CN102603637A - Pyrazol compound and purpose of pyrazol compound used as receptor tyrosine kinases (RTK) and phosphatidyl inositol 3-kinase (PI3K) dual inhibitors - Google Patents
Pyrazol compound and purpose of pyrazol compound used as receptor tyrosine kinases (RTK) and phosphatidyl inositol 3-kinase (PI3K) dual inhibitors Download PDFInfo
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- CN102603637A CN102603637A CN2012100144348A CN201210014434A CN102603637A CN 102603637 A CN102603637 A CN 102603637A CN 2012100144348 A CN2012100144348 A CN 2012100144348A CN 201210014434 A CN201210014434 A CN 201210014434A CN 102603637 A CN102603637 A CN 102603637A
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- amino
- pyrazole
- carboxamido
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BDDIUTHMWNWMRJ-UHFFFAOYSA-N octane;hydrobromide Chemical compound Br.CCCCCCCC BDDIUTHMWNWMRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000002894 organic compounds Chemical class 0.000 description 1
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- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一组新型酪氨酸激酶和PI3K激酶双重抑制剂，这些抑制剂具有较强的抗肿瘤活性。本发明合成新型酪氨酸激酶和PI3K激酶双重抑制剂的制备方法是人工合成获得。本发明合成新型酪氨酸激酶和PI3K激酶双重抑制剂可以用于制备治疗癌症的药物。The invention provides a group of novel dual inhibitors of tyrosine kinase and PI3K kinase, and these inhibitors have strong antitumor activity. The preparation method for synthesizing novel dual inhibitors of tyrosine kinase and PI3K kinase of the present invention is obtained by artificial synthesis. The novel double inhibitor of tyrosine kinase and PI3K kinase synthesized by the invention can be used to prepare medicine for treating cancer.
Description
技术领域 technical field
本发明涉及一组具有药理活性的新的吡唑化合物，它们的制备方法和含有它们的药用组合物。The present invention relates to a group of novel pyrazole compounds with pharmacological activity, their preparation method and pharmaceutical compositions containing them.
背景技术 Background technique
磷脂酰激醇3-激酶(PI3-K)是细胞内一种重要的激酶(Carpenter et al，Mol.Cell.Biol.1993，13：1657-1665)。其通过活化Akt/PKB、MAPK、PKC等信号途径参与细胞内信号转导，引起细胞发生许多生化反应.PI3-K还具有丝/苏氨酸蛋白激酶活性，可以调节自身磷酸肌醇激酶活性；PI3-K的活化与细胞的生长、分化和细胞的生存有很大的关系。PI3K-Akt信号传导通路的失调控对于多种肿瘤的发生是一种刺激信号，信号传导通路中任何激酶表达的异常都可能诱导肿瘤的发生。Phosphatidyl kinase 3-kinase (PI3-K) is an important kinase in cells (Carpenter et al, Mol. Cell. Biol. 1993, 13: 1657-1665). It participates in intracellular signal transduction by activating Akt/PKB, MAPK, PKC and other signaling pathways, causing many biochemical reactions in cells. PI3-K also has serine/threonine protein kinase activity, which can regulate its own phosphoinositide kinase activity; The activation of PI3-K has a great relationship with cell growth, differentiation and cell survival. Deregulation of PI3K-Akt signaling pathway is a stimulating signal for the occurrence of various tumors, and abnormal expression of any kinase in the signaling pathway may induce tumorigenesis.
随着对PI3-K信号传导方面的研究和信号传导通路中不同激酶的抑制剂的结构的不断深入研究，已有许多研究者对这些抑制剂的结构和功能进行研究。发现激发PI3-K信号传导通路的上游受体酪氨酸激酶(RTK)的异常表达会过度激活PI3K通路，因此临床有用受体酪氨酸激酶抑制剂来治疗肿瘤。但是，PI3K通路的异常会导致对受体酪氨酸抑制剂产生耐药性。(Clark，A.S.et al，Mol.Cancer Ther.2002，1，707.Nagata，Y.et al，Cancer Cell.2004，6，117-127.)PI3K抑制会导致肿瘤的ERK信号通路的补偿性激活，RTK抑制对ERK抑制有作用。临床前研究表明，联合PI3-K抑制剂和RTK抑制剂对肿瘤的治疗有利(Fan，Q.W.et al，Cancer Res.2007，67，7960-7965.Mohi，M.G.et al，Proc.Natl.Acad.Sci.U.S.A.2004，101，3130-3135.)。With the research on PI3-K signal transduction and the in-depth research on the structure of inhibitors of different kinases in the signal transduction pathway, many researchers have studied the structure and function of these inhibitors. It was found that the abnormal expression of the upstream receptor tyrosine kinase (RTK) that stimulates the PI3-K signaling pathway can over-activate the PI3K pathway, so receptor tyrosine kinase inhibitors are clinically useful to treat tumors. However, abnormalities in the PI3K pathway lead to resistance to receptor tyrosine inhibitors. (Clark, A.S. et al, Mol. Cancer Ther. 2002, 1, 707. Nagata, Y. et al, Cancer Cell. 2004, 6, 117-127.) PI3K inhibition leads to compensatory activation of the ERK signaling pathway in tumors , RTK inhibition has an effect on ERK inhibition. Preclinical studies have shown that combining PI3-K inhibitors and RTK inhibitors is beneficial to the treatment of tumors (Fan, Q.W.et al, Cancer Res.2007, 67, 7960-7965.Mohi, M.G.et al, Proc.Natl.Acad. Sci. U.S.A. 2004, 101, 3130-3135.).
本发明的目的是提供PI3-K和RTK的强抑制剂。还有一个目的是提供单独使用或者与其它已知的药物组合调节需要治疗的患者的细胞增殖。The object of the present invention is to provide potent inhibitors of PI3-K and RTKs. Yet another object is to provide modulation of cell proliferation in a patient in need of treatment, alone or in combination with other known agents.
此外，本发明的目的是提供用于治疗癌症的药物Furthermore, the object of the present invention is to provide a drug for the treatment of cancer
发明内容 Contents of the invention
本发明涉及一种新颖的3，4，5-三取代吡唑化合物，这类化合物同时抑制受体酪氨酸激酶(RTK)和磷脂酰肌醇3-激酶(PI3-K)的方法，以及治疗癌症的方法。The present invention relates to novel 3,4,5-trisubstituted pyrazole compounds, methods of simultaneously inhibiting receptor tyrosine kinase (RTK) and phosphatidylinositol 3-kinase (PI3-K), and Methods of treating cancer.
一方面提供结构式(I)的小分子化合物，其异构体，药学上可接受的盐以及前药：On the one hand, small molecular compounds of structural formula (I), their isomers, pharmaceutically acceptable salts and prodrugs are provided:
其中R1选自：wherein R is selected from:
(1)取代或未取代的C8-C10的烷基，(1) A substituted or unsubstituted C 8 -C 10 alkyl group,
(2)取代或未取代的C8-C10的烯基，(2) Substituted or unsubstituted C 8 -C 10 alkenyl,
(3)取代或未取代的C8-C10的炔基，(3) substituted or unsubstituted C 8 -C 10 alkynyl,
(4)取代或未取代的芳基，(4) substituted or unsubstituted aryl,
(5)取代或未取代的杂环基，和(5) a substituted or unsubstituted heterocyclic group, and
(6)取代或未取代的杂芳基；(6) substituted or unsubstituted heteroaryl;
R2选自： R2 is selected from:
(1)氧原子，(1) Oxygen atom,
(2)硫原子；(2) Sulfur atom;
R3选自： R3 is selected from:
(1)氢，(1) hydrogen,
(2)氨基，和(2) amino groups, and
(3)羟基；(3) Hydroxyl;
X选自：X is selected from:
(1)直接相连，(1) directly connected,
(2)取代或未取代的C1-C3的烷基；(2) A substituted or unsubstituted C 1 -C 3 alkyl group;
Y选自：Y is selected from:
(1)氢，(1) hydrogen,
(2)取代或未取代的芳基，(2) substituted or unsubstituted aryl,
(3)取代或未取代的杂环基，和(3) a substituted or unsubstituted heterocyclic group, and
(4)取代或未取代的杂芳基；(4) substituted or unsubstituted heteroaryl;
在一个实施方式中，本发明提供结构式(I)的化合物，式中，In one embodiment, the present invention provides a compound of structural formula (I), wherein,
R1选自： R1 is selected from:
(1)取代或未取代的C8-C10的烷基，(1) A substituted or unsubstituted C 8 -C 10 alkyl group,
(2)取代或未取代的C8-C10的烯基；(2) substituted or unsubstituted C 8 -C 10 alkenyl;
R2选自： R2 is selected from:
(1)氧原子，(1) Oxygen atom,
(2)硫原子；(2) Sulfur atom;
R3选自： R3 is selected from:
(1)氢，(1) hydrogen,
(2)氨基，和(2) amino groups, and
(3)羟基；(3) Hydroxyl;
X选自：X is selected from:
(1)直接相连，(1) directly connected,
(2)取代或未取代的C1-C3的烷基；(2) A substituted or unsubstituted C 1 -C 3 alkyl group;
Y选自：Y is selected from:
取代或未取代的芳基。substituted or unsubstituted aryl.
另一个实施方式中，本发明提供结构式(I)的化合物，式中，In another embodiment, the present invention provides a compound of structural formula (I), wherein,
R1选自： R1 is selected from:
(1)取代或未取代的C8-C10的烷基；(1) A substituted or unsubstituted C 8 -C 10 alkyl group;
R2选自： R2 is selected from:
氧原子；Oxygen atom;
R3选自： R3 is selected from:
氨基；Amino;
X选自：X is selected from:
(1)直接相连，(1) directly connected,
(2)取代或未取代的C1-C3的烷基；(2) A substituted or unsubstituted C 1 -C 3 alkyl group;
Y选自：Y is selected from:
取代或未取代的芳基。substituted or unsubstituted aryl.
另一个实施方式中，本发明提供结构式(I)的化合物，式中，In another embodiment, the present invention provides a compound of structural formula (I), wherein,
R1选自： R1 is selected from:
未取代的C8-C10的烷基；Unsubstituted C 8 -C 10 alkyl;
R2选自： R2 is selected from:
氧原子；Oxygen atom;
R3选自： R3 is selected from:
氨基；Amino;
X选自：X is selected from:
(1)直接相连，(1) directly connected,
(2)未取代的C1-C3的烷基；(2) unsubstituted C 1 -C 3 alkyl;
Y选自：Y is selected from:
取代或未取代的芳基。substituted or unsubstituted aryl.
另一个实施方式中，本发明提供结构式(II)的式(I)化合物，式中，In another embodiment, the present invention provides a compound of formula (I) of structural formula (II), wherein,
R1选自： R1 is selected from:
取代或未取代C8-C10的烷基；Substituted or unsubstituted C 8 -C 10 alkyl;
X选自：X is selected from:
(2)直接相连，(2) directly connected,
(3)取代或未取代的C1-C3的烷基；(3) A substituted or unsubstituted C 1 -C 3 alkyl group;
Y选自：Y is selected from:
取代或未取代的芳基。substituted or unsubstituted aryl.
另一个实施方式中，本发明提供结构式(II)的式(I)化合物，式中，In another embodiment, the present invention provides a compound of formula (I) of structural formula (II), wherein,
R1选自： R1 is selected from:
未取代的C8-C10的烷基；Unsubstituted C 8 -C 10 alkyl;
X，Y一起选自：X, Y together are selected from:
另一个实施方式中，本发明提供结构式(III)的式(I)化合物，式中，In another embodiment, the present invention provides a compound of formula (I) of structural formula (III), wherein,
R1选自： R1 is selected from:
未取代的C8-C10的烷基；Unsubstituted C 8 -C 10 alkyl;
Y选自Y selected from
取代或未取代的芳基。substituted or unsubstituted aryl.
另一个实施方式中，本发明提供结构式(III)的式(I)化合物，式中，In another embodiment, the present invention provides a compound of formula (I) of structural formula (III), wherein,
R1选自： R1 is selected from:
未取代的C8-C10的烷基；Unsubstituted C 8 -C 10 alkyl;
Y选自Y selected from
其优选化合物为：Its preferred compounds are:
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正辛烷基-1H-吡唑(III1)3-Amino-4-carboxamido-5-(2-nitrophenyl)-1-n-octyl-1H-pyrazole (III 1 )
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正壬烷基-1H-吡唑(III2)3-amino-4-carboxamido-5-(2-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 2 )
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正癸烷基-1H-吡唑(III3)3-Amino-4-carboxamido-5-(2-nitrophenyl)-1-n-decyl-1H-pyrazole (III 3 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正辛烷基-1H-吡唑(III4)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-octyl-1H-pyrazole (III 4 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正壬烷基-1H-吡唑(III5)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 5 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正癸烷基-1H-吡唑(III6)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-decyl-1H-pyrazole (III 6 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正辛烷基-1H-吡唑(III7)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-octyl-1H-pyrazole (III 7 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正壬烷基-1H-吡唑(III8)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 8 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正癸烷基-1H-吡唑(III9)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-decyl-1H-pyrazole (III 9 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正辛烷基-1H-吡唑(III10)3-Amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-octyl-1H-pyrazole (III 10 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正壬烷基-1H-吡唑(III11)3-amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-nonyl-1H-pyrazole (III 11 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正癸烷基-1H-吡唑(III12)3-Amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-decyl-1H-pyrazole (III 12 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正辛烷基-1H-吡唑(III13)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 13 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正壬烷基-1H-吡唑(III14)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-nonyl-1H-pyrazole (III 14 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正癸烷基-1H-吡唑(III15)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-decyl-1H-pyrazole (III 15 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正辛烷基-1H-吡唑(III16)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 16 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正壬烷基-1H-吡唑(III17)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-nonyl-1H-pyrazole (III 17 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正癸烷基-1H-吡唑(III18)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-decyl-1H-pyrazole (III 18 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正辛烷基-1H-吡唑(III19)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-octyl-1H-pyrazole (III 19 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正壬烷基-1H-吡唑(III20)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-nonyl-1H-pyrazole (III 20 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正癸烷基-1H-吡唑(III21)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-decyl-1H-pyrazole (III 21 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正辛烷基-1H-吡唑(III22)3-amino-4-carboxamido-5-(2-chlorophenyl)-1-n-octyl-1H-pyrazole (III 22 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正壬烷基-1H-吡唑(III23)3-Amino-4-carboxamido-5-(2-chlorophenyl)-1-n-nonyl-1H-pyrazole (III 23 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正癸烷基-1H-吡唑(III24)3-Amino-4-carboxamido-5-(2-chlorophenyl)-1-n-decyl-1H-pyrazole (III 24 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正辛烷基-1H-吡唑(III25)3-amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 25 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正壬烷基-1H-吡唑(III26)3-Amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 26 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正癸烷基-1H-吡唑(III27)3-Amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 27 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正辛烷基-1H-吡唑(III28)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 28 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正壬烷基-1H-吡唑(III29)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 29 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正癸烷基-1H-吡唑(III30)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 30 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正辛烷基-1H-吡唑(III31)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 31 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正壬烷基-1H-吡唑(III32)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 32 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正癸烷基-1H-吡唑(III33)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 33 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正辛烷基-1H-吡唑(III34)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 34 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正壬烷基-1H-吡唑(III35)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 35 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正癸烷基-1H-吡唑(III36)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 36 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正辛烷基-1H-吡唑(III37)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 37 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正壬烷基-1H-吡唑(III38)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 38 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正癸烷基-1H-吡唑(III39)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 39 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正辛烷基-1H-吡唑(III40)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-octyl-1H-pyrazole (III 40 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正壬烷基-1H-吡唑(III41)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-nonyl-1H-pyrazole (III 41 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正癸烷基-1H-吡唑(III42)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-decyl-1H-pyrazole (III 42 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正辛烷基-1H-吡唑(III43)3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-octyl-1H-pyrazole (III 43 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正壬烷基-1H-吡唑(III44)3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-nonyl-1H-pyrazole (III 44 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正癸烷基-1H-吡唑(III45)3-Amino-4-carboxamido-5-(4-aminophenyl)-1-n-decyl-1H-pyrazole (III 45 )
优选实施方式的详细说明Detailed Description of the Preferred Embodiment
本发明提供新颖的化合物，可用作酪氨酸激酶(RTK)和磷脂酰肌醇3-激酶(PI3-K)双重抑制的抑制剂。本文提供的化合物可配制成治疗需要抑制RTK和PI3K的患者的药物制剂，尤其在具体实施方式中，提供用于降低细胞增殖和治疗癌症的组合物和方法。The present invention provides novel compounds useful as inhibitors of dual inhibition of tyrosine kinases (RTKs) and phosphatidylinositol 3-kinases (PI3-K). The compounds provided herein can be formulated as pharmaceutical formulations for the treatment of patients in need of inhibition of RTKs and PI3Ks, and particularly in specific embodiments, compositions and methods for reducing cell proliferation and treating cancer are provided.
在本申请文本中使用下列缩写和定义：The following abbreviations and definitions are used in the text of this application:
词语“烷基”指不含杂原子的烷基。因此该词语包括直链烷基如甲基，乙基，丙基，丁基，戊基，己基，庚基，辛基，壬基，揆基，十一烷基，十二烷基等。该词语还包括直链烷基的支链异构体，例如包括但不限于下列烷基：-CH(CH3)2，-CH(CH3)(CH2CH3)，-C(CH3)3等。还包括环烷基，如环丙基，环丁基，环戊基，环己基，环庚基和环辛基，这样的环可以被上述直链和支链烷基取代。因此，词语烷基包括伯烷基，仲烷基和叔烷基。优选的烷基包括含有1-10个碳原子的直链和支链烷基以及环烷基。The word "alkyl" refers to an alkyl group that does not contain heteroatoms. The term thus includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, kidyl, undecyl, dodecyl and the like. The term also includes branched chain isomers of straight chain alkyl groups such as but not limited to the following: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 etc. Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are also included, and such rings may be substituted by the aforementioned straight and branched chain alkyl groups. Thus, the word alkyl includes primary, secondary and tertiary alkyl groups. Preferred alkyl groups include straight and branched chain alkyl groups and cycloalkyl groups containing 1 to 10 carbon atoms.
词语“取代的烷基”指上述烷基中一个或多个连接碳或氢的键被连接于非氢原子和非碳原子的键取代，非氢原子和非碳原子例如但不限于：卤素原子如氟原子，氯原子，溴原子和碘原子；再如羟基，烷氧基，芳氧基和酯基中的氧原子；再如硫醇，烷基硫和芳基硫，砜基，磺酰基和亚砜基等基团中的硫原子；再如胺，酰胺，芳胺，N-氧化物，烯胺中的氮原子；以及在各种其它基团中的杂原子。取代的烷基还包括其中一个或多个连接碳或氢原子的键被连接于杂原子的高级键(如，双键或三键)取代的基团，杂原子如在氧代，羰基，羧基和酯基中的氧；在如亚胺，肟，腙和腈基中的氮。取代烷基还包括其中一个或多个连接碳或氢原子的键被连接于芳基，杂环基或环烷基的键取代。优选的取代基还包括，其中一个或多个连接碳或氢原子的键被连接于氟原子的一个或多个键取代的烷基。另一种优选的取代烷基是三氟甲基和含有三氟烷基的烷基。其它优选基团包括其中一个或多个连接碳或氢原子的键被连接于氧原子的键取代的哪些，而使取代烷基包含羟基，烷氧基或芳氧基。还有一些优选的取代的烷基包括有胺，或取代或未取代的烷基胺，二烷基胺，芳胺，(烷基)(芳基)胺，二芳胺，杂环基胺，二杂环基胺，(烷基)(杂环基)胺或(芳基)(杂环基)氨基的烷基。The term "substituted alkyl" means that one or more bonds to carbon or hydrogen in the above-mentioned alkyl group are replaced by bonds to non-hydrogen atoms and non-carbon atoms, such as but not limited to: halogen atoms Such as fluorine atom, chlorine atom, bromine atom and iodine atom; another example is oxygen atom in hydroxyl group, alkoxy group, aryloxy group and ester group; another example is thiol, alkyl sulfur and aryl sulfur group, sulfone group, sulfonyl group and sulfur atoms in groups such as sulfoxide groups; nitrogen atoms in amines, amides, arylamines, N-oxides, and enamines; and heteroatoms in various other groups. Substituted alkyl also includes groups in which one or more bonds to a carbon or hydrogen atom is replaced by a higher bond (eg, double or triple bond) to a heteroatom, such as in oxo, carbonyl, carboxyl and oxygen in ester groups; nitrogen in groups such as imines, oximes, hydrazones and nitriles. Substituted alkyl also includes those wherein one or more bonds to a carbon or hydrogen atom is replaced by a bond to an aryl, heterocyclyl or cycloalkyl group. Preferred substituents also include alkyl groups wherein one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds to a fluorine atom. Another preferred substituted alkyl group is trifluoromethyl and trifluoroalkyl-containing alkyl groups. Other preferred groups include those in which one or more bonds to a carbon or hydrogen atom are replaced by a bond to an oxygen atom such that the substituted alkyl group comprises a hydroxy, alkoxy or aryloxy group. Still other preferred substituted alkyl groups include amines, or substituted or unsubstituted alkylamines, dialkylamines, arylamines, (alkyl)(aryl)amines, diarylamines, heterocyclylamines, Diheterocyclylamine, alkyl of (alkyl)(heterocyclyl)amine or (aryl)(heterocyclyl)amino.
词语：“烯基”指直链和支链以及环基团，如上面定义的烷基所述的哪些，但在两个碳原子间至少有一个双键。例子包括但不限于：乙烯基，丙烯基，异丙烯基，丁烯基，异丁烯基，环己烯基，丁二烯基，环己二烯基。词语“取代的烯基”具有和烯基相同的含意，与取代的烷基和未取代的烷基含义相同。取代的烯基包括其中一个非碳原子或非氢原子连接于另一个碳原子的碳双键上的烯基以及其中一个非碳原子或非氢原子连接的碳不包含在连接另一个碳原子的碳双键上的烯基以及其中一个非碳原子或非氢原子连接的碳不包含在连接另一个碳原子的碳双键上的烯基。The term: "alkenyl" refers to straight and branched chain and cyclic groups such as those described above for alkyl, but having at least one double bond between two carbon atoms. Examples include, but are not limited to: vinyl, propenyl, isopropenyl, butenyl, isobutenyl, cyclohexenyl, butadienyl, cyclohexadienyl. The word "substituted alkenyl" has the same meaning as alkenyl, and the same meaning as substituted alkyl and unsubstituted alkyl. Substituted alkenyl groups include alkenyl groups in which a non-carbon atom or non-hydrogen atom is attached to a carbon double bond of another carbon atom and in which the carbon to which a non-carbon atom or non-hydrogen atom is attached is not included in the carbon double bond to another carbon atom. Alkenyl on a carbon double bond and in which a carbon other than a carbon atom or non-hydrogen atom is attached does not include alkenyl on a carbon double bond attached to another carbon atom.
词语“炔基”指直链和支链基团，如上面定义的烷基所述的那些，但在两个碳原子间至少有一个三键。例子包括但不限于：乙炔基，丙炔基。词语“取代的炔基”具有和炔基相同的含意，与取代的烷基和未取代的烷基含义相同。取代的炔基包括其中一个非碳原子或非氢原子连接于另一个碳原子的碳三键上的炔基以及其中一个非碳原子或非氢原子连接的碳不包含在连接另一个碳原子的碳三键上的炔基。The word "alkynyl" refers to straight and branched chain groups such as those described above for alkyl, but having at least one triple bond between two carbon atoms. Examples include, but are not limited to: ethynyl, propynyl. The word "substituted alkynyl" has the same meaning as alkynyl, and the same meaning as substituted alkyl and unsubstituted alkyl. Substituted alkynyl groups include alkynyl groups in which a non-carbon or non-hydrogen atom is attached to a carbon triple bond to another carbon atom and in which the carbon to which a non-carbon or non-hydrogen atom is attached is not included in the carbon to which another carbon atom is attached. Alkynyl on carbon triple bond.
词语“芳基”指不含杂原子的芳基。因此，该词语包括但不限于：如苯基，二苯基，萘基。芳基可连接于母体化合物中的一个或多个碳原子，氧原子，氮原子和/或硫原子上。词语“取代的芳基”具有和与未取代芳基相同的含义，与取代的烷基和未取代的烷基含义相同。然而，取代的芳基还包括其中一个芳基碳原子连接有上述一个非碳或非氢原子的芳基以及其中一个或多个芳基碳原子连接有本文中所述的取代和/或未取代的烷基，烯基或炔基的芳基。这包括连接键的方式，其中任一芳基的两个碳原子，定义为稠合环体系。因此，词语“取代的芳基”包括但不限于甲苯基和羟基苯基。The word "aryl" refers to an aryl group that does not contain heteroatoms. Thus, the term includes, but is not limited to, eg, phenyl, diphenyl, naphthyl. The aryl group can be attached to one or more carbon atoms, oxygen atoms, nitrogen atoms and/or sulfur atoms in the parent compound. The word "substituted aryl" has the same meaning as unsubstituted aryl, and the same meaning as substituted alkyl and unsubstituted alkyl. However, substituted aryl groups also include aryl groups in which one of the aryl carbon atoms is bonded to one of the above-mentioned non-carbon or non-hydrogen atoms and in which one or more aryl carbon atoms are bonded to substituted and/or unsubstituted as described herein. An alkyl, an alkenyl or an alkynyl an aryl. This includes the manner of linkage, wherein the two carbon atoms of any aryl group, defines a fused ring system. Thus, the phrase "substituted aryl" includes, but is not limited to, tolyl and hydroxyphenyl.
词语“杂环基”指芳族或非芳香族含有氮，氧，硫等杂原子的环状化合物，包括：单环，二环和多环化合物，例如但不限于：吲唑基，奎宁环基，咪唑基。词语“取代的杂环基”指上面定义的杂环基，环中的一个原子连接有非氢原子，如上述取代的烷基和取代的芳基。例如包括但不限于：2-甲苯并咪唑基，5-氯苯并噻唑基，2-溴吡啶基。The term "heterocyclic group" refers to aromatic or non-aromatic cyclic compounds containing heteroatoms such as nitrogen, oxygen, sulfur, etc., including: monocyclic, bicyclic and polycyclic compounds, such as but not limited to: indazolyl, quinine Cyclic, imidazolyl. The phrase "substituted heterocyclyl" refers to a heterocyclyl as defined above, wherein an atom in the ring is attached to a non-hydrogen atom, such as the above-mentioned substituted alkyl and substituted aryl. Examples include but are not limited to: 2-methylbenzimidazolyl, 5-chlorobenzothiazolyl, 2-bromopyridyl.
词语“杂芳基”指每个环有5-10个环原子的单环或双环芳基，其中每个环上的一个环原子选自O，S，N；1或2个环原子是其它独立选自O，S，N的杂原子；其余的环原子是碳，该基团通过任一环原子连接于分子的其余部分，例如，吡啶基，嘧啶基，咪唑基，异喹啉基和呋喃基等。本文所用的术语“取代的杂芳基”指其中的1，2或3个氢原子被下列取代基团取代的杂芳基：氯，溴，氟，碘，羟基，腈基，C1-C10烷基，C1-C10烷氧基。此外，任何一个取代基可以是芳基，杂芳基或杂环烷基。The term "heteroaryl" means a monocyclic or bicyclic aryl group having 5-10 ring atoms per ring, wherein one ring atom on each ring is selected from O, S, N; 1 or 2 ring atoms are other Heteroatoms independently selected from O, S, N; the remaining ring atoms are carbon, and the group is attached to the rest of the molecule through any ring atom, for example, pyridyl, pyrimidinyl, imidazolyl, isoquinolyl and furyl etc. As used herein, the term "substituted heteroaryl" refers to a heteroaryl group in which 1, 2 or 3 hydrogen atoms are replaced by the following substituent groups: chlorine, bromine, fluorine, iodine, hydroxyl, nitrile, C 1 -C 10 alkyl, C 1 -C 10 alkoxy. In addition, any one of the substituents may be aryl, heteroaryl or heterocycloalkyl.
“药学上可接受的盐”包括与无机碱，有机碱，无机酸，有机酸，或碱式氨基酸或酸式氨基酸的盐。对无机碱的盐，本发明包括，例如，碱金属如钠或钾盐；碱金属如钙，镁或铝盐；和铵。作为有机碱的盐，本发明包括，例如，三甲基胺，三乙基胺，吡啶，甲基吡啶，乙醇胺，二乙醇胺和三乙醇胺盐。作为无机酸的盐，本发明包括，例如盐酸，硫酸，硝酸和磷酸和磷酸盐。作为有机酸的盐，本发明包括，例如，甲酸，乙酸，三氟乙酸，富马酸，草酸，酒石酸，马来酸，柠檬酸，苹果酸，琥珀酸，甲磺酸，苯磺酸和对甲苯磺酸盐。作为碱式氨基酸的盐，本发明包括，例如精氨酸，赖氨酸和鸟氨酸盐。酸式氨基酸包括，例如，天冬氨酸和谷氨酸盐。"Pharmaceutically acceptable salt" includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. For salts of inorganic bases, the present invention includes, for example, alkali metals such as sodium or potassium; alkali metals such as calcium, magnesium or aluminum; and ammonium. As salts of organic bases, the present invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine and triethanolamine salts. As salts of inorganic acids, the present invention includes, for example, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid and phosphate salts. As salts of organic acids, the present invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, malic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p- Tosylate. As salts of basic amino acids, the present invention includes, for example, arginine, lysine and ornithine salts. Acid amino acids include, for example, aspartic acid and glutamate.
如本文所用术语“药学上可接受的前药”指本发明化合物的前药，在合理的医学判断范围之内，适合用于人和低等动物的组织接触，而无不适当毒性，刺激，变态反应等，与合理的效益/风险之比相当，对预订用途有效，以及可能是本发明化合物的两性离子形式。术语“前药”指能在体内迅速转化，例如通过血液中水解产生上面结构式的母体化合物。The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in human and lower animal tissue contact without undue toxicity, irritation, allergy reactions, etc., with a reasonable benefit/risk ratio, are effective for the intended use, and may be zwitterionic forms of the compounds of the invention. The term "prodrug" refers to a parent compound that is rapidly transformed in vivo, eg, by hydrolysis in blood, to yield the above formula.
总体上，本发明提供具有结构式I的化合物。本发明还提供所述化合物的互变体，药学上可接受的盐和前药，以及药学上可接受的盐和互变体的前药。式I化合物具有下面的结构：In general, the present invention provides compounds of formula I. The present invention also provides tautomers, pharmaceutically acceptable salts and prodrugs of the compounds, and pharmaceutically acceptable salts and prodrugs of the tautomers. The compound of formula I has the following structure:
在一个实施方式中，R1是未取代的C8-C10的烷基，R2是氧原子或硫原子，R3是氨基或羟基；X是取代或未取代的C1-C3-烷基，Y是取代或未取代的芳基。In one embodiment, R 1 is an unsubstituted C 8 -C 10 alkyl group, R 2 is an oxygen atom or a sulfur atom, R 3 is an amino group or a hydroxyl group; X is a substituted or unsubstituted C 1 -C 3 - Alkyl, Y is substituted or unsubstituted aryl.
在化合物(I)的另一个更加具体的实施方式中，R1是未取代的C8-C10的烷基。In another more specific embodiment of compound (I), R 1 is unsubstituted C 8 -C 10 alkyl.
本发明的一方面提供提供具有结构式II的化合物，其互变体，药学上可接受的盐和前药，以及药学上可接受的盐和互变体的前药。式II化合物具有下面的结构：One aspect of the present invention provides compounds having structural formula II, tautomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts and prodrugs of the tautomers. The compound of formula II has the following structure:
式中R1是未取代的C8-C10的烷基。X，Y一起选自In the formula, R 1 is an unsubstituted C 8 -C 10 alkyl group. X, Y together selected from
本发明的一方面提供提供具有结构式III1-45的化合物，其互变体，药学上可接受的盐和前药，以及药学上可接受的盐和互变体的前药。式III化合物具有下面的结构：One aspect of the present invention provides compounds having structural formula III 1-45 , tautomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts and prodrugs of the tautomers. The compound of formula III has the following structure:
式中R1是未取代的C8-C10的烷基。Y选自In the formula, R 1 is an unsubstituted C 8 -C 10 alkyl group. Y selected from
其优选化合物为：Its preferred compounds are:
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正辛烷基-1H-吡唑(III1)3-Amino-4-carboxamido-5-(2-nitrophenyl)-1-n-octyl-1H-pyrazole (III 1 )
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正壬烷基-1H-吡唑(III2)3-amino-4-carboxamido-5-(2-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 2 )
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正癸烷基-1H-吡唑(III3)3-Amino-4-carboxamido-5-(2-nitrophenyl)-1-n-decyl-1H-pyrazole (III 3 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正辛烷基-1H-吡唑(III4)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-octyl-1H-pyrazole (III 4 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正壬烷基-1H-吡唑(III5)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 5 )
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正癸烷基-1H-吡唑(III6)3-Amino-4-carboxamido-5-(3-nitrophenyl)-1-n-decyl-1H-pyrazole (III 6 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正辛烷基-1H-吡唑(III7)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-octyl-1H-pyrazole (III 7 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正壬烷基-1H-吡唑(III8)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-nonyl-1H-pyrazole (III 8 )
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正癸烷基-1H-吡唑(III9)3-Amino-4-carboxamido-5-(4-nitrophenyl)-1-n-decyl-1H-pyrazole (III 9 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正辛烷基-1H-吡唑(III10)3-Amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-octyl-1H-pyrazole (III 10 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正壬烷基-1H-吡唑(III11)3-amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-nonyl-1H-pyrazole (III 11 )
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正癸烷基-1H-吡唑(III12)3-Amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-decyl-1H-pyrazole (III 12 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正辛烷基-1H-吡唑(III13)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 13 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正壬烷基-1H-吡唑(III14)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-nonyl-1H-pyrazole (III 14 )
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正癸烷基-1H-吡唑(III15)3-Amino-4-carboxamido-5-(4-fluorophenyl)-1-n-decyl-1H-pyrazole (III 15 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正辛烷基-1H-吡唑(III16)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 16 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正壬烷基-1H-吡唑(III17)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-nonyl-1H-pyrazole (III 17 )
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正癸烷基-1H-吡唑(III18)3-Amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-decyl-1H-pyrazole (III 18 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正辛烷基-1H-吡唑(III19)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-octyl-1H-pyrazole (III 19 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正壬烷基-1H-吡唑(III20)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-nonyl-1H-pyrazole (III 20 )
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正癸烷基-1H-吡唑(III21)3-Amino-4-carboxamido-5-(2-aminophenyl)-1-n-decyl-1H-pyrazole (III 21 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正辛烷基-1H-吡唑(III22)3-amino-4-carboxamido-5-(2-chlorophenyl)-1-n-octyl-1H-pyrazole (III 22 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正壬烷基-1H-吡唑(III23)3-Amino-4-carboxamido-5-(2-chlorophenyl)-1-n-nonyl-1H-pyrazole (III 23 )
3-氨基-4-甲酰胺基-5-(2-氯苯基)-1-正癸烷基-1H-吡唑(III24)3-Amino-4-carboxamido-5-(2-chlorophenyl)-1-n-decyl-1H-pyrazole (III 24 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正辛烷基-1H-吡唑(III25)3-amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 25 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正壬烷基-1H-吡唑(III26)3-Amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 26 )
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正癸烷基-1H-吡唑(III27)3-Amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 27 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正辛烷基-1H-吡唑(III28)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 28 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正壬烷基-1H-吡唑(III29)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 29 )
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正癸烷基-1H-吡唑(III30)3-Amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 30 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正辛烷基-1H-吡唑(III31)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 31 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正壬烷基-1H-吡唑(III32)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 32 )
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正癸烷基-1H-吡唑(III33)3-Amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 33 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正辛烷基-1H-吡唑(III34)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 34 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正壬烷基-1H-吡唑(III35)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-nonyl-1H-pyrazole (III 35 )
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正癸烷基-1H-吡唑(III36)3-Amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 36 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正辛烷基-1H-吡唑(III37)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 37 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正壬烷基-1H-吡唑(III38)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 38 )
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正癸烷基-1H-吡唑(III39)3-Amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 39 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正辛烷基-1H-吡唑(III40)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-octyl-1H-pyrazole (III 40 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正壬烷基-1H-吡唑(III41)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-nonyl-1H-pyrazole (III 41 )
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正癸烷基-1H-吡唑(III42)3-Amino-4-carboxamido-5-(3-aminophenyl)-1-n-decyl-1H-pyrazole (III 42 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正辛烷基-1H-吡唑(III43)3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-octyl-1H-pyrazole (III 43 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正壬烷基-1H-吡唑(III44)3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-nonyl-1H-pyrazole (III 44 )
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正癸烷基-1H-吡唑(III45)3-Amino-4-carboxamido-5-(4-aminophenyl)-1-n-decyl-1H-pyrazole (III 45 )
在上面本发明概述中描述了本发明的其它化合物。Other compounds of the invention are described in the Summary of the Invention above.
在其它方面，本发明提供包含本文所述的使用磷脂酰肌醇3-激酶和酪氨酸激酶双重抑制剂的方法。In other aspects, the invention provides methods comprising the use of dual inhibitors of phosphatidylinositol 3-kinase and tyrosine kinase as described herein.
另一方面，本发明提供使用本文所述化合物的方法。例如，本文所述化合物可用于治疗癌症。本文所述化合物还可用于制造治疗癌症的药物。In another aspect, the invention provides methods of using the compounds described herein. For example, the compounds described herein are useful in the treatment of cancer. The compounds described herein are also useful in the manufacture of medicaments for the treatment of cancer.
在一个实施方式中，本发明提供抑制人或动物个体酪氨酸激酶和磷脂酰肌醇-3激酶活性的合成方法。In one embodiment, the present invention provides a synthetic method for inhibiting the activity of tyrosine kinase and phosphatidylinositol-3 kinase in human or animal subjects.
另一个实施方式中，本发明提供该方法中，给予人或动物个体抑制酪氨酸激酶和磷脂酰肌醇-3激酶活性有效量的本文所述化合物。In another embodiment, the present invention provides the method of administering to the human or animal subject an amount of a compound described herein effective to inhibit the activity of tyrosine kinase and phosphatidylinositol-3 kinase.
通过参考下面的实施例能更好理解上面概述的本发明，这些实施例用于说明，不意味对本发明的限制。The invention outlined above may be better understood by reference to the following examples, which are presented by way of illustration and are not meant to limit the invention.
根据本发明，通式III n化合物可以按照下面通用的方法制备：According to the present invention, the compound of general formula III can be prepared according to the following general methods:
n＝1-45，Y，R1的定义如前所述。n=1-45, Y, R 1 are as defined above.
该方法主要包括以下步骤：The method mainly includes the following steps:
取代的苯甲酸在回流的条件下和氯化亚砜反应，产生相应的酰氯(通式IV化合物)。IV在THF溶液中用NaH处理后和丙二腈缩合，优选0-5摄氏度反应，得到2-取代的丙二腈化合物(通式V化合物)，然后对化合物V进行甲基化反应，优选硫酸二甲酯作为甲基化试剂。得到化合物VI.化合物4在0-90摄氏度下和水合肼环合，优选70-90摄氏度。得到3取代的4-腈基-5-氨基吡唑化合物(通式VII化合物)。5在碳酸钾存在下和卤代化合物反应，优选溴代和碘代化合物，生成化合物VIII及其异构体。化合物VIII在室温条件下水解，优选浓硫酸作为水解试剂，得到目标化合物III n。The substituted benzoic acid reacts with thionyl chloride under reflux to produce the corresponding acid chloride (compound of general formula IV). IV is treated with NaH in THF solution and then condensed with malononitrile, preferably reacted at 0-5 degrees Celsius to obtain a 2-substituted malononitrile compound (compound of general formula V), and then carry out methylation reaction to compound V, preferably sulfuric acid Dimethyl ester as a methylating agent. Compound VI is obtained. Compound 4 is cyclized with hydrazine hydrate at 0-90°C, preferably 70-90°C. 3-substituted 4-cyano-5-aminopyrazole compounds (compounds of general formula VII) are obtained. 5 is reacted with halogenated compounds, preferably bromo and iodo compounds, in the presence of potassium carbonate to give compound VIII and its isomers. Compound VIII is hydrolyzed at room temperature, preferably with concentrated sulfuric acid as the hydrolysis reagent, to obtain the target compound III n.
产物III n与药学上可用的酸反应即可获得通式I化合物药学上可接受的盐。The product III can be reacted with a pharmaceutically available acid to obtain a pharmaceutically acceptable salt of the compound of general formula I.
按照上面的合成方法，合成下面实施例的化合物According to the synthetic method above, synthesize the compound of following example
具体实施方式 Detailed ways
实施例1Example 1
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正辛烷基-1H-吡唑(III1)：2-硝基苯甲酸30克在回流的条件下和180毫升氯化亚砜反应6小时，减压浓缩得到2-硝基苯甲酰氯。将丙二腈30克溶解在THF中，0摄氏度小心加入2倍量的NaH。加完后反应2小时，将前面制备的2-硝基苯甲酰氯滴加到上述溶液中，反应温度不超过5摄氏度。滴加完成后继续反应6小时。将反应液倾如冰水中。氯仿萃取，有机相干燥后浓缩。浓缩液加入100毫升THF和20毫升水，加入60克碳酸钾，回流反应2小时，减压浓缩后小心加入40毫升水合肼。90度反应2小时后加水稀释。乙酸乙酯萃取，干燥后浓缩，加入30毫升DMF，15克碳酸钾和15克溴代正辛烷，90度反应2小时后用氯仿萃取，水洗后浓缩。浓缩液加入30克浓硫酸，室温搅拌24小时得到目标化合物3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正辛烷基-1H-吡唑(III1)：12克。1HNMR(DMSO，300MHz)δ(ppm)：8.00(d，1H，J＝9.0Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.30(br，4H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，10H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：360.2(M+H)+ 3-Amino-4-carboxamido-5-(2-nitrophenyl)-1-n-octyl-1H-pyrazole (III 1 ): 30 grams of 2-nitrobenzoic acid under reflux React with 180 ml of thionyl chloride for 6 hours, and concentrate under reduced pressure to obtain 2-nitrobenzoyl chloride. Dissolve 30 g of malononitrile in THF, and carefully add 2 times the amount of NaH at 0°C. After the addition, react for 2 hours, add the previously prepared 2-nitrobenzoyl chloride dropwise to the above solution, and the reaction temperature does not exceed 5 degrees Celsius. After the dropwise addition was completed, the reaction was continued for 6 hours. The reaction solution was poured into ice water. Chloroform extraction, the organic phase was dried and concentrated. Add 100 ml of THF and 20 ml of water to the concentrated solution, add 60 g of potassium carbonate, reflux for 2 hours, concentrate under reduced pressure and carefully add 40 ml of hydrazine hydrate. After reacting at 90 degrees for 2 hours, add water to dilute. Extract with ethyl acetate, dry and concentrate, add 30ml of DMF, 15g of potassium carbonate and 15g of n-octane bromide, react at 90°C for 2 hours, extract with chloroform, wash with water and concentrate. Add 30 grams of concentrated sulfuric acid to the concentrated solution, stir at room temperature for 24 hours to obtain the target compound 3-amino-4-formamido-5-(2-nitrophenyl)-1-n-octyl-1H-pyrazole (III 1 ): 12 grams. 1 HNMR (DMSO, 300MHz) δ (ppm): 8.00 (d, 1H, J = 9.0Hz), 7.75 (t, 1H, J = 6.9Hz), 7.61 (t, 1H, J = 6.9Hz), 6.30 ( br, 4H), 3.86(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 10H), 0.84(t, 3H, J=6.6Hz); MS (ESI, m/z ): 360.2(M+H) +
实施例2Example 2
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正壬烷基-1H-吡唑(III2)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.00(d，1H，J＝9.0Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.30(br，4H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，12H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：374.2(M+H)+ The synthesis method of 3-amino-4-carboxamido-5-(2-nitrophenyl)-1-nonyl-1H-pyrazole (III 2 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ(ppm): 8.00(d, 1H, J=9.0Hz), 7.75(t, 1H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.30(br, 4H) , 3.86(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 12H), 0.84(t, 3H, J=6.6Hz); MS (ESI, m/z): 374.2( M+H) +
实施例3Example 3
3-氨基-4-甲酰胺基-5-(2-硝基苯基)-1-正癸烷基-1H-吡唑(III3)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.00(d，1H，J＝9.0Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.30(br，4H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，14H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：388.2(M+H)+ The synthesis method of 3-amino-4-carboxamido-5-(2-nitrophenyl)-1-n-decyl-1H-pyrazole (III 3 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ(ppm): 8.00(d, 1H, J=9.0Hz), 7.75(t, 1H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.30(br, 4H) , 3.86(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 14H), 0.84(t, 3H, J=6.6Hz); MS (ESI, m/z): 388.2( M+H) +
实施例4Example 4
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正辛烷基-1H-吡唑(III4)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.28(d，1H，J＝9.0Hz)，7.79(t，1H，J＝6.9Hz)，7.71(t，1H，J＝6.9Hz)，6.39(br，4H)，3.76(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，10H)，0.83(t，3H，J＝6.6Hz)；(ESI，m/z)：360.2(M+H)+ The synthetic method of 3-amino-4-carboxamido-5-(3-nitrophenyl)-1-n-octyl-1H-pyrazole (III 4 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.28 (d, 1H, J = 9.0Hz), 7.79 (t, 1H, J = 6.9Hz), 7.71 (t, 1H, J = 6.9Hz), 6.39 (br, 4H) , 3.76(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 10H), 0.83(t, 3H, J=6.6Hz); (ESI, m/z): 360.2(M +H) +
实施例5Example 5
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正壬烷基-1H-吡唑(III5)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.26(d，1H，J＝9.3Hz)，7.79(t，1H，J＝6.9Hz)，7.73(t，1H，J＝6.9Hz)，6.39(br，4H)，3.76(t，2H，J＝6.3Hz)，1.62(br，2H)，1.23(br，12H)，0.83(t，3H，J＝6.3Hz)；(ESI，m/z)：374.2(M+H)+ The synthetic method of 3-amino-4-carboxamido-5-(3-nitrophenyl)-1-nonyl-1H-pyrazole (III 5 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.26 (d, 1H, J = 9.3Hz), 7.79 (t, 1H, J = 6.9Hz), 7.73 (t, 1H, J = 6.9Hz), 6.39 (br, 4H) , 3.76(t, 2H, J=6.3Hz), 1.62(br, 2H), 1.23(br, 12H), 0.83(t, 3H, J=6.3Hz); (ESI, m/z): 374.2(M +H) +
实施例6Example 6
3-氨基-4-甲酰胺基-5-(3-硝基苯基)-1-正癸烷基-1H-吡唑(III6)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.28(d，1H，J＝8.7Hz)，7.79(t，1H，J＝7.2Hz)，7.71(t，1H，J＝7.2Hz)，6.39(br，4H)，3.76(t，2H，J＝6.6Hz)，1.62(br，2H)，1.23(br，10H)，0.83(t，3H，J＝6.6Hz)；(ESI，m/z)：388.2(M+H)+ The synthetic method of 3-amino-4-carboxamido-5-(3-nitrophenyl)-1-n-decyl-1H-pyrazole (III 6 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.28 (d, 1H, J = 8.7Hz), 7.79 (t, 1H, J = 7.2Hz), 7.71 (t, 1H, J = 7.2Hz), 6.39 (br, 4H) , 3.76(t, 2H, J=6.6Hz), 1.62(br, 2H), 1.23(br, 10H), 0.83(t, 3H, J=6.6Hz); (ESI, m/z): 388.2(M +H) +
实施例7Example 7
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正辛烷基-1H-吡唑(III7)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.37(d，2H，J＝9.0Hz)，7.72(d，2H，J＝9.0Hz)，5.44(s，2H)，3.68(t，2H，J＝4.0Hz)，1.59(br，2H)，1.06-1.26(m，10H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：360.2(M+H)+ The synthetic method of 3-amino-4-carboxamido-5-(4-nitrophenyl)-1-n-octyl-1H-pyrazole (III 7 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.37 (d, 2H, J = 9.0Hz), 7.72 (d, 2H, J = 9.0Hz), 5.44 (s, 2H), 3.68 (t, 2H, J = 4.0Hz) , 1.59 (br, 2H), 1.06-1.26 (m, 10H), 0.84 (t, 3H, J=6.6Hz); MS (ESI, m/z): 360.2 (M+H) +
实施例8Example 8
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正壬烷基-1H-吡唑(III8)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.35(d，2H，J＝9.0Hz)，7.71(d，2H，J＝9.0Hz)，5.44(s，2H)，3.68(t，2H，J＝4.0Hz)，1.59(br，2H)，1.06-1.26(m，12H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：374.2(M+H)+ The synthesis method of 3-amino-4-carboxamido-5-(4-nitrophenyl)-1-nonyl-1H-pyrazole (III 8 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.35 (d, 2H, J = 9.0Hz), 7.71 (d, 2H, J = 9.0Hz), 5.44 (s, 2H), 3.68 (t, 2H, J = 4.0Hz) , 1.59 (br, 2H), 1.06-1.26 (m, 12H), 0.84 (t, 3H, J=6.6Hz); MS (ESI, m/z): 374.2 (M+H) +
实施例9Example 9
3-氨基-4-甲酰胺基-5-(4-硝基苯基)-1-正癸烷基-1H-吡唑(III9)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：8.35(d，2H，J＝9.0Hz)，7.71(d，2H，J＝9.0Hz)，5.44(s，2H)，3.68(t，2H，J＝4.0Hz)，1.59(br，2H)，1.06-1.26(m，14H)，0.84(t，3H，J＝4.2Hz)；MS(ESI，m/z)：388.2(M+H)+ The synthetic method of 3-amino-4-carboxamido-5-(4-nitrophenyl)-1-n-decyl-1H-pyrazole (III 9 ) refers to the general method above: 1 H NMR (DMSO , 300MHz) δ (ppm): 8.35 (d, 2H, J = 9.0Hz), 7.71 (d, 2H, J = 9.0Hz), 5.44 (s, 2H), 3.68 (t, 2H, J = 4.0Hz) , 1.59 (br, 2H), 1.06-1.26 (m, 14H), 0.84 (t, 3H, J=4.2Hz); MS (ESI, m/z): 388.2 (M+H) +
实施例10Example 10
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正辛烷基-1H-吡唑(III10)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.65(dd，1H，J＝8.4Hz andJ＝2.4Hz)，7.56(d，1H，J＝2.4Hz)，7.51(1H，d，J＝8.7Hz)，6.30(br，2H)，3.90(t，2H，J＝6.9Hz)，1.68(m，2H)，1.24-1.26(m，10H)，0.85(t，3H，J＝6.9Hz)；MS(ESI，m/z)：427.1The synthetic method of 3-amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-octyl-1H-pyrazole (III 10 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.65 (dd, 1H, J=8.4Hz and J=2.4Hz), 7.56 (d, 1H, J=2.4Hz), 7.51 (1H, d, J=8.7Hz) , 6.30(br, 2H), 3.90(t, 2H, J=6.9Hz), 1.68(m, 2H), 1.24-1.26(m, 10H), 0.85(t, 3H, J=6.9Hz); MS( ESI, m/z): 427.1
实施例11Example 11
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正壬烷基-1H-吡唑(III11)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.68(dd，1H，J＝8.4Hz andJ＝2.4Hz)，7.64(d，1H，J＝2.4Hz)，7.51(1H，d，J＝8.7Hz)，6.31(br，2H)，3.90(t，2H，J＝6.9Hz)，1.68(m，2H)，1.23-1.26(m，12H)，0.84(t，3H，J＝6.9Hz)；MS(ESI，m/z)：441.1The synthetic method of 3-amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-nonyl-1H-pyrazole (III 11 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.68 (dd, 1H, J = 8.4Hz and J = 2.4Hz), 7.64 (d, 1H, J = 2.4Hz), 7.51 (1H, d, J = 8.7Hz) , 6.31(br, 2H), 3.90(t, 2H, J=6.9Hz), 1.68(m, 2H), 1.23-1.26(m, 12H), 0.84(t, 3H, J=6.9Hz); MS( ESI, m/z): 441.1
实施例12Example 12
3-氨基-4-甲酰胺基-5-(2-氯-5-溴苯基)-1-正癸烷基-1H-吡唑(III12)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.65(dd，1H，J＝8.4Hz andJ＝2.4Hz)，7.56(d，1H，J＝2.4Hz)，7.51(d，1H，J＝8.7Hz)，6.30(br，2H)，3.90(t，2H，J＝6.9Hz)，1.68(m，2H)，1.24-1.26(m，14H)，0.85(t，3H，J＝6.9Hz)；MS(ESI，m/z)：455.1The synthetic method of 3-amino-4-carboxamido-5-(2-chloro-5-bromophenyl)-1-n-decyl-1H-pyrazole (III 12 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.65 (dd, 1H, J = 8.4Hz and J = 2.4Hz), 7.56 (d, 1H, J = 2.4Hz), 7.51 (d, 1H, J = 8.7Hz) , 6.30(br, 2H), 3.90(t, 2H, J=6.9Hz), 1.68(m, 2H), 1.24-1.26(m, 14H), 0.85(t, 3H, J=6.9Hz); MS( ESI, m/z): 455.1
实施例13Example 13
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正辛烷基-1H-吡唑(III13)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.63(d，1H，J＝8.4Hz)，7.44-7.54(m，3H)，6.24(s，2H)，4.43-4.52(t，2H，J＝6.6)，1.34-1.37(m，10H)，0.85(t，3H，J＝6.9Hz)；MS(ESI，m/z)：333.2The synthesis method of 3-amino-4-carboxamido-5-(4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 13 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.63 (d, 1H, J = 8.4Hz), 7.44-7.54 (m, 3H), 6.24 (s, 2H), 4.43-4.52 (t, 2H, J = 6.6), 1.34- 1.37(m, 10H), 0.85(t, 3H, J=6.9Hz); MS(ESI, m/z): 333.2
实施例14Example 14
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正壬烷基-1H-吡唑(III14)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.63(d，1H，J＝8.4Hz)，7.44-7.54(m，3H)，6.24(s，2H)，4.43-4.52(t，2H，J＝6.6)，1.34-1.37(m，12H)，0.85(t，3H，J＝6.9Hz)；MS(ESI，m/z)：347.2The synthesis method of 3-amino-4-carboxamido-5-(4-fluorophenyl)-1-nonyl-1H-pyrazole (III 14 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.63 (d, 1H, J = 8.4Hz), 7.44-7.54 (m, 3H), 6.24 (s, 2H), 4.43-4.52 (t, 2H, J = 6.6), 1.34- 1.37(m, 12H), 0.85(t, 3H, J=6.9Hz); MS(ESI, m/z): 347.2
实施例15Example 15
3-氨基-4-甲酰胺基-5-(4-氟苯基)-1-正辛烷基-1H-吡唑(III15)的合成方法参考上面的通用方法：1H NMR(DMSO，300MHz)δ(ppm)：7.63(d，1H，J＝8.4Hz)，7.44-7.54(m，3H)，6.24(s，2H)，4.43-4.52(t，2H，J＝6.6)，1.34-1.37(m，14H)，0.85(t，3H，J＝6.9Hz)；MS(ESI，m/z)：361.2The synthesis method of 3-amino-4-carboxamido-5-(4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 15 ) refers to the general method above: 1 H NMR (DMSO, 300MHz) δ (ppm): 7.63 (d, 1H, J = 8.4Hz), 7.44-7.54 (m, 3H), 6.24 (s, 2H), 4.43-4.52 (t, 2H, J = 6.6), 1.34- 1.37(m, 14H), 0.85(t, 3H, J=6.9Hz); MS(ESI, m/z): 361.2
实施例16Example 16
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正辛烷基-1H-吡唑(III16)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.53(dd，1H，J＝8.7Hz andJ＝2.4Hz)，7.26(dd，1H，J＝8.4Hz and J＝6.3Hz)，7.13(m，1H)，6.17(br，1H)，3.70(t，2H，J＝6.9Hz)，1.48(m，2H)，1.04-1.06(m，10H)，0.65(t，3H，J＝4.2Hz)；MS(ESI，m/z)：411.1The synthetic method of 3-amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-octyl-1H-pyrazole (III 16 ) refers to the general method above: 1 H NMR (DMSO-d 6 , 300MHz) δ (ppm): 7.53 (dd, 1H, J=8.7Hz and J=2.4Hz), 7.26 (dd, 1H, J=8.4Hz and J=6.3Hz), 7.13 (m , 1H), 6.17(br, 1H), 3.70(t, 2H, J=6.9Hz), 1.48(m, 2H), 1.04-1.06(m, 10H), 0.65(t, 3H, J=4.2Hz) ; MS (ESI, m/z): 411.1
实施例17Example 17
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正壬烷基-1H-吡唑(III17)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.58(dd，1H，J＝8.7Hz andJ＝2.4Hz)，7.28(dd，1H，J＝8.7Hz and J＝3.3Hz)，7.18(m，1H)，6.21(br，1H)，3.75(t，2H，J＝6.6Hz)，1.43(m，2H)，1.08(s，12H)，0.65(t，3H，J＝4.2Hz)；MS(ESI，m/z)：425.1The synthetic method of 3-amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-nonyl-1H-pyrazole (III 17 ) refers to the general method above: 1 H NMR (DMSO-d 6 , 300MHz) δ (ppm): 7.58 (dd, 1H, J = 8.7Hz and J = 2.4Hz), 7.28 (dd, 1H, J = 8.7Hz and J = 3.3Hz), 7.18 (m , 1H), 6.21(br, 1H), 3.75(t, 2H, J=6.6Hz), 1.43(m, 2H), 1.08(s, 12H), 0.65(t, 3H, J=4.2Hz); MS (ESI, m/z): 425.1
实施例18Example 18
3-氨基-4-甲酰胺基-5-(2-溴-4-氟苯基)-1-正癸烷基-1H-吡唑(III18)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.67(dd，1H，J＝8.7Hz andJ＝2.4Hz)，7.56(d，1H，J＝2.4Hz)，7.49(d，1H J＝8.4Hz)，6.30(br，1H)，3.90(t，2H，J＝6.9Hz)，1.69(m，2H)，1.23(s，14H)，0.84(t，3H，J＝6.3Hz)；MS(ESI，m/z)：439.1The synthetic method of 3-amino-4-carboxamido-5-(2-bromo-4-fluorophenyl)-1-n-decyl-1H-pyrazole (III 18 ) refers to the general method above: 1 H NMR (DMSO-d 6 , 300MHz) δ (ppm): 7.67 (dd, 1H, J = 8.7Hz and J = 2.4Hz), 7.56 (d, 1H, J = 2.4Hz), 7.49 (d, 1H, J = 8.4 Hz), 6.30(br, 1H), 3.90(t, 2H, J=6.9Hz), 1.69(m, 2H), 1.23(s, 14H), 0.84(t, 3H, J=6.3Hz); MS( ESI, m/z): 439.1
实施例19Example 19
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正辛烷基-1H-吡唑(III19)的合成方法参考上面的通用方法：δ(ppm)：8.02(d，1H，J＝9.0Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.73(d，1H，J＝6.0Hz)，6.30(br，2H)，6.12(br，2H)3.84(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，10H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：330.2The synthetic method of 3-amino-4-formamido-5-(2-aminophenyl)-1-n-octyl-1H-pyrazole (III 19 ) refers to the general method above: δ (ppm): 8.02 (d, 1H, J=9.0Hz), 7.75(t, 1H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.73(d, 1H, J=6.0Hz), 6.30(br , 2H), 6.12(br, 2H) 3.84(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 10H), 0.84(t, 3H, J=6.6Hz); MS( ESI, m/z): 330.2
实施例20Example 20
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正壬烷基-1H-吡唑(III20)的合成方法参考上面的通用方法：δ(ppm)：8.00(d，1H，J＝8.7Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.76(d，1H，J＝6.0Hz)，6.30(br，4H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，12H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：344.2The synthetic method of 3-amino-4-carboxamido-5-(2-aminophenyl)-1-n-nonyl-1H-pyrazole (III 20 ) refers to the general method above: δ (ppm): 8.00 (d, 1H, J=8.7Hz), 7.75(t, 1H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.76(d, 1H, J=6.0Hz), 6.30(br , 4H), 3.86(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 12H), 0.84(t, 3H, J=6.6Hz); MS (ESI, m/z) : 344.2
实施例21Example 21
3-氨基-4-甲酰胺基-5-(2-氨基苯基)-1-正癸烷基-1H-吡唑(III21)的合成方法参考上面的通用方法：δ(ppm)：8.00(d，1H，J＝9.0Hz)，7.75(t，1H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.79(d，1H，J＝6.0Hz)，6.30(br，2H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，14H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：358.2The synthetic method of 3-amino-4-formamido-5-(2-aminophenyl)-1-n-decyl-1H-pyrazole (III 21 ) refers to the general method above: δ (ppm): 8.00 (d, 1H, J=9.0Hz), 7.75(t, 1H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.79(d, 1H, J=6.0Hz), 6.30(br , 2H), 3.86(t, 2H, J=6.0Hz), 1.62(br, 2H), 1.23(br, 14H), 0.84(t, 3H, J=6.6Hz); MS (ESI, m/z) : 358.2
实施例22Example 22
3-氨基-4-甲酰胺基-5-(2-氯基苯基)-1-正辛烷基-1H-吡唑(III22)的合成方法参考上面的通用方法：δ(ppm)：7.44-7.60(m，4H)，3.86(t，2H，J＝6.0Hz)，1.62(t，2H J＝6.0Hz)，1.23(br，10H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：349.2The synthetic method of 3-amino-4-carboxamido-5-(2-chlorophenyl)-1-n-octyl-1H-pyrazole (III 22 ) refers to the general method above: δ (ppm): 7.44-7.60(m, 4H), 3.86(t, 2H, J=6.0Hz), 1.62(t, 2H, J=6.0Hz), 1.23(br, 10H), 0.84(t, 3H, J=6.6Hz) ; MS (ESI, m/z): 349.2
实施例23Example 23
3-氨基-4-甲酰胺基-5-(2-氯基苯基)-1-正壬烷基-1H-吡唑(III23)的合成方法参考上面的通用方法：7.40-7.57(m，4H)，3.86(t，2H，J＝6.3Hz)，1.67(t，2H J＝6.3Hz)，1.26(br，12H)，0.83(t，3H，J＝6.6Hz)；MS(ESI，m/z)：363.2The synthetic method of 3-amino-4-formamido-5-(2-chlorophenyl)-1-n-nonyl-1H-pyrazole (III 23 ) refers to the general method above: 7.40-7.57(m , 4H), 3.86(t, 2H, J=6.3Hz), 1.67(t, 2H J=6.3Hz), 1.26(br, 12H), 0.83(t, 3H, J=6.6Hz); MS(ESI, m/z): 363.2
实施例24Example 24
3-氨基-4-甲酰胺基-5-(2-氯基苯基)-1-正癸烷基-1H-吡唑(III24)的合成方法参考上面的通用方法：7.44-7.61(m，4H)，3.83(t，2H，J＝6.0Hz)，1.61(t，2H J＝6.0Hz)，1.24(br，14H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：377.2The synthetic method of 3-amino-4-carboxamido-5-(2-chlorophenyl)-1-n-decyl-1H-pyrazole (III 24 ) refers to the general method above: 7.44-7.61(m , 4H), 3.83(t, 2H, J=6.0Hz), 1.61(t, 2H J=6.0Hz), 1.24(br, 14H), 0.82(t, 3H, J=6.6Hz); MS(ESI, m/z): 377.2
实施例25Example 25
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正辛烷基-1H-吡唑(III25)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.36(d，2H，J＝8.7Hz)，6.99(d，2H，J＝8.7Hz)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，3.79(s，3H)，1.65-1.69(m，2H)，1.24(br，10H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：345.2The synthetic method of 3-amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 25 ) refers to the general method above: 1 H NMR ( DMSO- d6 , 300MHz) δ (ppm): 7.36 (d, 2H, J = 8.7Hz), 6.99 (d, 2H, J = 8.7Hz), 6.29 (s, 2H), 3.84 (t, 2H, J =6.6Hz), 3.79(s, 3H), 1.65-1.69(m, 2H), 1.24(br, 10H), 0.82(t, 3H, J=6.6Hz); MS(ESI, m/z): 345.2
实施例26Example 26
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正壬烷基-1H-吡唑(III26)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.38(d，2H，J＝8.7Hz)，7.02(d，2H，J＝8.7Hz)，6.39(s，2H)，3.84(t，2H，J＝6.9Hz)，3.79(s，3H)，1.65-1.69(m，2H)，1.24(br，10H)，0.87(t，3H，J＝6.9Hz)；MS(ESI，m/z)：359.2The synthetic method of 3-amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 26 ) refers to the general method above: 1 H NMR ( DMSO- d6 , 300MHz) δ (ppm): 7.38 (d, 2H, J = 8.7Hz), 7.02 (d, 2H, J = 8.7Hz), 6.39 (s, 2H), 3.84 (t, 2H, J =6.9Hz), 3.79(s, 3H), 1.65-1.69(m, 2H), 1.24(br, 10H), 0.87(t, 3H, J=6.9Hz); MS(ESI, m/z): 359.2
实施例27Example 27
3-氨基-4-甲酰胺基-5-(4-甲氧基苯基)-1-正癸烷基-1H-吡唑(III27)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.36(d，2H，J＝8.7Hz)，6.99(d，2H，J＝8.7Hz)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，3.79(s，3H)，1.65-1.69(m，2H)，1.24(br，10H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：373.2The synthetic method of 3-amino-4-carboxamido-5-(4-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 27 ) refers to the general method above: 1 H NMR ( DMSO- d6 , 300MHz) δ (ppm): 7.36 (d, 2H, J = 8.7Hz), 6.99 (d, 2H, J = 8.7Hz), 6.29 (s, 2H), 3.84 (t, 2H, J =6.6Hz), 3.79(s, 3H), 1.65-1.69(m, 2H), 1.24(br, 10H), 0.82(t, 3H, J=6.6Hz); MS(ESI, m/z): 373.2
实施例28Example 28
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正辛烷基-1H-吡唑(III28)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.43(d，2H，J＝8.7Hz)，6.99(d，2H，J＝8.7Hz)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，10H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：331.2The synthesis method of 3-amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 28 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.43(d, 2H, J=8.7Hz), 6.99(d, 2H, J=8.7Hz), 6.29(s, 2H), 3.84(t, 2H, J=6.6 Hz), 1.65-1.69 (m, 2H), 1.24 (br, 10H), 0.81 (t, 3H, J=6.6Hz); MS (ESI, m/z): 331.2
实施例29Example 29
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正壬烷基-1H-吡唑(III29)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.41(d，2H，J＝8.7Hz)，6.99(d，2H，J＝8.7Hz)，6.30(s，2H)，3.83(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，12H)，0.81(t，3H，J＝6.3Hz)；MS(ESI，m/z)：345.2The synthesis method of 3-amino-4-carboxamido-5-(4-hydroxyphenyl)-1-nonyl-1H-pyrazole (III 29 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.41(d, 2H, J=8.7Hz), 6.99(d, 2H, J=8.7Hz), 6.30(s, 2H), 3.83(t, 2H, J=6.6 Hz), 1.65-1.69 (m, 2H), 1.24 (br, 12H), 0.81 (t, 3H, J=6.3Hz); MS (ESI, m/z): 345.2
实施例30Example 30
3-氨基-4-甲酰胺基-5-(4-羟基苯基)-1-正癸烷基-1H-吡唑(III30)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.41(d，2H，J＝8.7Hz)，6.99(d，2H，J＝8.7Hz)，6.30(s，2H)，3.83(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，14H)，0.81(t，3H，J＝6.3Hz)；MS(ESI，m/z)：359.2The synthesis method of 3-amino-4-carboxamido-5-(4-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 30 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.41(d, 2H, J=8.7Hz), 6.99(d, 2H, J=8.7Hz), 6.30(s, 2H), 3.83(t, 2H, J=6.6 Hz), 1.65-1.69 (m, 2H), 1.24 (br, 14H), 0.81 (t, 3H, J=6.3Hz); MS (ESI, m/z): 359.2
实施例31Example 31
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正辛烷基-1H-吡唑(III31)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：8.59(br，1H)7.99(d，2H，J＝8.7Hz)，7.59(d，2H，J＝8.7Hz)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，10H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：331.2The synthesis method of 3-amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 31 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 8.59(br, 1H), 7.99(d, 2H, J=8.7Hz), 7.59(d, 2H, J=8.7Hz), 3.84(t, 2H, J=6.6Hz ), 1.65-1.69 (m, 2H), 1.24 (br, 10H), 0.81 (t, 3H, J=6.6Hz); MS (ESI, m/z): 331.2
实施例32Example 32
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正壬烷基-1H-吡唑(III32)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：8.55(br，1H)7.89(d，2H，J＝8.7Hz)，7.67(d，2H，J＝8.7Hz)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，12H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：345.2The synthesis method of 3-amino-4-carboxamido-5-(2-hydroxyphenyl)-1-nonyl-1H-pyrazole (III 32 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 8.55(br, 1H), 7.89(d, 2H, J=8.7Hz), 7.67(d, 2H, J=8.7Hz), 3.84(t, 2H, J=6.6Hz ), 1.65-1.69 (m, 2H), 1.24 (br, 12H), 0.81 (t, 3H, J=6.6Hz); MS (ESI, m/z): 345.2
实施例33Example 33
3-氨基-4-甲酰胺基-5-(2-羟基苯基)-1-正癸烷基-1H-吡唑(III33)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：8.57(br，1H)7.99(d，2H，J＝8.7Hz)，7.59(d，2H，J＝8.7Hz)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，14H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：359.2The synthesis method of 3-amino-4-carboxamido-5-(2-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 33 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 8.57(br, 1H), 7.99(d, 2H, J=8.7Hz), 7.59(d, 2H, J=8.7Hz), 3.84(t, 2H, J=6.6Hz ), 1.65-1.69 (m, 2H), 1.24 (br, 14H), 0.81 (t, 3H, J=6.6Hz); MS (ESI, m/z): 359.2
实施例34Example 34
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正辛烷基-1H-吡唑(III34)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：9.15(br，1H)7.89-7.67(m，4H)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，10H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：331.2The synthesis method of 3-amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-octyl-1H-pyrazole (III 34 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 9.15(br, 1H) 7.89-7.67(m, 4H), 3.84(t, 2H, J=6.6Hz), 1.65-1.69(m, 2H), 1.24(br, 10H), 0.81 (t, 3H, J=6.6Hz); MS (ESI, m/z): 331.2
实施例35Example 35
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正壬烷基-1H-吡唑(III35)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：9.10(br，1H)7.89-7.67(m，4H)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.24(br，12H)，0.81(t，3H，J＝6.3Hz)；MS(ESI，m/z)：345.2The synthetic method of 3-amino-4-carboxamido-5-(3-hydroxyphenyl)-1-nonyl-1H-pyrazole (III 35 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 9.10(br, 1H) 7.89-7.67(m, 4H), 3.84(t, 2H, J=6.6Hz), 1.65-1.69(m, 2H), 1.24(br, 12H), 0.81 (t, 3H, J=6.3Hz); MS (ESI, m/z): 345.2
实施例36Example 36
3-氨基-4-甲酰胺基-5-(3-羟基苯基)-1-正癸烷基-1H-吡唑(III36)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：9.00(br，1H)7.72-7.79(m，4H)，3.80(t，2H，J＝6.3Hz)，1.65-1.69(m，2H)，1.24-1.26(m，14H)，0.81(t，3H，J＝6.3Hz)；MS(ESI，m/z)：359.2The synthesis method of 3-amino-4-carboxamido-5-(3-hydroxyphenyl)-1-n-decyl-1H-pyrazole (III 36 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 9.00(br, 1H) 7.72-7.79(m, 4H), 3.80(t, 2H, J=6.3Hz), 1.65-1.69(m, 2H), 1.24-1.26( m, 14H), 0.81 (t, 3H, J=6.3Hz); MS (ESI, m/z): 359.2
实施例37Example 37
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正辛烷基-1H-吡唑(III37)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.00-7.19(m，4H)，6.29(s，2H)，3.82(t，2H，J＝6.3Hz)，3.70(s，3H)，1.65-1.69(m，2H)，1.24(br，10H)，0.83(t，3H，J＝6.6Hz)；MS(ESI，m/z)：345.2The synthetic method of 3-amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-octyl-1H-pyrazole (III 37 ) refers to the general method above: 1 H NMR ( DMSO-d 6 , 300MHz) δ (ppm): 7.00-7.19 (m, 4H), 6.29 (s, 2H), 3.82 (t, 2H, J=6.3Hz), 3.70 (s, 3H), 1.65-1.69 (m, 2H), 1.24 (br, 10H), 0.83 (t, 3H, J=6.6Hz); MS (ESI, m/z): 345.2
实施例38Example 38
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正壬烷基-1H-吡唑(III38)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：6.99-7.32(m，4H)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，3.70(s，3H)，1.65-1.69(m，2H)，1.24(br，12H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：359.2The synthetic method of 3-amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-nonyl-1H-pyrazole (III 38 ) refers to the general method above: 1 H NMR ( DMSO-d 6 , 300MHz) δ (ppm): 6.99-7.32 (m, 4H), 6.29 (s, 2H), 3.84 (t, 2H, J=6.6Hz), 3.70 (s, 3H), 1.65-1.69 (m, 2H), 1.24 (br, 12H), 0.82 (t, 3H, J=6.6Hz); MS (ESI, m/z): 359.2
实施例39Example 39
3-氨基-4-甲酰胺基-5-(2-甲氧基苯基)-1-正癸烷基-1H-吡唑(III39)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.01-7.29(m，4H)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，3.70(s，3H)，1.65-1.69(m，2H)，1.24(m，14H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：373.2The synthetic method of 3-amino-4-carboxamido-5-(2-methoxyphenyl)-1-n-decyl-1H-pyrazole (III 39 ) refers to the general method above: 1 H NMR ( DMSO-d 6 , 300MHz) δ (ppm): 7.01-7.29 (m, 4H), 6.29 (s, 2H), 3.84 (t, 2H, J=6.6Hz), 3.70 (s, 3H), 1.65-1.69 (m, 2H), 1.24 (m, 14H), 0.82 (t, 3H, J=6.6Hz); MS (ESI, m/z): 373.2
实施例40Example 40
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正辛烷基-1H-吡唑(III40)的合成方法参考上面的通用方法：δ(ppm)：8.00(d，1H，J＝9.0Hz)，7.75(m，2H，J＝6.9Hz)，7.61(t，1H，J＝6.9Hz)，6.30(br，4H)，3.86(t，2H，J＝6.0Hz)，1.62(br，2H)，1.23(br，10H)，0.84(t，3H，J＝6.6Hz)；MS(ESI，m/z)：330.2The synthetic method of 3-amino-4-carboxamido-5-(3-aminophenyl)-1-n-octyl-1H-pyrazole (III 40 ) refers to the general method above: δ (ppm): 8.00 (d, 1H, J=9.0Hz), 7.75(m, 2H, J=6.9Hz), 7.61(t, 1H, J=6.9Hz), 6.30(br, 4H), 3.86(t, 2H, J= 6.0Hz), 1.62(br, 2H), 1.23(br, 10H), 0.84(t, 3H, J=6.6Hz); MS(ESI, m/z): 330.2
实施例41Example 41
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正壬烷基-1H-吡唑(III41)的合成方法参考上面的通用方法：δ(ppm)：8.03(d，1H，J＝9.0Hz)，7.76(m，2H，J＝6.9Hz)，7.71(t，1H，J＝6.9Hz)，6.33(br，4H)，3.85(t，2H，J＝6.0Hz)，1.61(br，2H)，1.23(br，12H)，0.83(t，3H，J＝6.6Hz)；MS(ESI，m/z)：344.2The synthetic method of 3-amino-4-carboxamido-5-(3-aminophenyl)-1-n-nonyl-1H-pyrazole (III 41 ) refers to the general method above: δ (ppm): 8.03 (d, 1H, J=9.0Hz), 7.76(m, 2H, J=6.9Hz), 7.71(t, 1H, J=6.9Hz), 6.33(br, 4H), 3.85(t, 2H, J= 6.0Hz), 1.61(br, 2H), 1.23(br, 12H), 0.83(t, 3H, J=6.6Hz); MS(ESI, m/z): 344.2
实施例42Example 42
3-氨基-4-甲酰胺基-5-(3-氨基苯基)-1-正癸烷基-1H-吡唑(III42)的合成方法参考上面的通用方法：δ(ppm)：8.03(d，1H，J＝9.0Hz)，7.76(m，2H，J＝6.9Hz)，7.71(t，1H，J＝6.9Hz)，6.33(br，4H)，3.85(t，2H，J＝6.0Hz)，1.61(br，2H)，1.26(br，14H)，0.81(t，3H，J＝6.6Hz)；MS(ESI，m/z)：358.2The synthetic method of 3-amino-4-carboxamido-5-(3-aminophenyl)-1-n-decyl-1H-pyrazole (III 42 ) refers to the general method above: δ (ppm): 8.03 (d, 1H, J=9.0Hz), 7.76(m, 2H, J=6.9Hz), 7.71(t, 1H, J=6.9Hz), 6.33(br, 4H), 3.85(t, 2H, J= 6.0Hz), 1.61(br, 2H), 1.26(br, 14H), 0.81(t, 3H, J=6.6Hz); MS(ESI, m/z): 358.2
实施例43Example 43
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正辛烷基-1H-吡唑(III43)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.36(d，2H，J＝9.3Hz)，6.99(d，2H，J＝9.3Hz)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.23(br，10H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：330.2The synthesis method of 3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-octyl-1H-pyrazole (III 43 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.36(d, 2H, J=9.3Hz), 6.99(d, 2H, J=9.3Hz), 6.29(s, 2H), 3.84(t, 2H, J=6.6 Hz), 1.65-1.69 (m, 2H), 1.23 (br, 10H), 0.82 (t, 3H, J=6.6Hz); MS (ESI, m/z): 330.2
实施例44Example 44
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正壬烷基-1H-吡唑(III44)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.35(d，2H，J＝8.7Hz)，6.99(d，2H，J＝9.0Hz)，6.29(s，2H)，3.84(t，2H，J＝6.6Hz)，1.65-1.69(m，2H)，1.21-1.23(m，12H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：344.2The synthesis method of 3-amino-4-carboxamido-5-(4-aminophenyl)-1-nonyl-1H-pyrazole (III 44 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.35(d, 2H, J=8.7Hz), 6.99(d, 2H, J=9.0Hz), 6.29(s, 2H), 3.84(t, 2H, J=6.6 Hz), 1.65-1.69 (m, 2H), 1.21-1.23 (m, 12H), 0.82 (t, 3H, J=6.6Hz); MS (ESI, m/z): 344.2
实施例45Example 45
3-氨基-4-甲酰胺基-5-(4-氨基苯基)-1-正癸烷基-1H-吡唑(III45)的合成方法参考上面的通用方法：1H NMR(DMSO-d6，300MHz)δ(ppm)：7.34(d，2H，J＝9.0Hz)，6.99(d，2H，J＝9.0Hz)，6.29(s，2H)，3.83(t，2H，J＝6.6Hz)，1.65-1.66(m，2H)，1.21(br，10H)，0.82(t，3H，J＝6.6Hz)；MS(ESI，m/z)：358.2The synthesis method of 3-amino-4-carboxamido-5-(4-aminophenyl)-1-n-decyl-1H-pyrazole (III 45 ) refers to the general method above: 1 H NMR (DMSO- d 6 , 300MHz) δ(ppm): 7.34(d, 2H, J=9.0Hz), 6.99(d, 2H, J=9.0Hz), 6.29(s, 2H), 3.83(t, 2H, J=6.6 Hz), 1.65-1.66 (m, 2H), 1.21 (br, 10H), 0.82 (t, 3H, J=6.6Hz); MS (ESI, m/z): 358.2
实施例46受试化合物对MCF-7细胞的细胞毒作用The cytotoxic effect of embodiment 46 test compounds on MCF-7 cells
MCF-7细胞用含10％小牛血清的RPMI 1640培养基在37度，5％CO2饱和湿度的条件下培养。取对数生长期的细胞，以1X 105/mL密度接种于96孔培养板中，每孔180μL在37度，5％CO2饱和湿度的条件下培养。分为空白对照组，受试化合物组，阳性对照组。受试化合物组中加入不同的受试化合物，终浓度均为10μM；阳性对照组给予10μM 5-FU。空白对照组给予等体积的PBS。给药体积均为20μL。再培养48小时，加入MTT工作液，4小时后离心，倾去培养液，每孔加入150μL DMSO溶解，然后在酶标仪上于波长492处读取光密度，计算化合物对细胞的存活率的影响。MCF-7 cells were cultured in RPMI 1640 medium containing 10% calf serum at 37°C and 5% CO 2 saturated humidity. The cells in the logarithmic growth phase were seeded in a 96-well culture plate at a density of 1X 10 5 /mL, and cultured at 180 μL per well under the conditions of 37 degrees and 5% CO 2 saturated humidity. Divided into blank control group, test compound group and positive control group. Different test compounds were added to the test compound group with a final concentration of 10 μM; the positive control group was given 10 μM 5-FU. The blank control group was given an equal volume of PBS. The administration volume was 20 μL. Cultivate for another 48 hours, add MTT working solution, centrifuge after 4 hours, pour off the culture solution, add 150 μL DMSO to each well to dissolve, then read the optical density at a wavelength of 492 on a microplate reader, and calculate the effect of the compound on the survival rate of the cells Influence.
细胞抑制率＝1-(试验组OD平均值/对照组OD平均值)X 100％Cell inhibition rate=1-(OD average value of test group/OD average value of control group) X 100%
MTT法测试受试化合物对MCF-7细胞的细胞毒作用。结果见表1。由数据可知：化合物III12III27，III31-33有较强的细胞毒作用，其它化合物有中等的细胞毒作用。MTT method was used to test the cytotoxic effect of test compounds on MCF-7 cells. The results are shown in Table 1. It can be seen from the data that compounds III 12 III 27 and III 31-33 have strong cytotoxicity, and other compounds have moderate cytotoxicity.
表1MTT法测量受试化合物对MCF-7细胞的细胞毒作用(mean±s，n＝6)(Tab 1cytotoxicity to MCF-7 cell as determined by MTT assay(mean±s，n＝6))Table 1 MTT method to measure the cytotoxic effect of the test compound on MCF-7 cells (mean ± s, n = 6) (Tab 1cytotoxicity to MCF-7 cell as determined by MTT assay (mean ± s, n = 6))
PI3K实验方法PI3K experimental method
将测试化合物溶解在DMSO中，直接分配到384孔的flashplate内，每孔1.25微升。然后在每孔中加入20微升的6nM的PI3激酶，接着加入20微升400nM ATP(其中含有少量放射性标记的ATP)和900nM 1-α-磷脂酰肌醇。离心此版除去所有的空气间隙。进行15分钟的反应，然后加入20微升100mM EDTA终止反应。反应物室温下培育过夜，使酯质底物通过疏水反应结合到闪蒸板的表面。洗去孔中的液体，用闪烁计数器测定标记底物。Test compounds were dissolved in DMSO and dispensed directly into a 384-well flashplate at 1.25 microliters per well. Then 20 microliters of 6nM PI3 kinase was added to each well, followed by 20 microliters of 400nM ATP (containing a small amount of radioactively labeled ATP) and 900nM 1-α-phosphatidylinositol. Centrifuge this plate to remove all air gaps. Reactions were performed for 15 minutes and then terminated by adding 20 μl of 100 mM EDTA. The reaction was incubated overnight at room temperature to allow the ester substrate to bind to the surface of the flash plate through a hydrophobic reaction. The liquid in the wells was washed away, and the labeled substrate was measured with a scintillation counter.
在如上述方法检测时，III1-45的化合物显示的PI3K的IC50值小于50μM。Compounds of III 1-45 exhibited IC50 values for PI3K of less than 50 [mu]M when assayed as described above.
RTK实验方法RTK experiment method
以黑色96孔板为实验容器，每孔加入20μl缓冲液(或酪氨酸激酶抑制剂溶液)，10μl反应底物，10μl酪氨酸激酶，10μl ATP。在37℃的孵箱中孵育30min。然后，依次加入25μl的链激酶素标记的XL-665及25μl EuK标记的抗磷酸化的酪氨酸激酶抗体，室温反应60min。用Tecan Genios Pro检测荧光信号。Use a black 96-well plate as the experimental container, add 20 μl buffer (or tyrosine kinase inhibitor solution), 10 μl reaction substrate, 10 μl tyrosine kinase, and 10 μl ATP to each well. Incubate in an incubator at 37°C for 30min. Then, 25 μl of streptokinin-labeled XL-665 and 25 μl of EuK-labeled anti-phosphorylated tyrosine kinase antibody were added sequentially, and reacted at room temperature for 60 min. Fluorescent signals were detected with Tecan Genios Pro.
在如上述方法检测时，III1-45的化合物显示的PI3K的IC50值小于50μM。Compounds of III 1-45 exhibited IC50 values for PI3K of less than 50 [mu]M when assayed as described above.
应理解，本发明的有机化合物可显示互变异构现象。因在本说明书的化学结构式中仅代表了-种可能的互变体形式，故应理解本发明包括所示结构的所有互变体形式。It is to be understood that the organic compounds of the present invention may exhibit tautomerism. Since only one possible tautomeric form is represented in the chemical structural formulas in this specification, it should be understood that the present invention includes all tautomeric forms of the shown structures.
应理解，本发明不限于部分列出的为说明目的的实施方法，而包括上述公开范围内的所有形式。It should be understood that the present invention is not limited to the methods of implementation partially set forth for purposes of illustration, but includes all forms within the scope of the foregoing disclosure.
尽管描述并说明了本发明的优选实施方法，但可理解在不偏离本发明精神和范围时可作出各种变动。While the preferred practice of the invention has been described and illustrated, it will be understood that various changes may be made without departing from the spirit and scope of the invention.
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