CN104211692A - Derivative as Aurora kinase inhibitor - Google Patents

Derivative as Aurora kinase inhibitor Download PDF

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CN104211692A
CN104211692A CN201410245663.XA CN201410245663A CN104211692A CN 104211692 A CN104211692 A CN 104211692A CN 201410245663 A CN201410245663 A CN 201410245663A CN 104211692 A CN104211692 A CN 104211692A
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CN104211692B (en
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刘兵
张英俊
张吉泉
李燕平
杨学绮
张健存
郑常春
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Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The present invention relates to a substituted pyrazole derivative used for inhibiting Aurora kinase and represented by formula (I) or formula (Ia), or stereo isomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, a medicinal composition containing the above compounds as active ingredients, and a use of the compounds and the medicinal composition in preparation of medicines for protecting, processing, treating or mitigating proliferative diseases of patients.

Description

As the derivative of Ou Ruola kinase inhibitor
Invention field
The present invention relates to and be used for the treatment of some disease, particularly proliferative disease is as cancer, and some novel cpd and preparation method thereof of medicine for the preparation for the treatment of proliferative disease, and containing its pharmaceutical composition as activeconstituents.
Background of invention
The feature of cancer and other hyperproliferative disease is uncontrolled cell proliferation.The forfeiture of cell proliferation normal regulating normally occurs because the gene regulating and controlling the cell passage that the whole cell cycle carries out sustains damage.
Research shows, in eukaryotic cell, the orderly cascade Mach-Zehnder interferometer of protein phosphorylation the cell cycle.Identify the proteolytic enzyme of several families in this cascade with vital role at present.Compared with healthy tissues, many above-mentioned kinase whose activity obviously increase in people's tumour.This may be because protein expression level improves or assisted activation albumen or resist the expression of albumen and change and caused.
To identify at first and the cell cycle regulatory factors be widely studied is cell cycle protein dependent kinase (CDK), specific C DK in the activity of specified time for initiation and assist the process of whole cell cycle to be indispensable.Such as, CDK4 albumen seems by making retinoblast oncoprotein pRb phosphorylation and controls to enter the cell cycle (G0-G1-S conversion).This stimulation transcription factor E2F discharges from pRb, and then E2F works, and increases and enters the necessary genetic transcription of S phase.CDK4 stimulates its catalytic activity by combining pairing protein, Cyclin D.There is one of initial evidence contacted directly between cancer and cell is in many people's tumours, observe that cyclin D1 gene is amplified and Cyclin D1 concentration increases (see Science, 1996,274,1672-1677, Sherr etc.).Other research (see Nature Medicine, 1997,3,231-234, Loda etc.) has also confirmed the negative regulatory factor of CDK function normally negative regulator or disappearance in people's tumour, causes these kinases by inappropriate activation.
Identify protein kinase structure being different from CDK family recently, it has keying action in the adjustment cell cycle, seems to be formed also very important for tumour.These kinases comprise the new Drosophila Ou Ruola (Drosophila aurora) of qualification and people's homologue of yeast saccharomyces cerevisiae (S.cerevisiae) Ipl1 albumen.Three-type-person's homologue Ou Ruola-A, the Ou Ruola-B of these genes and the serine-threonine protein kinase enzyme of Ou Ruola-C (Aurora-A, Aurora-B and Aurora-C) coding and regulating cell cycle are (see Trends in Cell Biology, 2001,11,49-54, Adams etc.).At G2 and mitotic stages, they occur that one is expressed and kinase activity peak value, some observation display people's Ou Ruola albumen and related to cancer.Ou Ruola-A gene is positioned at karyomit(e) 20q13, a region be usually amplified in people's tumour.Ou Ruola-A may be the major target gene of this amplification, and research finds in the Central European Ruo La-A of the primary Human colorectal carcinoma more than 50% DNA cloning, mRNA overexpression.Compared with adjacent normal tissue, the Ou Ruola-A protein level in these tumours significantly raises.Research (see Nature Genetics, 1998,20,189-93, Zhou etc.) has confirmed that people is that overexpression Ou Ruola-A causes centrosome number obviously to increase, and this is the known procedure that cancer occurs.The research (see Chromsoma, 2001,110,65-74, Adams etc.) of crossing a step confirms compared with normal cell, and the expression of the Central European Ruo La-B of tumour cell also obviously increases.
Existing research confirms: expression and the function (WO1997022702 and WO1999037788) of being eliminated Ou Ruola-A by antisense oligonucleotide handler tumor cell line, cause the cell cycle suppressed, in these tumour cells, produce antiproliferative effect.In addition, confirmed that the micromolecular inhibitor of Ou Ruola-A and Ou Ruola-B has antiproliferative effect in human tumor cells, only siRNA process alternative eliminates Ou Ruola-B expression.This illustrates and suppresses the function of Ou Ruola-A and Ou Ruola-B to produce antiproliferative effect, and this can be used for treatment people's tumour and other hyperproliferative disease.In addition, compared with the signal transduction path for cell cycle upstream, Ou Ruola (Aurora) kinases is suppressed to have obvious advantage as the methods for the treatment of of these diseases.Because the cell cycle is in the most downstream of all these unlike signal conduction activities, so will be effective to all proliferating tumor cells for the therapy of cell cycle, and for signal specific transduction molecule if the method for EGF-R ELISA is by only effective to the tumour cell of expressing these acceptors.
Many pyrimidine derivatives are disclosed for suppressing Ou Ruola kinases, WO2002057259, WO2002059111, WO2004000833, WO2008115973 describe some substituted pyrimidines compound, but still have the compound with Ou Ruola kinase inhibiting properties more.
Abstract of invention
The present invention proposes the derivative that new the having of a class suppresses Ou Ruola kinases especially Ou Ruola-A kinases and/or Ou Ruola-B zymogenesis.The compounds of this invention or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, can be used for treating proliferative disease.Specifically, the compounds of this invention can be used for treating the proliferative disease of known Aurora A effect as cancer, it is no matter the form of solid tumor or blood borne knurl, especially, such as colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, neck cancer, central nervous system cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, chronic inflammatory diseases, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, myelomatosis, acute lymphoblastic leukemia, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, chronic hepatitis, liver cirrhosis, ovarian cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
One aspect of the present invention provides a kind of substituted pyrazole derivatives, it is for such as formula the structure shown in (I) or formula (Ia), or such as formula the steric isomer of the structure shown in (I) or formula (Ia), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q is-NH-, or-O-
R 1for morpholinyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12condensed-bicyclic base, or C 5-12condense assorted bicyclic group;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-6alkyl;
Or R 2and R 3five-membered ring is formed together with its connected carbon atom; Wherein, described five-membered ring can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl or C 6-10aryl; Or, R 4and R 4ac is formed together with its connected atom N 2-9heterocyclic radical;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-6alkyl or C 6-10aryl;
Wherein, R 7for C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
Wherein, each R 8and R 8abe hydrogen independently, C 6-10aryl, C 1-6alkoxyl group, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-6during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, or C 1-9heteroaryl; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, described R 1, R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in bridge to mix bicyclic group, bridge bicyclic group, condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, carbocylic radical, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroaryl, aryl, heterocyclic radical, carbocylic radical and alkoxyl group, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is,
Q is-NH-;
R 1for morpholinyl, or following subformula:
Wherein, each Q 1and X 3be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic radical, carbocylic radical, cycloalkylalkyl, and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-4during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl.
Other embodiment is,
R 1for morpholinyl, or following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
or wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl, cyclohexyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 8and R 8acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclopropylmethylene, phenylmethylene, heterocyclic radical, phenyl and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, methyl, ethyl, or during propyl group,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl.
In certain embodiments, the invention provides a kind of substituted pyrazole derivatives, it is for such as formula the substituted pyrazole derivatives shown in (II) or formula (IIa), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 1for following subformula:
Wherein, each Q 1and X 3be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, each R 7be C independently 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is, R 1for following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclobutyl, cyclopentyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl, cyclohexyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl.
In certain embodiments, the invention provides a kind of substituted pyrazole derivatives, it is for such as formula the substituted pyrazole derivatives shown in (IIb) or formula (IIab), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5athe carbocylic radical of 5-6 unit is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, each R 7be cyclopropyl independently, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, butyl, 1-Ethyl-propyl, amyl group, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocylic radical, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
On the one hand, the present invention also provides a kind of pharmaceutical composition simultaneously, comprises at least one formula (I) or (Ia), formula (II) or (IIa), shown compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
In some embodiments, pharmaceutical composition of the present invention, comprises pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
In some embodiments, described pharmaceutical composition, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine and is used for the treatment of at least one of medicine of pulmonary fibrosis.
In some embodiments, described pharmaceutical composition, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
On the other hand, the present invention also provides a kind of formula (I) or (Ia), formula (II) or the compound shown in (IIa) or pharmaceutical composition of the present invention protect, and process, treats or alleviate the purposes of the disease that patient Ou Ruola kinases mediates.
In some embodiments, purposes of the present invention, wherein said Ou Ruola kinases refers to Ou Ruola-A kinases or Ou Ruola-B kinases.
On the one hand, the present invention also provides a kind of use formula (I) or (Ia), formula (II) or the compound shown in (IIa) or pharmaceutical composition of the present invention come for the preparation of protection, process, treats or alleviates the purposes of medicine of patient's proliferative disease.
In some embodiments, medicine containing the compounds of this invention can be used for treating proliferative disease, particularly as colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, neck cancer, central nervous system cancer, glioblastoma, or myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, chronic inflammatory diseases, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, myelomatosis, acute lymphoblastic leukemia, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, chronic hepatitis, liver cirrhosis, ovarian cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
Content noted earlier only outlines some aspect of the present invention, but the content being not limited to these aspects and other aspect will do more specifically complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim defines.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the scope that the present patent application controls.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry; " by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to: F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
The term " halogen " that the present invention uses, " halogen atom " or " halogen atom " comprises fluorine, chlorine, bromine, iodine.
The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkyl can independently optionally replace by one or more substituting group described in the invention.Some of them embodiment is, alkyl group contains 1-10 carbon atom, and other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is, alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom.Alkyl group further example comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), amyl group (-CH 2cH 2cH 2cH 2cH 3), 1-Ethyl-propyl (-CH (CH 2cH 3) 2) etc.Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.
The term " alkoxyl group " used in the present invention, is related to alkyl, defines as the present invention, be connected in main carbochain by Sauerstoffatom.Such embodiment comprises, but is not limited to methoxyl group, oxyethyl group, propoxy-etc.
Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxyl group can by one or more identical or different halogen atom situation about replacing.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy, chloromethyl, chlorine methoxyl group etc.
Term " hydroxyalkyl ", " hydroxyl substituted alkyl group " or " hydroxy alkoxy base " represents that alkyl or alkoxyl group can be optionally substituted with one or more hydroxyl replaced situation.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to methylol, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxyl methoxyl group, 1-hydroxy ethoxy etc.
Term " alkoxyalkyl " represent alkyl can by one or more alkoxyl group situation about replacing.Wherein alkyl group has implication as described in the present invention, and such example comprises, but is not limited to methoxymethyl, ethoxyethyl group, etc.
Term " aryl " can be used alone or conduct " aralkyl ", most of " aralkoxy " or " aryloxy alkyl ", represent the monocycle altogether containing 6-14 ring, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " arylalkyl " represent alkyl can by one or more aryl situation about replacing.Wherein alkyl group and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to phenyl methyl, phenylethyl, etc.
Term " heteroaryl " can be used alone or as the part of " heteroarylalkyl " or " heteroarylalkoxy ", represent the monocycle altogether containing 5-14 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Other embodiment is, hetero-aromatic ring comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidine-5-base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, 1, 3, 4-thiadiazoles-2-base, pyrazinyl, pyrazine-2-base, 1, 3, 5-triazinyl, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridine-6-base, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) etc.
Term " heteroarylalkyl " represent alkyl can by one or more heteroaryl situation about replacing.Wherein alkyl group and heteroaryl groups have implication as described in the present invention, and such example comprises, but is not limited to imidazolyl methyl, thiazolylethyl, etc.
Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " refers to monovalence or multivalence, non-aromatic, the unsaturated ring of saturated or part, and do not comprise heteroatoms, comprising the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom or three rings.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable cyclic aliphatic group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group comprises further, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, adamantyl etc.And described " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " cycloalkylalkyl " represent alkyl can by one or more cycloalkyl situation about replacing.Wherein alkyl group and group of naphthene base have implication as described in the present invention, and such example comprises, but is not limited to Cvclopropvlmethvl, cyclohexyl-ethyl, cyclohexyl methyl etc.
Term " heterocyclic radical ", " heterocycle ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein on ring one or more atom independent optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but is never the fragrant same clan, only has a tie point to be connected to other molecules and gets on.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocyclic radical ", " heterocycle ", " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom be selected from N, O, P, 1-3 the heteroatoms of S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group).
" heterocyclic radical " can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, thioxane base, azelidinyl, oxetanylmethoxy, thietanyl, piperidyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, N-morpholinyl, 2-morpholinyl, morpholinyl, thio-morpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazine base, 4-Methoxy-piperidin-1-base, 1, 2, 3, 6-tetrahydropyridine-1-base, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrroline-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl, imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 1, 2, 6-thiadiazine alkane 1, 1-dioxy-2-base, quinolizinyl and N-pyridyl urea.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represent saturated or undersaturated fused ring system, relate to the bicyclic system of non-aromatic, have at least a ring to be nonaromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).Each ring in condensed-bicyclic is carbocyclic ring or is that assorted alicyclic, such example comprises, but is not limited to, six hydrogen-furo [3,2-b] furyl, 2,3,3a, 4,7,7a-six hydrogen-1H-indenyl, 7-azabicyclo [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl, condensed-bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl, these are included within the system of condensed-bicyclic.And described condensed-bicyclic base can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " condenses assorted bicyclic group " and represents saturated or undersaturated fused ring system, relates to the bicyclic system of non-aromatic, has at least a ring to be nonaromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group, such example comprises, but be not limited to six hydrogen-2H-[1, 4] dioxin [2, 3-c] pyrryl, 3-azabicyclo [3.3.0] octyl, 3-methyl-3, 7-diazabicyclo [3.3.0] octyl, 8-azabicyclo [4.3.0] nonyl, 8-azabicyclo [4.3.0] nonane 3-base, 3-azabicyclo [4.3.0] nonane-3-base, 1, 5-dioxy-8-azabicyclo [4.3.0] nonyl, (1R, 6S)-2, 5-dioxy-8-azabicyclo [4.3.0] nonyl, (1R, 6R)-2, 5-dioxy-8-azabicyclo [4.3.0] nonyl, isoindoline base, 1, 2, 3, 4-tetrahydric quinoline group, (1S, 5S)-1-hydroxyl-3-azabicyclo [3.1.0] hexyl, (1R, 5S)-1-hydroxyl-3-azabicyclo [3.1.0] hexyl, (1R, 5S)-1-N, N-dimethylamino-3-azabicyclo [3.1.0] hexyl, (1S, 5R, 6R)-1-methyl-6-alcohol-3-azabicyclo [3.2.0] heptane base, 3-nitrogen-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2, 6-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 3-ethyl-3, 7-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 7-ethanoyl-2, 7-diazabicyclo [3.3.0] octyl, 2, 8-diazabicyclo [4.3.0] nonyl, 3, 8-diazabicyclo [4.3.0] nonyl, 2-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxygen-8-azabicyclo [4.3.0] nonyl, 2-oxygen-8-azabicyclo [4.3.0] nonyl, 2, 8-phenodiazine-5-oxabicyclo [4.3.0] nonyl, (1S, 6R)-2-methyl-2, 8-phenodiazine-5-oxabicyclo [4.3.0] nonyl, 3-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 4, 9-diazabicyclo [4.3.0] nonyl, 2, 9-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 3-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 3-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 2-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 2-oxo-3-oxygen-8-azabicyclo [4.3.0] nonyl, 3-oxo-2, 4, 8-tri-azabicyclo [4.3.0] nonyl, 3-oxo-4-oxygen-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 8-diazabicyclo [4.3.0] nonyl, 3, 8-diazabicyclo [4.3.0] nonyl, 8-methyl-2, 8-diazabicyclo [4.3.0] nonyl, 3, 7-diazabicyclo [4.3.0] nonyl, 3, 9-diazabicyclo [4.3.0] nonyl, 3-oxygen-8-azabicyclo [4.3.0] nonyl, 3-sulphur-8-azabicyclo [4.3.0] nonyl, 9-methyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-methyl-3, 7-diazabicyclo [4.3.0] nonyl, 9-ethyl-3, 9-diazabicyclo [4.3.0] nonyl, 7-ethyl-3, 7-diazabicyclo [4.3.0] nonyl, 8-ethyl-2, 8-diazabicyclo [4.3.0] nonyl, 5, 6-dihydro-4H-pyrrolo-[3, 4-c] isoxazolyl, 3-ethyl-[1, 2, 4] triazole [4, 3-a] and piperidyl, [1, 2, 4] triazole [4, 3-a] and piperidyl, 3-methyl-isoxzzole also [4, 3-c] piperidyl, 3-methyl-5, 6-dihydro-4H-pyrrolo-[3, 4-c] isoxazolyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene-1H-imidazo [4, 5-c] pyridyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene oxazole also [4, 5-c] pyridyl, 2-methyl-4, 5, 6, 7-tetrahydrochysene-1H-thiazole also [4, 5-c] pyridyl, isoxzzole also [4, 3-c] piperidyl, 4, 5, 6, 7-tetrahydrochysene isoxzzole also [3, 4-c] pyridyl, [1, 2, 4] triazole also [4, 3-a] piperazinyl, 3-trifluoromethyl-[1, 2, 4] triazole also [4, 3-a] piperazinyl, 3-methyl-[1, 2, 4] triazole also [4, 3-a] piperazinyl, 2-oxo-3-oxygen-8-azabicyclo [4.3.0] nonyl, 1, 3-dimethyl-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [4, 3-c] pyridin-2-yl-, 2-oxygen-7-azabicyclo [4.4.0] decyl, 1, 5-dioxy-9-azabicyclo [4.4.0] decyl, 2, 3-dimethyl-4, 5, 6, 7-tetrahydrochysene-2H-pyrazolo [4, 3-c] pyridin-2-yl-, 3-azabicyclo [4.4.0] decyl, 2, 7-diaza decahydro naphthyl or 2-oxygen-8-azabicyclo [4.4.0] decyl etc.
Term " bridge mix bicyclic group " represents saturated or undersaturated bridged-ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group, such example comprises, but be not limited to 2-oxygen-5-azabicyclo [2.2.1] heptane base, 7-oxygen-2-azabicyclo base [2.2.1] heptane base, 2-oxygen-5-azabicyclo [2.2.2] octyl, 8-oxygen-3-azabicyclo [3.2.1] octyl, 2-sulphur-5-azabicyclo [2.2.1] heptane base, etc.And described bridge is mixed, bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " bridge bicyclic group " represents saturated or undersaturated bridged-ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or aromatic ring (but aromatic series can as the substituting group on it).Wherein each member ring systems comprises 3-7 ring, and such example comprises, but is not limited to, dicyclo [2.2.1] heptane base, 2-methyl-assorted two rings [2.2.1] heptane base, etc.And described bridge bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " volution base ", " volution ", " spiral shell bicyclic group ", " spiral shell dicyclo " represents that a ring originates from ring-type carbon special on another ring.Such as, as below described by formula a, a saturated bridged-ring system (ring B and B') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".Each ring inside volution is carbocyclic ring or is assorted alicyclic.Such example comprises, but is not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.And described spiral shell bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring.Such as, as above described by formula a, a saturated bridged-ring system (ring B and B') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group, such example comprises, but is not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base, 2-azaspiro [4.5] decyl, 2-azepine spiroheptane base, 2-azaspiro [4.4] nonyl, 2-methyl-2,6-diaza spiro [4.5] decyl, etc.And described spiral shell is mixed, bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro etc.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): the R such as containing asymmetric center, S configuration, (Z) of double bond, (E) isomer, (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S is used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) is used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into bonding electron.
Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can be transformed mutually by lower energy barrier.Such example comprises, but is not limited to, and proton tautomer (i.e. prototropy isomer) comprises the change by proton shifting, the isomerization of such as keto-enol and imine-enamine.Valence tautomer comprises the restructuring change of some bonding electronss.
" hydrate " of the present invention refers to that solvent molecule is the associated complex that water is formed.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.
" ester " of the present invention refers to that formula (I) compound containing hydroxyl can hydrolyzable ester in organizer.Such ester is that such as in human or animal body, hydrolysis produces the pharmaceutically acceptable ester of parent alcohol.In formula (I) chemical combination object containing hydroxyl, the group of hydrolyzable ester comprises; but be not limited to; phosphate, acetoxymethoxy, 2; 2-dimethylpropionyloxymethoxy; alkyloyl, benzoyl, benzene first and second acyl group; alkoxy carbonyl, dialkyl carbamoyl and N-(di-alkyaminoethyl group)-N-alkyl-carbamoyl etc.
" oxynitride " of the present invention refers to when compound is containing several amine functional group, 1 or the nitrogen-atoms oxidation being greater than 1 can be formed N-oxide compound.The particular example of N-oxide compound is the N-oxide compound of tertiary amine or the N-oxide compound of nitrogen heterocyclic ring nitrogen-atoms.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine and form N-oxide compound (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).Especially, N-oxide compound can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, wherein such as in inert solvent such as methylene dichloride, amine compound and m-chlorine peroxybenzoic acid (MCPBA) is reacted.
Can be there is multiple different geometrical isomer and tautomer in compound, described formula (I) compound comprises this type of forms all.For avoiding feeling uncertain, when compound to exist with one of several geometrical isomer or tautomer and only specifically describe or display is a kind of time, obviously other forms all are included in formula (I).
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, oxysuccinic acid, 2 hydroxy propanoic acid, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.It is suitable that pharmacy acceptable salt comprises further, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of the composition that pharmaceutically can connect-be subject to.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, topical, containing taking administration, or by the administration of implantable medicine box.Term as used herein " through injection " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent according to known technology, and wetting agent and suspension agent manufacture by formula.
The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent according to known technology, wetting agent and suspension agent prepare by pharmaceutical formulation.Aseptic injection can be the nontoxic aseptic parenteral solution made through acceptable thinner or solvent parenterally, suspension or emulsion, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can pass through dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.
Active compound can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.
Compound of the present invention by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.
Compound of the present invention is preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the seriousness of illness and the illness be treated for any one special patient or organism, the activity of particular compound, concrete composition used, the age of patient, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The description of the compounds of this invention
One aspect of the present invention provides a kind of substituted pyrazole derivatives, it is for such as formula the structure shown in (I) or formula (Ia), or such as formula the steric isomer of the structure shown in (I) or formula (Ia), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q is-NH-, or-O-;
R 1for morpholinyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12condensed-bicyclic base, or C 5-12condense assorted bicyclic group;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-6alkyl;
Or R 2and R 3form five-membered ring together with its connected carbon atom, described five-membered ring can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl or C 6-10aryl; Or, R 4and R 4ac is formed together with its connected atom N 2-9heterocyclic radical;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-6alkyl or C 6-10aryl;
Wherein, R 7for C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
Wherein, each R 8and R 8abe hydrogen independently, C 6-10aryl, C 1-6alkoxyl group, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-6during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, or C 1-9heteroaryl; Or,
R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, described R 1, R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in bridge to mix bicyclic group, bridge bicyclic group, condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, carbocylic radical, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroaryl, aryl, heterocyclic radical, carbocylic radical and alkoxyl group, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is,
Q is-NH-, or-O-;
R 1for morpholinyl, or following subformula:
Wherein, each Q 1, X 3, X 8and X 9be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic radical, carbocylic radical, cycloalkylalkyl, and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-4during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl.
Other embodiment is,
Q is-NH-, or-O-;
R 1for morpholinyl, or following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
or wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl or phenyl;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclopropylmethylene, phenylmethylene, heterocyclic radical, phenyl and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, methyl, ethyl, or during propyl group,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl.
In certain embodiments, the invention provides a kind of substituted pyrazole derivatives, it is for such as formula the substituted pyrazole derivatives shown in (II) or formula (IIa), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 1for following subformula:
Wherein, each Q 1, X 3, X 8and X 9be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is, R 1for following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclobutyl, cyclopentyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl or phenyl;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, butyl, 1-Ethyl-propyl, amyl group, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocylic radical, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
In certain embodiments, the invention provides a kind of substituted pyrazole derivatives, it is for such as formula the substituted pyrazole derivatives shown in (IIb) or formula (IIab), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5athe carbocylic radical of 5-6 unit is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, each R 7be cyclopropyl independently, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, butyl, 1-Ethyl-propyl, amyl group, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocylic radical, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
In certain embodiments, the invention provides a kind of substituted pyrazole derivatives, have such as formula the substituted pyrazole derivatives shown in (III), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 1for morpholinyl, or following subformula:
Wherein, each Q 1, X 3, X 8and X 9be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-4alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Some of them embodiment is,
R 1for morpholinyl, or following subformula:
Described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
Wherein, some embodiments are, R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclopentyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl or phenyl;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclopentyl together with its connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, butyl, 1-Ethyl-propyl, amyl group, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocylic radical, cyclopropyl, cyclopentyl, phenyl, cyclohexyl and phenylmethylene, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
In certain embodiments, formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or the compound shown in formula (III), comprise one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
On the one hand, the present invention also provides a kind of pharmaceutical composition simultaneously, comprises at least one formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or the compound shown in formula (III) or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
In some embodiments, pharmaceutical composition of the present invention, comprises pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
In some embodiments, described pharmaceutical composition, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine and is used for the treatment of at least one of medicine of pulmonary fibrosis.
In some embodiments, described pharmaceutical composition, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
On the other hand, the present invention also provides a kind of formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or the compound shown in formula (III) or pharmaceutical composition of the present invention protect, process, treats or alleviates the purposes of the disease that patient Ou Ruola kinases mediates.
In some embodiments, purposes of the present invention, wherein said Ou Ruola kinases refers to Ou Ruola-A kinases or Ou Ruola-B kinases.
On the one hand, the present invention also provides a kind of use formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or the compound shown in formula (III) or pharmaceutical composition of the present invention come for the preparation of protection, process, treats or alleviates the purposes of medicine of patient's proliferative disease.
In some embodiments, medicine containing the compounds of this invention can be used for treating proliferative disease, particularly as colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, neck cancer, central nervous system cancer, glioblastoma, or myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, chronic inflammatory diseases, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, myelomatosis, acute lymphoblastic leukemia, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, chronic hepatitis, liver cirrhosis, ovarian cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises material or composition must be applicable to chemistry or toxicologic, relevant with the Mammals be used for the treatment of with other components of composition preparation.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to mineral acid or organic acid, as fumaric acid, and methylsulfonic acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, phosphoric acid and sulfuric acid etc.The salt that pharmaceutically acceptable nontoxic alkali is formed comprises, but is not limited to mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle's ammonia, parahelium and tertiary ammonia, with ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, the inorganic salt that aluminium and lithium etc. obtain.
The composition of compound of the present invention, preparation and administration
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I) or (Ia), the compound listed by the present invention, or the compound of embodiment 1-31, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound detectably can suppress the protein kinase in biological sample or patient body effectively.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but is not limited to, ion-exchanger; Aluminium; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein is as human serum protein; Buffer substance is as phosphoric acid salt; Glycine; Sorbic Acid; Potassium sorbate; The partial glyceride mixtures of saturated vegetable fatty acid; Water; Ionogen as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate; Salt as sodium-chlor, zinc salt; Colloidal silicon; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylate; Wax; Polyethylene-polyoxypropylene-blocking-up polymer; Lanolin; Sugared as lactose, dextrose plus saccharose; Starch is as W-Gum and potato starch; Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia; Natural gum powder; Fructus Hordei Germinatus; Gelatin; Talcum powder; Auxiliary material is as cocoa butter and suppository wax; Oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol compound, as propylene glycol and polyoxyethylene glycol; Ester class is as ethyl oleate and Ethyl Lauroyl acid esters; Agar; Buffer reagent is as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic salt; Lin Ge (family name) solution; Ethanol; Phosphate buffer solution; With other nontoxic proper lubrication agent as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, per rectum administration, nose administration, containing taking administration, and vagina administration or by the administration of implantable medicine box.Term as used herein " through injection " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent according to known technology, and wetting agent and suspension agent manufacture by formula.Aseptic injection can be aseptic parenteral solution or suspension, is the nontoxic acceptable thinner of injection or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Lipid acid, as oleic acid and its glyceride derivative can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain alcohol diluents or dispersion agent, and as carboxymethyl cellulose or similar dispersing agents, the pharmaceutical preparation being generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.Other conventional tensio-active agents, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of targeted drug formulation.
The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can with the form rectal administration of suppository.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum, thus melts in the rectum and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal relating to region or organ easily reaches, as eye, and the disease of skin or lower intestinal tract.Suitable using topical preparations can prepare and be applied to these fields or organ.
Rectal suppository (see above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot also can medication like this.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carrier containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitable carrier comprises, but is not limited to, mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
For eye, pharmaceutically acceptable composition can be prepared into preparation, as isotonic micronized suspension; the Sterile Saline of pH regulator or other aqueous solution; preferably, the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by the gaseous solvents of nose or inhalation.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, uses phenylcarbinol or other suitable sanitass, absorption enhancer, and fluorocarbon or other conventional solubilizing agent or dispersion agent improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent according to known technology, wetting agent and suspension agent prepare by pharmaceutical formulation.Aseptic injection can be the nontoxic aseptic parenteral solution made through acceptable thinner or solvent parenterally, suspension or emulsion, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can prepare by the auxiliary material of compound of the present invention and suitable non-perfusing or carrier being mixed, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can pass through dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.
Active compound can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.
Compound of the present invention by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.
Compound of the present invention is preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit type " refer to that patient obtains the physical dispersion unit of the required medicine of suitably treatment herein.But, should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the seriousness of illness and the illness be treated for any one special patient or organism, the activity of particular compound, concrete composition used, the age of patient, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The change that can produce the consumption of the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is, composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, and the amount being accepted composition by patient carries out administration.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with the agent of one or more other additional treatment (pharmacy), wherein drug combination causes acceptable untoward reaction, and this has special meaning for the treatment of high proliferative disease as cancer.In this case, compound of the present invention can in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, the disease that the normal drug treatment of additional treatment agent is special is exactly known " suitably disease therapy "." additional treatment agent " used in the present invention comprises chemotherapeutic agent or other antiproliferative medicines can in conjunction with compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, comprise with demethylating agent, but be not limited to, 5-mixes nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the compound described by Publication about Document: US6, 268137, US5, 578, 716, US5, 919, 772, US6, 054, 439, US6, 184, 211, US6, 020, 318, US6, 066, 625, US6, 506, 735, US6, 221, 849, US6, 953, 783, US11/393, 380.
Other embodiment is, chemotherapeutic agent or other anti-proliferative drugs can in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, with the chemotherapeutic agent of other accreditations, include, but are not limited to, alkylating drug (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate (Gleevec), Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (imatinib (Imatinib), Sutent (Sutent), Xarelto (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate cancer approach as mTOR, HIF (hypoxia inducible factor) approach and other.Http:// www.nci.nih.gov/ is shown in cancer therapy more widely forum, http://www.fda.gov/cder/cancer/druglist-rame.htm is shown in by the oncologic inventory of FAD accreditation, and Merck Manual, the 18 edition .2006, all contents are all combine reference.
Other embodiment is, compound of the present invention can in conjunction with cytotoxic anticancer agent.Such carcinostatic agent can find the 13 edition the Merck index (2001) is inner.These carcinostatic agents comprise, but be never limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (Mitomycin C), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan), stilboestrol, 2', 2'-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphate base-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
What other were suitable comprises newfound cytotoxic substance with the cytotoxin class carcinostatic agent of compound combined utilization of the present invention, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and derivative that is natural or synthesis thereof, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003, 21 (4), 646-651), tositumomab (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377).
Other embodiment is, compound of the present invention can in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their respective parts.Such reagent comprises, but is never limited to, antibody therapy as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but be never limited to, small molecule kinase inhibitors as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).
Other embodiment is, compound of the present invention is in conjunction with receptor kinase (VEGFR, FGFR, the PDGFR of other signal transduction inhibitor targetings in division kinase domain family, flt-3, c-kit, c-fins, Abl, Jak, Aurora-A, or Aurora-B etc.), and their respective parts.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but be never limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, Mar.24-28, 2001, abstract3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract2575), CP-547, 632 (Beebe et al., Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract476).
Other embodiment is, compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, and MGCDOI03 (US6 abstract3028), 897, 220).
Other embodiment is, compound of the present invention can in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to, Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract3849).Compound of the present invention in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, can also include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition comprising compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption (those compositions comprising an additional treatment agent are as described in the invention) of additional treatment agent in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises the amount of therapeutical agent as the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.Comprise in the composition of additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.
Embodiment
Usually, compound of the present invention can be prepared by method described in the invention, unless there are further instruction, wherein substituent definition is such as formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or shown in formula (III).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Chromatographic column uses silicagel column, and silica gel (200-300 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The compounds of this invention suppresses the serine-threonine kinase of Ou Ruola kinases (especially Ou Ruola-B) active, T suppression cell cycle and cell proliferation thus.This compounds passes through following Caliper Mobility Shify Assay method evaluation to the kinase whose restraining effect of Ou Ruola.
External Ou Ruola-A and the test of Ou Ruola-B kinase inhibition
In this test, determine that test-compound suppresses the ability of serine-threonine kinase activity.Adopt Caliper Mobility Shify Assay to test, this technology is applied in microfluidic environment by the basic concept of capillary electrophoresis, detects zymetology experiment when not adding and stopping reagent.Substrate for testing is with fluorescently-labeled polypeptide, in reaction system enzyme effect under substrate change product into, its with electric charge also there occurs corresponding change, Mobility-Shift Assay utilizes substrate and the charged difference of product just, the two is separated, and carry out respectively detecting.In the source of strength be separated sample in micro-fluid chip is different in two, electrodynamics and liquid pressure.During work, the suction needle of reaction system by chip bottom under suction function in 96 or 384 orifice plates is inhaled in the pipeline of chip internal.Owing to separate lines in chip being applied in voltage, with difference separated due to electric charge of fluorescently-labeled peptide substrate and reaction product, then carry out exciting of signal at detection window and detected.The amount of product is by calculating Conversion value, i.e. substrate peak and product peak heights sum (Product peak height/ (Substrate+Product peak height)) in the aspect ratio at product peak, assess.
The use of brief word below runs through the present invention:
DCM, CH 2cl 2methylene dichloride
EtOAc, EA ethyl acetate
PE sherwood oil
MeOH, CH 3oH methyl alcohol
EtOH, CH 3cH 2oH ethanol
HCl hydrochloric acid
AcOH acetic acid, acetic acid
Et 3n, TEA triethylamine
K 2cO 3salt of wormwood
NaHCO 3sodium bicarbonate
Na 2cO 3sodium carbonate
NaH sodium hydride
NaOH sodium hydroxide
KOH potassium hydroxide
Na 2sO 4sodium sulfate
DMF DMF
HOBt I-hydroxybenzotriazole
TBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid
HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
THF tetrahydrofuran (THF)
4-DMAP DMAP
DMAC N,N-DIMETHYLACETAMIDE
DMSO methyl-sulphoxide
DMSO-d 6six deuterated dimethyl sulfoxides
EDCI 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride
M-CPBA metachloroperbenzoic acid
Pd/C palladium carbon
SOCl 2thionyl chloride
SnCl 2tindichloride
TLC thin-layer chromatography
TsCl Tosyl chloride
CDI N, N'-carbonyl dimidazoles
(Boc) 2o tert-Butyl dicarbonate
H 2o water
ML milliliter
RT, rt room temperature
Rt retention time
Process description below prepares the universal method of the compounds of this invention.
General synthetic method
The synthetic method of intermediate
Intermediate 1
Compd A 1 acidylate becomes ester A2, then through reacting generating compound A3, compound A-13 by with compound A-45 reacting generating compound A4; compd A 6 is generated again through reduction; generate A8 through reacting with TsCl, then become A9 in alkaline condition pass ring, deprotection generates compd A 10.
Intermediate 2
Compd A 12 acidylate becomes ester A13, then through reacting generating compound A14, and compd A 14 generates compd A 15 through reduction, generates A16 through reacting with MsCl, then with Na 2s reaction is closed ring and is become A17, and deprotection generates compd A 18.
Intermediate 3
Compd A 19 generates compd A 20 through reduction.
Intermediate 4
Compd A 21 and m-CPBA reacting generating compound A22, be compd A 23 reacting generating compound A24, closes ring in the basic conditions and generate compd A 25, restores deprotection and generate compd A 26.
Synthetic schemes 1
Compound 1 and compound 2 reacting generating compound 3 in the basic conditions; compound 3 and hydrazine reaction generate compound 4, and the hydrolysis of compound 4 alkaline condition generates compound 5, generates compound 7 through carrying out two-step reaction with compound 6; restore deprotection and generate compound 8, compound 8 and R 7nH 2reaction generates final product 9.
Synthetic schemes 2
Compound R 1h and compound 11 reacting generating compound 13, compound 13 generates compound 6 through reduction reaction, compound 6 and compound 14 generate compound 15 through two step acidic conditionss, compound 16 is generated through reduction reaction, again with CDI reacting generating compound 17, compound 17 and 19 reacts and generates final product 18.
Synthetic schemes 3
Compound 4 is reacting generating compound 41 in the basic conditions, and compound 41 and compound 6 generate compound 42 through two-step reaction.
Synthetic schemes 4
Compound 16 by respectively with CDI, compound 19 reacts and generates final product 18.
Synthetic schemes 5
Compound 16 and compound 34 reacting generating compound 35.
Synthetic schemes 6
Compound 15 and (Boc) 2o reacting generating compound 36, by reduction reaction generate compound 37, with compound 39 reacting generating compound 38, by deprotection generate compound 40.
Synthetic schemes 7
Compound 4 generates compound 21 through reduction deprotection, then with compound 22 reacting generating compound 23, generate compound 24 in the basic conditions, compound 24 and compound 6 reacting generating compound 25.
Synthetic schemes 8
Compound R 1h and compound 26 reacting generating compound 27, compound 28 is generated by reduction, reduction generates compound 29 further again, compound 29 and compound 14 reacting generating compound 30, compound 30 and TsOH are reacted into ring and generate compound 31, compound 31 through reduction generate compound 32, then with compound 19 reacting generating compound 33.
Wherein R 1, R 4a, R 4, R 7, R 6, R 8a, R 8, R 5a, R 5there is definition of the present invention.
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
Embodiment
Embodiment 1
N-cyclopropyl-3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base)-4,6-pyrrolin [3,4-c] pyrazoles-5 (1H)-methane amide
Step one 2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester
Under ice bath, sodium joins dehydrated alcohol (60mL), stir 1.5 hours, then near-10 DEG C, by oxalic acid diethyl ester (7.72g, 52.8mmol) dropwise add, N-benzyl-3-pyrrolidone (9.24g, 52.8mmol) is dissolved in dehydrated alcohol (60mL) subsequently, adds in 1 hour, rise to room temperature reaction subsequently to spend the night, suction filtration obtains light yellow look solid, washs solid, drying under reduced pressure with ethanol (5mL), obtain product (9.3g, 63%).
LC-MS：276.1[M+1] +.
Step 2 5-benzyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles) base-3-ethyl formate
2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester (9.3g, 33.8mmol) be dissolved in acetic acid (50mL), be cooled to zero degree, hydrazine hydrate (1.7g, 34.1mmol) dropwise add, then reflux 3 hours, be cooled to room temperature, add water (50mL), ethyl acetate extracts (3 × 50mL), saturated sodium bicarbonate aqueous solution (50mL) is washed, anhydrous sodium sulphate (10g) is dry, after removal of solvent under reduced pressure, column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (6.3g, 69%).
LC-MS：272.2[M+1] +.
Step 3 5-benzyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles) base-3-formic acid
5-benzyl-1,4,5,6-Pyrrolidine (3,4-pyrazoles) base-3-ethyl formate (6.3g, 23.2mmol) be dissolved in tetrahydrofuran (THF) (40mL), add aqueous sodium hydroxide solution (10mol/L, 40mL) subsequently, heating reflux reaction 2 hours, react complete by mixture concentrated removing organic solvent, adjust ph to 5 ~ 6, separate out white solid, collected by suction product, with a small amount of cold water (10mL) washing, vacuum-drying obtains white solid product (5g, 89%).
LC-MS：244.3[M+1] +.
Step 4 4-((2-(5-benzyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine [3,4-c] pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine
Compound 5-benzyl-1, 4, 5, 6-Pyrrolidine (3, 4-pyrazoles) base-3-formic acid (2.8g, 11.52mmol) with 4-(morpholine methyl) benzene-1, 2-diamines (2.3g, 11.52mmol) be dissolved in DMF (25mL), add EDCI (2.64g subsequently, 13.8mmol) with HOBt (1.71g, 12.6mmol), room temperature reaction 24 hours, removal of solvent under reduced pressure, add acetic acid (40mL) subsequently, reflux 3 hours, be cooled to room temperature, removal of solvent under reduced pressure, residuum column chromatography (methylene chloride/methanol (V/V)=15/1) purifying obtains product (3g, 63%).
LC-MS：414.3[M+1] +.
Step 5 4-((2-(Isosorbide-5-Nitrae, 5,6-Pyrrolidine [3,4-c] pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine
By compound 4-((2-(5-benzyl-1,4,5,6-Pyrrolidine [3,4-c] pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine (3g, 7.24mmol) is dissolved in methyl alcohol (60mL), adds palladium hydroxide carbon (500mg), replacing hydrogen subsequently, room temperature reaction 24 hours.After completion of the reaction, solids removed by filtration, filtrate concentrates, and obtains product (2g, 86%) with column chromatography (methylene chloride/methanol (V/V)=5/1) purifying.
LC-MS：325.1[M+1] +.
Step 6 N-cyclopropyl-3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base)-4,6-pyrrolin [3,4-c] pyrazoles-5 (1H)-methane amide
By compound 4-((2-(1,4,5,6-Pyrrolidine [3,4-c] pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine (200mg, 0.62mmol) be dissolved in DMAC (5mL) with carbonyl dimidazoles (150mg, 0.92mmol), reaction is heated to 80 degree of stirrings and spends the night.Be down to room temperature and add cyclopropylamine (1mL), be heated to 60 degree and react 5 hours, after removal of solvent under reduced pressure, preparative chromatography obtains product (120mg, 40.7%). 1H?NMR(400MHz,DMSO-d 6):δ12.31(s,1H),10.18(s,1H),7.46-7.50(m,2H),7.15(d,J＝3.4Hz,1H),6.53(s,1H),4.53(d,J＝5.3Hz,4H),3.56-3.58(m,4H),2.55-2.68(m,1H),2.36(s,4H),1.22-1.27(m,2H),0.55-0.60(m,2H),0.44-0.47(m,2H).
LC-MS：408.1[M+1] +.
Embodiment 2
1-cyclopropyl-3-(3-(5-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Step one six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
Benzyl tetrahydro-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H) carbonic ether (10.3g, 39.12mmol) is dissolved in tetrahydrofuran (THF) (100mL), and add the stirring of 10%Pd/C (1.03g) post-heating to 50 degree and spend the night.Cross after filtering Pd/C, removal of solvent under reduced pressure, obtain weak yellow liquid (7.32g), directly carry out next step reaction.
Step 2: (3,4-dinitrophenyl) (tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) ketone
3,4-dinitrobenzoic acid (4.74g, 22.35mmol) and DMF (0.05mL) are dissolved in THF (50mL), then add SOCl 2(2.14mL, 29.5mmol) reflux 2.5 hours.Then mixed solution is cooled to 0 degree, adds triethylamine (4.7mL, 33.75mmol), adds six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles (5.05g, 39.12mmol) subsequently, and mixed solution recovers room temperature continuation stirring and spends the night.After removal of solvent under reduced pressure, add methylene dichloride (50mL) and water (50mL), extraction, anhydrous sodium sulphate (10g) dry organic layer, concentrated, column chromatography for separation (methylene chloride/methanol (V/V)=5/1), obtains faint yellow solid (5.67g, 78.5%).
LC-MS：324[M+1] +.
Step 3 6-(3,4-dinitrobenzyl) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
Sodium borohydride (1.44g, 37.18mmol) be dissolved in THF (200mL), mixed solution is cooled to 0 degree, drip boron trifluoride diethyl etherate (4.8mL, 37.18mmol), then add (3,4-dinitrophenyl) (tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) ketone (5.67g, 17.54mmol).Removing ice bath recovers stirring at room temperature 3.5 hours, and it is complete that TLC shows raw material reaction, and mixed solution is cooled to 0 degree again, slowly adds methyl alcohol and refluxes 1 hour to producing post-heating without gas.Removal of solvent under reduced pressure, ethyl acetate (50mL) is added and water (50mL) washs, anhydrous sodium sulphate (10g) dry organic layer in residuum, concentrated, obtain weak yellow liquid (7.9g, >100%).
LC-MS：310[M+1] +.
Step 4 4-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl) benzene-1,2-diamines
6-(3,4-dinitrobenzyl) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles (5.42g, 17.54mmol) be dissolved in methyl alcohol (200mL), add 10%Pd/C (0.5g), stirred overnight at room temperature under the condition of hydrogen.Cross and filter Pd/C, concentrating under reduced pressure filtrate, column chromatography for separation (methylene chloride/methanol (v/v)=10/1), obtains product (2.19g, 50%).
LC-MS：250[M+1] +.
Step 5 6-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
4-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl) benzene-1,2-diamines (2.19g, 8.78mmol), 4-nitro-1H-pyrroles-3-carboxylic acid (1.24g, 7.91mmol), EDCl (1.68g, 8.78mmol) and HOBt (1.19g, 8.78mmol) be dissolved in DMF (22mL), stirred overnight at room temperature.Removal of solvent under reduced pressure, AcOH (35mL) to add in residuum reflux 3.5 hours.Removal of solvent under reduced pressure, column chromatography for separation (methylene chloride/methanol (v/v)=10/1), obtains product (1.65g, 51%).
LC-MS：371[M+1] +.
Step 6 3-(5-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine
6-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) six hydrogen-2H-[1,4] dioxin [2,3-c] pyrroles (1.65g, 4.46mmol) be dissolved in DMF (50mL), 10%Pd/C (0.17g) is added, stirred overnight at room temperature under the condition of hydrogen in mixture.Cross and filter Pd/C, concentrating under reduced pressure filtrate, obtain product (1.52g, 100%).
LC-MS：341[M+1] +.
Step 7 9-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one
3-(5-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.68g, 2mmol) with CDI (0.64g, 3.9mmol) be dissolved in DMF (10mL), be heated to 80 degree and stir 10 hours, it is complete that TLC shows raw material reaction, directly carries out next step reaction.
LC-MS：438[M+1] +.
Step 8 1-cyclopropyl-3-(3-(5-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 9-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.73g, 2mmol) be dissolved in DMF (10mL) with cyclopropylamine (0.9mL), heat 50 degree of stirred overnight.After removal of solvent under reduced pressure, column chromatography for separation (methylene chloride/methanol (v/v)=10/1), obtains product (150mg, 18%).
1H?NMR(400MHz,DMSO-d 6):δ13.00(s,1H),12.80(s,1H),9.64(s,1H),8.05(s,1H),7.54(d,J＝8.4Hz,1H),7.40(d,J＝5.6Hz,1H),7.11-7.20(m,2H),4.00(s,2H),3.74(s,2H),3.69(t,J＝5.2Hz,2H),3.44-3.50(m,2H),2.78-2.82(m,2H),2.68-2.72(m,2H),2.60(s,1H),0.84(t,J＝2.8Hz,2H),0.54(s,2H)；
LC-MS：424[M+1] +.
Embodiment 3
1-(3-(5-(2-oxa--5-mix two rings [2.2.1] heptane-5-ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-3-cyclopropyl urea
Step one cis-4-hydroxyproline methyl ester hydrochloride
Cis-4-hydroxyproline hydrochloride (20g, 150mmol) is dissolved in methyl alcohol (200mL), under 0 degree, add SOCl 2(13.1mL, 180mmol) post-heating to 75 degree backflow 7 hours.Be cooled to solids removed by filtration after room temperature, removal of solvent under reduced pressure, directly carry out next step reaction.
Step 2 (2S, the 4S)-1-tertiary butyl-2-methyl 4-hydroxy-pyrrolidine-1,2-bis-carbonic ether
Cis-4-hydroxyproline methyl ester hydrochloride (54.03g, 372mmol) and sodium carbonate (102.57g, 968mmol) are dissolved in THF/H 2in O (2/1,600mL), add (Boc) under 0 degree 2o (107.75g, 484mmol), then stirred overnight at room temperature.Methylene dichloride (500mL) and water (500mL) add mixed solution, extraction, and anhydrous sodium sulphate (10g) dry organic layer is concentrated, directly carry out next step reaction.
Step 3 (2S, the 4S)-1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1,2-bis-carbonic ether
(2S, the 4S)-1-tertiary butyl-2-methyl 4-hydroxy-pyrrolidine-1,2-bis-carbonic ether (55g, 225mmol) be dissolved in methylene dichloride (450mL), add diisopropylethylamine (86mL, 495mmol), be then cooled to-40 degree, drip tertiary butyl dimethyl silyl triflate (58.3mL, 270mmol) and continue stirring 1 hour afterwards.Add water (100mL) and extract reaction of going out, add methylene dichloride (500mL) again to extract, anhydrous sodium sulphate (10g) dry organic layer, concentrated, column chromatography for separation (methylene chloride/methanol (v/v)=10/1), obtain yellow liquid (56.5g, 69.8%).
Step 4 (2S, the 4S)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carbonic ether
(2S, the 4S)-1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1,2-bis-carbonic ether (56.17g, 156.23mmol) be dissolved in the THF (400mL) of removing, be cooled to-10 degree, after adding lithium borohydride (8.95g, 390.58mmol), recover stirred overnight at room temperature in batches.Under 0 degree, slowly add methyl alcohol (10mL) extract reaction of going out, then filter, concentrated filtrate, cross post and carry out purifying (methylene chloride/methanol (v/v)=10/1), obtain yellow liquid (30g, 56%).
Step 5 (2S, the 4S)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carbonic ether
(2S, the 4S)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carbonic ether (29.96g, 86.7mmol) be dissolved in THF (200mL), add 4mol/L NaOH (208mL, 0 degree is cooled to 832mmol), TsCl (52.89g, 277mmol) adds mixed solution in batches, then recovers stirred overnight at room temperature.Methylene dichloride (500mL) and water (500mL) add mixed solution, extraction, and anhydrous sodium sulphate (10g) dry organic layer is concentrated, directly carries out next step.
Step 6 (2S, 4S)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carbonic ether
(2S, the 4S)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carbonic ether (34.92g, 71.89mmol) be dissolved in THF (200mL), add tetrabutyl ammonium fluoride (24.44g, 93.46mmol) stirring at room temperature 1 hour afterwards, add ethyl acetate (500mL) and water (500mL) extracts, anhydrous sodium sulphate (10g) dry organic layer, concentrated, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain white solid (12.3g, 46%).
The step 7 tertiary butyl-2-oxa--5-mixes two rings [2.2.1]-heptane-5-carbonic ether
(2S, 4S)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carbonic ether (12.3g, 33.1mmol) be dissolved in the THF that dewaters (150mL), be cooled to-15 degree and add NaH (3.97g, 99.34mmol), then stirring at room temperature is recovered 5 hours, after mixed solution is cooled to 0 degree, slowly add water (50mL) and extract reaction of going out, add ethyl acetate (50mL) to extract, anhydrous sodium sulphate (10g) dry organic layer, concentrated, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain white solid (5.52g, 84%).
Step 8 2-oxa--5-mixes two rings [2.2.1]-heptane
The tertiary butyl-2-oxa--5-mixes two rings [2.2.1] heptane-5-carbonic ether (5.52g, 27.7mmol) be dissolved in ethyl acetate (10mL), add ethyl acetate saturated solution (20mL) stirring at room temperature 5 hours of hydrogenchloride, filtration obtains white solid, solid is joined in ethyl acetate (100mL), then drip a small amount of ammoniacal liquor (5mL) to dissolve completely to solid, anhydrous sodium sulphate (10g) is dry, filter, filtrate concentrates, obtain colourless liquid (2.7g, 98%).
Step 9 2-oxa--5-mixes two rings [2.2.1]-heptane-5-base (3,4-dinitrophenyl) ketone
2-oxa--5-mixes two rings [2.2.1]-heptane (2.64g, 26.63mmol), 3,4-dinitrobenzoic acid (6.78g, 31.96mmol), HATU (15.19g, 39.95mmol) and diisopropylethylamine (14mL, 79.9mmol) be dissolved in THF (100mL), room temperature for overnight.Methylene dichloride (50mL) and water (50mL) is added in mixed solution, extraction, anhydrous sodium sulphate (10g) dry organic layer, concentrated, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain white solid (2.8g, 36%).
LC-MS：294[M+1] +.
Step 10 5-(3,4-dinitrophenyl)-2-oxa--5-mixes two rings [2.2.1]-heptane
Sodium borohydride (0.9g, 23.33mmol) be dissolved in THF (90mL), mixed solution is cooled to 0 degree, drip boron trifluoride diethyl etherate (2.94mL, 23.33mmol), then assorted two rings [2.2.1]-heptane-5-base (3, the 4-dinitrophenyl) ketone (2.28g, 7.78mmol) of 2-oxa--5-is added.Removing ice bath recovers stirred overnight at room temperature, and it is complete that TLC shows raw material reaction, and mixed solution is cooled to 0 degree again, slowly adds methyl alcohol and refluxes 1 hour to producing post-heating without gas.Removal of solvent under reduced pressure, ethyl acetate (50mL) is added and water (50mL) washs in residuum, anhydrous sodium sulphate (10g) dry organic layer, concentrated, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (1.64g, 76%).
LC-MS：280[M+1] +.
Step 11 4-(2-oxa--5-mix two rings [2.2.1]-heptane-5-ylmethyl) phenyl-1,2-diamines
5-(3,4-dinitrophenyl)-2-oxa--5-is assorted, and two rings [2.2.1]-heptane (1.23g, 4.4mmol) is dissolved in ethanol (50mL), adds SnCl 2(9.95g, 44.09mmol) stirring at room temperature 3.5 hours.Saturated NaHCO 3(50mL) add mixed solution, solids removed by filtration, concentrating under reduced pressure filtrate, cross post and purify (methylene chloride/methanol (v/v)=10/1), obtain yellow solid (0.85g, 89%).
LC-MS：220[M+1] +.
Step 12 5-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl)-2-oxa--5-mixes two rings [2.2.1]-heptane
4-(2-oxa--5-mix two rings [2.2.1]-heptane-5-ylmethyl) phenyl-1,2-diamines (0.85g, 3.88mmol), 4-nitro-1H-pyrroles-3-carboxylic acid (0.58g, 3.69mmol), EDCl (0.78g, 4.06mmol) and HOBt (0.55g, 4.06mmol) is dissolved in DMF (10mL) stirred overnight at room temperature.Removal of solvent under reduced pressure, AcOH (16mL) to add in residuum reflux 3.5 hours.Removal of solvent under reduced pressure, crosses post and carries out purifying (methylene chloride/methanol (v/v)=10/1), obtain yellow solid (0.79g, 63%).
LC-MS：341.1[M+1] +.
Step 13 3-(5-(2-oxa--5-mix two rings [2.2.1] heptane-5-ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine
5-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl)-2-oxa--5-mixes two rings [2.2.1]-heptane (0.74g, 2.17mmol) be dissolved in DMF (20mL), add 10%Pd/C (0.1g) stirred overnight at room temperature under the condition of hydrogen.Cross and filter Pd/C, concentrating under reduced pressure filtrate, directly carry out next step reaction.
LC-MS：311[M+1] +.
Step 14 8-(2-oxygen-5-azabicyclo [2.2.1] heptane-5-ylmethyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one
3-(5-(2-oxa--5-mix two rings [2.2.1] heptane-5-ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.67g, 2.17mmol) with CDI (0.69g, 4.25mmol) be dissolved in DMF (7mL), be heated to 80 degree of stirrings spend the night, it is complete that TLC shows raw material reaction, directly carries out next step reaction.
Step 15 1-(3-(5-(2-oxa--5-mix two rings [2.2.1] heptane-5-ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-3-cyclopropyl urea
Compound 8-(2-oxygen-5-azabicyclo [2.2.1] heptane-5-ylmethyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.73g, 2.17mmol) and cyclopropylamine (1.0mL) be dissolved in heating 80 degree of stirred overnight in DMF (8mL).After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain yellow solid (105mg, 12%).
1H?NMR(400MHz,DMSO-d6):δ12.83(s,1H),9.57(s,1H),8.03(s,1H),7.50(s,2H),7.35(s,1H),7.18(d,J＝8.0Hz,2H),4.34(s,2H),3.94(d,J＝7.2Hz,1H),3.80(d,J＝8.0Hz,2H),3.16(s,2H),2.73(d,J＝8.8Hz,1H),2.59(s,1H),1.81(d,J＝8.0Hz,1H),1.58(d,J＝9.2Hz,1H),0.84(d,J＝6.8Hz,2H),0.54(s,2H).
LC-MS：394.3[M+1] +.
Embodiment 4
1-(3-(5-(2-sulfo--5-azabicyclo [2.2.1] heptane-5-ylmethyl)-1H-benzimidazolyl-2 radicals-Ji)-1H-pyrazoles-4-base)-3-cyclopropyl urea
Step one trans-4-hydroxy-l-proline methyl esters
Oxyproline (1.0g, 7.63mmol) is dissolved in methyl alcohol (10mL), at room temperature SOCl 2(0.66mL, 9.15mmol) is added drop-wise to after in mixed solution and stirs 15 minutes, then heats mixed solution to backflow 4 hours.Pressurization is except desolventizing and SOCl 2, obtain white solid and directly carry out next step reaction.
Step 2 (2S, 4R)-N-(tertbutyloxycarbonyl) hydroxyproline methyl ester
Trans-4-hydroxy-l-proline methyl esters (1.38g, 9.51mmol) and triethylamine (1.6mL, 14.26mmol) are dissolved in methylene dichloride (20mL), mixed solution is cooled to 0 DEG C, (Boc) 2o (1.84mL, 9.99mmol) is added drop-wise in mixed solution, recovers room temperature continuation stirring and spends the night, until raw material is anti-complete.After removal of solvent under reduced pressure, directly carry out next step reaction..
Step 3 (2S, 4R)-N-(tertbutyloxycarbonyl) hydroxyl dried meat ammonia alcohol
By (2S, 4R)-N-(tertbutyloxycarbonyl) hydroxyproline methyl ester (1.87g, 7.62mmol) is dissolved in THF (30mL) and is cooled to 0 DEG C, adds Lithium Aluminium Hydride (0.29g in batches, 7.62mmol), continue to stir at 0 DEG C to spend the night.After reaction terminates, at 0 DEG C, add sodium hydroxide and the water (1/1,2mL) of 10%, solids removed by filtration, concentrated filtrate, crosses post and carries out purifying (methylene chloride/methanol (v/v)=10/1), obtain product (1.44g, 87%).
LC-MS：239[M+23].
Step 4 (2S, 4R)-4-((methylsulfonyl) oxygen base)-2-(((methylsulfonyl) oxygen base) methyl) pyrroles-1-carboxylate
(2S, 4R)-N-(tertbutyloxycarbonyl) hydroxyl dried meat ammonia alcohol (2.4g, 15.5mmol) with triethylamine (5.30mL, 53.59mmol) to be dissolved in methylene dichloride (40mL) and to be cooled to 0 DEG C, methane sulfonyl chloride (2.86mL, 53.17mmol) is added drop-wise in mixed solution and also continues to stir 3 hours at 0 DEG C.After reaction terminates, extract with the hydrochloric acid (5.30mL) of 1mol/L reaction of going out, be separated organic layer, by methylene dichloride (50mL) aqueous phase extracted, merge organic layer saturated aqueous common salt (50mL) to wash and drying, concentrate and obtain crude product, directly apply to next step reaction.
Step 5 2-sulfo--5-azabicyclo [2.2.1] heptane-5-carboxylate
Nine water cure sodium (6.64g; 33.17mmol) be dissolved in DMSO (30mL); (2S is added drop-wise under room temperature; 4R)-4-((methylsulfonyl) oxygen base)-2-(((methylsulfonyl) oxygen base) methyl) pyrroles-1-carboxylate (3.44g; in DMSO (20mL) solution 11.06mmol), to continue under the protection of nitrogen stirring at room temperature 45 minutes.Add water (35mL) and extract reaction of going out, mixed solution is extracted by ethyl acetate (50mL), merge organic layer, saturated aqueous common salt (50mL) is washed and drying, concentrated, cross post and carry out purifying (methylene chloride/methanol (v/v)=10/1), obtain product (1.28g, 65%).
Step 6 2-sulfo--5-azabicyclo [2.2.1] heptane hydrochloride
By 2-sulfo--5-azabicyclo [2.2.1] heptane-5-carboxylate (0.65g, 3.0mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate saturated solution (10mL) of hydrogenchloride, at room temperature stir 2 hours, except desolventizing directly applies to next step.
Step 7 2-sulfo--5-azabicyclo [2.2.1] heptane-5-base (3,4-dinitrophenyl) ketone
3,4-dinitrobenzoic acid (1.84g, 8.7mmol) is dissolved in sulfur oxychloride (1mL), adds two DMF, reflux 2.5 hours.Be cooled to room temperature, add tetrahydrofuran (THF) (20mL), triethylamine (1mL), is cooled to zero degree, and add 2-sulfo--5-azabicyclo [2.2.1] heptane (1g, 8.7mmol), rise to room temperature subsequently, reaction is spent the night.Add water (5mL) and extract reaction of going out, be spin-dried for, mixed solution is extracted by ethyl acetate (50mL), merge organic layer, saturated aqueous common salt (50mL) is washed and drying, concentrated, crosses post and is separated (methylene chloride/methanol (v/v)=10/1), obtain product (1.7g, 65%).
LC-MS：310[M+1].
Step 8 5-(3,4-dinitrobenzyl)-2-sulfo--5-azabicyclo [2.2.1] heptane
Under nitrogen protection; sodium borohydride (0.938g; 11.55mmol) join in tetrahydrofuran (THF) (40mL), be cooled to zero degree, add boron trifluoride ether solution (1.64g; 11.55mmol); disposablely subsequently add 2-sulfo--5-azabicyclo [2.2.1] heptane-5-base (3,4-dinitrophenyl) ketone (1.7g, 5.5mmol); reaction rises to room temperature, and stirring is spent the night.Reaction with methyl alcohol (10mL) cancellation, reflux half an hour, removal of solvent under reduced pressure, extract mixed solution by ethyl acetate (50mL), merge organic layer, saturated aqueous common salt (50mL) is washed and drying, concentrate and obtain product (1.2g, 75%).
LC-MS：296[M+1].
Step 9 4-(2-sulfo--5-azabicyclo [2.2.1] heptane-5 – ylmethyl) benzene-1,2-diamines
By 5-(3,4-dinitrobenzyl)-2-sulfo--5-azabicyclo [2.2.1] heptane (1.2g, 4mmol) be dissolved in ethanol (30mL), add palladium hydroxide carbon (200mg), following reaction replacing hydrogen, under nitrogen atmosphere, room temperature reaction spends the night.Suction filtration goes out solid, and filtrate being spin-dried for obtains product (0.8g, 84%).
LC-MS：236[M+1].
Step 10 5-((2-(4-1H-pyrazole-3-yl)-1H-benzoglyoxaline-6-base)-methyl)-2-sulfo--5-azabicyclo [2.2.1] heptane
By 4-(2-sulfo--5-azabicyclo [2.2.1] heptane-5 – ylmethyl) benzene-1,2-diamines (0.7g, 3mmol), 4-nitro-1 hydrogen-pyrazoles-3-formic acid (0.47g, 3mmol) be dissolved in DMF (15mL), add EDCI (0.63g, 3.3mmol) and HOBt (0.45g subsequently, 3.3mmol), stirring at room temperature is reacted 24 hours.Removal of solvent under reduced pressure, adds acetic acid (20mL), reflux 3 hours.React complete, concentrated, cross post and carry out purifying (methylene chloride/methanol (v/v)=10/1), obtain product (0.5g, 50%).
LC-MS：357[M+1].
Step 11 3-(5-(2-sulfo--5-azabicyclo [2.2.1] heptane-5-ylmethyl)-1H-benzimidazolyl-2 radicals-Ji)-1H-pyrazoles-4-amine
By 5-((2-(4-1H-pyrazole-3-yl)-1H-benzoglyoxaline-6-base)-methyl)-2-sulfo--5-azabicyclo [2.2.1] heptane (0.5g, 1.4mmol) be dissolved in methyl alcohol (30mL), add palladium carbon (50mg), following reaction replacing hydrogen, under nitrogen atmosphere, room temperature reaction spends the night.Suction filtration goes out solid, and filtrate being spin-dried for obtains product (0.3g, 66%).
LC-MS：327[M+1].
Step 12 1-(3-(6-(2-sulfo--5-azabicyclo [2.2.1] heptane-5-ylmethyl)-1H-benzimidazolyl-2 radicals-Ji)-1H-pyrazoles-4-base)-3-cyclopropyl urea
By 3-(6-(2-sulfo--5-azabicyclo [2.2.1] heptane-5-ylmethyl)-1H-benzimidazolyl-2 radicals-Ji)-1H-pyrazoles-4-amine (0.3g, 0.92mmol), N-N '-carbonyl dimidazoles (0.3g, 1.84mmol) be dissolved in DMF (6mL), be heated to 80 DEG C of reactions 8 hours, add cyclopropylamine (2mL) subsequently, reaction is heated to 60 DEG C of reactions 5 hours.React complete, removal of solvent under reduced pressure, residuum preparative chromatography purifying obtains product (0.12g, 32%).
LC-MS：410[M+1]；
1H?NMR(400MHz,DMSO-d 6):δ12.81(d,J＝78.8Hz,2H),9.61(s,1H),8.05(s,1H),7.53(d,J＝43.4Hz,2H),7.17(s,2H),3.80(s,2H),3.47(s,2H),3.03-3.08(m,2H),2.74-2.83(m,2H),2.61(s,1H),2.16(d,J＝9.8Hz,1H),11.65-1.68(m,1H),0.84(s,2H),0.55(s,2H).
Embodiment 5
1-cyclopropyl-3-(3-(5-(morpholine methyl) benzoxazoles-2-base)-1H-pyrazoles-4-base) urea
Step one (4-hydroxyl-3-nitrophenyl) (morpholinyl) ketone
Under room temperature, 4-hydroxyl-3-nitrobenzoic acid (14g, 76.5mmol) is dissolved in tetrahydrofuran (THF) (150mL), morpholine (6.7g, 84.1mmol) is added, HATU (31g in solution, 84.1mmol), stirred overnight at room temperature.After question response terminates, be spin-dried for solvent, ethyl acetate extracts (3 × 60mL), and water (50mL) is washed, and anhydrous sodium sulphate (10g) is dry, is spin-dried for and obtains crude product yellow solid (12g), is directly used in next step reaction.
Step 2 4-(morpholine methyl)-2-nitrophenols
Under zero degree, sodium borohydride (3.36g, 89mmol) is joined in anhydrous tetrahydro furan (30mL), N 2under protection; boron trifluoride ether solution (11.3mL, 89mmol) is dropwise added, subsequently by compound (4-hydroxyl-3-nitrophenyl)-(morpholinyl) ketone (11.93g; 42mmol) disposablely to add, rise to stirred overnight at room temperature.Under ice bath, add methyl alcohol (50mL), reaction mixture reflux stirs 30 minutes.After being spin-dried for solvent, ethyl acetate extracts (3 × 60mL), uses sodium bicarbonate aqueous solution respectively, and washing, anhydrous sodium sulfate drying, is spin-dried for and obtains yellow solid (9.54g, 83%).
LC-MS：253.1[M+1] +.
Step 3 2-amino-4-(morpholine methyl) phenol
To compound 4-(morpholine methyl)-2-nitrophenols (11g, 10% palladium carbon (1g) is added in ethanol (150mL) solution 41.2mmol), replacing hydrogen, room temperature reaction 24 hours, suction filtration removing solid, filtrate being spin-dried for obtains product (8g, 94%).
LC-MS：209.1[M+1] +.
Step 4 N-(2-hydroxyl-5-(morpholine methyl) phenyl)-4-nitro-1H-pyrazole-3-formamide
Compound 2-amino-4-(morpholine methyl) phenol (2.54g, 16mmol) be dissolved in DMF (15mL), add 4-nitro-1 hydrogen-pyrazoles-3-formic acid (3.4g respectively, 16mmol) with HATU (7.4g, 19.6mmol), under room temperature, reaction is spent the night, react complete, be spin-dried for solvent, ethyl acetate extracts (3 × 50mL), washing (2 × 50mL), and anhydrous sodium sulphate (10g) is dry, be spin-dried for and obtain crude product (1.5g), be directly used in next step.LC-MS：348.1[M+1] +.
Step 5 5-(morpholine methyl)-2-(4-nitro-1H-pyrazole-3-yl) benzoxazoles
By compound N-(2-hydroxyl-5-(morpholine methyl) phenyl)-4-nitro-1H-pyrazole-3-formamide (1g, 2.89mmol) with tosic acid (0.5g, 2.89mmol) add in toluene (50mL), heated overnight at reflux.React complete, be down to room temperature, removal of solvent under reduced pressure, residuum column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=20/1), obtain product (0.6g, 75%).
LC-MS：330.3[M+1] +.
Step 6 3-(5-(morpholine methyl) benzoxazoles-2-base)-1H-pyrazoles-4-amine
To compound 5-(morpholine methyl)-2-(4-nitro-1 hydrogen-pyrazole-3-yl) benzoxazoles (0.6g, 10% palladium carbon (10mg) is added in methyl alcohol (30mL) solution 1.82mmol), replacing hydrogen, room temperature reaction 24 hours, suction filtration removing solid, filtrate being spin-dried for obtains product (0.5g, 93%).LC-MS：300.1[M+1] +.
Step 7 1-cyclopropyl-3-(3-(5-(morpholine methyl) benzoxazoles-2-base)-1H-pyrazoles-4-base) urea
By compound 3-(5-(morpholine methyl) benzoxazoles-2-base)-1 hydrogen-pyrazoles-4-amine (500mg, 1.67mmol), with carbonyl dimidazoles (400mg, 2.5mmol) be dissolved in DMF (10mL), reaction is heated to 80 degree of stirrings and spends the night.Be down to room temperature and add cyclopropylamine (2mL), be heated to 60 degree and react 5 hours, after removal of solvent under reduced pressure, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=20/1), obtain product (120mg, 17%). 1H?NMR(400MHz,DMSO-d 6):δ12.34(s,1H),10.18(s,1H),8.49(s,1H),7.60-7.63(d,1H),7.31-7.36(m,1H),7.15(s,1H),6.77(s,1H),3.75(s,1H),3.51(s,4H),3.39-3.43(m,2H),2.43-2,47(m,2H),1.91-2.01(m,4H),1.76-1.81(m,2H).
LC-MS：383.1[M+1] +.
Embodiment 6
1-cyclopropyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Step one 6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate
2,5-pyrrolin alkane-1-benzyl formate (10g, 49.24mmol) be dissolved in methylene dichloride (30mL), slowly be added drop-wise to metachloroperbenzoic acid (10.55g, in methylene dichloride (70mL) mixed solution 61.14mmol), stirring at room temperature reacts 16 hours.Filter, filtrate is respectively washed once with saturated sodium thiosulfate (100mL) and saturated sodium bicarbonate (100mL), anhydrous Na 2sO 4(10g) dry.Pressure reducing and steaming solvent, the direct column chromatography for separation of residue (ethyl acetate/petroleum ether (V/V)=1/3) obtains product (7.39g, 68.49%).
LC-MS:220(M+1).
Step 2 (3R, 4R)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate
6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate (6.0g, 27.37mmol) be dissolved in dry methylene chloride (100mL), add ethylene bromohyrin (3.73g, 30.13mmol), then diethyl ether solution (the 0.39g of boron trifluoride is at room temperature slowly added, 2.74mmol), stirred overnight at room temperature.Pressurization boils off solvent, obtains crude product, is directly used in the next step.
LC-MS:344(M+1).
Step 3 (4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] two dioxin [2,3-c] pyrroles-6 (3H)-benzyl carboxylate
(3R, 4R)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate (crude product) is dissolved in dehydrated alcohol (80mL), add the ethanolic soln of potassium hydroxide (1.54g, 27.39mmol), then reflux 6 hours.Filter, filter cake ethyl acetate (50mL) drip washing, merging filtrate, evaporated under reduced pressure, residue column chromatography for separation (ethyl acetate/petroleum ether (V/V)=1/1) obtains product (0.60g, 8.40%).
LC-MS:264(M+1)；
1H?NMR(400MHz,CDCl 3):δ7.30-7.36(m,5H),5.17(s,2H),3.81-3.87(m,5H),3.59-3.77(m,2H),3.12-3.18(m,2H),1.24-1.27(m,1H).
Step 4 (4aR, 7aR)-six hydrogen-2H-[Isosorbide-5-Nitrae] two dioxin [2,3-c] pyrroles
(4aR, 7aR)-tetrahydrochysene-2H-[1,4] two dioxins [2,3-c] pyrroles-6 (3H)-benzyl carboxylate (0.60g, 2.28mmol) be dissolved in dry THF (10mL), add 10%Pd/C (0.30g), hydrogen exchange twice, be then heated to 50 DEG C of hydrogenolysis 6 hours.Filter, filtrate evaporate to dryness obtains product, is directly used in the next step.
Step 5 (3,4-dinitrophenyl) (4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) ketone
3,4-dinitrobenzoic acid (0.58g, 2.74mmol) is dissolved in THF (20mL), adds DMF (2), SOCl 2(0.24mL, 3.62mmol), reflux 2 hours.Then mixed solution is cooled to 0 DEG C, adds triethylamine (0.59mL, 4.14mmol), add (4aR, 7aR)-six hydrogen-2H-[Isosorbide-5-Nitrae] two dioxin [2 subsequently, 3-c] THF (5mL) solution of pyrroles, mixed solution rises to room temperature and continues stirring 24 hours.After removal of solvent under reduced pressure, add methylene dichloride (50mL) and water (50mL), extraction, anhydrous sodium sulphate (10g) dry organic layer, concentrated, column chromatography for separation (EtOAc/PE (V/V)=1/1) obtains faint yellow solid (365mg, 41.29%).
LC-MS：324[M+1] +.
1H?NMR(400MHz,DMSO-d 6):δ8.10(d,1H),7.99(d,1H),7.89-7.91(m,1H),4.00-4.03(m,1H),3.87-3.98(m,5H),3.85-3.86(m,1H),3.73-3.79(m,2H),3.38-3.44(m,2H).
Step 6 (4aR, 7aR)-6-(3,4-dinitrobenzyl) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
Sodium borohydride (0.23g, 6.13mmol) be suspended in dry THF (20mL), mixed solution is cooled to 0 DEG C, drips boron trifluoride diethyl etherate (0.77mL, 6.13mmol), then (3,4-dinitrophenyl) (4aR, 7aR)-tetrahydrochysene-2H-[1 is added, 4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) ketone (0.90g, 2.79mmol), slowly rise to stirred overnight at room temperature.Mixed solution is cooled to 0 DEG C again, slowly adds methyl alcohol (5mL) and refluxes 1 hour to producing post-heating without gas.Removal of solvent under reduced pressure, adds ethyl acetate (50mL) in residuum and water (50mL) washs, anhydrous sodium sulphate (10g) dry organic layer, concentrated, obtains weak yellow liquid (0.60g, 71.69%).
LC-MS：333[M+23] +.
Step 7 4-(((4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl) benzene-1,2-diamines
(4aR, 7aR)-6-(3,4-dinitrobenzyl) six hydrogen-2H-[1,4] dioxin [2,3-c] pyrroles (1.40g, 4.53mmol) be dissolved in DMF (20mL), add 10%Pd/C (0.3g) stirred overnight at room temperature under the condition of hydrogen.Cross and filter Pd/C, filtrate is directly used in the next step.
LC-MS：250[M+1] +.
Step 8 (4aR, 7aR)-6-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
Upwards walk in reaction solution and add 4-nitro-1H-pyrroles-3-carboxylic acid (0.65g, 4.12mmol), EDCI (0.87g, 4.53mmol) and HOBt (0.61g, 4.53mmol), stirred overnight at room temperature.Removal of solvent under reduced pressure, adds AcOH (20mL) in residue, reflux 3 hours.Removal of solvent under reduced pressure, crosses post and carries out purifying (methylene chloride/methanol (v/v)=10/1), obtain product (2.10g, >100%).
LC-MS：371[M+1] +.
Step 9 3-(6-(((4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine
(4aR, 7aR)-6-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) six hydrogen-2H-[1,4] dioxin [2,3-c] pyrroles (2.10g, 5.7mmol) be dissolved in DMF (20mL), add 10%Pd/C (0.5g) stirred overnight at room temperature under the condition of hydrogen.Cross and filter Pd/C, concentrating under reduced pressure filtrate, column chromatography for separation (CH 2cl 2/ CH 3oH (V/V)=20/1) obtain product (0.37g, 19.17%).
LC-MS：341[M+1] +.
Step 10 1-cyclopropyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
3-(6-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.37g, 1.08mmol) with CDI (0.35g, 2.17mmol) be dissolved in DMF (15mL) and be heated to 75 DEG C of stirrings 12 hours, it is complete that TLC shows raw material reaction, directly carries out next step reaction.
Upwards walk in reaction solution and add cyclopropylamine (0.52mL), be heated to 75 DEG C of reactions 12 hours.After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain sterling (60mg, 13.13%).
LC-MS：424[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.09(s,1H),12.83(s,1H),9.64(s,1H),8.04(s,1H),7.53-7.56(m,1H),7.39-7.41(m,1H),7.11-7.21(m,1H),3.81-3.90(m,1H),3.62-3.68(m,2H),3.17(d,J＝7.2Hz,1H),2.86-2.90(m,2H),2.50-2.52(m,3H),1.10-1.20(m,4H),0.78-0.80(m,3H),0.50(s,2H).
Embodiment 7
1,1-diethyl-3-(3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.27g, 0.91mmol) with CDI (0.29g, 1.82mmol) be dissolved in DMF (15mL), be heated to 75 DEG C of reactions 12 hours.Mixed solution is cooled to room temperature, adds diethylamine (3mL), continues to be heated to 75 DEG C of reactions 12 hours.Be cooled to room temperature, the direct column chromatography purification (CH of reaction solution evaporate to dryness 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (57mg, 15.79%).
LC-MS：398[M+1] +.
1H?NMR(400MHz,DMSO-d 6):13.02(s,1H),12.92(s,1H),9.95(d,J＝9.3Hz,1H),8.00(s,1H),7.57-7.47(m,1H),7.43(d,J＝8.1Hz,1H),7.18(dd,J＝15.2,8.1Hz,1H),3.57(s,6H),2.38(s,4H),1.28-1.23(m,10H).
Embodiment 8
Sec.-propyl-3-(3-(5-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 9-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.55g, 1.5mmol) and Isopropylamine (1.3mL) be dissolved in heating 60 degree of stirred overnight in DMF (8mL).After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (160mg, 25%).
LC-MS：426[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.97(s,1H),12.75(s,1H),8.95(s,1H),8.86(s,1H),8.04(d,J＝2.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.40(d,J＝8.0Hz,1H),7.15(t,J＝8.8Hz,1H),4.02(s,2H),3.79(d,J＝6.4Hz,3H),3.68-3.72(m,2H),3.46-3.49(m,2H),2.84(s,2H),2.75(s,2H),1.13(d,J＝6.4Hz,6H).
Embodiment 9
1-(pentane-3-base)-3-(3-(5-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 9-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.55g, 1.5mmol) and 3-aminopentane (0.71mL) be dissolved in heating 80 degree of stirred overnight in DMF (7mL).After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (133mg, 32%).
LC-MS：454.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.72(s,1H),8.92(brs,1H),8.04-8.07(m,2H),7.72(s,1H),7.61(d,J＝8.4Hz,1H),7.39(d,J＝6.4Hz,1H),7.14(t,J＝7.6Hz,1H),3.99(s,2H),3.74(s,2H),3.69-3.71(m,2H),3.45-3.48(m,1H),3.38-3.44(m,2H),2.80-2.81(s,2H),2.69-2.73(m,2H),1.26-1.44(m,10H).
Embodiment 10
Cyclopentyl-3-(3-(5-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 9-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.55g, 1.5mmol) and cyclopentamine (0.6mL) be dissolved in heating 80 degree of stirred overnight in DMF (7mL).After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (110mg, 27%).
LC-MS：452.3[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.69(s,1H),8.93(brs,1H),8.04(s,2H),7.60(s,1H),7.39(s,1H),7.28(s,1H),7.12(d,J＝7.2Hz,1H),3.98-4.02(m,2H),3.74(s,1H),3.67-3.70(m,2H),3.46-3.47(m,2H),2.79-2.83(m,2H),2.69-2.73(m,2H),1.85-1.88(m,2H),1.68-1.69(m,2H),1.52-1.56(m,2H),1.44-1.47(m,2H),0.83-0.85(m,2H).
Embodiment 11
1-(2-fluorophenyl)-3-(3-(5-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 3-(5-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.34g, 1.0mmol) and 2-fluorophenylisocyanate (0.17mL) be dissolved in stirred overnight at room temperature in DMAC (20mL).1mol/L KOH (30mL) adds mixed solution stirring at room temperature 2 hours.After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (253mg, 53%).
LC-MS：478.3[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.13(s,1H),12.77(s,1H),9.63(s,1H),9.47(s,1H),8.14(s,1H),7.95-8.00(m,1H),7.61(s,1H),7.41(s,1H),7.08-7.27(m,4H),4.00-4.05(m,2H),3.75(s,2H),3.68-3.70(m,2H),2.81(s,2H),2.73(s,2H),1.98(s,2H).
Embodiment 12
1-cyclohexyl-3-(3-(5-((tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Compound 9-((tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazo [3,4-e] pyrazoles-5 (4H)-one (0.55g, 1.5mmol) and hexahydroaniline (1.7mL) be dissolved in heating 80 degree of stirred overnight in DMF (8mL).After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (92mg, 13%).
LC-MS：466[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.79(s,1H),8.97(s,1H),8.87(s,1H),8.03(d,J＝2.0Hz,1H),7.59(d,J＝7.6Hz,1H),7.39(d,J＝4.8Hz,1H),7.23(s,1H),7.14(d,J＝6.8Hz,1H),4.00(s,2H),3.74(d,J＝3.2Hz,2H),3.67-3.71(m,2H),3.58-3.60(m,1H),3.42-3.45(m,2H),2.79-2.82(m,2H),2.69-2.72(m,2H),1.85(d,J＝9.6Hz,2H),1.64-1.73(m,4H),1.13-1.29(m,4H).
Embodiment 13
(R)-2-methoxyl group-1-(3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base-) pyrroles [3,4-c] pyrazoles-5-(1H, 4H, 6H)-Ji)-2-methyl phenyl ketone
Step one 2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester
Under ice bath, sodium joins dehydrated alcohol (60mL), stir 1.5 hours, then near-10 DEG C, by oxalic acid diethyl ester (7.72g, 52.8mmol) dropwise add, N-benzyl-3-pyrrolidone (9.24g, 52.8mmol) is dissolved in dehydrated alcohol (60mL) subsequently, adds in 1 hour, rise to room temperature reaction subsequently to spend the night, suction filtration obtains light yellow look solid, with a small amount of washing with alcohol solid, and drying under reduced pressure, obtain product (9.3g, 63%).
LC-MS：276.1[M+1] +；
Step 2 5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate
2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester (9.3g, 33.8mmol) be dissolved in acetic acid (50mL), be cooled to zero degree, hydrazine hydrate (1.7g, 34.1mmol) dropwise add, then reflux 3 hours, be cooled to room temperature, add water (50mL), ethyl acetate extracts (3 × 50mL), saturated sodium bicarbonate water (50mL) is washed, anhydrous sodium sulphate (10g) is dry, after removal of solvent under reduced pressure, and column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (6.3g, 69%).
LC-MS：272.2[M+1] +.
Step 3 Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate
To compound 5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate (6.3g, 23.2mmol) ethanol (80mL) solution in add palladium hydroxide carbon (600mg), replacing hydrogen, room temperature reaction 12 hours, suction filtration goes out solid, and filtrate is spin-dried for, column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (4.0g, 95%).
LC-MS：182.2[M+1] +.
Step 4 (R)-5-(2-methoxyl group-2-phenylacetyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate
(R)-2-methoxyl group-2-toluylic acid (0.734g, 4.4mmol) with 1,4,5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate (0.8g, 4.4mmol) adds DMF (10mL), then TBTU (1.7g is added, 5.3mmol), room temperature reaction spends the night, and adds ethyl acetate (100mL), washing (2 × 30mL), after anhydrous sodium sulphate (10g) drying, desolventizing of reducing pressure out, crude product column chromatography purification is purified (methylene chloride/methanol (v/v)=10/1), obtain product (0.75g, 53%).
Step 5 (R)-5-(2-methoxyl group-2-phenylacetyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-formic acid
(R)-5-(2-methoxyl group-2-phenylacetyl)-1; 4; 5; 6-Pyrrolidine (3; 4-pyrazoles)-Ji-3-ethyl formate (0.75g; 2.13mmol) be dissolved in tetrahydrofuran (THF) (20mL), add aqueous sodium hydroxide solution (10mol/L, 20mL) subsequently; heating reflux reaction 2 hours; react complete by mixture concentrated removing organic solvent, adjust ph to 5, separates out white solid; collected by suction product; with cold water (50mL) washing, vacuum-drying obtains white solid product (380mg, 59%).
LC-MS：302.1[M+1] +.
Step 6 (R)-2-methoxyl group-1-(3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base-) pyrroles [3,4-c] pyrazoles-5-(1H, 4H, 6H)-Ji)-2-methyl phenyl ketone
Compound (R)-5-(2-methoxyl group-2-phenylacetyl)-1, 4, 5, 6-Pyrrolidine (3, 4-pyrazoles)-Ji-3-formic acid (0.38g, 1.28mmol) with 4-(morpholine methyl) benzene-1, 2-diamines (0.317g, 1.53mmol) be dissolved in DMF (10mL), add EDCI (0.27g subsequently, 1.4mmol) with HOBt (0.19g, 1.4mmol), room temperature reaction 24 hours, removal of solvent under reduced pressure, add acetic acid (20mL) subsequently, reflux three hours, be cooled to room temperature, removal of solvent under reduced pressure, residuum preparative chromatography obtains product (50mg, 21%).
LC-MS：491.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.31(s,1H),12.69(s,1H),7.17-7.54(m,8H),5.74(s,5H),4.43-4.65(m,2H),4.08(s,1H),3.56-3.58(m,4H),3.17-3.19(m,4H),2.36(s,2H).
Embodiment 14
4-((2-(5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazole-3-yl)-1H-benzoglyoxaline-6-base) methyl) morpholine
Step one 2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester
Under ice bath, sodium joins dehydrated alcohol (60mL), stir 1.5 hours, then near-10 DEG C, by oxalic acid diethyl ester (7.72g, 52.8mmol) dropwise add, N-benzyl-3-pyrrolidone (9.24g, 52.8mmol) is dissolved in dehydrated alcohol (60mL) subsequently, adds in one hour, rise to room temperature reaction subsequently to spend the night, suction filtration obtains light yellow look solid, with a small amount of washing with alcohol solid, and drying under reduced pressure, obtain product (9.3g, 63%).
LC-MS：276.1[M+1] +.
Step 2 5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles) base-3-ethyl formate
2-(1-benzyl-4-oxo pyrroles-3-base)-glyoxylic acid ethyl ester (9.3g, 33.8mmol) be dissolved in acetic acid (50mL), be cooled to zero degree, hydrazine hydrate (1.7g, 34.1mmol) dropwise add, then reflux 3 hours, be cooled to room temperature, add water (50mL), ethyl acetate extracts (3 × 50mL), saturated sodium bicarbonate water (50mL) is washed, anhydrous sodium sulphate (10g) is dry, after removal of solvent under reduced pressure, and column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (6.3g, 69%).
LC-MS：272.2[M+1] +.
Step 3 5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles) base-3-formic acid
5-phenyl-1,4,5,6-Pyrrolidine (3,4-pyrazoles) base-3-ethyl formate (6.3g, 23.2mmol) be dissolved in tetrahydrofuran (THF) (40mL), add aqueous sodium hydroxide solution (10mol/L, 40mL) subsequently, heating reflux reaction 2 hours, react complete by mixture concentrated removing organic solvent, adjust ph to 5 ~ 6, separate out white solid, collected by suction product, with a small amount of cold water (50mL) washing, vacuum-drying obtains white solid product (5g, 89%).
LC-MS：244.3[M+1] +.
Step 4 4-((2-(5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazole-3-yl)-1H-benzoglyoxaline-6-base) methyl) morpholine
Compound 5-phenyl-1,4,5,6-Pyrrolidine (3,4-pyrazoles) base-3-formic acid (0.5g, 2mmol) with 4-(morpholine methyl) benzene-1,2-diamines (0.51g, 2.46mmol) is dissolved in DMF (15mL), adds EDCI (0.3g subsequently, 2.26mmol) with HOBt (0.43g, 2.26mmol), room temperature reaction 24 hours, removal of solvent under reduced pressure, add acetic acid (30mL) subsequently, reflux 3 hours, is cooled to room temperature, removal of solvent under reduced pressure, residuum preparative chromatography obtains product (50mg, 21%).
LC-MS：454.1[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.31(s,1H),10.42(s,1H),10.18(s,1H),8.60(s,1H),8.05(s,1H),7.61(d,J＝12.3Hz,2H),7.30-7.37(m,2H),6.85-6.89(m,1H),6.27(s,1H),4.16(s,2H),3.79-3.82(m,2H),3.60-3.68(m,4H),3.51(s,3H),3.4-3.47(m,4H).
Embodiment 15
2-(3-fluorophenyl)-1-(3-(5-(morpholine methyl)-1H--benzo [d] imidazoles-2-base-) pyrroles [3,4-c] pyrazoles-5-(1H, 4H, 6H)-Ji) ethyl ketone
Step one Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate
To compound 5-phenyl-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate (6.3g, 23.2mmol) ethanol (80mL) solution in add palladium hydroxide carbon (600mg), replacing hydrogen, room temperature reaction 12 hours, suction filtration goes out solid, and filtrate is spin-dried for, column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (4g, 95%).
LC-MS：182.2[M+1] +.
Step 2 5-(2-(3-fluorophenyl) ethanoyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate
2-(3-fluorophenyl) acetic acid (1.0g, 5.52mmol) with 1,4,5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-ethyl formate (0.8g, 4.4mmol) adds DMF (20mL), then HATU (2.3g is added, 6.07mmol), room temperature reaction spends the night, and adds ethyl acetate (100mL), washing (2 × 30mL), after anhydrous sodium sulphate (10g) drying, removal of solvent under reduced pressure, crude product is with column chromatography purification (methylene chloride/methanol (v/v)=10/1), obtain product (1.5g, 86%).
Step 3 5-(2-(3-fluorophenyl) ethanoyl)-Isosorbide-5-Nitrae, 5,6-Pyrrolidine (3,4-pyrazoles)-Ji-3-formic acid
5-(2-(3-fluorophenyl) ethanoyl)-1; 4; 5; 6-Pyrrolidine (3; 4-pyrazoles)-Ji-3-ethyl formate (1.5g; 4.73mmol) be dissolved in tetrahydrofuran (THF) (30mL), add aqueous sodium hydroxide solution (10mol/L, 30mL) subsequently; heating reflux reaction 2 hours; react complete by mixture concentrated removing organic solvent, by concentrated hydrochloric acid (60mL) adjust ph to 5, separate out white solid; collected by suction product; with a small amount of cold water (50mL) washing, vacuum-drying obtains white solid product (600mg, 46%).
LC-MS：300.1[M+1] +.
Step 4 2-(3-fluorophenyl)-1-(3-(5-(morpholine methyl)-1H-benzo [d] imidazoles-2-base-) pyrroles [3,4-c] pyrazoles-5-(1H, 4H, 6H)-Ji) ethyl ketone
Compound 5-(2-(3-fluorophenyl) ethanoyl)-1, 4, 5, 6-Pyrrolidine (3, 4-pyrazoles)-Ji-3-formic acid (0.6g, 2mmol) with 4-(morpholine methyl) benzene-1, 2-diamines (0.43g, 2mmol) be dissolved in DMF (15mL), add EDCI (0.44g subsequently, 2.3mmol) with HOBt (0.31g, 2.3mmol), room temperature reaction 24 hours, removal of solvent under reduced pressure, add acetic acid (20mL) subsequently, reflux 3 hours, be cooled to room temperature, removal of solvent under reduced pressure, residuum preparative chromatography obtains product (50mg, 21%).
LC-MS：461.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.31(s,1H),10.42(s,1H),7.49(s,2H),7.35-7.39(m,1H),7.09-7.17(m,1H),7.05-7.09(m,3H),4.56-4.94(m,4H),3.85(d,J＝19.9Hz,2H),3.55-3.58(m,4H),2.49-2.50(m,2H),2.29(s,4H).
Embodiment 16
1-ethyl-1-methyl-3-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
Step one (3,4-dinitrophenyl) (morpholino) ketone
3,4-dinitrobenzoic acid (10.0g, 47mmol) and DMF (0.1mL) are dissolved in THF (100mL), then SOCl 2(7.4g, 62mmol) to be added drop-wise in mixed solution reflux 2.5 hours.Mixed solution is cooled to 0 DEG C, drips triethylamine (10mL, 71mmol) and keeps temperature to be longer than 20 minutes lower than 5 DEG C of times, then morpholine (7.2mL is dripped, 82mmol) time is longer than 15 minutes, and now a large amount of solids occurs, mixed solution slowly recovers stirred overnight at room temperature.Add frozen water (250mL) in mixed solution, be cooled to 0 DEG C and then filter, obtain yellow solid, wash with frozen water (50mL), dry, obtain product (11.95g, 90%).
Step 2 4-(3,4-dinitrobenzene methyl) morpholine
NaBH under the protection of nitrogen 4(3.36g, 89.78mmol) be dispersed in THF (360mL), after being cooled to 0 DEG C, add boron trifluoride diethyl etherate (11.3mL, 89.78mmol), note now having hydrogen to release, then (3 are once added, 4-dinitrophenyl) (morpholino) ketone (11.91g, 42mmol), shifts out cryostat, and slowly recovers stirring at room temperature 2 hours.Carefully add methyl alcohol (100mL), heating mixed-liquor return 1 hour.Concentrated liquid, dissolves with EtOAc (100mL), saturated NaHCO 3/ H 2o (1/1,100mL) washes organic phase, EtOAc (50mL) aqueous phase extracted, merges organic phase, saturated aqueous common salt (50mL) is washed, dry, concentrates to obtain solid, carry out recrystallization with methyl alcohol (10mL), obtain product (10g, 89.3%).
Step 3 4-(morpholinomethyl) phenyl-1,2-diamines
10%Pd/C (0.525g) and 4-(3 under the protection of nitrogen; 4-dinitrobenzene methyl) morpholine (10.5g; 39.29mmol) be dissolved in ethanol (200mL); mixed solution is cooled to 0 DEG C; be hydrogen by nitrogen replacement, recover stirred overnight at room temperature.Filter mixed liquor, concentrated filtrate, crosses post and carries out purifying (methylene chloride/methanol (v/v)=10/1), obtain product (6.34g, 61%).
1H?NMR(400MHz,DMSO-d 6):δ6.47(d,J＝2.0Hz,1H),6.40-6.42(d,J＝7.6Hz,1H),6.27-6.29(m,1H),4.32-4.38(d,J＝21.2Hz,4H),3.52-3.54(t,J＝4.8Hz,4H),3.18(d,J＝2.0Hz,2H),2,28(s,4H).
Step 4 4-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine
4-(morpholinomethyl) phenyl-1,2-diamines (2.3g, 1.11mmol), 4-nitro-1H-pyrazoles-3-formic acid (1.57g, 1mmol), EDCl (2.13g, 1.11mmol) and HOBt (1.5g, 1.11mmol) be dissolved in dry DMF (25mL), stirred overnight at room temperature.Removal of solvent under reduced pressure, add Glacial acetic acid (40mL), be heated to backflow 3 hours, in removal of solvent under reduced pressure, cross post and carry out purifying (methylene chloride/methanol (v/v)=10/1), then use methyl alcohol (10mL) to wash, namely the yellow solid being insoluble to methyl alcohol is product, obtain product (0.9g, 27%).
LC-MS：329[M+1] +,327[M-1] -.
Step 5 3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine
4-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine (0.9g under nitrogen protection; 2.74mmol) be dissolved in DMF (30mL); add 10%Pd/C (0.088g); hydrogen is replaced; stirring at room temperature is after 5 hours, and solids removed by filtration, washes solid with methyl alcohol (10mL); concentrated filtrate obtains brownish black solid, directly carries out next step reaction.Obtain product (0.84g, >100%).
Step 6 8-(morpholinomethyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoline [3,4-e] pyrimidine-5 (4H)-one
3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.6g, 2.0mmol) with CDI (0.64g, 3.96mmol) be dissolved in THF (10mL), reflux 16 hours.Mixed solution is cooled to room temperature, filters, and collects filter cake, washes with THF (5mL), dry, directly carries out next step reaction.Obtain pale solid (0.56g, 86.59%).
Step 7 1-ethyl-1-methyl-3-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(morpholinomethyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoline [3,4-e] pyrimidine-5 (4H)-one (0.145g, 0.45mmol) with methyl ethyl-amine (0.38mL, 3.67mmol) be dissolved in DMF (6mL), be heated to 100 DEG C of reactions 16 hours.Mixed solution is concentrated after being cooled to room temperature, crosses column purification (methylene chloride/methanol (v/v)=10/1), obtains faint yellow solid (0.163g, 76%).
LC-MS：384.3[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.02(s,1H),12.91(s,1H),9.93(d,J＝7.2Hz,1H),8.01(s,1H),7.54(t,J＝8.0Hz,1H),7.42(d,J＝8.4Hz,1H),7.14-7.20(m,1H),3.56(d,J＝7.6Hz,5H),3.41-3.47(m,2H),3.03(d,J＝6.8Hz,4H),2.36(s,4H),1.19(t,J＝7.2Hz,3H).
Embodiment 17
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) cyclopentane formamide
3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.83g, 2.78mmol), chaulmoogric acid (0.317g, 2.78mmol) with HATU (1.16g, 3.06mmol) be dissolved in DMF (8mL), stirring at room temperature crosses liquid, mixed solution concentrates, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain faint yellow solid (0.12g, 12%).
LC-MS：395.1[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.16(s,1H),12.96(s,1H),10.44(s,1H),8.24(s,1H),7.59(s,1H),7.43(s,1H),7.18(d,J＝8Hz,1H),3.57(t,J＝5.4Hz,6H),2.86-2.93(m,1H),2.37(s,4H),1.96-2.01(m,2H),1.79-1.82(m,2H),1.71-1.76(m,2H),1.62-1.65(m,2H).
Embodiment 18
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) piperidines-1-methane amide
8-(morpholinomethyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoline [3,4-e] pyrimidine-5 (4H)-one (0.25g, 0.76mmol) with piperidines (0.73mL, 6.11mmol) be dissolved in DMF (5mL), be heated to 100 DEG C of reactions 16 hours.Mixed solution is concentrated after being cooled to room temperature, crosses column purification (methylene chloride/methanol (v/v)=10/1), obtains faint yellow solid (0.32g, 84%).
LC-MS：410.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.04(s,1H),12.93(s,1H),10.03(d,J＝13.2Hz,1H),8.02(s,1H),7.55(t,J＝8.4Hz,1H),7.42(d,J＝8.0Hz,1H),7.17(dd,J＝8.3Hz,15.8Hz,1H),3.56(d,J＝6.8Hz,6H),3.51(s,4H),2.37(s,4H),1.58(s,6H).
Embodiment 19
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) cyclohexane carboxamide
3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.6g, 2.0mmol), cyclohexylenedinitrilotetraacetic acid (0.31g, 2.41mmol) be dissolved in DMF (7mL) with HATU (0.91g, 2.41mmol), stirring at room temperature crosses liquid, mixed solution concentrates, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain faint yellow solid (0.17g, 21%).
LC-MS：409.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.18(s,1H),12.95(s,1H),10.47(s,1H),8.26(s,1H),7.60(d,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.14-7.20(m,1H),3.55(d,J＝4.8Hz,6H),2.36(s,4H),1.97(d,J＝12.0Hz,2H),1.77(d,J＝12.4Hz,2H),1.65(d,J＝12.0Hz,1H),1.45-1.53(m,2H),1.19-1.33(m,4H).
Embodiment 20
Sec.-propyl (3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) carbamate
Step one tertiary butyl-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-4-nitro-1H-pyrazoles-1-carbonic ether
4-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine (1.2g, 3.68mmol), (Boc) 2o (0.92g, 4.23mmol) and 4-DMAP (0.047g, 0.39mmol) is dissolved in methylene dichloride (100mL), and stirring at room temperature 1 is little to be clarified up to solution.After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (870mg, 55%).
LC-MS：429.1[M+1] +.
The step 2 tertiary butyl-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-4-amino-1H-pyrazoles-1-carbonic ether
The tertiary butyl-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-4-nitro-1H-pyrazoles-1-carbonic ether (0.87g, 2.03mmol) be dissolved in methyl alcohol (10mL), add 10%Pd/C (0.1g) stirred overnight at room temperature under the condition of hydrogen.Cross and filter Pd/C, after removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain product (0.69mg, 85%).
LC-MS：399.3[M+1] +.
The step 3 tertiary butyl-4-((butyloxycarbonyl) is amino)-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-1-carbonic ether
The tertiary butyl-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-4-amino-1H-pyrazoles-1-carbonic ether (0.68g, 1.71mmol), isopropyl chlorocarbonate (0.63g, 5.13mmol), 4-DMAP (0.021g, 0.17mmol) be dissolved in methylene dichloride (15mL) with pyridine (0.405g, 5.13mmol), room temperature for overnight.Go out pyridine with 0.5mol/L hydrochloric acid (30mL) cleaning mixture, after concentrating under reduced pressure, directly carry out next step.
LC-MS：483.3[M-1] -.
Step 4 sec.-propyl (3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) carbamate
The tertiary butyl-4-((butyloxycarbonyl) is amino)-3-(6-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-1-carbonic ether (0.82g, 1.71mmol) be dissolved in DCM (5mL), add the ethyl acetate solution (10mL) of saturated hydrogenchloride, stirring at room temperature 10 hours.Filter, the dissolution of solid obtained is at saturated NaHCO 3solution (10mL), extract with methylene dichloride (50mL), after anhydrous sodium sulphate (10g) drying, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain sterling (30mg, 4.6%).
LC-MS：383.1[M-1] -；
1H?NMR(400MHz,DMSO-d 6):δ13.19(s,1H),12.92(d,J＝7.6Hz,1H),9.42(d,J＝24.8Hz,1H),8.02(s,1H),7.62(t,J＝8.4Hz,1H),7.42(d,J＝7.6Hz,1H),7.14-7.20(m,1H),4.91-4.97(m,1H),3.56(d,J＝6.0Hz,6H),2.37(s,4H),1.30(d,J＝6.4Hz,6H).
Embodiment 21
1,1-diethyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine-5 (4H)-one (0.3g, 0.82mmol) be dissolved in DMAC (6mL), then add diethylamine (2mL, 19.45mmol) and be heated to 80 DEG C of reactions 24 hours.Reaction solution evaporate to dryness, residue is dissolved in methylene chloride/methanol (10/1,55mL), and saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) are respectively washed once, and anhydrous sodium sulphate (50g) is dry.Boil off solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (29mg, 8.1%).
LC-MS：440[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.01(s,1H),12.90(s,1H),9.96(d,1H),8.00(s,1H),7.48-7.52(m,1H),7.40-7.42(m,1H),7.13-7.19(m,1H),3.90(s,1H),3.78-3.87(s,3H),3.72-3.77(m,2H),3.51-3.55(m,6H),2.86-2.89(m,2H),2.56-2.61(m,2H),1.23-1.25(m,6H).
Embodiment 22
1-ethyl-1-methyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine-5 (4H)-one (0.25g, 0.68mmol) be dissolved in DMAC (10mL), then add N-methyl ethyl-amine (6mL, 6.83mmol) and be heated to 100 DEG C of reactions 24 hours.Reaction solution evaporate to dryness, residue is dissolved in methylene chloride/methanol (20/1,105mL), and saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) are respectively washed once, and anhydrous sodium sulphate (50g) is dry.Boil off solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (88mg, 30.34%).
LC-MS：426[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.91-13.01(s,2H),9.95(d,1H),8.01(s,1H),7.53(d,J＝6.8Hz,1H),7.41(d,J＝15.4Hz,1H),7.12-7.18(m,1H),3.89(s,1H),3.81-3.86(m,3H),3.71-3.76(m,2H),3.61-3.64(m,3H),3.03(d,J＝11.0Hz,3H),2.60-2.87(m,2H),2.56-2.58(m,2H),1.18-1.21(m,4H).
Embodiment 23
N-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) tetramethyleneimine-1-methane amide
Step one 8-(((4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one
3-(6-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (1.6g, 4.81mmol) with CDI (1.53g, 2.17mmol) be dissolved in THF (25mL) and be heated to 75 DEG C of stirrings and spend the night, it is complete that TLC shows raw material reaction, filtration obtains pale solid (0.82g, 46%).
LC-MS：367.2[M+1] +.
Step 2 N-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) tetramethyleneimine-1-methane amide
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.54mmol) be dissolved in DMF (5mL), add tetramethyleneimine (0.5mL), be heated to 100 DEG C of reactions and spend the night.After removal of solvent under reduced pressure, cross column purification (methylene chloride/methanol (v/v)=10/1), obtain sterling (110mg, 57%).
LC-MS：438.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.02(s,1H),12.89(s,1H),9.64(d,J＝8.8Hz,1H),8.06(s,1H),7.55(d,J＝9.6Hz,1H),7.40(d,J＝8.0Hz,1H),7.15(q,J＝8.0Hz,1H),3.89(d,J＝13.2Hz,2H),3.76-3.82(m,4H),3.62-3.64(m,6H),2.89(t,J＝7.2Hz,2H),2.59(t,J＝8.8Hz,2H),1.94(s,2H),1.22(s,2H).
Embodiment 24
N-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) ring penta methane amide
3-(6-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.3g, 0.88mmol) be dissolved in DMF (6mL), then add heptanaphthenic acid (0.12g, 1.06mmol) and HATU (0.4g successively, 1.06mmol), stirring at room temperature reacts 24 hours.Reaction solution evaporate to dryness, in residue solution dichloromethane/methyl alcohol (10/1,55mL), saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) are respectively washed once, and anhydrous sodium sulphate (50g) is dry.Boil off solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (35mg, 9.11%).
LC-MS：437[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.18(brs,1H),10.44(s,1H),9.64(d,J＝8.0Hz,1H),8.24(s,1H),7.54-7.58(m,1H),7.49-7.51(m,1H),7.15-7.17(m,1H),4.01-4.03(m,1H),3.87(s,1H),3.81(s,1H),3.74-3.78(m,2H),3.62-3.64(m,2H),3.54-3.57(m,2H),1.96-1.98(m,4H),1.65-1.80(m,2H),1.55-1.60(m,4H),1.15-1.25(m,2H).
Embodiment 25
1-(Cvclopropvlmethvl)-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine-5 (4H)-one (0.48g, 1.31mmol) be dissolved in DMAC (12mL), then add cyclopropylmethylamine (1.1mL, 13.20mmol) and be heated to 100 DEG C of reactions 24 hours.Reaction solution evaporate to dryness, residue is dissolved in methylene chloride/methanol (20/1,105mL), and saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) are respectively washed once, and anhydrous sodium sulphate (50g) is dry.Boil off solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (53mg, 9.27%).
LC-MS：438[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.96(s,1H),12.73(s,1H),9.02(d,J＝5.1Hz,2H),8.04(s,1H),7.59(d,J＝14.5Hz,1H),7.39(d,J＝4.5Hz,2H),7.14(t,J＝9.2Hz,1H),4.01-4.03(m,1H),3.90(s,1H),3.82-3.87(m,3H),3.72-3.78(m,2H),3.01(d,J＝19.2Hz,2H),2.99(s,2H),2.59-2.60(d,J＝6.7Hz,2H),0.98(s,1H),0.443-0.45(d,J＝5.3Hz,2H),0.20-0.21(m,2H).
Embodiment 26
1-(pentane-3-base)-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.54mmol) be dissolved in DMF (5mL), add 3-aminopentane (0.5mL), be heated to 100 DEG C of reactions and spend the night.After removal of solvent under reduced pressure, cross column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain sterling (196mg, 80%).
LC-MS：454.2[M+1] +；
1HNMR(400MHz,DMSO-d 6):δ12.95(s,1H),12.72(s,1H),8.92(d,J＝44.0Hz,1H),8.06(s,1H),7.64(d,J＝17.6Hz,1H),7.39(s,1H),7.14(t,J＝7.2Hz,1H),3.79-3.91(m,2H),3.62-3.77(m,4H),3.56(s,2H),3.47-3.50(m,2H),2.89(t,J＝7.2Hz,2H),2.60(t,J＝8.0Hz,2H),1.47-1.52(m,2H),1.37-1.43(m,2H),0.88(t,J＝7.2Hz,6H).
Embodiment 27
1-sec.-propyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.55mmol) be dissolved in DMF (5mL), add Isopropylamine (0.37mL), be heated to 100 DEG C of reactions and spend the night.After removal of solvent under reduced pressure, cross column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain sterling (230mg, 98%).
LC-MS：427.3[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.96(s,1H),12.73(s,1H),8.90(d,J＝44.8Hz,1H),8.06(s,1H),7.64(d,J＝17.6Hz,1H),7.39(s,1H),7.14(t,J＝7.2Hz,1H),3.89(d,J＝13.2Hz,1H),3.79-3.87(m,3H),3.62-3.77(m,4H),3.56(s,2H),3.47-3.50(m,2H),2.89(t,J＝7.2Hz,2H),2.57-2.63(m,2H),1.13(d,J＝6.4Hz,4H).
Embodiment 28
1-(cyclopentyl-3-base)-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.54mmol) be dissolved in DMF (5mL), add cyclopentyl amine (0.5mL), be heated to 100 DEG C of reactions and spend the night.After removal of solvent under reduced pressure, cross column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain sterling (120mg, 62%).
LC-MS：454.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.96(s,1H),12.73(s,1H),8.95(brs,J＝34.8Hz,1H),8.06(s,1H),7.59(s,1H),7.39(s,1H),7.28(s,1H),7.13(d,J＝8.0Hz,1H),3.95-4.00(m,1H),3.80-3.90(m,2H),3.61-3.77(m,4H),3.53-3.56(m,2H),2.88(t,J＝7.6Hz,2H),2.59(t,J＝8.8Hz,2H),1.85-1.97(m,2H),1.65-1.67(m,2H),1.42-1.55(m,4H).
Embodiment 29
N-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) piperidines-1-methane amide
Step one N-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) piperidines-1-methane amide
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.54mmol) be dissolved in DMF (5mL), add 3-aminopentane (0.5mL), be heated to 100 DEG C of reactions and spend the night.After removal of solvent under reduced pressure, cross column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain sterling (80mg, 36%).
LC-MS：451.2[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ13.03(s,1H),12.91(s,1H),10.03(d,J＝12.0Hz,1H),8.01(s,1H),7.53(t,J＝6.4Hz,1H),7.41(d,J＝10.0Hz,1H),7.13-7.19(m,1H),3.81-3.90(m,2H),3.62-3.78(m,4H),3.51-3.58(m,6H),2.88(t,J＝7.2Hz,2H),2.58(t,J＝7.6Hz,2H),1.58(s,6H).
Embodiment 30
1,1-di-isopropyl-3-(3-(5-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(((4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) methyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.55mmol) be dissolved in DMAC (8mL), then add diisopropylamine (2.77mL, 19.78mmol) and be heated to 100 DEG C of reactions 48 hours.Reaction solution evaporate to dryness, residue is dissolved in methylene chloride/methanol (50/1,51mL), and saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) are respectively washed once, and anhydrous sodium sulphate (10g) is dry.Boil off solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain a crude product, then send preparative chromatography purifying to obtain sterling (60mg, 23.43%).
LC-MS：468[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.99(s,1H),12.88(s,1H),9.71(d,J＝15.2Hz,1H),8.03(s,1H),7.49(t,J＝12.8Hz,1H),7.41(d,J＝10.0Hz,1H),7.13-7.19(m,1H),4.06-4.12(m,2H),3.82-3.90(m,2H),3.63-3.78(m,4H),3.56(t,J＝5.6Hz,2H),2.86-2.90(m,2H),2.58-2.61(m,2H),1.36(d,J＝6.8Hz,12H).
Embodiment 31
1,1-di-isopropyl-3-(3-(5-(Ma Lindai methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) urea
8-(morpholinomethyl)-2H-benzo [4,5] imidazoles [1,2-c] pyrazoline [3,4-e] pyrimidine-5 (4H)-one (0.2g, 0.54mmol) with diisopropylamine (0.61mL, 4.35mmol) be dissolved in DMF (8mL), be heated to 120 DEG C of reactions 24 hours.Mixed solution is concentrated after being cooled to room temperature, crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain white solid (11mg, 4.8%).
LC-MS：423.3[M+1] +；
1H?NMR(400MHz,DMSO-d 6):δ12.98(s,1H),12.87(s,1H),9.71(d,J＝14.0Hz,1H),8.03(s,1H),7.50(t,J＝8.0Hz,1H),7.41(s,1H),7.12-7.23(m,1H),4.06-4.12(m,2H),3.56-3.62(m,4H),3.51(s,2H),3.34(s,2H),2.37(s,2H),1.36(d,J＝6.4Hz,12H).
Biological activity
External Aurora-A and Aurora-B kinase inhibition test
Adopt 100%DMSO by the highest final concentration 50 times of diluted chemical compound.The compound solution of 100 these concentration of μ L is transferred to a hole of 96 orifice plates.Such as, if the highest inhibition concentration time 10 μMs, prepare the solution that 500 μMs are dissolved in DMSO.Then hole-specifically carry out the concentration gradient dilution of 4 times with 100%DMSO, prepare 10 isoconcentration solution.Then by each concentration dilute with water 10 times.Subsequently, in each hole of check-out console, 5 μ L compounds are added." completely " and " blank " control wells 10%DMSO of 10 μ L replaces.Wherein, " completely " control wells is without compound group, and " blank " control wells is without kinases group.Then, kinases (is added 1.25 × kinases basis buffer (62.5mM HEPES pH7.5,0.001875%Brij-35,12.5mM MgCl by 10 μ L2.5 × kinase solution 2, 2.5mM DTT) formulated) be added in each hole of check-out console.Incubated at room 10 minutes.By 10 μ L2.5 × peptide solution (FAM-labeled peptide and ATP being added 1.25 × kinases basis buffer formulated) add in each hole of check-out console.Hatch 1 hour for 28 DEG C.Add 25 μ L stop buffers (100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA) termination reaction.Then Caliper reads plate and detects, and finally calculates IC according to Conversion value and inhibition concentration mapping 50value.
Test-results is in table 2:
Table 2 data declaration is in this test, and the compounds of this invention has suppression Aurora-A kinases, and the ability of Aurora-B kinase activity is the derivative that a class has the Ou Ruola kinase inhibitor of better inhibit activities.

Claims (16)

1. a substituted pyrazole derivatives, it is for such as formula the structure shown in (I) or formula (Ia), or such as formula the steric isomer of the structure shown in (I) or formula (Ia), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Q is-NH-, or-O-
R 1for morpholinyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12condensed-bicyclic base, or C 5-12condense assorted bicyclic group;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-6alkyl;
Or R 2and R 3five-membered ring is formed together with its connected carbon atom; Wherein, described five-membered ring can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl or C 6-10aryl; Or, R 4and R 4ac is formed together with its connected atom N 2-9heterocyclic radical;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-6alkyl or C 6-10aryl;
Wherein, R 7for C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 1-9heteroaryl, or C 6-10aryl;
Wherein, each R 8and R 8abe hydrogen independently, C 6-10aryl, C 1-6alkoxyl group, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-6during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, or C 1-9heteroaryl; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, described R 1, R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in bridge to mix bicyclic group, bridge bicyclic group, condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, carbocylic radical, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroaryl, aryl, heterocyclic radical, carbocylic radical and alkoxyl group, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
2. compound according to claim 1, wherein,
Q is-NH-;
R 1for morpholinyl, or following subformula:
Wherein, each Q 1and X 3be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic radical, carbocylic radical, cycloalkylalkyl, and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, or C 1-4during alkyl,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclohexyl or cyclopentyl is formed together with its connected carbon atom;
R 6for C 1-4alkyl.
3. compound according to claim 2, wherein,
R 1for morpholinyl, or following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
or wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl, cyclohexyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 8and R 8acyclopropyl is formed, cyclopentyl, cyclobutyl together with its connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclopropylmethylene, phenylmethylene, heterocyclic radical, phenyl and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted;
1) wherein, when Q is NH, and R 1for morpholinyl, R 3for H, methyl, ethyl, or during propyl group,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl.
4. compound according to claim 1, it is for such as formula the substituted pyrazole derivatives shown in (II) or formula (IIa),
Wherein:
R 1for following subformula:
Wherein, each Q 1and X 3be N independently, or CH;
Each X 1, X 2, X 4, X 5, X 6and X 7be-CH independently 2-,-O-,-NR 9a-, or-S-;
Each q, m, p, r and s are 0,1,2,3 independently, or 4;
Each R 9abe H independently, ethanoyl, methyl or ethyl;
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl;
R 4afor C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, or C 6-10aryl; Or, R 4and R 4athe heterocyclic radical of 5-6 unit is formed together with its connected atom N;
Each R 5and R 5abe H independently, or C 3-6cycloalkyl; Or, R 5and R 5ac is formed together with its connected carbon atom 3-6carbocylic radical;
R 6for C 1-4alkyl or C 6-10aryl;
Wherein, each R 7be C independently 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1-4alkyl, amino, C 1-4alkoxyl group, cyano group, hydroxyl, C 1-4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
5. compound according to claim 4, wherein,
R 1for following subformula:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for H, methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
R 4afor methyl, ethyl, propyl group, sec.-propyl, 1-Ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 4and R 4afollowing subformula is formed together with its connected atom N:
Each R 5and R 5abe H independently, cyclopropyl, cyclopentyl, or cyclohexyl; Or, R 5and R 5acyclopropyl is formed, cyclobutyl, cyclopentyl together with its connected carbon atom, or cyclohexyl;
R 6for methyl, ethyl, propyl group, sec.-propyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-;
Wherein, R 7for cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl, cyclohexyl, the fluoro-phenyl of 2-or the fluoro-phenyl of 3-; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl.
6. substituted pyrazole derivatives according to claim 1, it is for such as formula the substituted pyrazole derivatives shown in (IIb) or formula (IIab), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein:
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
R 3for H, or C 1-4alkyl;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, C 6-10aryl C 1-6alkyl, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, R 4for C 2-6alkyl;
R 4afor C 1-6alkyl, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5athe carbocylic radical of 5-6 unit is formed together with its connected carbon atom;
R 6for C 1-4alkyl;
Wherein, R 7for C 3-6cycloalkyl, or C 6-10aryl C 1-4alkyl;
Wherein, each R 8and R 8abe hydrogen independently, C 1-4alkoxyl group, C 6-10aryl, or C 3-6cycloalkyl; Or, R 8and R 8ac is formed together with its connected carbon atom 3-6carbocylic radical;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in alkyl, cycloalkyl, aryl, heterocyclic radical, cycloalkylalkyl, arylalkyl, carbocylic radical and described R 1representative subformula, can independently by F, Cl, Br, C 1 ?4alkyl, amino, C 1 ?4alkoxyl group, cyano group, hydroxyl, C 1 ?4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
7. compound according to claim 6, wherein,
R 2for R 4r 4an-C (=O)-NH-, R 5r 5acH-C (=O)-NH-or R 6o-C (=O)-NH-;
Wherein, R 4for ethyl, propyl group, sec.-propyl, butyl or 1-Ethyl-propyl;
R 4afor methyl, ethyl, sec.-propyl, butyl, 1-Ethyl-propyl or amyl group, or, R 4and R 4afollowing subformula is formed together with its connected atom N:
R 5and R 5acyclopentyl or cyclohexyl is formed together with its connected carbon atom;
R 6for methyl, ethyl, sec.-propyl, propyl group or butyl;
R 3for H, methyl, ethyl, or propyl group;
Or R 2and R 3following subformula is formed together with its connected carbon atom:
wherein, described R 2and R 3the subformula formed together with its connected carbon atom can by R 7nH-C (=O)-, phenylmethylene, or R 8r 8acH-C (=O)-, monosubstituted or identical or different is polysubstituted;
Wherein, each R 7be cyclopropyl independently, cyclopentyl, cyclohexyl, or phenylmethylene;
Wherein, each R 8and R 8abe hydrogen independently, methoxyl group, oxyethyl group, phenyl, cyclopentyl or cyclohexyl; Or, R 8and R 8acyclopropyl is formed, cyclobutyl, cyclopentyl together with connected carbon atom, or cyclohexyl;
Wherein, described R 2, R 3, R 4, R 4a, R 5, R 5a, R 6, R 7, R 8and R 8adescribed in methyl, ethyl, propyl group, sec.-propyl, butyl, 1 ?Yi Ji ?propyl group, amyl group, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocylic radical, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and described R 1representative subformula, can independently by F, Cl, Br, C 1 ?4alkyl, amino, C 1 ?4alkoxyl group, cyano group, hydroxyl, C 1 ?4alkylamino, oxo (=O), ethanoyl, trifluoromethyl or nitro, monosubstituted or identical or different is polysubstituted.
8. compound according to claim 1, comprises one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
9. pharmaceutical composition, comprises compound as claimed in claim 1.
10. pharmaceutical composition according to claim 9, comprises pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
11. pharmaceutical compositions according to claim 9, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine and is used for the treatment of at least one of medicine of pulmonary fibrosis.
12. pharmaceutical compositions according to claim 11, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
13. use compound described in claim 1 or pharmaceutical composition according to claim 9, protect, and process, treats or alleviate the purposes of the disease that patient is mediated by Ou Ruola kinases.
14. purposes according to claim 13, if its Central Europe draws kinases to be Ou Ruola-A kinases or Ou Ruola-B kinases.
15. 1 kinds use the compound described in claim 1 or pharmaceutical composition according to claim 9 to come for the preparation of protection, process, treat or alleviate the purposes of medicine of patient's proliferative disease.
16. purposes according to claim 15, wherein said proliferative disease refers to colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, neck cancer, central nervous system cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatism, chronic inflammatory diseases, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecular disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, myelomatosis, acute lymphoblastic leukemia, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colorectal carcinoma, the rectum cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterus carcinoma, chronic hepatitis, liver cirrhosis, ovarian cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer or myelomatosis.
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CN114617969A (en) * 2020-12-14 2022-06-14 上海市肿瘤研究所 Application of lenvatinib and Aurora-A kinase inhibitor in preparation of drugs for inhibiting cancers
US11433073B2 (en) 2019-12-12 2022-09-06 Ting Therapeutics Llc Compositions and methods for the prevention and treatment of hearing loss

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CN101379058A (en) * 2004-12-30 2009-03-04 阿斯特克斯治疗有限公司 Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases

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CN101379058A (en) * 2004-12-30 2009-03-04 阿斯特克斯治疗有限公司 Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases

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CN114617969A (en) * 2020-12-14 2022-06-14 上海市肿瘤研究所 Application of lenvatinib and Aurora-A kinase inhibitor in preparation of drugs for inhibiting cancers
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