosis; N.Engl.J.Med., Nov.10,1994; 331 (19): 1286-92), intravital TGF-β 1 level can raise.When these diseases took place, the expression of TGF-β 1 was relevant with the generation of extracellular matrix.Article three, the generation of evidence showed cell outer room matter is caused by TGF-β 1.The first, external, the TGF-β 1 of external source can induce normal renal glomerulus, mesangium and non-kidney cell to produce extracellular matrix, and the activity of arrestin enzyme.The second, the compacting antibody of TGF-β 1 can stop the accumulation of extracellular matrix in the mouse kidney.The 3rd, in the mouse of genetically modified TGF-β 1 or the body transfection kidney of normal mouse of TGF-β 1 gene glomerular sclerosis fast (Kopp J.B., Factor V.M. can take place; Mozes M., Nagy P., Sanderson N.; Bottinger E.P., Klotman P.E., Thorgeirsson S.S.; Lab Invest, June 1996; 74 (6): 991-1003), the activity that therefore suppresses TGF-β 1 possibly be effective to the treatment chronic renal disease.
Research shows, in the injured blood vessel TGF-β 1 and acceptor thereof increase show relevant with the formation of neointima (Saltis J., Agrotis A., Bobik A., Clin Exp PharmacolPhysiol, March 1996; 23 (3): 193-200).In addition, TGF-β 1 is the strong effect promotor of smooth muscle cell (＂ SMC ＂) in external transfer, and the migration of the SMC on the ductus arteriosus wall helps to take place arteriosclerosis and valvular stenosis.In addition, TGF-beta receptor ALK5 shows relevant with total cholesterol (P < 0.001) (Blann A.D., Wang J.M., Wilson P.B., KumarS., Atherosclerosis, February1996 in the diversity of the anti-total cholesterol product of endotheliocyte is analyzed; 120 (1-2): 221-6), high ALK5/>TGF-β type II acceptor ratio is arranged among the SMC at atherosclerotic lesions position in addition, this is overexpression because of TGF-β 1 in the infringement of fibroplasia property vascular; Receptor variant cell can excessively produce extracellular matrix (McCaffrey T.A., Consigli S. simultaneously with the growth of slow and not controlled way; DuB., Falcone D.J., Sanborn T.A.; Spokojny A.M., Bush H.L., Jr.; J Clin Invest, December 1995; 96 (6): 2667-75).
TGF-β 1 is in the character that the immunity trend takes place the scavenger cell of non-foam shape to be shown in the matter synthetic atherosclerotic lesions between active; This scavenger cell that shows non-foam shape maybe be through the expression of gene of matter between a kind of responsible adjusting of mechanism participation of TGF-β dependence in the plastotype again of atherosclerotic lesions, and therefore the effect through 1 couple of ALK5 of inhibition TGF-β can have therapeutic action to TGF-β 1 atherosclerosis and the stricture of artery that causes thus.
That TGF-β also shows is relevant with peritoneal adhesion (Saed G.M., Zhang W., Chegini N., Holmdahl L., and Diamond M P., Wound Repair Regeneration.7 (6): 504-510,1999November-December).Therefore, suppress ALK5 and have fibrosis adhesion under the prevention of postoperative of benefiting peritonaeum and the corium.
The strong effect selective depressant of ALK5 possibly be used to treat the various diseases relevant with the ALK5 kinases with prevention: like not syndromes, arteriosclerosis, peritonaeum or the subcutaneous adhesion of chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, the necrosis of congested heart, ulcer, corneal wound, dn-, nervous function damage, A Erzi sea; And any main pathology relevant with fibrosis; Including, but not limited to pulmonary fibrosis, hepatic fibrosis and valvular stenosis.
The term ALK5 suppressor factor here refers to that a compound can optionally suppress the ALK5 acceptor; And p38 kinases or Type II acceptor or some other kinases are not had restraining effect or have only weak restraining effect, and not to play a role through Smads albumen such as Smad6 and the Smad7 that suppresses outside Smad2 and the Smad3.
Here said term " ulcer " but comprise and be not limited to diabetic ulcer, chronic ulcer, stomach ulcer, duodenal ulcer etc.
Summary of the invention
The objective of the invention is searching and developmental function in the kinase whose micromolecular inhibitor of ALK5; Through suppressing the phosphorylation of ALK5 to its downstream signal Smad2 or Smad3; Blocking-up or part are blocked the TGF signal to intramolecular propagation; Thereby correct unusual TGF-signal, treat and prevent the unusual relevant disease of TGF signals of various and ALK5 media.
The inventor is through discovering; Compound with following general formula I has the effect of ALK5 to the phosphorylation of Smad3/2 that suppress; Can block or the part block the TGF-signal to intracellular propagation; Therefore can be used to treat and the unusual relevant various diseases of prevention and TGF-signal, thereby accomplish the present invention.
On the one hand, the present invention relates to compound, its all possible isomer or its pharmaceutically useful salt or the hydrate of general formula I
Figure S06178014020060914D000051
Wherein:
R1 and R2 are optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl independently of each other; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R1 and R2 are and the heterocyclic fused phenyl of a 5-7 unit fragrance or non-fragrance independently of each other, and said here heterocycle is meant and contains the heteroatomic ring that one or two is selected from N, O and S;
Perhaps R1 and R2 are substitutedly containing the heterocyclic radical of proton donor or proton acceptor with the ortho position of parent nucleus connection site, for example substituted pyridine-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base; Or the substituted substituent phenyl that on 2, contains as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R ' or-CONHR ';
Perhaps R3 is substituted formamyl; Substituting group is selected from 4-(phenoxy) phenyl, pyridin-3-yl, benzyl, pyridine-3-methylene radical, 3-(imidazoles-1-yl) propyl group, (furans-2-yl) methylene radical, cyclohexyl, 4-(benzyloxy) phenyl, 4-(phenyl) phenyl, naphthalene-1-base, 3; 3-(phenylbenzene) propyl group, 3,4-(methylene-dioxy) phenyl, 2-(phenoxy) phenyl and fluorenes-2-base.
Term " the C that this paper uses 1-6Alkyl ", no matter be himself or as other more macoradical such as C 1-6The part of alkoxyl group all refers to the atomic group that contains 1-6 carbon atom of straight or branched include but are not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-and the tertiary butyl etc.
Term " the C that this paper uses 1-6Haloalkyl " be meant that wherein one or more hydrogen are by the substituted C of halogen atom 1-6Alkyl need should be mentioned that trifluoromethyl (CF here especially 3).
The term " halogen (halo) " that this paper uses is meant fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) ".
The term " aryl " that this paper uses refers to the substituted or non-substituted aromatic ring system of 5-14 unit, maybe possibly comprise condensed dicyclo or trinucleated aromatic ring system, but comprises and be not limited to phenyl and naphthyl.
In one embodiment,
R1 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R1 is and the heterocyclic fused phenyl of a 5-7 unit fragrance or non-fragrance, and said here heterocycle is meant and contains the heteroatomic ring that one or two is selected from N, O and S;
R2 is substitutedly containing the heterocyclic radical of proton donor or proton acceptor with the ortho position of parent nucleus connection site, for example substituted pyridine-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base; Or the substituted substituent phenyl that on 2, contains as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
Perhaps R2 is and the heterocyclic fused phenyl of a 5-7 unit fragrance or non-fragrance, and said here heterocycle is meant and contains the heteroatomic ring that one or two is selected from N, O and S;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R ' or-CONHR ';
Perhaps R3 is substituted formamyl; Substituting group is selected from 4-(phenoxy) phenyl, pyridin-3-yl, benzyl, pyridine-3-methylene radical, 3-(imidazoles-1-yl) propyl group, (furans-2-yl) methylene radical, cyclohexyl, 4-(benzyloxy) phenyl, 4-(phenyl) phenyl, naphthalene-1-base, 3; 3-(phenylbenzene) propyl group, 3,4-(methylene-dioxy) phenyl, 2-(phenoxy) phenyl and fluorenes-2-base.
In another embodiment,
R2 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R2 is and the heterocyclic fused phenyl of a 5-7 unit fragrance or non-fragrance, and said here heterocycle is meant and contains the heteroatomic ring that one or two is selected from N, O and S;
R1 is substitutedly containing the heterocyclic radical of proton donor or proton acceptor with the ortho position of parent nucleus connection site, for example substituted pyridine-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base; Or the substituted substituent phenyl that on 2, contains as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
Perhaps R1 is and the heterocyclic fused phenyl of a 5-7 unit fragrance or non-fragrance, and said here heterocycle is meant and contains the heteroatomic ring that one or two is selected from N, O and S;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R ' or-CONHR ';
Perhaps R3 is substituted formamyl; Substituting group is selected from 4-(phenoxy) phenyl, pyridin-3-yl, benzyl, pyridine-3-methylene radical, 3-(imidazoles-1-yl) propyl group, (furans-2-yl) methylene radical, cyclohexyl, 4-(benzyloxy) phenyl, 4-(phenyl) phenyl, naphthalene-1-base, 3; 3-(phenylbenzene) propyl group, 3,4-(methylene-dioxy) phenyl, 2-(phenoxy) phenyl and fluorenes-2-base.
In a preferred embodiment,
R1 is a phenyl; One replaces or dibasic phenyl, and substituting group is selected from halogen (for example fluorine or chlorine), C 1-6Alkoxyl group (for example methoxyl group), hydroxyl and 3, the 4-methylene-dioxy; Pyridyl.
R2 is a phenyl; One replaces or dibasic phenyl, and substituting group is selected from halogen (for example fluorine or chlorine), C 1-6Alkoxyl group (for example methoxyl group), hydroxyl and 3, the 4-methylene-dioxy; Pyridyl; C 1-6The substituted pyridyl of alkyl (for example methyl); Thiazolyl;
R3 is substituted phenyl, and substituting group is selected from cyanic acid, formamyl, carboxyl, methylol; C 1-6Alkoxyl group (for example oxyethyl group); Thiol; Substituted formamyl; Substituting group is selected from 4-(phenoxy) phenyl, pyridin-3-yl, benzyl, pyridine-3-methylene radical, 3-(imidazoles-1-yl) propyl group, (furans-2-yl) methylene radical, cyclohexyl, 4-(benzyloxy) phenyl, 4-(phenyl) phenyl, naphthalene-1-base, 3; 3-(phenylbenzene) propyl group, 3,4-(methylene-dioxy) phenyl, 2-(phenoxy) phenyl and fluorenes-2-base.
In another preferred embodiment,
R1 is 3,4-methylenedioxyphenyl, pyridine-2-base, 2-fluorophenyl, 3,4-Dimethoxyphenyl, 3,4-dihydroxy phenyl, 4-fluorophenyl, phenyl or 3,4-dichlorophenyl;
R2 is pyridine-2-base, 2-fluorophenyl, 3,4-methylenedioxyphenyl, thiazol-2-yl, 2-trifluoromethyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl, 6-picoline-2-base, phenyl, 2-nitrophenyl or 2-chloro-phenyl-;
R3 is to cyano-phenyl, to the formamyl phenyl, to carboxyl phenyl, to hydroxymethyl phenyl, oxyethyl group, thiol, [4-(phenoxy) phenyl]-formamyl, (pyridin-3-yl)-formamyl, benzyl-formamyl, (pyridine-3-methylene radical)-formamyl, [3-(imidazoles-1-yl) propyl group]-formamyl, [(furans-2-yl) methylene radical]-formamyl, cyclohexyl-formamyl, [4-(benzyloxy) phenyl]-formamyl, [4-(phenyl) phenyl]-formamyl, (naphthalene-1-yl)-formamyl, [3; 3-(phenylbenzene) propyl group]-formamyl, [3,4-(methylene-dioxy) phenyl]-formamyl, [2-(phenoxy) phenyl]-formamyl or (fluorenes-2-yl)-formamyl.
Compound below the special preferred compound of formula I of the present invention or its pharmaceutically useful salt or hydrate are preferred:
(1) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
(2) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(3) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
(4) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
(5) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(6) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
(7) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(8) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
(9) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(10) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
(11) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(12) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] benzene nitrile
(13) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] BM
(14) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] benzene nitrile
(15) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] BM
(16) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
(17) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
(18) 4-[5-(3, the 4-dihydroxy phenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
(19) 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
(20) 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
(21) 4-[5-(4-fluorophenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
(22) 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(23) 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(24A) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] benzene nitrile
(24B) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] BM
(25) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] benzene nitrile
(26) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] BM
(27) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(28) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-pyrazole-3-yl] phenylformic acid
(29) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] phenylcarbinol
(30) 5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
(31) 5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-3-oxyethyl group-1H-pyrazoles
(32) 5-(4-fluorophenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
(33) 5-phenyl-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
(34) 5-(4-fluorophenyl)-1-(pyridine-2-yl)-3-thiol-1H-pyrazoles
(35) N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(36) N-(pyridin-3-yl)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(37) N-[4-(phenoxy) phenyl]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(38) N-benzyl-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(39) N-(pyridine-3-methylene radical)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(40) N-[3-(imidazoles-1-yl) propyl group]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(41) N-[(furans-2-yl) methylene radical]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(42) N-benzyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(43) N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(44) N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(45) N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(46) N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(47) N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(48) N-cyclohexyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(49) N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(50) N-(pyridine-3-methylene radical)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(51) N-(pyridine-3 base)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(52) N-benzyl-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(53) N-[3-(imidazoles-1-yl) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(54) N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(55) N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(56) N-benzyl-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(57) N-(pyridine-3 base)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(58) N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(59) N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(60) N-[4-(benzyloxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(61) N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(62) N-benzyl-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(63) N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(64) N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(65) N-(pyridin-3-yl)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(66) N-(pyridine-3-methylene radical)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(67) N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(68) N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(69) N-benzyl-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(70) N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(71) N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(72) N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
(73) N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(74) N-[4-(benzyloxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(75) N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(76) N-(naphthalene-1-yl)-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(77) N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(78) N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(79) N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(80) N-[3,4-(methylene-dioxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(81) N-[4-(phenyl) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(82) N-[3,3-(phenylbenzene) propyl group]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(83) N-[2-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(84) preparation of N-(naphthalene-1-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(85) N-(fluorenes-2-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(86) N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(87) N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(88) N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
(89) N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(90) N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(91) N-[4-(phenyl) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(92) N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
(93) N-[2-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
And pharmacologically acceptable salt or hydrate.
The invention still further relates to the suitable pharmaceutically useful salt or the hydrate of compound shown in general formula I; But wherein pharmaceutically useful salt comprise be not limited to salt that compound of Formula I become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that is become like toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, Hydrocerol A, acetate, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, possibly form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvolytes, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.Part of compounds possibly exist with the form of optical isomer or tautomer among the present invention, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and compound method or three-dimensional method single-minded or asymmetric synthesis that perhaps certain isomer can various routines obtain.Since compound of Formula I is purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% is meant weight percent).The preparation method of pure compound not can be used to be used for the purer form of medicinal compsns.At least contain 1% in these pure inadequately products, be more suitable for 5%, better at least 10% the compound shown in general formula I or its pharmaceutically useful verivate.
On the other hand, the present invention relates to prepare the compound method of compound of Formula I.The compound of general formula I can be a raw material from the known compound that maybe can buy, through the method preparation of synthetic.If raw material can not be buied, their preparation method then is provided, or they can be through the method preparation of bibliographical information here.
Specifically, the invention provides the method for preparing compound of Formula I or its pharmacologically acceptable salt or hydrate, it comprises:
Method I: as the R1 of compound of Formula I, R2, can use following method preparation when R3 is aromatic nucleus:
(i) earlier with substituted aromatic aldehyde and the reaction of substituted acetyl aromatic ring, prepare substituted chalcone compounds
Wherein the definition of R1 and R3 is with the definition in the compound of Formula I,
(ii) substituted chalcone compounds and fragrant hydrazine or the reaction of fragrant hydrazonium salt hydrochlorate obtain substituted pyrazoline compounds
Figure S06178014020060914D000172
Wherein the definition of R1, R2 and R3 is with the definition in the compound of Formula I,
(iii) substituted pyrazoline compounds is with oxygenant (MnO for example 2) oxydehydrogenation obtains the compound of general formula I
Figure S06178014020060914D000173
(iv) the substituting group on the R3 of compound of Formula I can transform again, when for example R3 is the substituted phenyl of itrile group, can itrile group be converted into aminocarboxyl or carboxyl
Figure S06178014020060914D000174
Method II: in general formula I, when R3 is alkoxyl group or thiol, available following method preparation:
(i) earlier with the former xanthate acid compounds of alcohol, dithiocarbonic anhydride, methyl iodide prepared in reaction under the effect of phase-transfer catalyst
Figure S06178014020060914D000181
Wherein R3 is an alkoxyl group,
The compound reaction of (ii) former xanthate acid compounds and formula
Figure S06178014020060914D000182
; Preparation 3-aryl-3-oxo thiopropionate
Figure S06178014020060914D000183
Wherein the definition of R1 is with the definition in the compound of Formula I, and R3 is an alkoxyl group,
(iii) the reaction of 3-aryl-3-oxo thiopropionate and fragrant hydrazine or fragrant hydrazonium salt hydrochlorate obtains compound of Formula I
Figure S06178014020060914D000184
Wherein the definition of R1, R2 is with the definition in the compound of Formula I, and R3 is alkoxyl group or thiol;
Method III: when R3 in the general formula I be-COOR ' or-during CONHR ', available following method preparation:
(i) react earlier with substituted arone and dimethyl oxalate, prepare substituted 2,4-diketone methyl-butyrate compounds
Figure S06178014020060914D000185
Wherein the definition of R1 is with the definition in the compound of Formula I,
(ii) substituted 2,4-diketone methyl-butyrate compounds and the reaction of fragrant hydrazonium salt hydrochlorate obtain substituted 1H-pyrazoles-3-methyl-formiate compounds
Wherein the definition of R1, R2 is with the definition in the compound of Formula I,
(iii) substituted 1H-pyrazoles-3-methyl-formiate compounds obtains substituted 1H-pyrazoles-3-formic acid compounds through the saponification hydrolysis reaction
Figure S06178014020060914D000192
Wherein the definition of R1, R2 is with the definition in the compound of Formula I,
(iv) substituted 1H-pyrazoles-3-formic acid compounds and various amine or alcohol compound coupling obtain compound of Formula I
Wherein the definition of R1, R2 and R ' is with the definition in the compound of Formula I.
In the process of synthetic general formula (I) compound, variable or reaction process had dysgenic group, like acid amides, the N on carboxyl, hydroxyl, carbonyl or amino and the pyridine can be protected earlier, sloughs protection at proper step again.About the protection of organo-functional group and deprotection at pertinent literature such as Protective Groups in Organic Chemistry; T.W.Greeneand P.G.M.Wuts, (Wiley-Interscience, New York; 2nd edition, 1991) existing detailed argumentation in.Also can be earlier exist, change into required group at proper step again with the form of its potential functional group.
Compound of Formula I can use ordinary method single synthetic; Also mixed-the separating method or the parallel synthetic method of available combination chemistry (contain two at least with the storehouse in each storehouse; Or 5-1000; 10-100 compound preferably) synthetic for unit, promptly can in liquid phase, synthesize also and can use solid phase synthesis process.
See embodiment about the more detailed data of preparation compound of Formula I.
On the other hand; Compound, its all possible isomer or its pharmaceutically useful salt or the hydrate that the present invention relates to general formula I is used for the purposes of the medicine of the mammiferous disease by the ALK5 acceptor media of production for treating; Said disease by the ALK5 acceptor media is including, but not limited to following disease: not syndromes, arteriosclerosis, peritonaeum or the subcutaneous adhesion of chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, kidney disease, the necrosis of congested heart, ulcer, eye disease, corneal wound, dn-, nervous function damage, A Erzi sea; And any main pathology relevant with fibrosis, including, but not limited to pulmonary fibrosis, hepatic fibrosis and valvular stenosis.
The invention still further relates to the method for the mammiferous disease by the ALK5 acceptor media of treatment, this method comprises compound, its all possible isomer or its pharmaceutically useful salt or the hydrate that the Mammals of needs treatment is given the general formula I of effective dose with suitable manner.The invention also discloses effective dose to mammiferous administering mode, compound of Formula I or its suitable pharmacologically acceptable salt or the hydrate of needs treatment.
On the other hand, the present invention relates to compound, its all possible isomer or its pharmaceutically useful salt of general formula I or the purposes that hydrate is used to produce the medicine that can suppress the interior TGF-signal of mammalian body.
The invention still further relates to the method that suppresses TGF-signal in the mammalian body; For example suppress TypeI or the ALK5 acceptor phosphorylation to Smad2 or Smad3, this method comprises that the Mammals to needs inhibition TGF-signal gives compound of Formula I, its all possible isomer or the suitable pharmacologically acceptable salt or the hydrate of effective dose with suitable manner.
On the other hand, compound, its all possible isomer or its pharmaceutically useful salt or the hydrate that the present invention relates to general formula I are used to produce the purposes that is used to suppress the medicine that matter forms between the Mammals cells in vivo.
The invention still further relates to and in Mammals, suppress the method that intercellular substance forms; For example through suppressing Type I or the ALK5 acceptor phosphorylation to Smad2 and Smad3, this method comprises that the Mammals that needs inhibition intercellular substance is formed gives compound of Formula I, its all possible isomer or its pharmaceutically useful salt or the hydrate of effective dose with suitable manner.
On the other hand; The compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; Or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; When using with the form of pharmaceutical composition; Usually the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner are combined to process suitable administration form or dosage form, this program comprises through suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer or its pharmaceutically useful salt or the hydrate and at least a pharmaceutically useful carrier of general formula I.
The medicinal compsns of The compounds of this invention; Any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input; Or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as human serum protein; Buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid, water; Salt or ionogen, like protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloided silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, like syrup, and gum arabic, sorbyl alcohol, tragacanth, or Vinylpyrrolidone polymer; Weighting agent, like lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol; Padil, lubricant, like Magnesium Stearate, talcum, polyoxyethylene glycol; Tripoli, disintegrating agent, like yam starch, or acceptable dibutyl phthalate, like bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be processed the suspension-s of water and oil, solution, and emulsion, syrup or elixir also can be processed dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, like suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup; Gel, Natvosol, CMC 99.5, aluminium stearate gel, hydrogenant food oils; Emulsifying agent, like Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (possibly comprise edible oil), like Prunus amygdalus oil, grease such as glycerine, terepthaloyl moietie, or ethanol; Sanitas is like methyl paraben or propyl ester, Sorbic Acid.Can add seasonings or tinting material like needs.
Suppository can comprise conventional suppository base, like cocoa butter or other glyceryl ester.
Stomach is offerd medicine outward, and liquid formulation is processed by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.According to the different of selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when processing injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be processed suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, can contain weight ratio 0.1% in the component, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 50-500 milligram activeconstituents.Different according to route of administration and administration frequency, the suitable therapeutic dose that is used to be grown up is 100-3000 milligram every day, like 1500 milligrams of every days.This dosage is corresponding to 1.5-50 milligram/kg/day, and proper dosage is 5-20 milligram/kg/day.
Must recognize; The best dosage of compound of Formula I and be at interval by compound property with such as form, path and the position of administration and external conditionss such as the specific Mammals decision of being treated, and this best dosage can use conventional technology to confirm.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is confirmed.
Embodiment
Following specific embodiment is the preferred embodiments of the invention, and it should not be construed as the present invention is constituted any restriction.
The fusing point of compound is measured by RY-1 fusing point appearance, and TM is calibration not.Mass spectrum is measured by Micromass ZabSpec HRMS (resolving power 1000). 1H NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR appearance, operating frequency 1H NMR400MHz.
Embodiment
Embodiment 1The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000231
Step 1The preparation of 1-(4-itrile group phenyl)-3-(3,4 methylenedioxyphenyl) acrylketone
Get piperonylaldehyde 450mg (3mmol) and 4-phenyl methyl ketone nitrile 435mg (3mmol), use the 10mL anhydrous alcohol solution, add the sodium hydroxide of 24mg (0.6mmol), stir under the room temperature; Have a large amount of solids to separate out very soon, with the reaction mixture suction filtration, cold washing with alcohol is to redfree, and filtrating is left standstill had yellow solid to separate out in one day again; Suction filtration once more, the filter cake of twice gained is air-dry, obtains 1-(4-itrile group phenyl)-3-(3 of 710mg; 4 methylenedioxyphenyls) acrylketone, mp:173-176 ℃, yield 85%. 1HNMR(400Hz，CDCl 3)6.05(2H，s)，6.86(1H，d，J＝7.87Hz)，7.14(1H，dd，J＝7.87，1.67Hz)，7.17(1H，d，J＝1.67Hz)，7.25(2H，d，J＝15.45Hz)，7.76(2H，d，J＝15.45Hz，)，7.80(2H，d，J＝8.43Hz)，8.07(2H，d，J＝8.43Hz)。FAB-MS(m/e)278(M ++1)。
Step 24-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl]] preparation of benzene nitrile
Get 1-(4-itrile group phenyl)-3-(3, the 4-methylenedioxyphenyl) acrylketone 556mg (2mmol) and 2-hydrazino pyridine 260mg (2.4mmol), suspend 80 ℃ of following backwash of oil bath with the 20mL absolute ethyl alcohol;, react and stop heating after 16 hours, reduce to after the room temperature concentrating under reduced pressure reaction solution to doing; Resistates is used purification by silica gel column chromatography, and the methylene dichloride wash-out reclaims raw material 120mg; The recovery 22% continues to obtain expecting product 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4 with methylene chloride 100/0.5 wash-out; 5-dihydro-1 h-pyrazole-3-yl]] 440mg of benzene nitrile, yield 60%, mp:149-151 ℃. 1H-NMR(400Hz，CDCl 3)3.13(1H，dd，J＝17.12，5.04Hz)，3.77(1H，dd，J＝17.12，12.36Hz)，5.79(1H，dd，J＝12.36，5.04Hz)，5.90(2H，s，O-CH2-O)，6.70-6.74(4H，m)7.45(1H，d，J＝8.16Hz)，7.55(1H，dd，J＝8.16，7.04Hz)7.66(2H，d，J＝8.40Hz)，7.81(2H，d，J＝8.40Hz)，8.09(1H，d，J＝4.20Hz)，EIMS(m/e，100)368(M +，8)，239(100)。
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Get 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole 3-yl] benzene nitrile 150mg (0.4mmol),, add the MnO of new system with the dissolving of 5mL dry-out benzene 2/ SiO 2500mg stirred 24 hours under the room temperature, and TLC detects and generates the point that polarity is big slightly, and suction filtration adds the methanol wash filter cake with methylene dichloride, and filtrating concentrates back preparation Thin-layer separation, obtains title compound, 120mg yield 80%.mp：164-166℃， 1HNMR(400Hz，CDCl 3)6.00(2H，s，O-CH2-O)，6.74(1H，s)，6.79(2H，s)，6.81(1H，s)，7.29(1H，dd，J＝7.04，4.04Hz)，7.53(1H，d，J＝8.56Hz)，7.72(2H，d，J＝8.08Hz)，7.81[1H，dd，J＝8.56，7.04Hz]，8.03(2H，d，J＝8.08Hz)，8.46(1H，d，J＝4.04Hz)，EIMS(m/e，100)，366(M +，82)，365(M +-H，100)。
Embodiment 2
The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000251
Get compound 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen instance 1) 100mg (0.27mmol),, add KOH 60mg (porphyrize) with the dissolving of the 3ml trimethyl carbinol; 100 ℃ of heating of oil bath backwash reacted 2 hours, and TLC detects and finds to generate the point that polarity is big; After reducing to room temperature, be evaporated to driedly, directly mix a kind column chromatography; Methylene chloride 100/2 wash-out must be expected product, mp:165-167 ℃ of yield 79%. 1HNMR(400Hz，CDCl 3)6.05(2H，s，O-CH2-O)，6.76(1H，dd，J＝8.04，1.76Hz)，6.83(1H，d，J＝1.76Hz)，6.91(1H，d，J＝8.04Hz)，7.22(1H，s)，7.41(1H，brs，NH)，7.46(1H，dd，J＝6.32，4.80Hz)，7.75(1H，d，J＝8.04Hz，)，7.99(4H，dd，J＝8.56，8.56Hz)，8.04(1H，dd，J＝8.40，6.32Hz)，8.39(1H，d，J＝4.80Hz)。EIMS(m/e，100)，384(M +，90)，383(M +，100)。
Embodiment 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000252
Step 1The preparation of 2-fluorophenyl hydrazine hydrochloride
Get 2-fluoroaniline 481mg (5mmol), with the dissolving of 5mL concentrated hydrochloric acid, cryosel is bathed and is cooled to below-5 ℃, adds the 3mL aqueous solution of 350mg NaNO3 (5mmol) in batches; Temperature finishes below 5 ℃ in keeping, and reacts 20min down at-5 ℃, is cooled to-10 ℃ then; Splash into 2.25gSnC12 (10mmol), warm in keeping below-10 ℃, and under this temperature, stir 20min, rose to stirring at room then 1 hour; Again the temperature of reaction mixture is reduced under-5 ℃, have a large amount of solids to separate out suction filtration; Obtain the pale solid yield after air-dry: 44%, mp:170-173 ℃ 1HNMR (400Hz, CDCl 3) 6.95 (1H, m), 7.13 (2H, m), 7.17 (1H, and m) 8.27 (1H, br s, N-H), 10.22 (3H, br s) .FABMS 127 (MH +, 100), 110 (M +-NH 2, 50).
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Get 1-(4-itrile group phenyl)-3-(3; 4 methylenedioxyphenyls) (embodiment 1 step 1) 417mg (.1.5mmol) and 2-fluorophenyl hydrazine hydrochloride 294mg (1.8mmol) are seen in preparation to acrylketone; Suspend with the 20mL absolute ethyl alcohol, add 4.5g silica gel, backwash under the oil bath 80C; Reacted 4 hours, it is slightly little and the point of yellow fluorescence arranged that TLC detect to generate polarity.Stop heating, reduce to the room temperature after-filtration, concentrating under reduced pressure filtrating liquid is to doing, and direct column chromatography, methylene dichloride wash-out obtain expecting product, and oily matter 480mg solidifies in the ether, yield 83%.Mp:125-127 ℃, 1HNMR (400Hz, CDCl 3) 3.23 (1H, dd, J=17.0,4.80Hz), 3.74 (1H, dd, J=17.0,12.1Hz), 5.65 (1H; Dd, J=12.1,4.80Hz), 5.87 (2H, s, O-CH2-O), 6.61 (1H, X in the ABX system, J=0.8Hz) 6.64 (1H; A in the ABX system, J=17.9Hz), 6.65 (1H, B in the ABX system, J=17.9,0.8Hz), 6.82-6.94 (2H, m); 7.03 (1H, ddd, J=7.76,7.50,1.44Hz) 7.56 (1H, ddd, J=8.48,8.16; 1.40Hz), 7.67 (2H, d, J=8.2Hz), 7.78 (2H, J=8.2Hz), EI-MS (m/e, 100) 385 (M +, 100), 109 (70).
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole 3-yl] benzene nitrile to obtain 4-[5-(3; The 4-methylenedioxyphenyl)-and 1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile, yield 92%; Mp:149-151 ℃ 1H-NMR (400M, CDCl 3) δ 5.97 (2H, s, O-CH2-O), 6.72 (1H, s), 6.73 (2H, s), 6.81 (1H, s), 7.14 (1H, m), 7.26 (1H, m), 7.42 (1H, m), 7.53 (1H, m), 7.71 (2H, d, J=8.56Hz), 7.98 (2H, d, J=8.56Hz); FABMS (m/e, 100) 384 (MH +, 100).
Embodiment 4The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000271
Step 1The preparation of 3-(4-itrile group phenyl)-1-(pyridine-2-yl)-acrylketone
2-pyridylaldehyde (1.07g 10mmol) and 4-phenyl methyl ketone nitrile (1.45g 10mmol) are dissolved in the 10mL absolute ethyl alcohol; Splash into the DBU of 1mmol, stir 1 hour under the room temperature with the reaction solution suction filtration, filter cake separates (methylene dichloride wash-out) with silica gel column chromatography and obtains 3-(4-itrile group phenyl)-1-(pyridine-2-yl)-acrylketone; 186mg; Yield 8%, mp:255-260 ℃ 1H-NMR (400M, CDC13) δ 7.35 (1H, dd, J=7.68,4.52Hz), 7.50 (1H, d, J=7.72Hz; C3H), 7.78 (1H, dd, J=7.72,7.68Hz), 7.79 (1H, d, J=15.4Hz; CH=), 7.82 (2H, d, J=8.36Hz), 8.11 (1H, d, J=15.4Hz; CH=), 8.18 (2H, d, J=8.36Hz), 8.71 (1H, d, J=4.52Hz).EIMS(m/e，100).234(M +，20)，468(2M +，5)。
Step 2The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, and just with 3-(4-itrile group phenyl)-1-(pyridine-2-yl)-acrylketone and 3,4-methylenedioxybenzenes nitrile replaces 1-(4-itrile group phenyl)-3-(3 respectively; 4 methylenedioxyphenyls) acrylketone and 2-hydrazino pyridine; Obtain 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Yield 24% 1H-NMR (400M, CDC13) δ 3.23 (1H, dd, J=17.12,7.28Hz), 3.89 (1H, dd, J=17.12,12.84Hz), 5.47 (1H, dd, J=12.84,7.28Hz), 5.89 (2H, s, O-CH 2-O), 6.31 (1H, dd, J=8.56,2.24Hz), 6.63 (1H, d; J=8.56Hz), 6.89 (1H, d, J=2.24Hz), 7.22 (2H, m), 7.64 (2H; D, J=8.56Hz), 7.75 (2H, d, J=8.56Hz), 7.64 [1H; M ,], 8.63 (1H, d, J=4.76Hz) .FABMS (m/e, 100) .369 (MH +, 100).
Step 3The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, just with 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole 3-yl] benzene nitrile to obtain 4-[1-(3; The 4-methylenedioxyphenyl)-and 5-(pyridine-2-yl)-1H-pyrazole-3-yl] the benzene nitrile; Yield 77%, mp:132-135 ℃ 1H-NMR (400M, CDCl 3) δ 6.04 (2H, s, O-CH2-O), 6.79 (1H, d, J=8.12Hz), 6.80 (1H, dd, J=8.12,1.96Hz); 6.93 (1H, d, J=1.96Hz), 7.18 (1H, s), 7.19 (1H, d, J=7.84Hz), 7.25 (1H; Dd, J=7.84,7.84Hz), 7.65 (1H, dd (t), J=7.84,4.20Hz), 7.71 (2H, d; J=6.72Hz), 8.00 (1H, d, J=6.72Hz), 8.65 (1H, d, J=4.20Hz), EIMS (m/e, %) 366 (M +, 5), 365 (M +-H, 8), 277 (100).
Embodiment 5The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000281
Method is with embodiment 2; Just [1-(3 with 4-; The 4-methylenedioxyphenyl)-and 5-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 4) replaces 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-azoles 3-yl] benzene nitrile to obtain 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] BM; Mp:180-182 ° 1H-NMR (400M, DMSO-d6) δ 6.02 (2H, s, O-CH2-O), 6.78 (1H, d, J=1.68Hz), 6.82 (1H, dd; J=8.12,1.68Hz), 6.90 (1H, d, J=8.12Hz), 7.20 (1H, s), 7.40 (1H, brs.; NH), 7.50 (1H, dd, J=6.72,5.04Hz), 7.70 (1H, d, J=8.12Hz) 7.97 (2H; D, J=8.40Hz), 8.02 (2H, d, J=8.40Hz), 8.04 (1H, dd, (δ 8.02)); 8.41 (1H, d, J=5.04Hz), 8.17 (1H, brs., NH) .EIMS (m/e, 100), 384 (M +, 92), 383 (M +-H, 100), 365 (M +-H-H 2O, 42).
Embodiment 6The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000291
Step 13, the preparation of 4-methylenedioxybenzenes hydrazonium salt hydrochlorate LXZ313
Method is identical with embodiment 3 steps 1, and just with 3, the 4-methylene dioxo group aniline replaces the 2-fluoroaniline, and bullion is used the absolute ethyl alcohol recrystallization, yield 55%, and mp:177-178 ℃, 1HNMR (400Hz, DMSO-d6) 5.97 (12H, s, O-CH2-O), 6.47 (1H, dt (ddd), J=8.48,2.24,1.88Hz (has 15N- 1The H coupling)), 6.71 (1H, t (dd), 2.40,2.24Hz), 6.85 (1H, d, J=8.48Hz), 7.97 (1H, br s, NH), 10.06 (3H, br s, NH), EI-MS (m/e, %) 152 (M +, 99), 136 (M +-NH 2, 100).
Step 2The preparation of 3-(4-itrile group phenyl)-1-(2-fluorophenyl)-acrylketone
Method just replaces the 2-pyridylaldehyde with the 2-fluorobenzaldehyde with embodiment 4 steps 1, obtains 3-(4-itrile group phenyl)-1-(2-fluorophenyl)-acrylketone, and mp:95-97 ℃, 1H-NMR (400M, CDCl 3) δ 7.16 (1H, dd, J=10.92,8.10Hz), 7.23 (1H, dd, J=7.28,7.56Hz); 7.43 (1H, m), 7.62 (1H, d, J=16.0Hz, CH=), 7.65 (1H, ddd; J=7.56,7.56,1.68Hz), 7.82 (2H, d, J=8.44Hz); 7.93 (1H, d, J=16.0Hz, CH=), 8.10 (2Hd, J=8.44Hz) .EI-MS (m/e, %) 251 (M +, 80), 130 (NC-Ph-CO +, 66), 121 (M +-130,50), 101 (100).
Step 3The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, and just with 3-(4-itrile group phenyl)-1-(2-fluorophenyl)-acrylketone and 3,4-methylene-dioxy phenylhydrazine replaces 1-(4-itrile group phenyl)-3-(3 respectively; 4 methylenedioxyphenyls) acrylketone and 2-hydrazino pyridine obtain 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile; Yield 27%, mp:175-178 ℃ 1H-NMR (400M, CDCl 3) δ 3.09 (1H, dd J=17.1,7.0Hz), 3.86 (1H, dd, J=17.1,12.6Hz), 5.60 (1H, dd, J=12.6,7.0Hz), 5.88 (2H, sO-CH 2-O), 6.30 (1H, dd, J=8.40,1.96Hz), 6.33 (1H, d, J=8.40Hz), 6.87 (1H, d, J=1.96Hz), 7.03-7.29 (4H, m), 7.64 (2H, d, J=8.4Hz, C3 ' ' H), 7.75 (2H, d, J=8.4Hz) .EIMS (m/e, %) 385 (M +, 100).
Step 4The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, just with 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole 3-yl] benzene nitrile to obtain 4-[1-(3; The 4-methylenedioxyphenyl)-and 5-(2-fluorophenyl)-1H-pyrazole-3-yl] the benzene nitrile; Yield 88%, mp:154-156 ℃ 1H-NMR (400M, CDCl 3) δ 6.01 (2H, s, O-CH 2-O), 6.73 (2H, the AB system, J=8.08Hz), 6.89 (1H, s), 6.91 (1H, s), 7.10-7.17 (2H, m), 7.24 (1H, m), 7.37 (1H, m), 7.72 (2H, d, J=8.68Hz), 8.01 (2H, d, J=8.68Hz) .EIMS (m/e, %) 383 (M +, 100).
Embodiment 7The preparation of 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000301
Method is with embodiment 2; Just [1-(3 with 4-; The 4-methylenedioxyphenyl)-and 5-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 6) replaces 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] BM; Mp:171-173 ℃ 1H-NMR (400M, DMSO-d6) δ 6.09 (2H, s, O-CH2-O), 6.72 (1H, dd, J=8.40; 2.24Hz), 6.90 (1H, d, J=8.40Hz), 6.98 (1H, d, J=2.24Hz;), 7.23 (1H, s), 7.23-7.52 (5H, m contain NH), 7.97 (4H; The AB system, J=8.68Hz) 7.97 (2H, d, J=8.40Hz), 8.03 (1H, brs, NH).EIMS(m/e，100)，401(M +，100)。
Embodiment 8The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000311
Step 1The preparation of 1-(4-itrile group phenyl)-3-(3, the 4-Dimethoxyphenyl) acrylketone
Method is with embodiment 1 step 1, and just with 3, the 4-dimethoxy benzaldehyde replaces piperonylaldehyde to obtain 1-(4-itrile group phenyl)-3-(3, the 4-Dimethoxyphenyl) acrylketone, and mp:162-164 ℃, yield 73%, 1H-NMR (400M, CDCl3) δ 3.95 (1H, s, O-CH3), 3.96 (1H, s, O-CH3), 6.92 (1H; J=8.32), 7.16 (1H, d, J=2.04Hz), 7.26 (1H, dd, J=8.32,2.04Hz); 7.34 (1H, d, J=15.6Hz, CH=), 7.77 (1H, d, J=15.6Hz, CH=); 7.82 (2H, d, J=6.56Hz), 8.07 (2H, d, J=6.56Hz) .EIMS (m/e, 100), 293 (M +, 100), 278 (M +-CH3,35), 262 (M +-CH30,58).
Step 2The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces 1-(4-itrile group phenyl)-3-(3 with 1-(4-itrile group phenyl)-3-(3, the 4-Dimethoxyphenyl) acrylketone with embodiment 1 step 2; 4 methylenedioxyphenyls) acrylketone obtains 4-[5-(3,4-methylenedioxy group phenyl)-1-(pyridine-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile; Yield 86%, mp:151-154 ℃ 1H-NMR (400M, CDCl 3) δ 3.18 (1H, dd, J=17.24,5.52Hz), 3.78 (1H, dd, J=17.24,12.32Hz), 3.82 (6H; S+s), 5.80 (1H, dd, J=12.32,5.52Hz), 6.76-6.80 (5H, m), 7.45 (1H, d; J=8.28Hz), 7.55 (1H, dd, J=8.28,7.04Hz), 7.67 (2H, d, J=8.44Hz); 7.81 (2H, d, J=8.44Hz), 8.09 (1H, d, J=5.80) .EIMS (m/e, 100), 384 (M +, 40), 255 (100).
Step 3The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, just with 4-[5-(3,4-methylenedioxy group phenyl)-1-(pyridine-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] [5-(3 for benzene nitrile replacement 4-; The 4-methylenedioxyphenyl)-and 1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile obtains 4-[5-(3,4-methylenedioxy group phenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile; Mp:202-204 ℃ 1H-NMR (400M, CDCl 3) δ 3.73 (3H, s, OCH 3), 3.91 (3H, s, OCH 3), 6.78 (1H, d, J=1.40Hz), 6.84 (1H, d, J=8.12Hz), 6.89 (1H, dd; J=8.12,1.40Hz), 7.32 (1H, dd, J=6.76,4.52Hz), 7.47 (1H, d; J=8.12Hz), 7.73 (2H, d, J=8.40Hz), 7.82 (1H, dd, J=8.12,6.76Hz); 8.06 (2H, d, J=8.40Hz), 8.52 (1H, d, J=4.52Hz) .EIMS (m/e, 100), 382 (M +, 100).
Embodiment 9The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
Method is with embodiment 1 step; Just [5-(3 with 4-; 4-methylenedioxy group phenyl)-and 1-(pyridine-2-yl)-1H-pyrazole-3-yl] the benzene nitrile replaces 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-[5-(3,4-methylenedioxy group phenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM; Mp:219-221 ℃ 1H-NMR (400M, DMSO-d6) δ 3.72 (3H, s, O-CH3), 3.88 (3H, s, O-CH3), 5.68 (1H, brs, NH); 6.20 (1H, brs, NH), 6.77 (1H, d, J=1.68Hz), 6.84 (1H, d, J=8.4Hz), 6.86 (1H; S, C4H), 6.88 (1H, dd, J=8.4,1.68Hz), 7.28 (1H, dd, J=7.56,5.04Hz); 7.47 (1H, d, J=8.12Hz), 7.79 (1H, dd, J=8.12,7.56Hz), 7.89 (2H, d; J=8.4Hz), 8.02 (2H, d, J=8.4Hz), 8.49 (1H, d, J=5.04Hz) .EIMS (m/e, 100), 400 (M +, 100) and .EI-HRMS:C 23H 2ON 4O 3Calculated value: 400.1535 measured values: 387.1383.
Embodiment 10The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Step 1The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2, and just (method for making sees that embodiment 5 step 1) and 2-fluorobenzene hydrazine replace 1-(4-itrile group phenyl)-3-(3 respectively with 1-(4-itrile group phenyl)-3-(3, the 4-Dimethoxyphenyl) acrylketone; The 4-methylenedioxyphenyl) acrylketone and 2-hydrazino pyridine obtain 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile; Yield 78%, mp:147-149 ℃ 1H-NMR (400M, CDCl 3) δ 3.27 (1H, dd, J=16.84,5.04Hz), 3.76 (3H, s, O-CH3), 3.79 (3H, s; O-CH3), 5.66 (1H, m), 6.65 (1H, s), 6.72 (2H, AB, J=8.12Hz), 6.83-6.92 (2H; M), 7.02 (1H, t (dd), J=7.28,7.84Hz), 7.55 (1H, dd, J=8.40,8.40Hz); 7.66 (2H, d, J=8.4Hz), 7.79 (2H, d, J=8.4Hz) .EIMS (m/e, 100), 401 (M +, 100).
Step 2The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile to obtain 4-[5-(3; The 4-Dimethoxyphenyl)-and 1-(2-fluorophenyl)-1H-pyrazole-3-yl] the benzene nitrile; Mp:202-204 ℃ 1H-NMR (400M, CDCl 3) δ 3.66 (3H, s, OCH3), 3.88 (3H, s, OCH3), 6.70 (1H, d; J=1.96Hz), 6.82 (1H, d, J=8.40Hz), 6.87 (1H, s), 6.88 (1H, dd; J=8.40,1.96Hz), 7.14 (1H, m), 7.27 (1H, m), 7.42 (1H, m); 7.55 (1H, m), 7.72 (2H, 8.40Hz), 8.00 (2H, 8.40Hz) .EIMS (m/e, 100), 399 (M +, 93), 384 (M +-CH3,10).
Embodiment 11The preparation of 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000341
Method is with embodiment 1 step 4; Just [5-(3 with 4-; The 4-Dimethoxyphenyl)-and 1-(2-fluorophenyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 8) replaces 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM; Mp:103-105 ℃ 1H-NMR (400M, CDCl 3) δ 3.66 (3H, s, O-CH3), 3.87 (3H, s, O-CH3), 5.77 (1H, brs, NH), 6.21 (1H, brs, NH); 6.71 (1H, brs, C2 " ' H), 6.81 (1H, d, J=8.4Hz, C6 " ' H), 6.88-6.90 (3H, m, C4H, C5 " ' H); 7.13 (1H, dd, J=9.52,8.68Hz, C5 " ' H), 7.28 (1H, dd, J-7.56,5.04Hz, C4 ' H), 7.41 (1H; D, J=8.12Hz, C6 ' H), 7.57 (1H, dd, J=8.12,7.56Hz, C5 ' H), 7.89 (2H, d, J=8.40; C3 " H), 8.02 (2H, d, J=8.40, c2 " H), 8.49 (1H, d, J=5.04Hz, C3 ' H) .EI-MS (m/e, %), 417 (M +, 100), 402 (M +-NH, 8), 374 (402-CO), EI-HRMS:C 24H 2ON 3O 3F calculated value 417.1488, measured value 417.1483.
Embodiment 12The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000351
Step 12-diazanyl thiazole hydrochloride is referring to document
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces the 2-hydrazino pyridine with 2-diazanyl thiazole hydrochloride with embodiment 1 step 2, obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, yield 72%, and mp:175-177 ℃, 1H-NMR (400M, CDCl 3) δ 3.23 (1H, dd, J=17.36,9.86Hz), 3.86 (1H, dd, J=17.36,12.04Hz), 5.67 (1H, dd, J=12.04,9.86Hz), 5.93 (2H, s, O-CH 2-O), 6.66 (1H, d, J=3.64Hz), 6.75 (1H, d, J=1.54Hz), 6.77 (1H, d; J=7.84Hz), 6.81 (1H, dd, J=7.84,1.54Hz), 7.21 (1H, d, J=3.64Hz), 7.70 (2H; D, J=8.12Hz), 7.80 (2H, d, J=8.12Hz) .EI-MS (m/e, %), 374 (M +, 100), 245 (70).
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile to obtain 4-[5-(3; The 4-methylenedioxyphenyl)-and 1-(thiazol-2-yl)-1H-pyrazole-3-yl] the benzene nitrile; Yield 92%, mp:200-202 ℃ 1H-NMR (400M, CDCl 3) δ 6.04 (2H, s, O-CH2-O), 6.78 (1H, s), 6.87 (1H, d, J=7.84Hz); 6.95 (1H, d, J=1.54Hz), 6.97 (1H, dd, J=7.84,1.54Hz); 7.20 (1H, d, J=3.36Hz), 7.52 (1H, d, J=3.36Hz), 7.74 (2H; D, J=8.12Hz), 8.00 (2H, d, J=8.12Hz) .EIMS (m/e, 100), 372 (M +, 93), 371 (M +-H, 100).
Embodiment 13The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000361
Method is with embodiment 1 step 4; [5-(3 just to replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 10); The 4-methylenedioxyphenyl)-and 1-(thiazol-2-yl)-1H-pyrazole-3-yl] BM; Yield: 80%, mp:188-190 ℃ 1H-NMR (400M, CDCl 3) δ 5.83 (1H, brs, NH), 6.04 (2H, s, O-CH2-O), 6.16 (1H, brs, NH); 6.79 (1H, s), 6.87 (1H, d, J=7.84Hz), 6.95 (1H, d, J=1.54Hz), 6.97 (1H; Dd, J=7.84,1.68Hz), 7.18 (1H, d, J=3.36Hz), 7.51 (1H, d, J=3.36Hz); 7.91 (2H, d, J=8.40Hz.), 8.00 (2H, d, J=8.40Hz) .EIMS (m/e, %), 390 (M +, 100), 389 (M +-H, 98), 371 (55).
Embodiment 14The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000362
Step 1The preparation of 2-trifluoromethyl phenyl hydrazine
Method is identical with embodiment 3 steps 1, just replaces the 2-fluoroaniline with the 2-5-trifluoromethylaniline, yield 52%, and mp:224-227 ℃, 1H-NMR (DMSO-d6) δ 7.16 [1H, dd (t), J=7.56,7.56Hz], 7.26 [1H, dd (t), J=8.12; 7.56Hz], 7.65 (1H, d, J=7.56) 7.67 (1H, d, J=8.12Hz); 8.13 (1H, brs), 10.35 (3H, brs) .ESIMS (+Q) (m/e, %), 177 (MH +, 70), 161 (MH +-NH 2, 100).
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces the 2-hydrazino pyridine with 2-trifluoromethyl phenyl hydrazine hydrochloride with embodiment 1 step 2, obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, yield 89%, mp:149-150 ℃ 1H-NMR (400M, CDCl 3) δ 3.18 (1H, dd, J=16.8,8.96Hz), 3.72 (1H, dd, J=16.8,11.76Hz), 5.43 (1H, dd; J=16.8,8.96Hz), 5.91 (2H, s, O-CH2-O), 6.72 (1H, d, J=8.40Hz), 6.75 (1H, dd; J=8.40,2.40Hz), 6.76 (1H, d, J=2.40Hz), 6.95 (1H, d, J=8.4Hz), 7.03 (1H; Dd (t), J=7.56,7.56Hz), 7.30 (1H, dd, J=8.40,7.56Hz), 7.66 (2H, d; J=8.4Hz), 6.67 (1H, d, J=7.56Hz), 7.74 (2H, d, J=8.4Hz) .EI-MS (m/e, %), 435 (M +, 100).
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-4; 5-dihydro-1 h-pyrazole-3-yl] benzene nitrile replacement 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Obtain 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] benzene nitrile, yield: 75%; Mp:106-108 ℃ 1H-NMR (400M, CDCl 3) δ 5.96 (2H, s, O-CH 2-O), 6.66 (1H, s), 6.69,6.70 (2H, the AB system, J=7.92Hz), 6.82 (1H, s), 7.32 (1H, m), 7.59 (2H, m), 7.71 (2H, d, J=8.12Hz), 7.84 (1H, m), 7.97 (2H, d, J=8.12Hz) .EI-MS (m/e, %), 433 (M +, 100).
Embodiment 15The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000381
Method is with embodiment 1 step 4; [5-(3 just to replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 12); The 4-methylenedioxyphenyl)-and 1-(2-trifluoromethyl)-1H-pyrazole-3-yl] BM; Yield: 66%, mp:132-134 ℃ 1H-NMR (400M, CDCl 3) δ 5.73 (1H, brs, NH), 5.95 (2H, s, O-CH 2-O), 6.17 (1H, brs, NH), 6.67 (1H, s), 6.70,6.71 (2H, AB systems; J=8.12Hz), 6.84 (1H, s), 7.35 (1H, m), 7.59 (2H, m), 7.85 (1H, m); 7.88 (2H, d, J=8.40Hz), 7.97 (2H, d, J=8.40Hz) .EI-MS (m/e, %), 451 (M +, 100), 433 (M +-H 2O, 40).
Embodiment 16The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
Step 1The preparation of 2-methoxyl group hydrazinobenzene hydrochloride salt
The benzene method is identical with embodiment 3 steps 1, just replaces the 2-fluoroaniline with the 2-anisidine, yield, and mp:116-118 ℃, 1H-NMR (400Hz, and DMSO-d6) 3.83 (3H, s, O-CH3), 5.97 (2H, s, O-CH 2-O), and 6.99-7.01 (4H, m, PhH), 7.62 (1H, br s NH), 9.94 (1H, br s NH).
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces the 2-hydrazino pyridine with 2-methoxyl group hydrazinobenzene hydrochloride salt with embodiment 1 step 2, obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, yield 55%, and mp:133-135 ℃, 1H-NMR (400M, CDCl 3) δ 3.25 (1H, dd, J=8.84,7.76Hz), 3.70 (1H, dd, J=16.84,12.04Hz), 3.80 (3H, s, O-CH 3), 5.77 (1H, dd, J=12.04,7.76Hz), 5.84 (2H, s, O-CH 2-O), 6.57 (3H, m), 6.76 (1H, dd, J=8.12,1.4Hz); 6.86 (1H, ddd, J=7.84,7.56,1.4Hz), 6.93 (1H, ddd; J=8.12,7.56,1.68Hz), 7.48 (1H, dd, J=7.84,1.68Hz); 7.65 (2H, d, J=8.4Hz), 7.78 (2H, d, J=8.4Hz) .EIMS (m/e, %) 397 (M +, 100).
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] benzene nitrile replacement 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Obtain 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile, yield: 88%; Mp:160-161 ℃ 1H-NMR (400M, CDCl 3) δ 3.57 (3H, s, O-CH 3), 5.95 (2H, s, O-CH 2-O), 6.72 (3H, m), 6.80 (1H, s), 6.94 (1H, d; J=8.40Hz), 7.06 (1H, d, J=7.72,7.28,1.4Hz), 7.40 (1H; Dd, J=8.40,7.28Hz), 7.44 (1H, d, J=7.72Hz), 7.70 (2H; D, J=8.4Hz), 8.00 (2H, d, J=8.4Hz) .FAB-MS (m/e, %), 396 (MH +, 92), 302 (100), 274 (M +-
Figure S06178014020060914D00039122359QIETU
, 78).
Embodiment 17The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000401
Method is with embodiment 1 step 4; [5-(3 just to replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 14); The 4-methylenedioxyphenyl)-and 1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM; Yield: 76%, mp:202-204 ℃ 1H-NMR (400M, CDCl 3) δ 3.58 (3H, s, O-CH 3), 5.64 (1H, brs, NH), 5.95 (2H, s, O-CH 2-O), 6.17 (1H, brs, NH), 6.72 (1H, d, J=8.12Hz), 6.73 (1H, d, J=1.68Hz); 6.74 (1H, dd, J=8.12,1.68Hz), 6.94 (1H, dd, J=8.40,1.12Hz), 7.06 (1H, ddd; J=7.84,7.56,1.12Hz), 7.40 (1H, ddd, J=8.40,7.56,1.68Hz), 7.48 (1H, dd; J=7.84,1.68Hz), 7.87 (2H, d, J=8.40Hz), 7.99 (2H, d, J=8.40Hz) .EI-MS (m/e, %) 413 (M +, 100), 382 (M +-OCH 3, 28) and .EI-HRMS:C 24H 19N 3O 4Calculated value 413.1376, measured value 417.1370.
Embodiment 18The preparation of 4-[5-(3, the 4-dihydroxy phenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
Under nitrogen protection; In the 5mL dichloromethane solution of 130mg (0.32mmol) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM, add the BBr3 dichloromethane solution of 1.88mL 1M; Then under this room temperature with this mixture continuously stirring 20 hours; Be evaporated to driedly, resistates obtains 4-[5-(3, the 4-hydroxy phenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM with silica gel column chromatography column purification (methylene chloride 100/2 wash-out); 35mg yield 30% 1H-NMR (400M, CDCl 3) δ 6.56 (1H, dd, J=8.40,2.24Hz), 6.61 (1H, d, J=8.40Hz), 6.73 (1H, d; J=2.24Hz), 6.89 (1H, ddd, J=7.607.60,1.12Hz), 6.92 (1H, d, J=8.12Hz), 7.02 (1H; S), 7.26-7.30 (2H, m), 7.36 (1H, brs, NH), 7.93 (4H, s); 8.01 (1H, brs, NH), 8.2-9.8 (3H, br, OH) .EIMS (m/e, %), 387 (M +, 100), 270 (M +-OH, 20) .EI-HRMS:C 22H 17N 3O 4Calculated value 387.1219, measured value 387.1215.
Embodiment 19The preparation of 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
Figure S06178014020060914D000411
Step 1The preparation of 1-(4-itrile group phenyl)-3-(4-fluorophenyl) acrylketone
Method embodiment 1 step 1 just replaces piperonylaldehyde with the 4-fluorobenzaldehyde, obtains 1-(4-itrile group phenyl)-3-(4-fluorophenyl) acrylketone, yield 64%, and mp:161-163 ℃, 1H-NMR (400M, CDCl 3) δ 7.14 (1H, dd, J=8.40,8.68Hz), 7.41 (1H, d, J=13.16Hz, CH=); 7.66 (1H, dd, J=8.40,5.6Hz), 7.79 (1H, d, J=13.16Hz, CH=); 7.83 (2H, d, J=8.40Hz), 8.08 (2H, d, J=8.40Hz) .EIMS (m/e, 100), 251 (M +, 100).
Step 2The preparation of 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2; Just replace 2-hydrazino pyridine and 1-(4-itrile group phenyl)-3-(3, the 4-methylenedioxyphenyl) acrylketone respectively, obtain 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-4 with 2-methoxyl group hydrazinobenzene hydrochloride salt and 1-(4-itrile group phenyl)-3-(4-fluorophenyl) acrylketone; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile; Yield: 34%, mp:150-152 ℃ 1H-NMR (400M, CDCl 3) δ 3.27 (1H, dd, J=16.80,4.76Hz), 3.70-3.78 (4H, m), 5.83 (1H, dd, J=12.36; 4.76Hz), 6.74 (1H, dd, J=8.12,1.40Hz), 6.80-6.89 (3H, m), 6.92 (1H, dd; J=7.60,1.68Hz), 7.05-7.10 (2H, m), 7.49 (1H, dd, J=7.84,1.68Hz), 7.66 (2H; D, J=8.40Hz, 7.79 (2H, d, J=8.40Hz), EIMS (m/e, 100), 369 (M +, 100), 338 (M +-CH 3O, 58).
Step 3The preparation of 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, and [5-(3 just to replace 4-with 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; The 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile, obtain 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile, yield 86%; Mp:167-169 ℃ 1H-NMR (400M, CDCl 3) δ 3.49 (3H, s, O-CH 3), 6.85 (1H, s, C4H), 6.90 (1H, d, J=8.4Hz), 6.97 (2H, dd; J=8.8,8.7Hz), 7.08 (1H, dd, J=7.6,7.8Hz), 7.22 (2H, dd, J=8.8; 5.3Hz), 7.40 (1H, ddd, J=8.4,7.8,1.4Hz), 7.49 (1H, dd, J=7.6; 1.4Hz), 7.71 (2H, d, J=8.4Hz), 8.00 (2H, d, J=8.4Hz) .FAB-MS (m/e, %) 370 (M +, 10), 133 (100).
Embodiment 20The preparation of 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000421
Method is with embodiment 1 step 4; [5-(3 just to replace 4-with 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 17); The 4-methylenedioxyphenyl)-and 1-(pyridine-2-yl)-1H-pyrazole-3-yl] the benzene nitrile obtains 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM; Yield: 72%, mp:205-207 ℃ 1H-NMR (400M, CDCl 3) δ 3.49 (3H, s, OCH 3), 5.68 (1H, brs, NH), 6.18 (1H, brs, NH), 6.87 (1H, s, C4H), 6.90 (1H; Dd, J=8.00Hz), 6.96 (2H, dd, J=8.68,8.68Hz), 7.08 (1H, ddd, J=7.84,7.56,1.12Hz); 7.39 (1H, ddd, J=8.00,7.56,1.68Hz), 7.52 (1H, dd, J=7.84,1.68Hz, C5 ' H), 7.23 (2H; Dd, J=8.68,5.32Hz, C2 " ' H), 7.88 (2H, d, J=8.40Hz), 7.99 (2H, d, J=8.40Hz).EI-MS (m/e, %) 387 (M +, 100), 356 (M +-CH 3O, 37) .HREIMS:C 23H 18N 3O 2F calculated value 387.1385, measured value 387.1383.
Embodiment 21The preparation of 4-[5-(4-fluorophenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000431
Method just replaces 4-with 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM with embodiment 16, and [5-(3; The 4-methylenedioxyphenyl)-and 1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM obtains 4-[5-(4-fluorophenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM; 30mg yield 36%; Mp:218-220 ℃ 1H-NMR (400M, DMSO-d6) δ 6.92 (2H, dd, J=7.84,7.28Hz), 7.19 (2H, dd; J=9.00,8.96Hz), 7.23 (1H, s, C4H), 7.29-7.38 (5H, m; PhH, NH), 7.95 (4H, s, C2 " H, C3 " H), 8.02 (1H; Brs, NH), 9.92 (1H, brs, OH) .EI-MS (m/e, %) 373 (M +, 100), 356 (M +-OH, 27), (344 M +-H-CO, 50) .EI-HRMS: calculated value C 22H 16N 3O 2F 373.1226, measured value 387.1235.
Embodiment 22The preparation of 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000441
Step 1The preparation of 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2; Just replace 1-(4-itrile group phenyl)-3-(3, the 4-methylenedioxyphenyl) acrylketone respectively, obtain 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-4 with 1-(4-itrile group phenyl)-3-(4-fluorophenyl) acrylketone; 5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile; Yield: 58%, mp:130-133 ℃ 1H-NMR (400M, CDCl 3) δ 3.15 (1H, dd, J=17.36,5.32Hz, C4H), 3.80 (1H, dd, J=17.36,12.60Hz; C4H), 5.86 (1H, dd, J=12.6,5.32Hz, C5H), 6.70 (1H, dd, J=7.00; 4.52Hz), 6.97 (2H, dd, J=8.72,8.68Hz), 7.24 (2H, dd, J=8.68,5.36Hz); 7.48 (1H, d, J=8.40Hz), 7.56 (1H, dd, J=8.40,7.00Hz), 7.68 (2H, d; J=8.72Hz), 7.81 (2H, d, J=8.72Hz), 8.04 (1H, d, J=4.52Hz), EI-MS (m/e, %) 342 (M +, 30), 213 (100).
Step 2The preparation of 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
In the 10mL dry-out benzene solution of 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile 280mg, add MnO 2/ SiO 2600mg (method for making is seen document), at room temperature continuously stirring is 60 hours, adds MnO therebetween 2/ SiO 2600mg+600mg; Raw material point disappears afterwards reaction mixture suction filtration methylene dichloride and methanol wash; Resistates silica gel column chromatography purifying (methylene chloride 100/2 wash-out) after concentrating obtains 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM, 256mg, yield 91%; Mp:214-216 ℃ 1H-NMR (400M, CDCl 3) δ 5.63 (1H, brs, NH), 6.16 (1H, brs, NH), 6.86 (1H, s); 7.05 (1H, dd, J=8.72,8.68Hz), 7.26-7.32 (3H, m), 7.61 (1H, d; J=8.16Hz), 7.82 (1H, ddd, J=8.16,7.56,1.68Hz), 7.90 (2H, d; J=8.40Hz), 8.02 (2H, d, J=8.40Hz, C3 " H), 8.38 (1H, m) .EIMS (m/e, %) 358 (M +, 70), 357 (M +-H, 100).
Embodiment 23The preparation of 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000451
Step 1The preparation of 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 2; Just replace 1-(4-itrile group phenyl)-3-(3 respectively with 1-(4-itrile group phenyl)-3-(4-fluorophenyl) acrylketone and 2-fluorobenzene hydrazine; The 4-methylenedioxyphenyl) acrylketone and 2-hydrazino pyridine obtain 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Yield 81%mp:140-141 ℃ 1H-NMR (400M, CDCl 3) δ 3.26 (1H, dd, J=16.80,4.80Hz), 3.78 (1H, dd, J=16.80; 12.08Hz), 5.71 (1H, dd, J=12.08,4.80Hz), 6.83 (4H, m); 7.03 (1H, m), 7.14 (2H, m), 7.57 (1H, m), 7.68 (2H; D, J=8.40Hz), 7.80 (2H, d, J=8.40Hz) .FAB-MS (m/e, 100), 360 (MH +, 100).
Step 2The preparation of 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Method is with embodiment 20 steps 3; Just replace 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile with 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Obtain 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM; Yield 86%, mp:167-169 ℃ 1H-NMR (400M, DMSO-d6) δ 7.23 (2H, dd, J=8.96,8.64Hz), 7.32-7.41 (5H, m contain NH), 7.55 (1H, m, C5 ' H), 7.70 (1H, m), 7.97 (4H, the AB system, J=8.40Hz), 8.02 (1H, brs, NH) .EI-MS (m/e, %) 375 (M +, 100), 359 (M +-NH 2, 70) and .EI-HRMS:C 22H 15N 3OF 2Calculated value 375.1183 measured values 387.1185.
Embodiment 24The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] benzene nitrile and 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000461
Step 1The preparation of 6-methyl-2-chloropyridine
Get 2-amino-6-picoline 8.28g (75mmol), dissolve with the 25mL concentrated hydrochloric acid down, be cooled to-15 ℃ at 0 ℃; The 3mL aqueous solution that adds 10.4g (150mmol) NaNO2, warm in keeping at-15 ℃ to 10 ℃, and under this temperature, continue reaction 1 hour; Then temperature is not higher than that to use 30% the NaOH aqueous solution that reaction solution is modulated the pH value under 0 ℃ the condition be 7 in keeping, and with the reaction mixture filtration, the filter cake ether washs out the solvend thing; Filtrating is used extracted with diethyl ether, and it is dry with MgSO4 to merge organic phase, and resistates column chromatography (eluent ethyl acetate) obtains 6-methyl-2-chloropyridine behind the evaporating solvent; Oily matter, yield 14%. 1H-NMR(400M，CDCl3)δ2.54(3H，s，CH3)，7.07(1H，d，J＝7.56Hz，C4H)，7.13(1H，d，J＝7.84Hz，C6H，7.53(1H，dd，J＝7.84，7.53Hz，C5H)。
Step 2The preparation of 6-methyl-2-hydrazino pyridine
Get 6-methyl-2-chloropyridine 2.7g (21.3mmol), be dissolved in the 30mL propyl carbinol, add 85% Hydrazine Hydrate 80 14g (85mmol); 110 ℃ of following vigorous stirring reactions of oil bath 60 hours; Cooling back removal of solvent under reduced pressure is used dissolve with methanol with resistates, adds an amount of NaHCO3 to remove HBr; Concentrated filtrate behind the filtering solid, resistates column chromatography purification (CH 2Cl 2/ CH 3OH) obtain 6-methyl-2-hydrazino pyridine 1.2g, yield 45%, mp: 1H-NMR (400M, CDCl 3) δ 3.57 (2H, brs, NH), 5.90 (1H, brs, NH), 6.55 (2H, m, C4H, C6H), 7.40 (1H, dd, J=8.12,7.56Hz).
Step 3The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces the 2-hydrazino pyridine with 6-methyl-2-hydrazino pyridine with embodiment 1 step 2, obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, yield: 63%, and mp:175-177 ℃, 1H-NMR (400M, CDCl 3) δ 3.17 (1H, dd, J=17.40,5.60Hz, C4H), 3.73 (1H, dd, J=17.40,12.36Hz, C4H), 5.78 (1H, dd, J=12.36,5.60Hz, C5H), 5.90 (2H, AB system, J=1.40Hz, O-CH 2-O), 6.55 (1H, d, J=7.28Hz), 6.72 (1H, d, J=8.00Hz); 6.73 (1H, d, J=1.64Hz), 6.79 (1H, dd, J=8.00,1.64Hz), 7.19 (1H; D, J=8.40Hz), 7.42 (1H, dd, J=8.40,7.28Hz), 7.67 (2H; D, J=8.72Hz), 7.80 (2H, d, J=8.72Hz) .EIMS (m/e, 100), 382 (M +, 20), 253 (100).
Step 4The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] benzene nitrile and 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] BM
In the 20mL dry-out benzene solution of 280mg 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, add MnO 2/ SiO 2(method for making is seen document) 2g, at room temperature continuously stirring is 2 days, and raw material point disappears; Suction filtration methylene dichloride and methanol wash, filtrating concentrates back silica gel column chromatography separation (methylene chloride 100/0.5100/2 gradient elution) and obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] benzene nitrile; 70mg; Yield 25%, mp:163-165 ℃ 1H-NMR (400M, CDCl 3) δ 2.51 (1H, s, CH3), 5.99 (2H, s, O-CH 2-O), 6.77-6.81 (4H, m), 7.15 (1H, d, J=7.44Hz), 7.20 (1H, d, J=7.88Hz), 7.66 (1H, dd, J=7.88,7.44Hz), 7.72 (2H, d, J=7.70Hz), 8.02 (2H, d, J=7.70Hz) .EI-MS (m/e, %) 380 (M +, 75), 379 (M +-H, 100). and 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] BM, 190mg, yield 65%, mp:155-157 ℃, 1H-NMR (400M, DMSO-d6) δ 2.34 (3H, s, CH 3), 6.05 (2H, s, O-CH 2-O), 6.77 (1H, dd, J=8.16,1.68Hz), 6.86 (1H, d, J=1.68Hz), 6.90 (1H, d; J=8.16Hz), 7.21 (01H, s, C4H), 7.31 (1H, d, J=7.56Hz), 7.39 (1H, brs; NH), 7.45 (1H, d, J=7.84Hz), 7.88 (1H, dd, J=7.84,7.56Hz), 7.97 (2H; D, J=8.40Hz), 7.99 (2H, d, J=8.40), 8.03 (1H, brs, NH) .EI-MS (m/e, %) 398 (M +, 82), 397 (M +-H, 100), 379 (M +-H20,85).
Embodiment 25The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] benzene nitrile
Step 1The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile
Method just replaces the 2-hydrazino pyridine with 2-diazanyl benzene with embodiment 1 step 2, obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-phenyl base)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile, and yield 94%mp:141-143 ℃, 1H-NMR (400M, CDCl 3) δ 3.11 (1H, dd, J=17.12,6.72Hz), 3.78 (1H, dd, J=17.12,8.64Hz), 5.29 (1H; Dd, J=8.64,6.72Hz), 5.92 (2H, s), 6.70-6.79 (3H, m), 6.84 (1H, t; J=7.36Hz), 7.11 (2H, d, J=9.04Hz), 7.21 (2H, dd, J=9.04,7.36Hz); 7.65 (2H, d, J=8.40Hz), 7.76 (2H, d, J=8.40Hz) .EI-MS (m/e, %), 367 (M +, 100), 91 (65).
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] benzene nitrile
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] benzene nitrile replacement 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile; Obtain 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] benzene nitrile, yield 71%; Mp:136-138 ℃ 1H-NMR (400M, CDCl 3) 5.99 (2H, s), 6.70 (1H, m), 6.77 (2H, s+s), 6.79 (1H, s), 6.36-6.39 (5H, m), 7.72 (2H, d, J=8.40Hz), 8.00 (2H, d, J=8.40Hz) .EIMS (m/e), 365 (M +, 100).
Embodiment 26The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000491
Method is with embodiment 2; [5-(3 just to replace 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 6); The 4-methylenedioxyphenyl)-and 1-(phenyl)-1H-pyrazole-3-yl] BM; Yield 80%, mp:170-172 ℃ 1H-NMR (400M, CDCl3) δ 5.82 (1H, brs, NH), 5.99 (2H, s), 6.20 (1H, brs; NH), 6.71 (1H, s), 6.77 (2H, s+s), 6.80 (1H, s), 7.32-7.39 (5H; M), 7.89 (2h, d, J=8.40Hz), 7.99 (2H, d, J=8.40Hz) .EIMS (m/s), 383 (M +, 100).
Embodiment 27The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Figure S06178014020060914D000492
Step 1The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] BM
Method is with embodiment 1 step 4, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 3 steps 2) replaces 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] benzene nitrile to obtain 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] BM; Yield: 80%, mp:218-220 ℃ 1H-NMR (400M, CDCl 3) δ 3.27 (1H, dd, J=16.84,4.56Hz, C4H), 3.77 (1H, dd, J=16.84,11.68Hz; C4H), 5.63 (1H, brs, NH), 5.63 (1H, m, C5H), 5.87 (2H, s; O-CH2-O), 6.11 (1H, brs, NH), 6.65 (1H, dd, J=8.08,1.52Hz), 6.64 (1H; D, J=1.52Hz), 6.67 (1H, d, J=8.08Hz), 6.82-6.85 (1H, m), 6.88-6.94 (1H, m); 7.01-7.05 (1H, m), 7.59 (1H, m), 7.82 (4H, AB system, J=8.56Hz) .EI-MS (m/e, %) 403 (M +, 80), 368 (M +-H2O), 260 (100).
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
Method is with embodiment 1 step 3, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] [5-(3 for BM (compound method is seen embodiment 26) replacement 4-; The 4-methylenedioxyphenyl)-and 1-(pyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-yl] the benzene nitrile obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM; Yield 84%, mp:214-216 ℃ 1H-NMR (400M, DMSO) δ 6.04 (2H, s), 5.63 (1H, m, C5H), 6.67 (1H, dd, J=8.12,1.96Hz; C6 " ' H), 6.74 (1H, dd, J=8.04,1.76Hz), 6.84 (1H, d, J=1.76Hz), 6.89 (1H; d, J=8.04Hz), 7.25 (1H, s), 7.39 (3H, m contain NH), 7.55 (1H, m); 7.68 (1H, m), 7.96 (4H, s), 8.04 (1H, brs, NH) .EI-MS (m/e, %), 401 (M +, 100).
Embodiment 28The benzoic preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-pyrazole-3-yl]
Figure S06178014020060914D000501
Step 1The benzoic preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl]
Get 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] benzene nitrile (compound method is seen embodiment 3 steps 2); 383mg (1mmol) uses the 5mL dissolve with ethanol, adds the 3mL 20% NaOH aqueous solution again, and heating was reacted 3 hours down at 60 ℃; After reducing to room temperature reaction solution is concentrated into no ethanol, and then adds 4mL water, under ice bath with the careful acidifying of concentrated hydrochloric acid; Have solid to separate out, the washing back is air-dry, obtains the 390mg yellow solid; Yield 96%, mp:225-227 ℃ 1H-NMR (400M, DMSO-d6) δ 3.25 (1H, dd, J=17.36,4.76Hz), 3.84 (1H, dd, J=17.36,11.36Hz), 5.62 (1H; M), 5.92 (2H, s+s, O-CH2-O), 6.66 (1H, d, J=8.40Hz), 6.68 (1H, s), 6.75 (1H; D, J=8.40Hz), 6.84-6.90 (1H, m), 7.02-7.09 (2H, m), 7.52 (1H, ddd, J=8.72,8.12; 1.68Hz), 7.86 (2H, d, J=8.40Hz), 7.97 (2H, d, J=8.40Hz), 12.96 (1H, brs, COOH).FABMS(m/e，％)405(MH +，100)，387(M +-OH，35)。
Step 2The benzoic preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl]
Method is with embodiment 1 step 4, just with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4; 5-dihydro-1 h-pyrazole-3-yl] [5-(3 for phenylformic acid (compound method is seen embodiment 29) replacement 4-; The 4-methylenedioxyphenyl)-and 1-(pyridine-2-yl)-1H-pyrazole-3-yl] the benzene nitrile obtains 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] phenylformic acid, yield: 70%; Mp:206-208 ℃ 1H-NMR (400M, CDC13) 5.98 (2H, s, O-CH 2-O), 6.74-6.75 (3H, m), 6.68 (1H, s), 7.13 (1H, dd, J=8.40; 8.68Hz), 6.84-6.90 (1H, m), 7.02-7.09 (2H, m), 7.52 (1H, dd, J=8.72,8.12Hz); 7.26 (1H, dd,, J=7.84,7.52Hz), 7.40 (1H, m), 7.57 (1H, dd; J=7.84,7.52Hz), 8.00 (2H, d, J=8.40Hz), 8.16 (2H, d, J=8.40Hz).EIMS(m/e，100)，402(M +，100)。
Embodiment 29The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] phenylcarbinol
Figure S06178014020060914D000511
(method for making is seen embodiment 28 to phenylformic acid with 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl]; Step 1) 115mg (0.285mmol) is dissolved among the anhydrous THF of 3mL; Add 25mg LiA1H4 (98%) in two batches, react 1.5h under the room temperature, add by water saturated ether to dispose unreacted LiA1H4; Then with water washing once with reaction solution; Concentrate the back and obtain target compound 83mg, yield 75%, oily matter with silica gel column chromatography separation (methylene chloride wash-out). 1H-NMR(400M，CDCl3)δ3.23(1H，dd，J＝16.80，4.08Hz，C4H)，3.74(1H，dd，J＝16.80，11.76Hz，C4H)，5.13(2H，s，CH 2-OH)，5.56(2H，dd，J＝11.76，4.08Hz，C5H)，5.59(2H，s，O-CH 2-O)，6.61(1H，d，J＝7.84Hz)，6.64(1H，d，J＝1.68Hz)，6.66(1H，dd，J＝7.84，1.68Hz)，6.77-6.82(1H，m)，6.86-6.92(1H，m)，6.99-7.03(1H，m)，7.40(2H，d，J＝8.12Hz)，7.56-7.59(1H，m)，7.73(2H，d，J＝8.12Hz).FABMS(m/e，100)389(M +-H，10)，373(M +-OH，40)。
Step 2The preparation of 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] phenylcarbinol
4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-4,5-dihydro-1 h-pyrazole-3-yl] phenylformic acid (method for making is seen embodiment 32) 115mg (0.285mmol) is dissolved among the anhydrous THF of 3mL; Add 25mg LiA1H4 (98%) in two batches, react 1.5h under the room temperature, add by water saturated ether to dispose unreacted LiA1H4; Then with water washing once with reaction solution; Concentrate the back and obtain target compound 83mg, yield 75% with silica gel column chromatography separation (methylene chloride wash-out) 1H-NMR (400M, CDCl 3) δ 4.74 (2H, s, CH 2-OH), 5.97 (2H, s, O-CH 2-O), 6.72-6.77 (3H, m), 6.79 (1H, s, C4H), 7.11 (1H, m), 7.26 (1H, m), 7.39 (1H, m), 7.44 (2H, d, J=8.16Hz), 7.57 (1H, m), 7.89 (2H, d, J=8.16Hz) .EIMS (m/e, 100), 388 (M +, 100), 371 (M +-OH, 12).
Embodiment 30The preparation of 5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles.
Figure S06178014020060914D000521
Step 1The preparation of former yellow acid ethyl ester is referring to Synthesis Communication1989,19,533.
Step 2The preparation of 3-(3, the 4-methylenedioxyphenyl)-3-oxo ethyl thio.
The suspended substance of the 10ml trimethyl carbinol of trimethyl carbinol first 1.22g (10.95mmol) is cooled to 0 ℃, successively adds former yellow acid ethyl ester 497mg (3.65mmol) and 3,4-methylene-dioxy phenyl methyl ketone 600mg (3.65mmol) then; Reaction is at room temperature spent the night, and reaction solution is poured in the frozen water Hydrogen chloride acidifying with 5%; ETHYLE ACETATE washs out product, and organic layer is with washing back anhydrous sodium sulfate drying, and resistates is used purification by silica gel column chromatography behind the evaporating solvent; Petroleum ether obtains 3-(3, the 4-methylenedioxyphenyl)-3-oxo propane thioic acid second; 406mg, yield 47%, mp:80-83 ℃. 1H-NMR (400M, CDCl 3) δ 1.42 (3H, m, CH 2CH 3), 4.37 (0.6H, s), 4.52 (2H, m, CH 2CH 3), 6.04+6.06 (2H, s+s), 6.27 (0.7H, s), 6.86+6.87 (1H, d+d; J=8.12Hz), and 7.30+7.45 (1H, d+d, J=1.68Hz), 7.42+7.57 (1H, dd+dd; J=8.12,1.68Hz), 14.19 (0.7H, s) .FAB-MS (m/e, 100), 253 (MH +, 40) and 207 (M +OC 2H 5, 13).
Step 35-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
2-fluorophenyl hydrochloride 138mg (0.85mmol) and 3-(3, the 4-methylenedioxyphenyl)-3-oxo ethyl thio 200mg (0.85mmol) are dissolved with the 5mL acetonitrile, add triethylamine 258mg (255mmol); At room temperature continuous 14 hours; Directly mix kind column chromatography purification methylene dichloride/sherwood oil 1/1 wash-out behind the concentration of reaction solution and obtain 180mg, yield 65%; Mp:99-102 ℃ 1H-NMR (400M, CDCl 3), δ 1.42 (3H, t, J=7.00Hz, CH 2CH 3), 4.29 (2H, q, J=7.00Hz, CH 2CH 3), 5.92 (1H, s), 5.94 (2H, s), 6.67 (1H, d, J=1.68Hz); 6.68 (1H, d, J=1.68Hz), 6.69 (1H, s), 7.06-7.09 (1H, m), 7.17-7.23 (1H; M), and 7.29-7.33 (1H, m), 7.41-7.46 (1H, m) .FAB-MS (m/e, 100), 327 (MH +, 100).
Embodiment 31The preparation of 5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-3-oxyethyl group-1H-pyrazoles
Figure S06178014020060914D000541
Method just replaces 2-fluorophenyl hydrochloride with 2-p-methoxy-phenyl hydrochloride with embodiment 30 steps 3, obtains 5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-3-oxyethyl group-1H-pyrazoles, yield 68%, 1H-NMR (40M, CDCl 3), δ 1.41 (3H, t, J=7.00Hz, CH 2CH 3), 3.56 (3H, s), 4.28 (2H, q, J=7.00Hz, CH 2CH 3), 5.89 (1H, s), 5.91 (2H, s), 6.67 (3H, m), 6.88 (1H; D, J=8.12Hz), 6.69 (1H, dd, J=7.84,7.56Hz), 7.31 (1H, ddd; J=8.12,7.56,1.68Hz), 7.36 (1H, dd, J=7.84,1.68Hz) .FABMS (m/e, 100) 339 (MH +, 100).
Embodiment 32The preparation of 5-(4-fluorophenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles.
Figure S06178014020060914D000542
Step 1The preparation of 3-(4-fluorophenyl)-3-oxo ethyl thio.
Method just replaces 3 with 4-fluorobenzene acetyl with embodiment 30 steps 2, and 4-methylene-dioxy phenylacetyl obtains 3-(4-fluorophenyl)-3-oxo ethyl thio, yield 55%, 1H-NMR (400M, CDCl 3) δ 1.43 (3H, t, J=7.28Hz), 4.54 (2H, q, J=7.28Hz), 6.31 (1H, s), 7.17 (2H, m), 7.84 (2H, m), 14.17 (1H, s).
Step 25-(4-fluorophenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
Method is with embodiment 30 steps 3; Just obtain 5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles with what 3-(4-fluorophenyl)-3-oxo ethyl thio replaced 3-(3, the 4-methylenedioxyphenyl)-3-oxo ethyl thio; Yield 60% 1H-NMR (400M, CDCl 3), δ 1.40 (3H, t, J=6.92Hz, CH 2CH 3), 4.23 (2H, q, J=6.92Hz, CH 2CH 3), 5.93 (1H, s), 7.06-7.12 (2H, m), 7.19-7.28 (2H, m), 7.37-7.40 (1H, m), 7.53-7.58 (1H, m), 7.78-7.82 (2H, m) .FAB-MS (m/e, %), 301 (MH +, 100).
Embodiment 33The preparation of 5-phenyl-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles (LXZ906).
Figure S06178014020060914D000551
Step 1The preparation of 3-phenyl-3-oxo ethyl thio.
Method just replaces 3 with phenylacetyl with embodiment 30 steps 2, and 4-methylene-dioxy phenylacetyl obtains target compound, yield 55%, 1H-NMR (400M, CDCl 3) δ 1.43 (3H, t, J=7.28Hz), 4.54 (2H, q, J=7.28Hz), 6.31 (1H, s), 7.17 (2H, m), 7.84 (2H, m), 14.17 (1H, s).
Step 25-phenyl-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles
Method is with embodiment 30, and step 3 just obtains 5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-3-oxyethyl group-1H-pyrazoles, yield 60%, 1H-NMR (400M with what 3-(4-fluorophenyl)-3-oxo ethyl thio replaced 3-(3, the 4-methylenedioxyphenyl)-3-oxo ethyl thio; CDC13), and δ 1.41 (3H, t, J=6.92Hz, CH2CH3), 4.22 (2H; Q, J=6.92Hz, CH2CH3), 5.99 (1H, s), 7.19-7.27 (1H; M), and 7.31-7.38 (1H, m), 7.38-7.43 (3H, m), 7.56-7.60 (1H; M), 7.84-7.86 (2H, m) .FAB-MS (m/e, %), 282 (MH+, 100).
Embodiment 34The preparation of 5-(4-fluorophenyl)-1-(pyridine-2-yl)-3-thiol-1H-pyrazoles
Figure S06178014020060914D000561
Method is with embodiment 30 steps 3; Just replace 3-(3 respectively with 3-(4-fluorophenyl)-3-oxo ethyl thio and 2-hydrazino pyridine hydrochloride; The 4-methylenedioxyphenyl)-3-oxo ethyl thio and 2-fluorophenyl hydrochloride obtain 5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-3-oxyethyl group-1H-pyrazoles; Column chromatography for separation methylene dichloride/sherwood oil 1/1 wash-out obtains 5-(4-fluorophenyl)-1-(pyridine-2-yl)-3-thiol-1H-pyrazoles, yield 25%. 1H-NMR(400M，CDCl 3)，δ6.93(1H，s)，7.05(2H，m)，7.24(1H，dd，J＝7.28，5.60Hz)，7.80(2H，m)，7.89(1H，ddd，J＝8.40，7.28，1.96Hz)，8.10(1H，d，J＝8.40Hz)，8.49(1H，dd，J＝5.60，1.96Hz).ESI-MS(+Q)，270(M +-H，100)。
Embodiment 35The preparation of N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000562
Step 14-(4-fluorophenyl)-2, the preparation of 4-diketone methyl-butyrate
In three-necked bottle, add dimethyl oxalate (0.94g, 7.96mmol), 4-fluoro-methyl phenyl ketone (1.00g; 7.24mmol) and anhydrous methanol 15ml, stirring makes molten, slowly splashes into (15 minutes) 30% methanol solution of sodium methylate 3ml; 45 ℃ of reactions of oil bath heating 3 hours produce a large amount of white solids.Reduce to room temperature, vigorous stirring is 30 minutes in the impouring 15ml 2N HCI solution, and ice bath is reduced to 0 ℃ and stirred 30 minutes, suction filtration, and the frozen water washing, drying obtains 4-(4-fluorophenyl)-2,4-diketone methyl-butyrate 1.31g, yield 80.8%, mp123 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.87 (s, 3H), 7.14 (s, 1H), 7.39-7.44 (m, 2H), 8.17-8.19 (m, 2H), 14.88 (s, 1H).
Step 2The preparation of 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate
In eggplant-shape bottle, add 4-(4-fluorophenyl)-2,4-diketone methyl-butyrate (1.00g, 4.46mmol), 2-nitrophenyl hydrazine hydrochloride (0.93g; 4.91mmol) and anhydrous methanol 15ml, oil bath reflux 3 hours is reduced to room temperature, and ice bath is reduced to 0 ℃ and was stirred 30 minutes; Suction filtration, the frozen water washing obtains 1.29g 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate; Yield 84.8%, mp124 ℃ 1H-NMR (400MHz, DMSO-d6) δ 3.86 (s, 3H), 7.207.24 (m, 3H), 7.31-7.34 (m, 2H), 7.61-7.64 (m, 1H), 7.78-7.86 (m, 2H), 8.15-8.17 (m, 1H).
Step 3The preparation of 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid
In eggplant-shape bottle, add 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate (1.00g, 2.93mmol), 15ml THF, 1N NaOH 8ml, oil bath reflux 3 hours; Reduce to room temperature, add 6ml 2N HCI, CH2CI2 (2 * 20ml) extractions, combined dichloromethane solution; Anhydrous magnesium sulfate drying filters, and enriching soln is to 15ml; Ice bath is reduced to 0 ℃ and is separated out crystallization, and suction filtration obtains 0.92g 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid; Yield 96.0%, mp178 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.15-7.34 (m, 5H), 7.60-7.62 (m, 1H), 7.76-7.85 (m, 2H), 8.14-8.16 (m, 1H), 13.14 (s, 1H).
Step 4The preparation of N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
In three-necked bottle, add 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (0.25g, 0.76mmol), DCC (0.16g, 0.77mmol), HOBT (0.11g; 0.81mmol) and 10ml THF, stirring at room 30 minutes, 4-(phenoxy) phenylamino (0.14g; 0.76mmol) be dissolved among the 4ml THF and slowly splash into, stirring at room 24 hours removes by filter insolubles; Mix appearance, with ETHYLE ACETATE: sherwood oil 1:3 is an eluent, and silica gel column chromatography separates and obtains 0.25g N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-121; Yield 66.2%, mp185 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.98-7.13 (m, 5H), 7.21-7.25 (m, 3H), 7.34-7.40 (m, 4H), 7.71-7.88 (m, 5H), 8.17 (dd, J=7.8,1.5Hz, 1H), 10.29 (s, 1H); FAB-MS m/z [M+1] +495.1.
Embodiment 36The preparation of N-(pyridin-3-yl)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000581
Step 1The preparation of 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate
Method just replaces the 2-nitrophenyl hydrazine hydrochloride to obtain 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate with hydrazinobenzene hydrochloride salt with embodiment 35 steps 2, and mp124 ℃, 1H-NMR (400MHz, CD 3COCD 3-d6) δ 3.89 (s, 3H), 7.05 (s, 1H), 7.14-7.18 (m, 2H), 7.34-7.38 (m, 4H), 7.45-7.47 (m, 3H); FAB-MS m/z [M+1] +297.1.
Step 2The preparation of 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate; Mp178 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.08 (s, 1H), 7.19-7.24 (m, 2H), 7.29-7.34 (m, 4H), 7.44-7.47 (m, 3H), 13.00 (s, 1H).
Step 3The preparation of N-(pyridin-3-yl)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid; And replace 4-(phenoxy) phenylamino to obtain N-(pyridin-3-yl)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-014 with the 3-EL-970; Mp185 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.19-7.26 (m, 3H), 7.33-7.50 (m, 9H), 8.23-8.32 (m, 2H), 8.99-9.00 (m, 1H), 10.49 (s, 1H); FAB-MS m/z [M+1] +359.0.
Embodiment 37The preparation of N-[4-(phenoxy) phenyl]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000591
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-119 with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 36); Mp127 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.98-7.04 (m, 4H), 7.10-7.16 (m, 2H), 7.21-7.26 (m, 2H), 7.33-7.50 (m, 9H), 7.84-7.86 (m, 2H), 10.26 (s, 1H); FAB-MS m/z [M+1] +450.1.
Embodiment 38The preparation of N-benzyl-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 36); And replace 4-(phenoxy) phenylamino to obtain N-benzyl-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-112 with benzylamine; Mp149 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.46 (d, J=6.4Hz, 2H), 7.04 (s, 1H), 7.21-7.45 (m, 15H), 8.92 (t, J=6.4Hz, 1H); FAB-MS m/z [M+1] +372.1.
Embodiment 39The preparation of N-(pyridine-3-methylene radical)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 36); And replace 4-(phenoxy) phenylamino to obtain N-(pyridine-3-methylene radical)-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-118 with (pyridin-3-yl) methylamine; Mp149 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.47 (d, J=6.2Hz, 2H), 7.03 (s, 1H), 7.21-7.24 (m; 2H), 7.29-7.37 (m, 5H), 7.45 (m, 3H), 7.72-7.74 (m, 1H); 8.44-8.46 (m, 1H), 8.54-8.55 (m, 1H), 9.02 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +373.0.
Embodiment 40The preparation of N-[3-(imidazoles-1-yl) propyl group]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000602
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 36); And replace 4-(phenoxy) phenylamino to obtain N-[3-(imidazoles-1-yl) propyl group]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-115 with 3-(imidazoles-1-yl) propylamine; Mp65 ℃ 1H-NMR (400MHz, DMSO-d6) δ 1.94-1.97 (m, 2H), 3.24-3.26 (m, 2H), 4.00 (t, J=6.7Hz, 2H); 6.89 (s, 1H), 7.01 (s, 1H), 7.19-7.24 (m, 3H), 7.29-7.37 (m, 4H); 7.44-7.48 (m, 3H), 7.67 (s, 1H), 8.47 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +390.1.
Embodiment 41The preparation of N-[(furans-2-yl) methylene radical]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000611
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-phenyl-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 36); And replace 4-(phenoxy) phenylamino to obtain N-[(furans-2-yl) methylene radical]-1-phenyl-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-117 with (furans-2-yl) methylamine; Mp135 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.44 (d, J=5.9Hz, 2H), 6.25 (d, J=3.1Hz, 1H), 6.38-6.39 (m; 1H), 7.03 (s, 1H), 7.21-7.24 (m, 2H), 7.29-7.36 (m, 4H); 7.44-7.46 (m, 3H), 7.56 (s, 1H), 8.77 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +362.1.
Embodiment 42The preparation of N-benzyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000612
Step 14-[3,4-(methylene-dioxy) phenyl]-2, the preparation of 4-diketone methyl-butyrate
Method is with embodiment 35 steps 1, and just with 3,4-(methylene-dioxy) methyl phenyl ketone replaces 4-fluoro-methyl phenyl ketone to obtain 4-[3,4-(methylene-dioxy) phenyl]-2,4-diketone methyl-butyrate, and mp177 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.86 (s, 3H), 6.18 (s, 1H), 7.05-7.10 (m, 2H), 7.58 (s, 1H), 7.74-7.76 (m, 1H), 14.07 (s, 1H); EI-MS m/zM +250.0.
Step 2The preparation of 1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate
Method is with embodiment 35 steps 2, just with 4-[3,4-(methylene-dioxy) phenyl]-2; 4-diketone methyl-butyrate replaces 4-(4-fluorophenyl)-2, and 4-diketone methyl-butyrate obtains 1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate; Mp216 ℃ 1H-NMR (400MHz, DMSO-d6) δ 3.85 (s, 3H), 6.04 (s, 2H), 6.69 (dd, J=8.1,2.0Hz; 1H), 6.85-6.89 (m, 2H), 7.14 (s, 1H), 7.62 (dd, J=7.6,1.4Hz; 1H), 7.79-7.85 (m, 2H), 8.15 (dd, J=8.0,1.4Hz, 1H); FAB-MS m/z [M+1] +368.1.
Step 3The preparation of 1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid, mp202 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.04 (s, 2H), 6.69 (dd, J=8.1,1.7Hz, 1H), 6.84-6.89 (m; 2H), 7.06 (s, 1H), 7.60 (dd, J=7.8,1.4Hz, 1H), 7.76-7.84 (m; 2H), 8.14 (dd, J=8.0,1.4Hz, 1H), 13.09 (s, 1H); FAB-MS m/z [M+1] +354.0.
Step 4The preparation of N-benzyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-benzyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-221 with benzylamine; Mp165 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.42 (d, J=6.2Hz, 2H), 6.04 (s, 2H), 6.69 (dd, J=8.1; 1.7Hz, 1H), 6.83-6.89 (m, 2H), 7.02 (s, 1H), 7.23-7.32 (m; 5H), 7.65 (dd, J=7.8,1.4Hz, 1H), 7.77-7.85 (m, 2H); 8.13 (dd, J=8.1,1.4Hz, 1H), 8.86 (t, J=6.4Hz, 1H); FAB-MS m/z [M+1] +443.0.
Embodiment 43The preparation of N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000631
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-222, mp202 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.05 (s, 2H), 6.73 (dd, J=8.1,1.7Hz, 1H); 6.87-6.91 (m, 2H), 6.98-7.03 (m, 4H), 7.09-7.16 (m, 2H), 7.36-7.40 (m; 2H), 7.72 (dd, J=7.6,1.4Hz, 1H), 7.78-7.88 (m, 4H); 8.17 (dd, J=8.1,1.4Hz, 1H), 10.27 (s, 1H); FAB-MS m/z [M+1] +521.0.
Embodiment 44The preparation of N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000641
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-223 with the 3-EL-970; Mp233 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.05 (s, 2H), 6.73 (dd, J=8.1,1.7Hz, 1H); 6.88-6.91 (m, 2H), 7.18 (s, 1H), 7.38 (dd, J=8.4,4.8Hz; 1H), and 7.73-7.89 (m, 3H), 8.16-8.20 (m, 2H), 8.30 (dd, J=4.8; 1.7Hz, 1H), 8.97 (d, J=2.2Hz, 1H), 10.50 (s, 1H); FAB-MS m/z [M+1] +430.0.
Embodiment 45The preparation of N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000642
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-224 with (pyridin-3-yl) methylamine; Mp163 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.44 (d, J=6.2Hz, 2H), 6.04 (s, 2H), 6.69 (dd, J=8.1; 1.7Hz, 1H), 6.83-6.89 (m, 2H), 7.02 (s, 1H), 7.35-7.36 (m, 1H); 7.64-7.85 (m, 4H), 8.14 (dd, J=8.1,1.4Hz, 1H), 8.44 (dd, J=4.8; 1.7Hz, 1H), 8.52-8.53 (m, 1H), 8.97 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +444.2.
Embodiment 46The preparation of N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000651
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-225 with 3-(imidazoles-1-yl) propylamine replacement 4-(phenoxy) phenylamino; Mp214 ℃ 1H-NMR (400MHz, DMSO-d6) δ 1.92-1.95 (m, 2H), 3.21-3.22 (m, 2H), 3.98 (t, J=7.0Hz, 2H); 6.04 (s, 2H), 6.69 (dd, J=8.1,1.7Hz, 1H), 6.83-6.88 (m; 3H), 7.00 (s, 1H), 7.20 (s, 1H), 7.64-7.66 (m, 2H); 7.76-7.88 (m, 2H), 8.12-8.13 (m, 1H), 8.44 (t, J=5.8Hz, 1H); FAB-MS m/z [M+1] +461.1.
Embodiment 47The preparation of N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000661
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-226 with (furans-2-yl) methylamine replacement 4-(phenoxy) phenylamino; Mp151 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.41 (d, J=6.2Hz, 2H), 6.04 (s, 2H), 6.23 (d, J=2.5Hz, 1H); 6.38-6.39 (m, 1H), 6.69 (dd, J=8.1,1.7Hz, 1H), 6.83-6.89 (m, 2H), 7.02 (s; 1H), and 7.55-7.56 (m, 1H), 7.62-7.65 (m, 1H), 7.75-7.79 (m, 1H), 7.82-7.85 (m; 1H), 8.13 (dd, J=8.1,1.7Hz, 1H), 8.73 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +433.1.
Embodiment 48The preparation of N-cyclohexyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000662
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-cyclohexyl-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-227 with hexahydroaniline; Mp169 ℃ 1H-NMR (400MHz, DMSO-d6) δ 1.16-1.75 (m, 10H), 3.75-3.76 (m, 1H), 6.04 (s, 2H); 6.68 (dd, J--7.8,1.7Hz, 1H), 6.82-6.88 (m, 2H), 7.00 (s; 1H), 7.65 (dd, J=7.8,1.4Hz, 1H), 7.75-7.86 (m, 2H); 7.97 (d, J=8.4Hz, 1H), 8.13 (dd, J=8.1,1.4Hz, 1H); FAB-MS m/z [M+1] +435.1.
Embodiment 49The preparation of N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000671
Step 1The preparation of 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate
Method just replaces the 2-nitrophenyl hydrazine hydrochloride to obtain 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate with 2-chlorophenyl hydrazine hydrochloride with embodiment 35 steps 2, and mp109 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.86 (s, 3H), 7.17-7.31 (m, 5H), 7.52-7.74 (m, 4H); FAB-MS m/z [M+1] +331.0.
Step 2The preparation of 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate; Mp209 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.14-7.22 (m, 3H), 7.26-7.31 (m, 2H), 7.52-7.65 (m, 3H), 7.72 (dd, J=7.3,2.0Hz, 1H), 13.05 (s, 1H); FAB-MS m/z [M+1] +317.0.
Step 3The preparation of N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-131 with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid; Mp66 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.98-7.03 (m, 4H), 7.08-7.14 (m, 1H), 7.19-7.23 (m, 3H), 7.32-7.40 (m, 4H), 7.56-7.64 (m, 3H), 7.81-7.86 (m, 3H), 10.31 (s, 1H); FAB-MS m/z [M+1] +484.1.
Embodiment 50The preparation of N-(pyridine-3-methylene radical)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000681
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-(pyridine-3-methylene radical)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-132 with (pyridin-3-yl) methylamine; Mp133 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.45 (d, J=5.9Hz, 2H), 7.10 (s, 1H), 7.16-7.21 (m, 2H); 7.28-7.31 (m, 3H), 7.52-7.62 (m, 3H), 7.75-7.76 (m, 2H), 8.44-8.45 (m; 1H), 8.54 (d, J=1.7Hz, 1H), 9.04 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +407.1.
Embodiment 51The preparation of N-(pyridine-3 base)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000682
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-(pyridin-3-yl)-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-133 with the 3-EL-970; Mp220 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.19-7.40 (m, 6H), 7.56-7.64 (m, 3H), 7.84 (dd, J=7.1,2.2Hz, 1H), 8.22-8.25 (m, 1H), 8.30 (dd, J=4.5,1.4Hz, 1H), 9.00 (d, J=2.5Hz, 1H), 10.54 (s, 1H); FAB-MS m/z [M+1] +393.0.
Embodiment 52The preparation of N-benzyl-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-benzyl-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-134 with benzylamine; Mp161 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.43 (d, J=6.2Hz, 2H), 7.10 (s, 1H), 7.18-7.33 (m, 9H), 7.54-7.62 (m, 3H), 7.75-7.77 (m, 1H), 8.94 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +406.1.
Embodiment 53The preparation of N-[3-(imidazoles-1-yl) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000692
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-[3-(imidazoles-1-yl) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-135 with 3-(imidazoles-1-yl) propylamine; Mp165 ℃ 1H-NMR (400MHz, DMSO-d6) δ 1.93-1.96 (m, 2H), 3.23-3.24 (m, 2H), 3.99 (t, J=6.8Hz; 2H), 6.88 (s, 1H), 7.08 (s, 1H), 7.17-7.21 (m; 3H), and 7.28-7.31 (m, 2H), 7.53-7.66 (m, 4H), 7.76 (dd; J=7.4,1.7Hz, 1H), 8.52 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +424.0.
Embodiment 54The preparation of N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-136 with (furans-2-yl) methylamine; Mp131 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.42 (d, J=6.2Hz, 2H), 6.23-6.24 (m, 1H), 6.38-6.39 (m, 1H), 7.10-7.29 (m, 5H), 7.54-7.62 (m, 4H), 7.74-7.76 (m, 1H), 8.80 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +396.0.
Embodiment 55The preparation of N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000711
Method just replaces 4-(phenoxy) phenylamino to obtain N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-122 with (furans-2-yl) methylamine with embodiment 35 steps 4, and mp145 ℃, 1H-NMR (400MHz, DMSO-d6) δ 4.42 (d, J=5.9Hz, 2H), 6.23 (d, J=2.5Hz, 1H); 6.38-6.39 (m, 1H), 7.11 (s, 1H), 7.21-7.33 (m, 4H), 7.55-7.56 (m; 1H), and 7.63-7.66 (m, 1H), 7.78-7.84 (m, 2H), 8.14 (dd; J=7.8,1.4Hz, 1H), 8.76 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +407.1.
Embodiment 56The preparation of N-benzyl-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000712
Method just replaces 4-(phenoxy) phenylamino to obtain N-benzyl-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-123 with benzylamine with embodiment 35 steps 4, and mp152 ℃, 1H-NMR (400MHz, DMSO-d6) δ 4.42 (d, J=6.2Hz, 2H), 7.10 (s, 1H), 7.21-7.32 (m, 9H), 7.66 (dd, J=7.7,1.4Hz, 1H), 7.77-7.84 (m, 2H), 8.14 (dd, J=7.8,1.4Hz, 1H), 8.89 (t, J=6.2Hz, 1H); FAB-MSm/z [M+1] +417.1.
Embodiment 57The preparation of N-(pyridine-3 base)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000721
Method just replaces 4-(phenoxy) phenylamino to obtain N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-124 with the 3-EL-970 with embodiment 35 steps 4, and mp218 ℃, 1H-NMR (400MHz, DMSO-d6) δ 7.21-7.27 (m, 3H), 7.34-7.39 (m, 3H), 7.73-7.89 (m, 3H), 8.17-8.21 (m, 2H), 8.31 (dd, J=4.8,1.4Hz, 1H), 8.98 (d, J=2.2Hz, 1H), 10.52 (s, 1H); FAB-MS m/z [M+1] +404.0.
Embodiment 58The preparation of N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000722
Method just replaces 4-(phenoxy) phenylamino to obtain N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-125 with (pyridin-3-yl) methylamine with embodiment 35 steps 4, and mp177 ℃, 1H-NMR (400MHz, DMSO-d6) δ 4.44 (d, J=6.2Hz, 2H), 7.10 (s, 1H), 7.19-7.23 (m; 2H), and 7.30-7.36 (m, 3H), 7.65-7.85 (m, 4H), 8.15 (dd, J=8.0; 1.7Hz, 1H), 8.45 (dd, J=4.8,1.7Hz, 1H); 8.53 (d, J=1.7Hz, 1H), 8.99 (t, J=6.2Hz, 1H); FAB-MSm/z [M+1] +418.1.
Embodiment 59The preparation of N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000731
Method just replaces 4-(phenoxy) phenylamino to obtain N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-126 with 3-(imidazoles-1-yl) propylamine with embodiment 35 steps 4, and mp169 ℃, 1H-NMR (400MHz, DMSO-d6) δ 1.92-1.96 (m, 2H), 3.21-3.23 (m, 2H), 3.98 (t, J=7.0Hz; 2H), 6.88 (s, 1H), 7.08 (s, 1H), 7.19-7.23 (m, 3H); 7.30-7.34 (m, 2H), 7.64-7.67 (m, 2H), 7.77-7.86 (m, 2H), 8.15 (dd; J=8.0,1.7Hz, 1H), 8.47 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +435.1.
Embodiment 60The preparation of N-[4-(benzyloxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000732
Method just replaces 4-(phenoxy) phenylamino to obtain N-[4-(benzyloxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-127 with 4-(benzyloxy) aniline with embodiment 35 steps 4, and mp182 ℃, 1H-NMR (400MHz, DMSO-d6) δ 5.09 (s, 2H), 6.97-7.00 (m, 2H), 7.21-7.25 (m, 3H), 7.33-7.46 (m, 7H), 7.69-7.87 (m, 5H), 8.17 (dd, J=8.0,1.7Hz, 1H), 10.15 (s, 1H); FAB-MS m/z [M+1] +508.9.
Embodiment 61The preparation of N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000741
Method just replaces 4-(phenoxy) phenylamino to obtain N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-128 with 4-(phenyl) aniline with embodiment 35 steps 4, and mp182 ℃, 1H-NMR (400MHz, DMSO-d6) δ 7.22-7.27 (m, 3H), 7.34-7.39 (m, 3H), 7.44-7.48 (m, 2H); 7.66-7.69 (m, 4H), 7.74 (dd, J=7.8,1.1Hz, 1H), 7.81-7.95 (m; 4H), 8.19 (dd, J=8.1,1.1Hz, 1H), 10.39 (s, 1H); FAB-MS m/z [M+1] +478.9.
Embodiment 62The preparation of N-benzyl-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Step 1The preparation of 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate
Method just replaces the 2-nitrophenyl hydrazine hydrochloride to obtain 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate with 2-hydrazino pyridine hydrochloride with embodiment 35 steps 2, and mp140 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.88 (s, 3H), 7.16-7.22 (m, 3H), 7.29-7.33 (m, 2H), 7.50-7.52 (m, 1H), 7.74-7.76 (m, 1H), 8.05-8.10 (m, 1H), 8.36-8.37 (m, 1H); FAB-MS m/z [M+1] +298.0.
Step 2The system of 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid respectively
Method is with embodiment 35 steps 3; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate; Mp225 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.09 (s, 1H), 7.17-7.21 (m, 2H), 7.28-7.32 (m, 2H), 7.48-7.51 (m, 1H), 7.73-7.75 (m, 1H), 8.05-8.09 (m, 1H), 8.35-8.36 (m, 1H), 13.11 (s, 1H); FAB-MS m/z [M+1] +284.2.
Step 3The preparation of N-benzyl-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Be to replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid; And replace 4-(phenoxy) phenylamino to obtain N-benzyl-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-141 with benzylamine; Mp134 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.47 (d, J=6.4Hz, 2H), 7.04 (s, 1H), 7.19-7.26 (m, 3H); 7.30-7.33 (m, 6H), 7.47-7.49 (m, 1H), 7.77 (d, J=8.1Hz, 1H); 8.04-8.07 (m, 1H), 8.36-8.37 (m, 1H), 8.97 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +373.2.
Embodiment 63The preparation of N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-142 with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 62); Mp165 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.99-7.05 (m, 4H), 7.10-7.14 (m, 1H), 7.17-7.24 (m, 3H); 7.33-7.41 (m, 4H), 7.50-7.53 (m, 1H), 7.84-7.87 (m, 3H), 8.07-8.12 (m; 1H), 8.40 (dd, J=4.8,1.1Hz, 1H), 10.31 (s, 1H); FAB-MS m/z [M+1] +451.3.
Embodiment 64The preparation of N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000761
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 62); And replace 4-(phenoxy) phenylamino to obtain N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-143 with (furans-2-yl) methylamine; Mp170 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.46 (d, J=5.9Hz, 2H), 6.26-6.27 (m, 1H), 6.39-6.40 (m; 1H), 7.04 (s, 1H), 7.17-7.22 (m, 2H), 7.29-7.32 (m, 2H); 7.48-7.49 (m, 1H), 7.57-7.58 (m, 1H), 7.77-7.79 (m, 1H), 8.04-8.06 (m; 1H), 8.35-8.37 (m, 1H), 8.85 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +363.1.
Embodiment 65The preparation of N-(pyridin-3-yl)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 62); And replace 4-(phenoxy) phenylamino to obtain N-(pyridin-3-yl)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-144 with the 3-EL-970; Mp182 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.20-7.24 (m, 3H), 7.33-7.42 (m, 3H), 7.51-7.54 (m; 1H), 7.85 (d, J=7.8Hz, 1H), 8.08-8.12 (m, 1H); 8.24-8.33 (m, 2H), 8.41 (dd, J=5.0,1.1Hz, 1H); 9.00 (d, J=2.2Hz, 1H), 10.53 (s, 1H); FAB-MS m/z [M+1] +360.0.
Embodiment 66The preparation of N-(pyridine-3-methylene radical)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 62); And replace 4-(phenoxy) phenylamino to obtain N-(pyridine-3-methylene radical)-1-(pyridine-2-yl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-146 with (pyridin-3-yl) methylamine; Mp138 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.48 (d, J=6.2Hz, 2H), 7.04 (s, 1H), 7.17-7.22 (m; 2H), and 7.29-7.36 (m, 3H), 7.48-7.49 (m, 1H), 7.73-7.77 (m; 2H), and 8.04-8.06 (m, 1H), 8.37-8.38 (m, 1H), 8.45-8.46 (m; 1H), 8.55-8.56 (m, 1H), 9.08 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +374.0.
Embodiment 67The preparation of N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000772
Step 14-[3, the 4-dichlorophenyl]-2, the preparation of 4-diketone methyl-butyrate
Method is with embodiment 35 steps 1, and just with 3, the 4-dichloroacetophenone replaces 4-fluoro-methyl phenyl ketone to obtain 4-[3, the 4-dichlorophenyl]-2,4-diketone methyl-butyrate, and mp120 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.87 (s, 3H), 7.18 (s, 1H), 7.83-7.85 (m, 1H), 8.04-8.06 (m, 1H), 8.30 (s, 1H); FAB-MS m/z [M+1] +275.
Step 2The preparation of 1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazoles-3-methyl-formiate
Method is with embodiment 35 steps 2, and just with 4-[3, the 4-dichlorophenyl]-2,4-diketone methyl-butyrate replaces 4-(4-fluorophenyl)-2, and 4-diketone methyl-butyrate obtains 1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazoles-3-methyl-formiate, and mp218 ℃, 1H-NMR (400MHz, DMSO-d6) δ 3.86 (s, 3H), 7.16 (dd, J=8.4,2.0Hz, 1H), 7.39 (s, 1H), 7.61-7.69 (m, 3H), 7.81-7.89 (m, 2H), 8.20 (dd, J=7.7,2.0Hz, 1H); FAB-MS m/z [M+1] +392.0.
Step 3The preparation of 1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-methyl-formiate replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid, mp218 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.16 (dd, J=8.6,2.0Hz, 1H), 7.30 (s, 1H), 7.61-7.68 (m, 3H), 7.81-7.86 (m, 2H), 8.19 (dd, J=8.0,2.0Hz, 1H), 13.22 (s, 1H); FAB-MS m/z [M+1] +378.0.
Step 4The preparation of N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazole-3-formamide D-321, mp79 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.98-7.03 (m, 4H), 7.10-7.22 (m, 2H), 7.36-7.40 (m, 3H), 7.63-7.65 (m, 2H), 7.77-7.90 (m, 5H), 8.21 (dd, J=8.1,1.4Hz, 1H), 10.34 (s, 1H); FAB-MS m/z [M+1] +544.9.
Embodiment 68The preparation of N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000791
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 67) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[(furans-2-yl) methylene radical]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide D-322 with (furans-2-yl) methylamine replacement 4-(phenoxy) aniline; Mp132 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.41 (d, J=5.9Hz, 2H), 6.23 (d, J=3.1Hz, 1H); 6.37-6.39 (m, 1H), 7.17 (dd, J=8.4,2.0Hz, 1H), 7.25 (s; 1H), and 7.56-7.71 (m, 4H), 7.78-7.88 (m, 2H), 8.18 (dd; J=8.1,1.7Hz, 1H), 8.80 (t, J=6.0Hz, 1H); FAB-MS m/z [M+1] +456.9.
Embodiment 69The preparation of N-benzyl-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000792
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 67) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-benzyl-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide D-323 with benzylamine; Mp185 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.42 (d, J=6.2Hz, 2H), 7.18-7.32 (m, 7H), 7.60-7.63 (m, 2H), 7.70-7.73 (m, 1H), 7.80-7.87 (m, 2H), 8.18 (dd, J=8.2,1.4Hz, 1H), 8.92 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +467.0.
Embodiment 70The preparation of N-(pyridin-3-yl)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000801
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 67) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-(pyridine-3 base)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide D-324 with the 3-EL-970; Mp229 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.21 (dd, J=8.4,2.0Hz, 1H), 7.37-7.41 (m, 2H); 7.63-7.66 (m, 2H), 7.79-7.91 (m, 3H), 8.21-8.23 (m, 2H), 8.31-8.32 (m; 1H), 8.97 (d, J=2.2Hz, 1H), 10.56 (s, 1H); FAB-MS m/z [M+1] +454.0.
Embodiment 71The preparation of N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000811
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 67) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[3-(imidazoles-1-yl) propyl group]-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide D-325 with 3-(imidazoles-1-yl) propylamine replacement 4-(phenoxy) aniline; Mp188 ℃ 1H-NMR (400MHz, DMSO-d6) δ 1.93-1.95 (m, 2H), 3.21-3.24 (m, 2H), 3.98 (t; J=6.8Hz, 2H), 6.88 (s, 1H), 7.16-7.23 (m, 3H); 7.60-7.72 (m, 4H), 7.80-7.88 (m, 2H), 8.18 (dd, J=7.8; 1.7Hz, 1H), 8.51 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +485.1.
Embodiment 72The preparation of N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000812
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; The 4-dichlorophenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 67) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-(pyridine-3-methylene radical)-1-(2-nitrophenyl)-5-[3, the 4-dichlorophenyl]-1H-pyrazole-3-formamide D-326 with (pyridin-3-yl) methylamine; Mp186 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.44 (d, J=6.4Hz, 2H), 7.16-7.25 (m, 2H), 7.35-7.37 (m; 1H), and 7.60-7.73 (m, 4H), 7.81-7.87 (m, 2H), 8.18 (dd, J=8.0; 1.7Hz, 1H), 8.45 (dd, J=4.8,1.4Hz, 1H); 8.53 (d, J=1.7Hz, 1H), 9.03 (t, J=6.2Hz, 1H); FAB-MSm/z [M+1] +468.1.
Embodiment 73The preparation of N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000821
Step 1The preparation of 1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate
Method is with embodiment 35 steps 2, just with 4-[3,4-(methylene-dioxy) phenyl]-2; (method for making sees that embodiment 42 step 1) replace 4-(4-fluorophenyl)-2 to 4-diketone methyl-butyrate; 4-diketone methyl-butyrate, and replace the 2-nitrophenyl hydrazine hydrochloride to obtain 1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate with 2-chlorophenyl hydrazine hydrochloride; Mp167 ℃ 1H-NMR (400MHz, DMSO-d6) δ 3.85 (s, 3H), 6.02 (s, 2H), 6.67 (dd, J=8.1,2.0Hz, 1H), 6.82-6.87 (m, 2H), 7.15 (s, 1H), 7.53-7.72 (m, 4H); FAB-MS m/z [M+1] +357.
Step 2The preparation of 1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just with 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid, mp222 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.02 (s, 2H), 6.67 (dd, J=8.2,2.0Hz, 1H), 6.80-6.86 (m, 2H), 7.06 (s, 1H), 7.53-7.71 (m, 4H), 12.98 (s, 1H); FAB-MS m/z [M+1] +343.1.
Step 3The preparation of N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just with 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-231, mp161 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.03 (s, 2H), 6.73 (dd, J=8.1,2.0Hz, 1H), 6.85-7.02 (m, 6H), 7.08-7.15 (m, 2H), 7.33-7.40 (m, 2H), 7.55-7.86 (m, 6H), 10.26 (s, 1H); FAB-MS m/z [M+1] +510.1.
Embodiment 74The preparation of N-[4-(benzyloxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000831
Method is with embodiment 35 steps 4; Just with 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 73) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-[4-(benzyloxy) phenyl]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-232 with 4-(benzyloxy) aniline; Mp185 ℃ 1H-NMR (400MHz, DMSO-d6) δ 5.09 (s, 2H), 6.03 (s, 2H), 6.71-6.73 (m, 1H); 6.82-6.88 (m, 2H), 6.97-6.99 (m, 2H), 7.13 (s, 1H), 7.33-7.46 (m; 5H), 7.55-7.66 (m, 3H), 7.71-7.80 (m, 3H), 10.11 (s, 1H); FAB-MS m/z [M+1] +524.1.
Embodiment 75The preparation of N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000841
Method is with embodiment 35 steps 4; Just with 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 73) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[(furans-2-yl) methylene radical]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-234 with (furans-2-yl) methylamine replacement 4-(phenoxy) aniline; Mp136 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.41 (d, J=6.2Hz, 2H), 6.02 (s, 2H), 6.23-6.24 (m; 1H), 6.38-6.39 (m, 1H), 6.69 (dd, J=8.1,2.0Hz, 1H); 6.81-6.87 (m, 2H), 7.03 (s, 1H), 7.52-7.62 (m, 4H), 7.73 (dd; J=7.3,2.0Hz, 1H), 8.77 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +422.4.
Embodiment 76The preparation of N-(naphthalene-1-yl)-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000842
Method is with embodiment 35 steps 4; Just with 1-(2-chloro-phenyl-)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 73) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-(naphthalene-1-yl)-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-236 with naphthalidine; Mp165 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.04 (s, 2H), 6.74-6.91 (m, 3H), 7.20 (s, 1H), 7.53-7.66 (m, 7H), 7.85-7.99 (m, 4H), 10.39 (s, 1H); FAB-MS m/z [M+1] +468.0.
Embodiment 77The preparation of N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000851
Method just replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 73) with embodiment 35 steps 4; And with 3; 3-(phenylbenzene) propylamine replaces 4-(phenoxy) aniline to obtain N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-237; Mp99 ℃ 1H-NMR (400MHz, DMSO-d6) δ 2.28-2.30 (m, 2H), 3.15-3.17 (m, 2H), 4.00 (t, J=7.8Hz, 1H); 6.02 (s, 2H), 6.68 (dd, J=8.1,1.7Hz, 1H), 6.80-6.87 (m, 2H); 6.97 (s, 1H), 7.14-7.18 (m, 2H), 7.26-7.34 (m, 8H), 7.53-7.62 (m, 4H); 7.73 (dd, J=7.3,2.0Hz, 1H), 8.40 (t, J=5.9Hz, 1H); FAB-MS m/z [M+1] +536.2.
Embodiment 78The preparation of N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000852
Step 1The preparation of 1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate
Method is with embodiment 35 steps 2, just with 4-[3,4-(methylene-dioxy) phenyl]-2; (method for making sees that embodiment 42 step 1) replace 4-(4-fluorophenyl)-2 to 4-diketone methyl-butyrate; 4-diketone methyl-butyrate, and replace the 2-nitrophenyl hydrazine hydrochloride to obtain 1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate with 2-hydrazino pyridine hydrochloride; Mp144 ℃ 1H-NMR (400MHz, DMSO-d6) δ 3.87 (s, 3H), 6.04 (s, 2H), 6.69-6.89 (m, 3H), 7.09 (s, 1H), 7.50-7.53 (m, 1H), 7.69 (d, J=8.0Hz, 1H), 8.04-8.07 (m, 1H), 8.42-8.43 (m, 1H); FAB-MS m/z [M+1] +324.
Step 2The preparation of 1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid
Method is with embodiment 35 steps 3; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-methyl-formiate replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-methyl-formiate to obtain 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid, mp211 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.06 (s, 2H), 6.69-6.88 (m, 3H), 7.02 (s, 1H), 7.50-7.52 (m, 1H), 7.68 (d, J=8.1Hz, 1H), 8.04-8.08 (m, 1H), 8.41-8.42 (m, 1H), 13.06 (s, 1H); FAB-MS m/z [M+1] +310.2.
Step 3The preparation of N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid to obtain N-[4-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-241, mp168 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.05 (s, 1H), 6.73-7.13 (m, 9H), 7.36-7.54 (m, 3H), 7.77-7.86 (m, 3H), 8.06-8.10 (m, 1H), 8.45-8.46 (m, 1H), 10.27 (s, 1H); FAB-MS m/z [M+1] +476.9.
Embodiment 79The preparation of N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000871
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and obtains N-[(furans-2-yl) methylene radical]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-242 with (furans-2-yl) methylamine replacement 4-(phenoxy) aniline; Mp175 ℃ 1H-NMR (400MHz, DMSO-d6) δ 4.44 (d, J=6.2Hz, 2H), 6.04 (s, 2H), 6.25 (d, J=3.1Hz; 1H), 6.38-6.39 (m, 1H), 6.69-6.72 (m, 1H), 6.80 (d, J=1.7Hz, 1H); 6.87-6.89 (m, 1H), 6.97 (s, 1H), 7.48-7.57 (m, 2H), 7.70 (d, J=7.9Hz; 1H), 8.02-8.05 (m, 1H), 8.41-8.43 (m, 1H), 8.81 (t, J=6.2Hz, 1H); FAB-MS m/z [M+1] +389.4.
Embodiment 80The preparation of N-[3,4-(methylene-dioxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000872
Method just replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) with embodiment 35 steps 4; And with 3; 4-(methylene-dioxy) aniline replaces 4-(phenoxy) aniline to obtain N-[3,4-(methylene-dioxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-244; Mp198 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.01 (s, 2H), 6.04 (s, 2H), 6.73 (dd, J=8.1,1.7Hz; 1H), 6.83 (d, J=1.7Hz, 1H), 6.89 (d, J=8.1Hz, 2H), 7.07 (s; 1H), 7.29 (dd, J=8.5,2.2Hz, 1H), 7.48-7.53 (m, 2H), 7.77 (d; J=7.8Hz, 1H), 8.06-8.08 (m, 1H), 8.44-8.46 (m, 1H), 10.14 (s, 1H); FAB-MS m/z [M+1] +429.5.
Embodiment 81The preparation of N-[4-(phenyl) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000881
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-[4-(phenyl) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-245 with 4-(phenyl) aniline; Mp177 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.05 (s, 1H), 6.74-6.91 (m, 3H), 7.13 (s; 1H), and 7.34-7.36 (m, 1H), 7.44-7.55 (m, 3H), 7.66-7.69 (m; 4H), and 7.79-7.81 (m, 1H), 7.94-7.96 (m, 2H), 8.07-8.12 (m; 1H), 8.46-8.47 (m, 1H), 10.33 (s, 1H); FAB-MS m/z [M+1] +461.3.
Embodiment 82The preparation of N-[3,3-(phenylbenzene) propyl group]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000891
Method just replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) with embodiment 35 steps 4; And with 3; 3-(phenylbenzene) propylamine replaces 4-(phenoxy) aniline to obtain N-[3,3-(phenylbenzene) propyl group]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-246; Mp64 ℃ 1H-NMR (400MHz, DMSO-d6) δ 2.30-2.32 (m, 2H), 3.15-3.19 (m, 2H), 4.02 (t, J=7.6Hz; 1H), 6.03 (s, 2H), 6.69-6.92 (m, 4H), 7.15-7.18 (m; 2H), and 7.27-7.34 (m, 8H), 7.48-7.51 (m, 1H), 7.69 (d; J=8.1Hz, 1H), 8.03-8.05 (m, 1H), 8.39-8.43 (m, 2H); FAB-MS m/z [M+1] +503.2.
Embodiment 83The preparation of N-[2-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000892
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-[2-(phenoxy) phenyl]-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-247 with 2-(phenoxy) aniline; Mp170 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.04 (s, 2H), 6.71 (dd, J=8.1,1.7Hz, 1H), 6.82 (d, J=1.7Hz, 1H); 6.88 (d, J=8.1Hz, 1H), 6.98 (dd, J=8.1,1.4Hz, 1H), 7.06-7.09 (m, 3H), 7.15-7.23 (m; 3H), 7.37-7.41 (m, 2H), 7.49-7.52 (m, 1H), 7.61 (d, J=7.8Hz, 1H), 8.05-8.08 (m; 1H), 8.24 (dd, J=8.0,1.4Hz, 1H), 8.42-8.43 (m, 1H), 9.52 (s, 1H); FAB-MS m/z [M+1] +477.0.
Embodiment 84The preparation of N-(naphthalene-1-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000901
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-(naphthalene-1-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-248 with naphthalidine; Mp189 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.06 (s, 2H), 6.77 (dd, J=8.1,1.7Hz, 1H), 6.87-6.92 (m; 2H), 7.15 (s, 1H), 7.55-7.57 (m, 3H), 7.67 (d, J=7.0Hz; 1H), 7.85-8.11 (m, 6H), 8.46-8.47 (m, 1H), 10.41 (s, 1H); FAB-MS m/z [M+1] +435.1.
Embodiment 85The preparation of N-(fluorenes-2-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000911
Method is with embodiment 35 steps 4; Just with 1-(pyridine-2-yl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 78) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) aniline to obtain N-(fluorenes-2-yl)-1-(pyridine-2-yl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-249 with the 2-fluorenamine; Mp202 ℃ 1H-NMR (400MHz, DMSO-d6) δ 3.94 (s, 2H), 6.05 (s, 2H), 6.75-6.92 (m, 3H), 7.12 (s, 1H), 7.26-7.58 (m, 4H), 7.81-7.86 (m, 4H), 8.07-8.16 (m, 2H), 8.45-8.46 (m, 1H), 10.30 (s, 1H); FAB-MS m/z [M+1] +473.0.
Embodiment 86The preparation of N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000912
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-228 with 2-(phenoxy) aniline; Mp199 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.05 (s, 2H), 6.69 (dd, J=8.1,1.7Hz, 1H); 6.85-7.20 (m, 9H), 7.34-7.38 (m, 2H), 7.62 (dd, J=7.9,1.4Hz; 1H), 7.77-7.85 (m, 2H), 8.12-8.20 (m, 2H), 9.42 (s, 1H); FAB-MS m/z [M+1] +521.0.
Embodiment 87The preparation of N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000921
Method is with embodiment 35 steps 4; Just with 1-(2-nitrophenyl)-5-[3; 4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid, and replaces 4-(phenoxy) phenylamino to obtain N-[4-(phenyl) phenyl]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-229 with 4-(phenyl) aniline; Mp203 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.06 (s, 2H), 6.74 (dd, J=8.1,1.7Hz, 1H), 6.88-6.91 (m; 2H), 7.19 (s, 1H), 7.34-7.47 (m, 3H), 7.65-7.82 (m, 6H), 7.87-7.94 (m; 3H), 8.18 (dd, J=8.1,1.4Hz, 1H), 10.34 (s, 1H); FAB-MS m/z [M+1] +505.1.
Embodiment 88The preparation of N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide
Figure S06178014020060914D000922
Method just replaces 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazoles-3-formic acid (method for making is seen embodiment 42) with embodiment 35 steps 4; And with 3; 3-(phenylbenzene) propylamine replaces 4-(phenoxy) phenylamino to obtain N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-[3,4-(methylene-dioxy) phenyl]-1H-pyrazole-3-formamide D-2210; Mp132 ℃ 1H-NMR (400MHz, DMSO-d6) δ 2.27-2.29 (m, 2H), 3.13-3.16 (m, 2H), 3.99 (t, J=7.8Hz; 1H), 6.04 (s, 2H), 6.69 (dd, J=8.0,1.7Hz, 1H); 6.83-6.97 (m, 3H), 7.14-7.33 (m, 10H), 7.62-7.84 (m, 3H), 8.13 (dd; J=8.1,1.4Hz, 1H), 8.34 (t, J=5.6Hz, 1H); FAB-MS m/z [M+1] +547.2.
Embodiment 89The preparation of N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000931
Method is with embodiment 35 steps 4, and just with 3,3-(phenylbenzene) propylamine replaces 4-(phenoxy) phenylamino to obtain N-[3,3-(phenylbenzene) propyl group]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-129, and mp71 ℃, 1H-NMR (400MHz, DMSO-d6) δ 2.27-2.31 (m, 2H), 3.13-3.16 (m, 2H), 4.00 (t, J=7.8Hz; 1H), 7.06 (s, 1H), 7.14-7.33 (m, 14H), 7.63-7.65 (m, 1H); 7.76-7.86 (m, 2H), 8.14-8.16 (m, 1H), 8.39 (t, J=5.6Hz, 1H); FAB-MS m/z [M+1] +521.2.
Embodiment 90The preparation of N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000941
Method just replaces 4-(phenoxy) phenylamino to obtain N-[2-(phenoxy) phenyl]-1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-1210 with 2-(phenoxy) aniline with embodiment 35 steps 4, and mp182 ℃, 1H-NMR (400MHz, DMSO-d6) δ 6.93 (dd, J=7.8,1.4Hz, 1H), 7.04 (d, J=7.8Hz, 2H), 7.14-7.37 (m, 10H), 7.62-7.84 (m, 3H), 8.13-8.19 (m, 2H), 9.46 (s, 1H); FAB-MS m/z [M+1] +495.1.
Embodiment 91The preparation of N-[4-(phenyl) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000942
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-[4-(phenyl) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-137 with 4-(phenyl) aniline; Mp199 ℃ 1H-NMR (400MHz, DMSO-d6) δ 7.20-7.27 (m, 3H), 7.33-7.37 (m, 3H), 7.44-7.47 (m, 2H), 7.57-7.69 (m, 7H), 7.83-7.97 (m, 3H), 10.40 (s, 1H); FAB-MS m/z [M+1] +468.1.
Embodiment 92The preparation of N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000951
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And with 3,3-(phenylbenzene) propylamine replaces 4-(phenoxy) phenylamino to obtain N-[3,3-(phenylbenzene) propyl group]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-138; Mp73 ℃ 1H-NMR (400MHz, DMSO-d6) δ 2.28-2.31 (m, 2H), 3.15-3.17 (m, 2H), 4.00 (t, J=7.8Hz; 1H), 7.05 (s, 1H), 7.16-7.34 (m, 15H), 7.52-7.64 (m, 3H); 7.75 (dd, J=7.6,2.0Hz, 1H), 8.44 (t, J=5.3Hz, 1H); FAB-MS m/z [M+1] +510.2.
Embodiment 93The preparation of N-[2-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide
Figure S06178014020060914D000952
Method is with embodiment 35 steps 4; Just replace 1-(2-nitrophenyl)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid with 1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazoles-3-formic acid (method for making is seen embodiment 49); And replace 4-(phenoxy) phenylamino to obtain N-[2-(phenoxy) phenyl]-1-(2-chloro-phenyl-)-5-(4-fluorophenyl)-1H-pyrazole-3-formamide D-139 with 2-(phenoxy) aniline; Mp174 ℃ 1H-NMR (400MHz, DMSO-d6) δ 6.91 (dd, J=7.8,1.7Hz, 1H), 7.04-7.07 (m, 2H), 7.14-7.38 (m, 10H), 7.53-7.75 (m, 4H), 8.18 (dd, J=7.8,1.7Hz, 1H), 9.53 (s, 1H); FAB-MS m/z [M+1] +484.1.
The ALK5 of the compound that the present invention relates to suppresses active available following method and detects:
Embodiment 94
With the HB1117 cell cultures in the DMEM that contains 10% foetal calf serum, with the cell in recovery back 2-5 generation with 2-8 * 10 3The density of individual cells/well is seeded on 96 orifice plates.Renewed bright nutrient solution in 4-8 hour before the administration, to cell abundance 70-90% administration.Background contrast (nutrient solution), solvent control (nutrient solution that contains 0.1%DMSO) and positive control are established in administration, and (the positive medicine of SB431542 is referring to document J.Med.Chem. (2002) 45 (5); 999-1001), the compound final concentration is 0.1 μ mol/l and 1 μ mol/l.After the administration 4 hours, give final concentration 10ng/ml TGF-β 1Abduction delivering, nutrient solution is only given in the background contrast.Induce after 24 hours with chemoluminescence method examining report gene expression product Lampyridea luciferase activity.Detect the number of photons that each is organized with Chemiluminescence Apparatus, according to the inhibiting rate of following formula computerized compound to ALK5, the result sees attached list 1.
Multiple=abduction delivering is respectively organized number of photons average/background control group number of photons average
Compound inhibiting rate (%)=[(solvent control group multiple-administration group multiple)/solvent control group multiple] * 100%
The influence that table 1 compound is expressed the beta induced luciferase reporter gene of TGF-
Figure S06178014020060914D000961
Figure S06178014020060914D000971

Claims (13)

1. the compound of general formula I or its pharmaceutically useful salt
Figure FSB00000875707800011
Wherein:
R1 is a phenyl; One replaces or dibasic phenyl, and substituting group is selected from halogen, C 1-6Alkoxyl group, hydroxyl and 3, the 4-methylene-dioxy; Pyridyl.
R2 is a phenyl; One replaces or dibasic phenyl, and substituting group is selected from halogen, C 1-6Alkoxyl group, hydroxyl and 3, the 4-methylene-dioxy; Pyridyl; C 1-6The substituted pyridyl of alkyl; Thiazolyl;
R3 is substituted phenyl, and substituting group is a formamyl.
2. the compound of the general formula I of claim 1 or its pharmaceutically useful salt, wherein, said halogen is a fluorine or chlorine.
3. the compound of the general formula I of claim 1 or its pharmaceutically useful salt, wherein, the C in R1 and the R2 definition 1-6Alkoxyl group is a methoxyl group.
4. the compound of the general formula I of claim 1 or its pharmaceutically useful salt, wherein, the C in the R2 definition 1-6Alkyl is a methyl.
5. according to the compound of claim 1, wherein:
R1 is 3,4-methylenedioxyphenyl, pyridine-2-base, 2-fluorophenyl, 3,4-Dimethoxyphenyl, 3,4-dihydroxy phenyl, 4-fluorophenyl, phenyl or 3,4-dichlorophenyl;
R2 is pyridine-2-base, 2-fluorophenyl, 3,4-methylenedioxyphenyl, thiazol-2-yl, 2-trifluoromethyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl, 6-picoline-2-base, phenyl, 2-nitrophenyl or 2-chloro-phenyl-;
R3 is to the formamyl phenyl.
6. according to the compound of claim 1, it is selected from:
(1) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(2) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(3) 4-[1-(3, the 4-methylenedioxyphenyl)-5-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(4) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(5) 4-[5-(3, the 4-Dimethoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(6) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(thiazol-2-yl)-1H-pyrazole-3-yl] BM
(7) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-trifluoromethyl)-1H-pyrazole-3-yl] BM
(8) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
(9) 4-[5-(3, the 4-dihydroxy phenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
(10) 4-[5-(4-fluorophenyl)-1-(2-p-methoxy-phenyl)-1H-pyrazole-3-yl] BM
(11) 4-[5-(4-fluorophenyl)-1-(2-hydroxy phenyl)-1H-pyrazole-3-yl] BM
(12) 4-[5-(4-fluorophenyl)-1-(pyridine-2-yl)-1H-pyrazole-3-yl] BM
(13) 4-[5-(4-fluorophenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM
(14) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(6-picoline-2-yl)-1H-pyrazole-3-yl] BM
(15) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(phenyl)-1H-pyrazole-3-yl] BM
(16) 4-[5-(3, the 4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-yl] BM and pharmacologically acceptable salt thereof.
7. preparation is according to the method for the compound of the general formula I of claim 1, and it comprises:
Method I: as the R1 of compound of Formula I, R2, can use following method preparation when R3 is aromatic nucleus:
(i) earlier with substituted aromatic aldehyde and the reaction of substituted acetyl aromatic ring, prepare substituted chalcone compounds
Figure FSB00000875707800031
Wherein the definition of R1 and R3 is with the definition in the claim 1,
(ii) substituted chalcone compounds and fragrant hydrazine or the reaction of fragrant hydrazonium salt hydrochlorate obtain substituted pyrazoline compounds
Figure FSB00000875707800032
Wherein the definition of R1, R2 and R3 is with the definition in the claim 1,
(iii) substituted pyrazoline compounds obtains the compound of general formula I with the oxidizer oxygen fluidized dehydrogenation
Figure FSB00000875707800033
(iv) the substituting group on the R3 of compound of Formula I can transform again.
8. the method for claim 7, wherein, said oxygenant is MnO 2
9. pharmaceutical composition, it comprises each compound or its pharmaceutically useful salt and at least a pharmaceutically useful carrier of general formula I according to claim 1-6.
10. the purposes that is used for the medicine of the mammiferous disease by the ALK5 acceptor media of production for treating according to each compound or its pharmaceutically useful salt of general formula I of claim 1-6; Said disease by the ALK5 acceptor media comprises following disease: not syndromes, arteriosclerosis, peritonaeum or the subcutaneous adhesion of chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, kidney disease, the necrosis of congested heart, ulcer, eye disease, corneal wound, dn-, nervous function damage, A Erzi sea, and any main pathology relevant with fibrosis.
11. the purposes of claim 10, wherein, the said main pathology relevant with fibrosis is pulmonary fibrosis, hepatic fibrosis or valvular stenosis.
12. be used to produce the purposes that can suppress the medicine of TGF-signal in the mammalian body according to each compound or its pharmaceutically useful salt of general formula I of claim 1-6.
13. be used to produce the purposes that is used to suppress the medicine that matter forms between the Mammals cells in vivo according to each compound or its pharmaceutically useful salt of general formula I of claim 1-6.
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