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CN104447701A - Pyrazole derivative and application thereof - Google Patents

Pyrazole derivative and application thereof Download PDF

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CN104447701A
CN104447701A CN201410471458.5A CN201410471458A CN104447701A CN 104447701 A CN104447701 A CN 104447701A CN 201410471458 A CN201410471458 A CN 201410471458A CN 104447701 A CN104447701 A CN 104447701A
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alkyl
group
independently
bicyclic group
bicyclic
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CN104447701B (en
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张健存
刘兵
张英俊
聂凛凛
杨学绮
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Guangdong HEC Pharmaceutical
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • 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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    • 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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Abstract

The invention relates to a substituted pyrazole derivative for inhibiting over-expression of protein kinase, and a stereoisomer, a geometrical isomer, a tautomer, an oxynitride, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug of the substituted pyrazole derivative, a medicinal composition containing the compounds as active ingredients, and an application of the compounds and the medicinal composition in preparation of a medicament for preventing, handling, treating or relieving cell growth abnormal diseases of patients.

Description

Pyrazole derivatives and uses thereof
Invention field
The present invention relates to the novel pyrazole compounds of suppression or Function protein kinase activity; This compounds is a kind for the treatment of, alleviation or the prevention disease relevant with enzymic activity or illness, or the new compound of the purposes of its one or more symptoms; The present invention also provides medicinal compositions containing this compounds and new chemical intermediate, and the preparation method of this compounds.
Background of invention
Protein kinase (PKs) is the enzyme of the di of tyrosine, Serine and Threonine group on catalytic proteins, is responsible for controlling a variety of signal transduction process in cell.PKs can be divided into two classes: tyrosine protein kinase (PTKs) and serine-threonine protein kinase enzyme (STKs).Kinase whose Non-limiting examples ground in protein kinase family comprises Abl1 (v-Abl Abelson murine leukemia virus oncogene autoploid 1), Akt, Bcr-Abl1, Blk, Brk, Btk, c-Kit, c-Met, c-Src, c-Fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, EebB2, EebB3, EebB4, Erk, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FLT-3, Abl, Flt-5, Fps, Frk, Jak, KDR, MEK, PDGFR, PIK, PKC, PYK2, Ros, Raf, Ret, Aurora-A, Aurora-B, Aurora-C, Tie, Tie2, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Lck, Lyn, p38, Ros, TRK, Yes, and Zap70.
It is reported, numerous disease is replied relevant with the abnormal cells that the event that protein kinase mediates causes.These diseases comprise autoimmune disorder, inflammatory diseases, osteopathia, metabolic disease, sacred disease and neurodegenerative disease, cancer, cardiovascular disorder, transformation reactions and asthma, alzheimer's disease and hormone related condition.
Tyrosine protein kinase (PTKs)
Receptor tyrosine kinases (RTK) is the sub-receptor kinase of III class in Tyrosylprotein kinase (PTKs) family, comprise platelet derived growth factor receptor (pdgf receptor α and β), G CFS (CSF-1) acceptor (CSF-1R, c-Fms), FLT-3, Janus kinases (JAK), Abl (c-Abl) and stem cell factor receptor (c-kit) etc., relevant with diseases such as various kinds of cell hyperplasia and inflammation.
The patient suffering from neurotic glue knurl or sarcoma raises with gene amplification or PDGFR level.The activation of PDGFR-α is found in the patient suffering from chronic myelomonocytic leukemia (CMML).Also PDGFR-α transgenation and small segment disappearance is found in the patient suffering from gastroenteric tumor and the patient suffering from primary eosnophilia leukocytosis syndrome.In tumor vessel, find that there is PDGFR-β express, research shows to suppress PDGFR-β anti-angiogenicly to regenerate.Research finds have PDGFR-β to express in the tumor stroma of most of solid tumor, makes this receptor become the potential target spot of antineoplaston.
Tyrosylprotein kinase-3 (FLT-3) is also referred to as human stem cell kinases-1 (STK-1), be second member of PDGF acceptor (PDGFR) family, play an important role in the propagation and differentiation of hemopoietic stem cell.
In addition, Flt-3 suppresses relevant with inflammation and autoimmune response.Flt-3 inhibitor C EP-701 effectively can reduce the myelin loss of experimental autoimmune encephalomyelitis (EAE) in multiple sclerosis disease mouse model (see PNAS to have item research to show, 2005,102,16741-16746, Whartenby etc.).Flt-3 part in the serum of langerhans cells hamartoplasia disease patient and lupus erythematosus patient in high level, show further Flt-3 play in autoimmune disorder function (see J Immunol., 2005,174,3067-3071, Rolland etc.).
The change of Abl gene activity (performance) and multiple deficiency disorder, disease are relevant with other deleterious condition.Gene expression through changing may cause disease, deficiency disorder and symptom, comprises the disease of inflammation, proliferative, hyper-proliferative and immunity regulatin remedy.Bcr-Abl protein, it is in 90% of chronic myelogenous leukemia (CML) all patients and the cytoplasmic Tyrosylprotein kinase of constitutive activity that exists in the 15-30% of Acute Lymphoblastic Leukemia (ALL) adult patient.Much research has shown that the activation of bcr-Abl is required for this mosaic type protein carciongenic potency.
Janus kinases (JAK)
Janus kinases (JAK) is cytoplasmic tyrosine kinase, and its transducer cell factor signal transduction is from membrane receptor to STAT transcription factor.Four kinds of JAK family members are described, JAK1, JAK2, JAK3 and TYK2.When cytokine and its receptors bind, JAK family member autophosphorylation and/or turn phosphorylation each other, STAT phosphorylation subsequently, then migrates in nucleus and transcribes to regulate.JAK-STAT intracellular signal transduction is applicable to Interferon, rabbit, most of interleukin-and cytokine profiles and endocrine factor, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, PRL etc.
TYK2 is the potential target spot of Immunoinflammatory Disorders, rejects research confirmation by people's genetics and mouse.
JAK family member relates to other illness, comprises bone marrow proliferation sexual dysfunction (see MolImmunol., 2007,44 (10), 2497-506, O ' Sullivan etc.), wherein identifies the sudden change in JAK2.This shows that the inhibitor of JAK, particularly JAK2 can also be used for the treatment of bone marrow proliferation sexual dysfunction.In addition, JAK family, particularly JAK1, JAK2 and JAK3, with cancer, particularly leukemia such as acute myeloid leukaemia (see Mol Immunol., 2007,44 (10), 2497-506, O ' Sullivan etc.) and acute lymphoblastic leukemia or solid tumor such as leiomyosarcoma of uterus (see Trends in Biochemical Sciences, 2007,33 (3), 122-131, Constantinescu etc.), prostate cancer (see BritishJournal of Cancer, 2007,97,378-383, Tam etc.) relevant.These results show that the inhibitor of JAK, particularly JAK1 and/or JAK2 can also be used for the treatment of cancer (leukemia and solid tumor, such as leiomyosarcoma of uterus, prostate cancer).
In addition, Castleman disease, multiple myeloma, Pathology of Mesangial Proliferative Glomerulonephritis, psoriatic and Kaposi sarcoma may owing to the supersecretions of cytokine IL-6, the biological effect of IL-6 is by JAK-STAT intracellular signaling mediation (Arthritis Res in cell, 2002,4 (suppl3), S233-S242, Tetsuji Naka, Norihiro Nishimoto and Tadamitsu Kishimoto).This result shows to find that the inhibitor of JAK can also be used for the treatment of described disease.
Determine associating of JAK3 with Tyk2 and autoimmune disease.The sudden change of JAK3 and stream signal conductive components γ-c receptor chain and IL7 acceptor adds up to and accounts for ~ people's severe combined immunodeficiency example of 70%.Notice that JAK1 works in coordination with JAK3 from γ-c receptor chain transduction signal.Find Tyk2 polymorphism (see MolImmunol., 2007,44 (10), 2497-506, O ' Sullivan etc.) in the systemic lupus erythematous (SLE).Therefore, target JAK family can provide treatment machine meeting in immuno-inflammatory field.
Serine-threonine protein kinase enzyme (CSF-1R)
Serine-threonine protein kinase enzyme (CSF-1R) is macrophage colony pungency factor acceptor (M-CSF, CSF-1, or fms) express in a lot of mammary cancer, prostate gland, human epithelium's cancer, ovary, uterine endometrium and leukemia, this proves that CSF-1R may be that the therapy target of leukemia and solid tumor is (see Blood, 1997,89,2537-2545, Haran-Ghera).
Aurora A
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 kinases inhibitor are open, and it regulates or more particularly suppresses kinase activity, are used for treating the relevant illness of kinases or other obstacle.Such as, the open phentriazine as kinase inhibitor of US6596746 and WO2005096784; The benzoic amide that WO200181311 openly replaces is for inhibiting angiogenesis; The pyrimidine derivatives that US6440965 openly replaces is used for the treatment of in neurodegeneration or neurological disorder; WO2002008205 reports that pyrimidine derivatives has neurotrophic activity; WO2003014111 discloses aryl piperazines and Arylpiperidine and they purposes as inhibitors of metalloproteinase; WO2003024448 describes the inhibitor of compound as histone deacetylase enzymatic activity; WO2004058776 openly has the compound of anti-angiogenesis activity.The open quinazoline derivatives as kinase inhibitors of WO2001094341 and WO2002016352.The open pyrimidinyl derivatives as kinase inhibitor of WO2003026666 and WO2003018021.US6498165 reports the kinase inhibitor compounds of pyrimidine compound class.
Abstract of invention
The invention provides a series of pyrazole compound and pharmacy acceptable salt thereof as kinases inhibitor in preparation treatment and the application in the medicine of protein kinase activity relative disease.Experimental study proves: pyrazole compound and pharmaceutical salts thereof play an important role with regulating in the kinase activity such as Aurora A, Aurora B, JAK, Abl, FLT-3 of the protein kinase family of primary type and/or mutant form at therapeutic treatment.
The present invention proposes the pyrazole derivatives that a class is new, can effectively suppress or regulate related enzyme activity, and estimate that they can be used for preventing or treating the purposes of some kinase mediated disease or illness.
The present invention proposes a kind of such as formula the pyrazole derivatives shown in (I), or the steric isomer of the pyrazole derivatives shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Each R 1and R 1abe H independently, or C 1-4alkyl;
R 2for alkylamino, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical ,-Y 1-R 2agroup or carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, alkyl-S (=O) 2-alkyl, alkyl, cycloalkylalkyl, arylalkyl, cycloheteroalkylalkyl, alkylamino, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical, or carbocylic radical;
X 1cR 4ar 4or NR 6;
X 2cR 4aor N;
R 3for hydrogen, F, Cl, Br, I, C 1-4alkoxyl group, halo C 1-4alkyl or C 1-4alkyl;
Each R 4aand R 4be H or C independently 1-4alkyl;
R 6for H or C 1-4alkyl;
Each R 5be H independently, alkyl, thiazolinyl, alkynyl, alkoxyl group, haloalkyl, or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-, or-(CH 2) n-;
Each R 7be hydrogen independently, alkyl, alkylamino, carbocylic radical, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, and spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or heterocyclic radical;
Each R 8aand R 8be H or C independently 1-6alkyl;
Each t is 0,1 or 2 independently;
Each p is 1,2,3 or 4 independently;
Each n independently 0,1,2,3, or 4;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, alkyl-S (=O) 2-alkyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, and (HO-(CH 2) n)-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, halo C 1-4alkyl, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In some embodiments, R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 2-10heterocyclic radical C 1-6alkyl or C 3-10carbocylic radical;
Each R 8be H or C independently 1-6alkyl;
Wherein, described alkyl, alkyl-S (=O) 2-alkyl, carbocylic radical, heterocyclic radical, alkylamino, aryl, heteroaryl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, bridge bicyclic group, bridge is mixed bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, condensed-bicyclic base, with condense assorted bicyclic group, can independently by oxo (=O), F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
Other embodiment is:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical, or following subformula:
Wherein, each Z 1be N or CH independently;
Each Z 2be N or CH independently;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
In other embodiment, R 2for following subformula,
According to the present invention, the pyrazole derivatives shown in formula (I), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, wherein:
Each R 5be H, C independently 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, halo C 1-6alkyl, or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-4thiazolinyl, C 2-4alkynyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, halo C 1-4alkyl, C 5-12condensed-bicyclic base C 1-4alkyl, C 5-12condense assorted bicyclic group C 1-4alkyl, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12spiral shell bicyclic group C 1-4alkyl, C 5-12spiral shell is mixed bicyclic group C 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical C 1-4alkyl, C 3-10cycloalkyl C 1-4alkyl, C 5-12aryl C 1-4alkyl, C 5-12heteroaryl C 1-4alkyl, hydroxyl C 1-6alkyl, C 1-4alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8abe H independently, or C 1-4alkyl;
Wherein, described alkyl, alkylamino, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-, heterocyclic radical, condensed-bicyclic base, condenses assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-, and-(CH 2) n-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In some embodiments, each R 5be-Y independently 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 6-12aryl, C 1-9heteroaryl, C 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical; Or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe H independently, methyl or ethyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
In other embodiments, each R 7be following subformula independently:
According to pyrazole derivatives of the present invention, have such as formula the structural formula described in (II), or the steric isomer of compound described in formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl, C 1-4alkyl-S (=O) 2-C 1-4alkyl, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-4alkylamino, C 1-9heteroaryl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 2-10heterocyclic radical, or C 3-10carbocylic radical;
Wherein, Y 2be a key ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 5-10aryl, C 1-9heteroaryl, 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 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8be hydrogen independently, or C 1-6alkyl;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each n is 0,1,2,3 independently, or 4;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) 2-alkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, and (HO-(CH 2) n)-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In other embodiment, R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical, or following subformula:
Wherein, each Z 1be N independently, or CH;
Each Z 2be N independently, or CH;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkane
Oxygen base, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
In other embodiment, R 2for following subformula,
According to compound of the present invention, in some embodiments, R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, C 1-4thiazolinyl, C 1-4alkynyl, halo C 1-4alkyl, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, (HO-(CH 2) n)-N (R 8a)-or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
In other embodiments, R 7for following subformula:
On the one hand, the present invention is simultaneously containing comprising a kind of pharmaceutical composition, comprise a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, 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, at least one in assistant agent and vehicle.
In some embodiments, the present invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer simultaneously, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, be used for the treatment of atherosclerotic medicine, be used for the treatment of medicine or their combination of pulmonary fibrosis.
In some embodiments, the additional treatment agent mentioned in pharmaceutical composition of the present invention 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 invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.
In certain embodiments, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.Wherein said protein kinase is Abl, FLT-3, Jak, Aurora-A or Aurora-B.
In certain embodiments, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.Wherein said cell growth abnormity disease mainly proliferative disease.
Wherein, compound provided by the present invention and pharmaceutical composition can be used as protection, process, treatment or alleviate the purposes of medicine of patient's proliferative disease, described proliferative disease refers to acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), 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, lymphoblastoma, 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.
On the one hand, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, carry out the purposes for the preparation of the medicine of suppression or Function protein kinase activity in biological sample, wherein said purposes comprises use such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, contact with described biological sample.
In some of them embodiment, these compounds can be used as the inhibitor of protein kinase, and the protein kinase mentioned is tyrosine protein kinase or serine-threonine protein kinase enzyme.
In some embodiments, these compounds can be used as the inhibitor of tyrosine protein kinase, and the tyrosine protein kinase mentioned is FLT-3, Abl, Jak or their combination.
In some embodiments, these compounds can be used as the inhibitor of serine-threonine protein kinase enzyme, and the serine-threonine protein kinase enzyme mentioned is Aurora-A, Aurora-B or their combination.
On the other hand, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, for the preparation of the purposes of medicine protecting, process, treat or alleviate patient's proliferative disease.
Medicine containing the compounds of this invention has the purposes being used for the treatment of proliferative disease, particularly acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), 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, lymphoblastoma, 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 andJerry 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: hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O) 2-, haloalkyl, hydroxyalkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkoxy, cyano group, aryl, heteroaryl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxy alkoxy base or alkoxyalkyl 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) 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.
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 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 " 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, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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.TV structure and determining, heteroaryl can be monoradical or divalent group (that is, inferior heteroaryl).And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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 comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl, indyl (as 2-indyl), pseudoindoyl, isoindoline base, purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), tetralyl, benzopyrazoles base 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.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 be not limited to, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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).TV structure and determining, heterocyclic radical can be monoradical or divalent group (that is, sub-heterocyclic radical).
" 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, 2-indoline base, 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, six hydrogen-2H-[1, 4] dioxin [2, 3-c] pyrryl, quinolizinyl, thiomorpholine 1, 1-dioxide base, 2, 3, 3a, 7a-tetrahydrochysene-1H-pseudoindoyl, 1, 2, 3, 4-tetrahydroquinoline, isoindoline, with N-pyridyl urea.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl etc.Such as 1-picoline-2 (1H)-one, 6-methyl cyclohexane-2,4-dienone, (2S, 6R)-2,6-dimethylated morpholinyl 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, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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.And described in condense assorted bicyclic group can be substituted or non-substituted, wherein substituting group can be, but is not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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, 2-sulfo--5-azabicyclo [2.2.1] heptane base, 2-oxo-5-azabicyclo [2.2.1] heptane base, 2,5-diazabicylo [2.2.1] heptane base, 2-methyl-2,5-diazabicylo [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, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl 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, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl etc.
Term " bridge bicyclic group alkyl " represent alkyl group replace by one or more bridge bicyclic group group, wherein alkyl group and bridge bicyclic group group have implication as described in the present invention, such example comprises, but be not limited to dicyclo [2.2.1] heptane ylmethyl, 2-methyl-assorted two rings [2.2.1] heptane base ethyl, etc.
Term " bridge mix bicyclic group alkyl " represent alkyl group by one or more bridge mix bicyclic group group replace, wherein alkyl group and bridge bicyclic group group of mixing has implication as described in the present invention, such example comprises, but be not limited to 2-oxygen-5-azabicyclo [2.2.1] heptane base ethyl, 2-sulfo--5-azabicyclo [2.2.1] heptane base propyl group, 2,5-diazabicylo [2.2.1] heptane ylmethyl, 2-methyl-2,5-diazabicylo [2.2.1] heptane Ji Dingji etc.
Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, namely a C-C is sp triple bond, wherein alkynyl group can independently optionally replace by one or more substituting group described in the invention, concrete example comprises, but be not limited to, ethynyl (-C three CH), propargyl (-CH 2c tri-CH), etc.
Term " thiazolinyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and namely a C-C is sp 2double bond, wherein thiazolinyl group can independently optionally replace by one or more substituting group described in the invention, comprise the location that group has negation " just " or " E " " Z ", wherein concrete example comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2), etc.
Term " cycloalkylalkyl " represent alkyl group can replace by one or more group of naphthene base, wherein cycloalkyl and groups have implication as described in the present invention, such example comprises, but be not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc.
Term " cycloheteroalkylalkyl " represent alkyl group can replace by one or more heterocyclyl groups, wherein heterocyclic radical and alkyl group have implication as described in the present invention.
Term " arylalkyl " represent alkyl group replace by one or more aromatic yl group, wherein alkyl group and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to styroyl, phenmethyl, to methylphenylethyl, etc.
Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.
Term " alkylthio " comprises C 1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylthio is more rudimentary C 1-3alkylthio, such example comprises, but is not limited to methylthio group (CH 3s-), ethylmercapto group etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " cycloalkylalkyl " represent alkyl group can replace by one or more group of naphthene base, wherein cycloalkyl and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to cyclohexyl methyl, cyclopropylethyl etc.Described cycloalkyl can further by halogen, alkyl, and alkoxyl group and hydroxyl replaced.
Term " condensed-bicyclic base alkyl " represent alkyl group replace by one or more condensed-bicyclic base group, wherein alkyl group and condensed-bicyclic base group have implication as described in the present invention, and such example comprises, but is not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphtylethyl group, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl methyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthylpropyl, condensed-bicyclic [3.3.0] octyl methyl, condensed-bicyclic [3.1.0] hexyl ethyl etc.
Term " condense assorted bicyclic group alkyl " and represent alkyl group by one or more condense assorted bicyclic group group replace, wherein alkyl group and condense assorted bicyclic group group there is implication as described in the present invention, such example comprises, but be not limited to six hydrogen-furo [3,2-b] furans-2-base ethyl, six hydrogen-furo [3,2-b] furans-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-base ethyl, 7-azabicyclo [2.2.1] heptane-4-ylmethyl 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 described below, 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, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl etc.
Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring.Such as, as described above, 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, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, alkoxyl group, alkylamino, alkylthio, alkyl-S (=O) 2-, alkyl, thiazolinyl, or alkynyl etc.
Term " spiral shell bicyclic group alkyl " represent alkyl group replace by one or more spiral shell bicyclic group group, wherein alkyl and spiral shell bicyclic group group have implication as described in the present invention, such example comprises, but be not limited to spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl group, spiral shell [4.4] nonyl methyl, spiral shell [4.4] nonyl ethyl, 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
Term " spiral shell mix bicyclic group alkyl " represent alkyl group by one or more spiral shell mix bicyclic group group replace, wherein alkyl group and spiral shell bicyclic group group of mixing has implication as described in the present invention, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
As described in the present invention, substituent R is connected to by a key member ring systems that the ring at center is formed and represents substituent R and can replace in any desirable generation or any rational position on ring.Such as, formula arepresent any position that may be substituted on A ring or B ring all can be replaced by R, such as formula b, formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, substituting group (R) nbe connected to by a key member ring systems that the ring at center is formed to represent n substituent R and can replace any commutable position on ring.Such as, formula i represents any position that may be substituted on A ring or B ring and all can be replaced by n R.
As described in the invention, ring C has two tie points can be connected with molecule rest part, such as, shown in j, expression both can be E end also can be that E ' end is connected with the rest part of molecule, and namely the mode of connection at two ends can be exchanged.
As described in the present invention, attachment point can be connected with molecule rest part any attachable position on ring.Such as, formula k represents any position that may be connected on A ring or B ring and all can be used as the point of connection.
As described in the present invention, attachment point can be connected with molecule rest part any attachable position on ring, and the two ends simultaneously connected can exchange.Such as, formula m represents any position that may be connected on ring and all can be used as the point of connection, and the two ends of tie point can exchange simultaneously.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the whole text in this article " each ... with ... be independently ", " ... with ... be independently of one another " and " ... with ... be separately " can exchange; should be interpreted broadly, it both can refer in different group, did not affect mutually; also can represent in identical group between concrete option expressed between same-sign, did not affect mutually between concrete option expressed between same-sign.Such as, structural formula q and structural formula s each Z between the two 1concrete option mutually between unaffected, meanwhile, in same structure formula, such as formula q, the concrete option of multiple G is unaffected each other; Or such as formula s, multiple R 9concrete option mutually between unaffected.
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 Dictionaryof 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 are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are 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 " 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) containing hydroxyl or formula (II) compound can hydrolyzable esters 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) containing hydroxyl or formula (II) chemical combination object, 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-chloroperoxybenzoic 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 theA.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and ClinicalApplications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphatesand 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, 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.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, 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.
The description of the compounds of this invention
The invention provides a series of pyrazole compound and pharmacy acceptable salt thereof as kinases inhibitor in preparation treatment and the application in the medicine of protein kinase activity relative disease.Experimental study proves: pyrazole compound and pharmaceutical salts thereof play an important role with regulating in the kinase activities such as CDK8, CDK11 and HIPK4 of Kit, PDGF-α, PDGF-β, CSF1R, DDR1, Aurora A, Aurora B, JAK, Abl, FLT3 and/or CDK family of the protein kinase family of primary type and/or mutant form at therapeutic treatment.
The present invention proposes the pyrazole derivatives that a class is new, can effectively suppress or regulate related enzyme activity, and estimate that they can be used for preventing or treating the purposes of some kinase mediated disease or illness.
The present invention proposes a kind of such as formula the pyrazole derivatives shown in (I), or the steric isomer of compound shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Each R 1and R 1abe H independently, or C 1-4alkyl;
R 2for alkylamino, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical ,-Y 1-R 2agroup or carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, alkyl-S (=O) 2-alkyl, alkyl, cycloalkylalkyl, arylalkyl, cycloheteroalkylalkyl, alkylamino, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical, or carbocylic radical;
X 1cR 4ar 4or NR 6;
X 2cR 4aor N;
R 3for hydrogen, F, Cl, Br, I, C 1-4alkoxyl group, halo C 1-4alkyl or C 1-4alkyl;
Each R 4aand R 4be H or C independently 1-4alkyl;
R 6for H or C 1-4alkyl;
Each R 5be H independently, alkyl, thiazolinyl, alkynyl, alkoxyl group, haloalkyl, or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-, or-(CH 2) n-;
Each R 7be hydrogen independently, alkyl, alkylamino, carbocylic radical, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, and spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or heterocyclic radical;
Each R 8aand R 8be H or C independently 1-6alkyl;
Each t is 0,1 or 2 independently;
Each p is 1,2,3 or 4 independently;
Each n independently 0,1,2,3, or 4;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, alkyl-S (=O) 2-alkyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, and (HO-(CH 2) n)-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, halo C 1-4alkyl, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In some embodiments, R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 2-10heterocyclic radical C 1-6alkyl or C 3-10carbocylic radical;
Each R 8be H or C independently 1-6alkyl;
Wherein, described alkyl, alkyl-S (=O) 2-alkyl, carbocylic radical, heterocyclic radical, alkylamino, aryl, heteroaryl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, bridge bicyclic group, bridge is mixed bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, condensed-bicyclic base, with condense assorted bicyclic group, can independently by oxo (=O), F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
Some of them embodiment is:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical, or following subformula:
Wherein, each Z 1be N or CH independently;
Each Z 2be N or CH independently;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
In some embodiments, R 2for following subformula,
According to the present invention, pyrazole derivatives shown in formula (I), or the steric isomer of the pyrazole derivatives shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, wherein:
Each R 5be H, C independently 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, halo C 1-6alkyl, or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-4thiazolinyl, C 2-4alkynyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, halo C 1-4alkyl, C 5-12condensed-bicyclic base C 1-4alkyl, C 5-12condense assorted bicyclic group C 1-4alkyl, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12spiral shell bicyclic group C 1-4alkyl, C 5-12spiral shell is mixed bicyclic group C 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical C 1-4alkyl, C 3-10cycloalkyl C 1-4alkyl, C 5-12aryl C 1-4alkyl, C 5-12heteroaryl C 1-4alkyl, hydroxyl C 1-6alkyl, C 1-4alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8abe H independently, or C 1-4alkyl;
Wherein, described alkyl, alkylamino, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-, heterocyclic radical, condensed-bicyclic base, condenses assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-, and-(CH 2) n-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In some embodiments, each R 5be-Y independently 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 6-12aryl, C 1-9heteroaryl, C 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical; Or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe H independently, methyl or ethyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
In other embodiments, each R 7be following subformula independently:
According to pyrazole derivatives of the present invention, have such as formula the compound described in (II), or the steric isomer of compound described in formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl, C 1-4alkyl-S (=O) 2-C 1-4alkyl, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-4alkylamino, C 1-9heteroaryl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 2-10heterocyclic radical, or C 3-10carbocylic radical;
Wherein, Y 2be a key ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 5-10aryl, C 1-9heteroaryl, 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 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8be hydrogen independently, or C 1-6alkyl;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each n is 0,1,2,3 independently, or 4;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) 2-alkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, and (HO-(CH 2) n)-N (R 8a)-, can independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
In some embodiments, R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical, or following subformula:
Wherein, each Z 1be N independently, or CH;
Each Z 2be N independently, or CH;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
In other embodiments, R 2for following subformula,
According to compound of the present invention, in some embodiments, R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, C 1-4thiazolinyl, C 1-4alkynyl, halo C 1-4alkyl, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, (HO-(CH 2) n)-N (R 8a)-or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
In other embodiments, R 7for following subformula:
According to pyrazole derivatives of the present invention, comprise one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
On the one hand, the present invention is simultaneously containing comprising a kind of pharmaceutical composition, comprise a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
In some embodiments, pharmaceutical composition of the present invention, further comprises pharmaceutically acceptable carrier, vehicle, thinner, at least one in assistant agent and vehicle.
In some embodiments, the present invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer simultaneously, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, be used for the treatment of atherosclerotic medicine, be used for the treatment of medicine or their combination of pulmonary fibrosis.
In some embodiments, the additional treatment agent mentioned in pharmaceutical composition of the present invention 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 invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.
In certain embodiments, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.Wherein said protein kinase is Abl, FLT-3, Jak, Aurora-A or Aurora-B.
In certain embodiments, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, it can be used as the purposes of the medicine of the cell growth abnormity disease that arrestin kinases process LAN causes.Wherein said cell growth abnormity disease mainly proliferative disease.
Wherein, compound provided by the present invention and pharmaceutical composition can be used as protection, process, treatment or alleviate the purposes of medicine of patient's proliferative disease, described proliferative disease refers to acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), 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, lymphoblastoma, 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.
On the one hand, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, carry out the purposes for the preparation of the medicine of suppression or Function protein kinase activity in biological sample, wherein said purposes comprises use such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, contact with described biological sample.
In some of them embodiment, these compounds can be used as the inhibitor of protein kinase, and the protein kinase mentioned is tyrosine protein kinase or serine-threonine protein kinase enzyme.
In some embodiments, these compounds can be used as the inhibitor of tyrosine protein kinase, and the tyrosine protein kinase mentioned is FLT-3, Abl, Jak or their combination.
In some embodiments, these compounds can be used as the inhibitor of serine-threonine protein kinase enzyme, and the serine-threonine protein kinase enzyme mentioned is Aurora-A, Aurora-B or their combination.
On the other hand, the invention provides a kind of such as formula the pyrazole derivatives shown in (I) or (II) or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug, and comprise the pharmaceutical composition of above compound, for the preparation of the purposes of medicine protecting, process, treat or alleviate patient's proliferative disease.
Medicine containing the compounds of this invention has the purposes being used for the treatment of proliferative disease, particularly acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), 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, lymphoblastoma, 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 belongs to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) or formula (II) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I) or formula (II), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses 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 ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
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 formula (II), the compound listed by the present invention, or the compound of embodiment 1-11, 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 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, 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, wetting agent and suspension agent to manufacture by formula according to known technology.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 the disease of eye, 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.
Preparation can be prepared into for eye, pharmaceutically acceptable composition; 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, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to 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, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion made through acceptable thinner or solvent parenterally, 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 by 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, 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: WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO2004/035525, WO2005/030705, WO 2005/092899, 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: US 6, 268137, US5, 578, 716, US5, 919, 772, US 6, 054, 439, US 6, 184, 211, US 6, 020, 318, US 6, 066, 625, US 6, 506, 735, US6, 221, 849, US 6, 953, 783, US 11/393, 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.Cancer therapy more widely forum is shown in http:// www.nci.nih.gov/, the oncologic inventory of FAD accreditation is shown in http:// www.fda.gov/cder/cancer/druglist-rame.htm, 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 ofTherapeutics (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 ClinicalOncology, 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, abstract 3152), KRN-951 (Taguchi et al., 95th AACRMeeting, 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 ClinicalOncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract3025), MS-275 (Ryan et al., Proceedings of the American Association of CancerResearch, 2004, 45, abstract2452), FR-901228 (Piekarz et al., Proceedings of the American Society for ClinicalOncology, 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 ClinicalOncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of CancerResearch, 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.
The purposes of compound of the present invention and composition
The feature of pharmaceutical composition of the present invention comprises formula (I) or the compound shown in formula (II) or the compound listed by the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention compound amount can effectively detectably arrestin kinases as Abl, FLT-3, Jak, Aurora-A, or the activity of Aurora-B.Compound of the present invention using be applied to as antitumor drug treatment or reduce Abl, FLT-3, Jak, Aurora-A, or the deleterious effect of Aurora-B.
Compound of the present invention will be applied to, but never be limited to, and use the significant quantity of compound of the present invention or composition prevent patient's administration or treat patient's proliferative disease.Such disease comprises cancer, especially acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), metastatic carcinoma, atherosclerosis, and pulmonary fibrosis.
The treatment being applied to knurl is comprised proliferative disease by compound of the present invention, includes, but are not limited to acute myelocytic leukemia (AML) further, the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), 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, lymphoblastoma, 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.
Compound of the present invention also can be used for treatment eye disease such as corneal graft rejection, and the new vessel of eye is formed, and retinal neovascularazation comprises damage or metainfective new vessel is formed; Diabetic retinopathy; Retrolental fibroplasia, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention may be used for processing the situation relevant to diabetes as diabetic retinopathy and microangiopathy.Compound of the present invention is equally for the situation of cancer patients's volume of blood flow minimizing.Compound of the present invention reduces patient tumors transfer also has beneficial effect.
Compound of the present invention, except useful to human treatment, also can be applicable to veterinary treatment pet, the animal of introduced variety and the animal on farm, comprises Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and when salt etc., it also means single compound, salt etc.
Comprise the methods for the treatment of of compound of the present invention or composition administration, comprise the administration to patient's additional treatment agent (combination therapy) further, wherein additional treatment agent is selected from: chemotherapy, immunosuppressor, immunostimulant, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition are as single formulation, or the compound separated or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or different time administration.The situation of the latter, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carries out.
Additional treatment agent of the present invention refers to 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), brentuximabvedotin, 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.
The present invention comprises expression Abl, FLT-3, Jak, Aurora-A equally, or the cytostatic method of Aurora-B, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides and suppress Abl in biological sample, FLT-3, Jak, Aurora-A, or the method for Aurora-B kinase activity, this method comprises and compound of the present invention or composition being contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of vitro, include, but not limited to, cell cultures or cell extraction; From the examination of living tissue material that Mammals or its extract obtain; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly Abl, FLT-3, Jak, Aurora-A in biological sample, or Aurora-B kinase activity, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to, hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, has been used to overcome restenosis (shrinking again of vessel wall after injury).But patient uses stem or other implantable devices to have the risk of clot formation or platelet activation.These disadvantageous effects can stop by using the pharmaceutically acceptable composition precoating device comprising compound of the present invention or alleviate.
The general preparation method of suitable dressing and the dressing of implantable device at document US 6,099,562; US 5,886,026; With US 5,304, described by having in 121, dressing is that biocompatible polymeric material, as hydrogel polymer, gathers methyl two silicon ether, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester typically, and composition thereof.Dressing can optionally further cover by suitable dressing, as fluoro Simethicone, polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, carry out the feature of performance group compound Co ntrolled release.Another aspect of the present invention comprises the implantable device using compound of the present invention coating.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or provide " medicine storage institute " with polymkeric substance or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I) or formula (II).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 AldrichChemical 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.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 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 serial LC-MS of Agilent 6120 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 use of brief word below runs through the present invention:
Intermediate synthetic schemes 1
After compound 1 is oxidized to ring, by BrCH 2cH 2oH replaces open loop and generates compound 2, ring closure reaction occurs in the basic conditions and generates 3, be reduced further and generate 4a.
Reaction scheme 1
React generation 6 with compound 4 after compound 5 acidylate, through reduction generation 7,7 and 8 reacting generating compound 9,9 after reduction, react generation 10 with TCDI, generate product 11 with the salt substitution reaction of corresponding alkali or alkali further.
Reaction scheme 2
Compound 9, after reduction, reacts generation 12 with compound 13, generates product 11 further with the salt substitution reaction of corresponding alkali or alkali.
Wherein, R 2 'for condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, heterocyclic radical, or carbocylic radical; R 2a, Y 2, and R 7have and define as described herein.
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
(4aR, 7aR)-six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
Step 1:6-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 4dry.Pressure reducing and steaming solvent, the direct column chromatography for separation of residue (EA/PE (V/V)=1/3) obtains product (7.39g, 68.49%).
LC-MS:220(M+1).
Step 2:(4aR, 7aR)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles-6 (3H)-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.
(3R, 4R)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate (above walking crude product) is dissolved in dehydrated alcohol (80mL), add potassium hydroxide (1.54g, the aqueous solution (10mL) 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 (EA/PE (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 3:(4aR, 7aR)-six hydrogen-2H-[Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles
(4aR, 7aR)-tetrahydrochysene-2H-[1,4] dioxin [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.
Embodiment 2
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) thiocarbamide
Step 1:(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 2 DMF, 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] 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 water (20mL), dichloromethane extraction (150mL), anhydrous sodium sulphate (25g) dry organic layer, concentrated, column chromatography for separation (EA/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 2:(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) and extracts, wash with water (30mL) in residuum, anhydrous sodium sulfate drying (20g) organic layer, concentrated, obtain weak yellow liquid (0.60g, 71.69%).
LC-MS:333[M+23] +.
Step 3:4-(((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 4:(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 acetic acid (20mL) in residue, reflux 3 hours.Removal of solvent under reduced pressure, crosses post and carries out purifying, obtain product (1.10g, 54%).
LC-MS:371[M+1] +.
Step 5:3-(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
(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 6:8-(((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)-thioketones
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 (0.34g, 0.98mmol) with thio-carbonyldiimidazole (0.35g, 1.97mmol) be dissolved in DMAC (10mL) and be heated to 80 DEG C of stirrings 24 hours, it is complete that LC-MS shows raw material reaction, directly carries out next step reaction.
LC-MS:383[M+1] +.
Embodiment 3
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide
Step 1:(3,4-dinitrophenyl) synthesis of-(morpholinyl)-ketone
3,4-dinitrobenzoic acid (10.0g, 47.2mmol) and DMF (0.1mL) are dissolved in THF (100mL), then SOCl 2to be added drop-wise in mixed solution reflux 2.5 hours.Mixed solution is cooled to 0 DEG C, dripping triethylamine (10mL, 71.2mmol) keeps temperature to be longer than 20 minutes lower than 5 DEG C of times, and then dripping morpholine (7.2mL.82.1mmol) time is longer than 15 minutes, 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, dry, obtain yellow solid (11.95g, 90%).
The synthesis of step 2:4-(3,4-dinitrobenzyl)-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)-(morpholinyl)-ketone (11.91g, 42.35mmol), 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 by ethyl acetate (100mL), saturated NaHCO 3the aqueous solution (100mL) washes organic phase, ethyl acetate (3 × 50mL) aqueous phase extracted, merge organic phase, saturated common salt washing (50mL), drying, concentrates to obtain solid, carries out recrystallization with methyl alcohol (50mL), obtain product (10g, 89.3%).
The synthesis of step 3:4-(morpholinyl methyl)-phenyl-1,2-diamines
10%Pd/C (0.525g) and 4-(3 under the protection of nitrogen; 4-dinitrobenzyl)-morpholine (10.5g, 42.35mmol) dissolve in ethanol, 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 (CH 2cl 2/ CH 3oH (V/V)=20/1), obtain product (6.34g, 61%).
1H NMR(400MHz,d 6-DMSO):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).
The synthesis of step 4:4-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) morpholine
4-(morpholinyl methyl)-phenyl-1,2-diamines (2.3g, 11.1mmol), 4-nitro-1H-pyrazoles-3-formic acid (1.57g, 10mmol), EDCHCl (2.13g, 11.1mmol) and HOBt (1.5g, 11.1mmol) be dissolved in dry DMF (25mL), stirred overnight at room temperature.Removal of solvent under reduced pressure, adds Glacial acetic acid (40mL), is heated to backflow 3 hours, in removal of solvent under reduced pressure, crosses post and carries out purifying (CH 2cl 2/ CH 3oH (V/V)=20/1), then use methanol wash column (30mL), obtain solid (0.9g, 27%).
LC-MS:329[M+1] +,327[M-1] -.
Step 5:3-(5-(morpholinyl methyl)-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; 2.7mmol) be dissolved in DMF (30mL); add 10%Pd/C (88mg); hydrogen is replaced; stirring at room temperature is after 5 hours, and solids removed by filtration, uses methanol wash column solid; concentrated filtrate obtains brownish black solid, directly carries out next step reaction.Obtain product (0.84g, >100%).
Step 6:N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide
3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.596g, 2.0mmol) and N, N'-thiocarbonyldiimidazole (699mg, 3.92mmol) is dissolved in heated overnight at reflux in THF (8mL).Filtration obtains solid, carries out drying under reduced pressure, directly carries out next step reaction.
LC-MS:341.1[M+1] +.
Embodiment 4
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) thiocarbamide
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)-thioketones is dissolved in DMAC (10mL), add cyclopropylamine (2mL, 28.91mmol), be heated to 80 DEG C of reactions 24 hours.After removal of solvent under reduced pressure, residue is dissolved in methylene chloride/methanol ((V/V)=50mL/2mL), washing twice, and saturated sodium-chloride water solution is washed once (20mL), and anhydrous sodium sulphate (10g) is dry.Pressure reducing and steaming solvent, column chromatography purification (CH 2cl 2/cH 3oH (V/V)=10/1), obtain crude product, preparative chromatography purifying obtains sterling (107mg, 24.88%).
LC-MS:440[M+1] +.
1H NMR(400MHz,DMSO):δ13.16(s,1H),12.97(s,2H),11.33(brs,1H),8.96(s,1H),8.63(s,1H),7.49-7.53(m,1H),7.42-7.44(m,1H),7.13-7.21(m,1H),3.88(s,1H),3.75-3.77(m,3H),3.54-3.57(m,3H),3.16-3.18(d,1H),2.79-3.90(m,2H),2.58-2.59(m,1H),2.50(s,2H),1.06(s,2H),0.72(s,2H).
Embodiment 5
1,1-diethyl-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) thiocarbamide
Diethylamine (2mL is added in N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide reaction solution, 19.41mmol), 100 DEG C of reactions 24 hours are heated to.After removal of solvent under reduced pressure, residue is dissolved in methylene chloride/methanol ((V/V)=50mL/2mL), wash twice (2 × 20mL), saturated sodium-chloride water solution is washed once (30mL), and anhydrous sodium sulphate (10g) is dry.Pressure reducing and steaming solvent, column chromatography purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain crude product, preparative chromatography purifying obtains sterling (72mg, 16.17%), purity 99.21%.
LC-MS:456[M+1] +.
1H NMR(400MHz,DMSO):δ13.13(s,1H),13.02(s,2H),11.14(s,1H),8.92(s,1H),8.03(s,1H),7.50-7.55(m,1H),7.42-7.45(m,1H),7.15-7.22(m,1H),3.83-3.91(m,6H),3.75-3.79(m,2H),3.63-3.65(m,2H),3.16-3.18(m,1H),2.89(s,2H),2.57-2.61(m,2H),1.31-1.34(m,6H).
Embodiment 6
1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) thiocarbamide
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (0.316g, 0.93mmol) with cyclopropylamine (0.52mL, 7.4mmol) be dissolved in DMF (5mL), be heated to 100 degree of stirrings spend the night, mixed solution concentrates, and crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain white solid (0.06g, 16%).
LC-MS:398.1[M+1] +.
1H NMR(400MHz,DMSO):δ13.17(s,1H),12.97(s,1H),11.30(s,1H),8.95(s,1H),8.63(s,1H),7.50-7.54(t,J＝8.0Hz,1H),7.43-7.45(d,J＝8.4Hz,1H),7.14-7.22(m,1H),3.56-3.57(d,J＝4.8Hz,6H),2.78(s,1H),2.37(s,4H),1.05(s,2H),0.71(s,2H).
Embodiment 7
1,1-diethyl-3-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) thiocarbamide
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (316mg, 0.93mmol) with diethylamine (0.6mL, 7.4mmol) be dissolved in DMF (5mL), be heated to 100 degree of stirrings spend the night, mixed solution concentrates, and crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain white solid (0.16g, 42%).
LC-MS:414.1[M+1] +.
1H NMR(400MHz,d 6-DMSO):δ13.13(s,1H),13.03(s,1H),11.13-11.14(d,J＝5.2Hz,1H),8.92(s,1H),7.52-7.56(t,J＝8.4Hz,1H),7.43-7.46(d,J＝8.4Hz,1H),7.17-7.23(m,1H),3.87-3.88(d,J＝6.0Hz,4H),3.57(s,6H),2.38(s,4H),1.33(s,6H).
Embodiment 8
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) tetramethyleneimine-1-thioformamide
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (100mg, 0.29mmol) with tetramethyleneimine (0.24mL, 2.90mmol) be dissolved in DMAC (5mL), be heated to 100 DEG C of stirrings spend the night, mixed solution concentrates, and crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain light yellow solid (60mg, 50.10%).
LC-MS：[M+1] +＝412.3
1H NMR(400MHz,d 6-DMSO):δ13.16(s,1H),13.02(s,1H),10.91-10.97(d,J＝21.6Hz,1H),8.88(s,1H),7.56-7.60(t,J＝8.0Hz,1H),7.44-7.46(d,J＝8.4Hz,1H),7.16-7.23(m,1H),3.77(s,4H),3.57(s,6H),2.38(s,4H),1.99-2.03(d,J＝14.8Hz,4H).
Embodiment 9
1-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-3-isopropylthiourea
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (100mg, 0.29mmol) with tetramethyleneimine (0.24mL, 2.90mmol) be dissolved in DMAC (5mL), be heated to 100 DEG C of stirrings spend the night, mixed solution concentrates, and crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain light yellow solid (60mg, 50.10%).
1H NMR(400MHz,d 6-DMSO):δ13.18(s,1H),13.06(s,1H),10.96-11.01(d,J＝21.6Hz,1H),10.27((brs,1H)，8.89(s,1H),7.57-7.61(t,J＝8.0Hz,1H),7.44-7.46(d,J＝8.4Hz,1H),7.16-7.23(m,1H),4.35(s,1H),3.59(s,6H),2.38(s,4H),1.26(s,6H)
LC-MS：[M+1] +＝400.3
Embodiment 10
1-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-3-(pentane-3-base) thiocarbamide
N-(3-(5-(morpholinomethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (100mg, 0.29mmol) with 3-aminopentane (0.34mL, 2.90mmol) be dissolved in DMAC (5mL), be heated to 100 DEG C of stirrings spend the night, mixed solution concentrates, and crosses column purification (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain light yellow solid (20mg, 16.00%).
LC-MS：[M+1] +＝428.4
1H NMR(400MHz,d 6-DMSO):δ13.13(s,1H),13.03(s,1H),11.13-11.14(d,J＝5.2Hz,1H),8.92(s,1H),7.52-7.56(t,J＝8.4Hz,1H),7.43-7.46(d,J＝8.4Hz,1H),7.17-7.23(m,1H),6.96-6.98(m,1H),4.35-4.37(m,1H),3.87-3.88(d,J＝6.0Hz,4H),3.57(s,6H),2.38(s,4H),1.33(s,6H).
Embodiment 11
1-cyclopropyl-3-(3-(5-(octahydro pentamethylene [c] pyrroles is for methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) thiocarbamide
Step 1:(3,4-dinitrophenyl)-(octahydro pentamethylene [c] pyrryl)-ketone
DMF (0.1mL) solution of 3,4-dinitrobenzoic acid (15.0g, 70.75mmol) joins in THF (100mL), then 6.5ml SOCl 2be added drop-wise to reflux 2.5h, TLC in mixed solution to follow the tracks of, raw material disappears.Mixed solution is cooled to 0 DEG C, drip triethylamine (13mL, temperature 106.13mmol) is kept to be longer than 20min lower than 5 DEG C of times, then octahydro pentamethylene [c] pyrrole hydrochloride (15.5g is dripped, 84.90mmol) time is longer than 15min, now system separates out solid, and mixed solution slowly recovers stirred overnight at room temperature.Add 250mL frozen water in mixed solution, be cooled to 0 DEG C, with EA extraction, concentrated, obtain yellow solid, dry, obtain yellow solid.(20.1g,93.00％)。
LC-MS：[M+1] +＝306.2
Step 2:4-(3,4-dinitrobenzyl)-octahydro pentamethylene [c] pyrroles
NaBH under the protection of nitrogen 4(3.36g, 88.42mmol) be dispersed in THF (360mL), after being cooled to 0 DEG C, add boron trifluoride diethyl etherate (11.3mL, 88.42mmol) ,-(octahydro pentamethylene [c] pyrryl)-ketone (11.91g is then once added (3,4-dinitrophenyl), 42.11mmol), shift out cryostat, and slowly recover stirring at room temperature 2h.Carefully add methyl alcohol (100mL), heating mixed-liquor return 0.5h.Concentrated liquid, dissolves by ethyl acetate (100mL), saturated NaHCO 3solution (100mL) washes organic phase, extraction into ethyl acetate aqueous phase, merges organic phase, and saturated common salt is washed, dry, concentrates to obtain solid, carries out recrystallization, obtain yellow solid (10.0g, 66.30%) with methyl alcohol.
LC-MS：[M+1] +＝292.2
The synthesis of step 3:4-(octahydro pentamethylene [c] pyrrol ylmethyl)-phenyl-1,2-diamines
By 10%Pd/C (0.35g) and 4-(3,4-dinitrobenzyl)-octahydro pentamethylene [c] pyrroles (3.5g, 11.47mmol) dissolve in ethanol, mixed solution is cooled to 0 DEG C, be hydrogen by air displacement, recover stirred overnight at room temperature.Filter mixed liquor, concentrated filtrate, crosses post and carries out purifying (CH 2cl 2/ CH 3oH (V/V)=10/1), obtain black solid (859mg, 31.00%).
LC-MS：[M+1] +＝232.2
Step 4:4-((2-(4-nitro-1H-pyrazole-3-yl)-1H-benzo [d] imidazoles-5-base) methyl) octahydro pentamethylene [c] pyrroles
4-(octahydro pentamethylene [c] pyrrol ylmethyl)-phenyl-1,2-diamines (4.0g, 17.32mmol), 4-nitro-1H-pyrazoles-3-formic acid (2.47g, 17.32mmol), EDCHCl (4.98g, 19.05mmol) and HOBt (3.4g, 19.05mmol) be dissolved in dry DMF (25mL), stirred overnight at room temperature.Removal of solvent under reduced pressure, adds Glacial acetic acid (40mL), is heated to the 3h that refluxes, in removal of solvent under reduced pressure, cross post and carry out purifying, then use methanol wash column, namely the yellow solid being insoluble to methyl alcohol is product, obtains yellow solid (0.90g, 23.94%).
LC-MS:[M+1] +＝353.5
Step 4:3-(5-(octahydro pentamethylene [c] pyrrol ylmethyl)-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) octahydro pentamethylene [c] pyrroles (1g under nitrogen protection; 28.41mmol) be dissolved in dehydrated alcohol (20mL); add 10%Pd/C (0.1g); hydrogen is replaced; after stirring at room temperature 5h; solids removed by filtration; use methanol wash column solid; concentrated filtrate obtains brownish black solid (0.84g, 91.80%).
LC-MS：[M+1] +＝323.2
Step 6:N-(3-(5-(octahydro pentamethylene [c] pyrrol ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide
3-(5-(octahydro pentamethylene [c] pyrrol ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-amine (0.5g, 1.55mmol) with sulfo-carbon back diimidazole (0.53g, 1.64mmol) be dissolved in THF (10mL), reflux 16h.Mixed solution is cooled to room temperature, filters, and collects filter cake, washes with THF, dry, directly carries out next step reaction.Obtain pale solid (0.23g, 38.53%).
LC-MS：[M+1] +＝365.2
Step 7:1-cyclopropyl-3-(3-(5-(octahydro pentamethylene [c] pyrroles is for methyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base) thiocarbamide
N-(3-(5-(octahydro pentamethylene [c] pyrrol ylmethyl)-1H-benzo [d] imidazoles-2-base)-1H-pyrazoles-4-base)-1H-imidazoles-1-thioformamide (0.23g, 0.63mmol) with cyclopropylamine (252mg, 4.42mmol) be dissolved in DMF, be heated to 100 DEG C of reaction 16h.Mixed solution is concentrated after being cooled to room temperature, crosses column purification, obtains faint yellow solid (0.23g, 86.47%).
LC-MS：[M+1] +＝422.5
1H NMR(400MHz,d 6-DMSO):δ13.12(s,1H),12.86(s,1H),11.28(s,1H),8.87(s,1H),8.61(s,1H),7.48-7.50(t,J＝8.0Hz,1H),7.41-7.44(d,J＝8.4Hz,1H),7.15-7.24(m,1H),3.58-3.59(d,J＝4.8Hz,6H),2.78(s,1H),2.37(td,J＝8.0Hz,J＝8.6Hz,2H),2.37(d,J＝8.0Hz 4H),2.37(td,J＝8.8Hz,J＝8.0Hz,4H),1.05(s,2H).
Embodiment 12-40
The compound of embodiment 12-40 is prepared according to the synthetic method of embodiment 11 by selecting suitable starting raw material.
Embodiment 1
External Aurora-A and Aurora-B kinase inhibition test
Test-compound is formulated as 50 × concentration of highest response concentration with 100% methyl-sulphoxide (DMSO), draws in 100 μ L to 96 orifice plate one holes.Then hole-specifically carry out the concentration gradient dilution of 4 times with 100%DMSO, prepare 10 concentration.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 novel pyrazole compounds that a class has better arrestin kinase activity.

Claims (21)

1. a pyrazole derivatives, it is for such as formula the structure shown in (I), or such as formula the steric isomer of the structure shown in (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
Each R 1and R 1abe H or C independently 1-4alkyl;
R 2for alkylamino, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base, condenses assorted bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical ,-Y 1-R 2agroup or carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, alkyl-S (=O) 2-alkyl, alkyl, cycloalkylalkyl, arylalkyl, cycloheteroalkylalkyl, alkylamino, condensed-bicyclic base, condenses assorted bicyclic group, bridge bicyclic group, and bridge is mixed bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, aryl, heteroaryl, heterocyclic radical or carbocylic radical;
X 1cR 4ar 4or NR 6;
X 2cR 4aor N;
R 3for hydrogen, F, Cl, Br, I, C 1-4alkoxyl group, halo C 1-4alkyl or C 1-4alkyl;
Each R 4aand R 4be H or C independently 1-4alkyl;
R 6for H or C 1-4alkyl;
Each R 5be H independently, alkyl, thiazolinyl, alkynyl, alkoxyl group, haloalkyl or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-or-(CH 2) n-;
Each R 7be hydrogen independently, alkyl, alkylamino, carbocylic radical, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group, and condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, and spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyl substituted alkyl group, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or heterocyclic radical;
Each R 8aand R 8be H or C independently 1-6alkyl;
Each t is 0,1 or 2 independently;
Each p is 1,2,3 or 4 independently;
Each n is 0,1,2,3 or 4 independently;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, alkyl-S (=O) 2-alkyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyl substituted alkyl group, alkoxyl group and (HO-(CH 2) n)-N (R 8a)-, can independently by hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, halo C 1-4alkyl, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
2. compound according to claim 1, wherein:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-10carbocylic radical or-Y 1-R 2agroup;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 2-10heterocyclic radical C 1-6alkyl or C 3-10carbocylic radical;
Each R 8be H or C independently 1-6alkyl;
Wherein, described alkyl, alkyl-S (=O) 2-alkyl, carbocylic radical, heterocyclic radical, alkylamino, aryl, heteroaryl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, bridge bicyclic group, bridge is mixed bicyclic group, spiral shell bicyclic group, and spiral shell is mixed bicyclic group, condensed-bicyclic base and condense assorted bicyclic group, can independently by hydrogen, oxo (=O), F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
3. compound according to claim 2, wherein:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical or following subformula:
Wherein, each Z 1be N or CH independently;
Each Z 2be N or CH independently;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
4. compound according to claim 3, wherein:
R 2for following subformula,
5. compound according to claim 1, wherein:
Each R 5be H, C independently 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, halo C 1-6alkyl, or-Y 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-C (=S)-,-C (=O)-,-C (=O) O-,-S (=O) t-,-(CH 2) n-N (R 8a)-,-N (R 8a)-,-S (=O) tn (R 8a)-,-N (R 8a) C (=O)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-4thiazolinyl, C 2-4alkynyl, C 5-12bridge bicyclic group, C 5-12bridge is mixed bicyclic group, halo C 1-4alkyl, C 5-12condensed-bicyclic base C 1-4alkyl, C 5-12condense assorted bicyclic group C 1-4alkyl, C 5-12spiral shell bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12spiral shell bicyclic group C 1-4alkyl, C 5-12spiral shell is mixed bicyclic group C 1-4alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical C 1-4alkyl, C 3-10cycloalkyl C 1-4alkyl, C 5-12aryl C 1-4alkyl, C 5-12heteroaryl C 1-4alkyl, hydroxyl C 1-6alkyl, C 1-4alkoxyl group, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8abe H independently, or C 1-4alkyl;
Wherein, described alkyl, alkylamino, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-, heterocyclic radical, condensed-bicyclic base, condenses assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condenses assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group, (HO-(CH 2) n)-N (R 8a)-and-(CH 2) n-N (R 8a)-, can independently by hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
6. compound according to claim 5, wherein:
Each R 5be-Y independently 2-R 7group;
Wherein, each Y 2be a key independently ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
Each R 7be hydrogen independently, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 6-12aryl, C 1-9heteroaryl, C 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical; Or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe H independently, methyl or ethyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
7. compound according to claim 6, wherein:
Each R 7be following subformula independently:
8. pyrazole derivatives according to claim 1, have such as formula the structural formula described in (II), or the steric isomer of structural formula described in formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein:
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl, C 1-4alkyl-S (=O) 2-C 1-4alkyl, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, 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 6-10aryl, C 1-4alkylamino, C 1-9heteroaryl, C 3-10cycloalkyl C 1-4alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 2-10heterocyclic radical, or C 3-10carbocylic radical;
Wherein, Y 2be a key ,-O-,-(CH 2) n-N (R 8a)-, or-(CH 2) n-;
R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 5-10aryl, C 1-9heteroaryl, 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 3-10cycloalkyl, (HO-(CH 2) n)-N (R 8a)-or C 2-10heterocyclic radical;
Each R 8be hydrogen independently, or C 1-6alkyl;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each n is 0,1,2,3 independently, or 4;
Wherein, described alkyl, carbocylic radical, thiazolinyl, alkynyl, haloalkyl, alkyl-S (=O) 2-alkyl, bridge bicyclic group, bridge is mixed bicyclic group ,-(CH 2) n-,-(CH 2) n-N (R 8)-,-(CH 2) n-N (R 8a)-, heterocyclic radical, alkylamino, condensed-bicyclic base, condense assorted bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl, condense assorted bicyclic group alkyl, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group alkyl, spiral shell is mixed bicyclic group alkyl, cycloalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyl group and (HO-(CH 2) n)-N (R 8a)-, can independently by hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4monosubstituted or identical or different polysubstituted of alkynyl.
9. compound according to claim 8, wherein,
R 2for C 1-6alkylamino, C 5-12condensed-bicyclic base, C 5-12condense assorted bicyclic group, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical ,-Y 1-R 2agroup or C 3-10carbocylic radical;
Wherein, Y 1be a key ,-(CH 2) n-N (R 8)-,-N (R 8)-,-O-,-O-(CH 2) n-or-(CH 2) n-;
R 2afor H, C 1-6alkyl-S (=O) 2-C 1-6alkyl, C 1-6alkyl, C 1-6alkylamino, C 3-10carbocylic radical, or following subformula:
Wherein, each Z 1be N independently, or CH;
Each Z 2be N independently, or CH;
Each Z 3be-N (R independently 8)-, or-CH 2-;
Each E 1be a key independently ,-O-,-N (R 8)-,-SO 2-or-S-;
Each V 1be a key independently, or-(CH 2) n-;
Each T is-CH independently 2-(CH 2) n-, or-CH=CH-;
Each T 1and T 2be-N (R independently 8)-, or-CH 2-;
Each J 1be-O-independently, or-S-;
Each R 9be oxo (=O) independently, hydroxyl, amino, F, Cl, Br, I, cyano group, hydroxyalkyl, sulfydryl, nitro, carboxyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, C 1-4alkyl-S (=O) 2-, C 1-4alkyl, C 2-4thiazolinyl, or C 2-4alkynyl;
Each j is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4.
10. compound according to claim 9, wherein:
R 2for following subformula,
11. compounds according to claim 8, wherein,
R 7for hydrogen, C 1-4alkyl, C 1-4alkylamino, C 1-4thiazolinyl, C 1-4alkynyl, halo C 1-4alkyl, hydroxyl C 1-4alkyl, C 1-4alkoxyl group, C 3-10carbocylic radical, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, (HO-(CH 2) n)-N (R 8a)-or following subformula:
Wherein, each Q, Q 1, Q 2and Q 3be N or CH independently;
Each W and W 1be-CH independently 2-,-O-,-N (R 8a)-or-S-;
Each R 8abe hydrogen independently, or C 1-4alkyl;
Each q is 0,1,2,3 independently, or 4;
Each n is 0,1,2,3 independently, or 4;
Each m is 0,1,2,3 independently, or 4.
12. compounds according to claim 11, wherein, R 7for following subformula:
13. compounds according to claim 1, comprise one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, hydrate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
14. pharmaceutical compositions, comprise as arbitrary in claim 1-13 as described in compound.
15. pharmaceutical compositions according to claim 14, comprise pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
16. pharmaceutical compositions according to claim 14, wherein further comprise additional treatment agent, these additional treatment agent are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, is used for the treatment of atherosclerotic medicine, is used for the treatment of medicine or their combination of pulmonary fibrosis.
17. pharmaceutical compositions according to claim 14, 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.
The arbitrary described compound of 18. claim 1-13 or the arbitrary described pharmaceutical composition of claim 14-17, the purposes of the medicine of the cell growth abnormity disease caused as arrestin kinases process LAN.
19. purposes according to claim 18, wherein said protein kinase is Abl, FLT-3, Jak, Aurora-A or Aurora-B.
20. purposes according to claim 18, wherein said cell growth abnormity disease refers to proliferative disease.
21. purposes according to claim 18, wherein said proliferative disease refers to acute cell leukemia (AML), the chronic myelogenous leukemia (CML) of sudden change, acute lymphoblastic leukemia (ALL), colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, brain tumor, neck cancer, CNS 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, lymphoblastoma, 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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