CN103965199A - Aromatic heterocyclic compounds, pharmaceutical composition containing compounds and application of pharmaceutical composition - Google Patents
Aromatic heterocyclic compounds, pharmaceutical composition containing compounds and application of pharmaceutical composition Download PDFInfo
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- CN103965199A CN103965199A CN201410041929.9A CN201410041929A CN103965199A CN 103965199 A CN103965199 A CN 103965199A CN 201410041929 A CN201410041929 A CN 201410041929A CN 103965199 A CN103965199 A CN 103965199A
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- 0 CC(N1C=CC(c2cnc(*)c(N[N+]([O-])=O)c2)=C=C)=C(*)C=CC1=C Chemical compound CC(N1C=CC(c2cnc(*)c(N[N+]([O-])=O)c2)=C=C)=C(*)C=CC1=C 0.000 description 1
- XATVPNAFAYNECK-UHFFFAOYSA-N COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc[n]1nc2)cc1c2C#CCO Chemical compound COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc[n]1nc2)cc1c2C#CCO XATVPNAFAYNECK-UHFFFAOYSA-N 0.000 description 1
- JJRDGXZJOWUQHY-UHFFFAOYSA-N COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc[n]1nc2)cc1c2C#N Chemical compound COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc[n]1nc2)cc1c2C#N JJRDGXZJOWUQHY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention provides new aromatic heterocyclic compounds and applications of the aromatic heterocyclic compounds to the preparation of drugs for inhibiting or regulating the activity of a protein kinase in biological specimens. The invention further relates to pharmaceutical composition containing the compounds as well as an application and a method of the pharmaceutical composition for treating mammals, particularly human high-proliferation diseases.
Description
Invention field
The present invention relates to pharmaceutical field, be specifically related to a kind of heteroaromatic compounds, the composition and use thereof that comprises it and using method.Especially, compound of the present invention is for suppress or reconcile the compound of protein kinase activity in biological sample, can be used for protecting, process, treat or alleviating patient's proliferative disease.
Background of invention
Protein kinase (protein kinases) claims again protein phosphorylation enzyme (protein phosphakinase), be the enzyme of a class catalytic proteins phosphorylation reaction, it can be transferred to the γ-phosphoric acid on adenosine triphosphate (ATP) on the amino-acid residue of protein molecule.Up to the present, the protein kinase of having found approximately has 300 kinds of left and right, all has the catalytic structure district being made up of approximately 270 amino-acid residues of a homology in molecule.Wherein, receptor tyrosine kinase is the class in protein kinase, and it comprises again PI3K, mTOR etc.
Phosphoinositide 3-kinase (PI3 kinases or PI3K), as a family of lipid kinase, at many cellular processes, as the survival of cell, is bringing into play important regulating effect in breeding and differentiation.As the major influence factors in receptor tyrosine kinase and the conduction of G albumen-coupled receptor downstream, by producing phosphatide, PI3K will be transmitted in cell from the signal of all kinds of growth factors and the factor, activates Ser-ine-threonine protein kinase AKT(also referred to as protein kinase B (PKB)) and other downstream passages.Cancer suppressor gene or PTEN(homology Phosphoric acid esterase-tensin) be (" Small-molecule inhibitors of the PI3K signaling network. " the Future MedChem.2011 of most important reverse conditioning agent in PI3K signal path, 3 (5), 549-565).
Phosphoinositide 3-kinase (PI3K) path is to cause a tumorigenic common signal of interest Signal Transduction Pathways.The result that PI3K activates is to impel phosphatide-4, and 5-bisphosphate (PIP2) phosphorylation produces phosphatide-3,4,5-triphosphoric acid (PIP3).PIP3 can, by homology Phosphoric acid esterase-tensin (PTEN) dephosphorylation, stop PI3K signal transduction then.The PI3K of enrichment can activate such bars chain, first, impel phosphoinositide dependent kinases 1(PDK1) thr308 of phosphorylated protein silk-threonine kinase AKT, thereby activation AKT, afterwards, the AKT of phosphorylation activates Mammals rapamycin target protein, further guides the phosphorylation of other downstream molecules.
According to structure and character, PI3K can be divided three classes, and wherein, I class can be divided into again Ia and two kinds of hypotypes of Ib.II class PI3K is class macromolecule (170-210kDa) albumen, and the catalysis region of albumen can mediate calcium/fat bonding of classical Five Protein Kinase C Isoforms.III class PI3K, taking the Yeast protein by VSP34 genes encoding as representative, only phosphorylation PtdIns, impels and produces PtdIns (3) P; They are regarded as the attemperator (" Targeting PI3K signaling in cancer:opportunities, challenges and limitations. " Nature Review Cancer, 2009,9,550) of vesica transport.
Ia type PI3K(PI3K α, PI3K β, PI3K γ and PI3K δ) be to be respectively p110 α by the p110(of catalytic subunit, p110 β, p110 γ and p110 δ) and regulator subunit p85(is for example: p85 α, p85 β, p55 δ, p55 α and p50 α) dimer protein of composition.The p110 subunit with catalytic activity is used ATP phosphorylation Ptdlns, PtdIns4P and PtdIns (4,5) P2.The discovery of PI3K catalytic subunit α-subtype gene (PIK3CA), has confirmed the vital role of Ia type PI3K in cancer.This gene is encoded by p110 α, usually in human tumor, undergos mutation and increases, for example ovarian cancer (Campbell et al, Cancer Res2004,64,7678-7681; Levine et al., Clin Cancer Res2005,11,2875-2878; Wang et al., Hum Mutat2005,25,322; Lee et al., Gynecol Oncol2005,97,26-34), cervical cancer, breast cancer (Bachman, et al.Cancer Biol Ther2004,3,772-775; Levine, et al., supra; Li et al., Breast Cancer Res Treat2006,96,91-95; Saal et al., Cancer Res2005,65,2554-2559; Samuels and Velculescu, Cell Cycle2004,3,1221-1224), colorectal cancer (Samuels, et al.Science2004,304,554; Velho et al.Eur J Cancer2005,41,1649-1654), carcinoma of endometrium (Oda et al.Cancer Res.2005,65,10669-10673), cancer of the stomach (Byun et al., M J Cancer2003,104,318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene2005,24,1477-1480), liver cancer (Lee et al., id), minicell and nonsmall-cell lung cancer (Tang et al., Lung Cancer2006, Jl, 181-191; Massion et al.; Am J Respir Crit Care Meaf2004; 170; 1088-1094), thyroid carcinoma (Wu et al, J Clin Endocrinol Met α b2005; 90; 4688-4693), acute myelocytic leukemia (AML) (Sujobert et al., Blood1997; 106; 1063-1066), chronic myelocytic leukemia (CML) (Hickey and Cotter J BiolChem2006,281; 2441-2450); and glioblastoma multiforme (Hartmann et al.Acta Neurop α thol (Berl) 2005,109,639-642; Samuels et al., supra).
MTOR is the silk-threonine kinase of high conservative, has lipid kinase activity, is one of influence factor of PI3K/AKT path.There are two kinds of distinct mixtures in mTOR, mTORC1 and mTORC2, and by regulating nutrition supply and cellular energy level, bring into play its vital role in cell proliferation.The downstream targets of mTORC1 is ribosomal protein S6K 1 and eukaryotic translation initiation factor 4E Binding Protein 1, both albumen is synthesized and has important effect (" Present and future of PI3K pathway inhibition in cancer:perspectives andlimitations. " Current Med.Chem.2011,18,2647-2685).
MTOR signal conducts imbalance and brings out the research that the conclusion of cancer comes from pharmacology interference mTOR, and the medicine of research comprises rapamycin, and its homologue has temsirolimus (CCI-779) and everolimus (RAD001).Rapamycin is mTOR inhibitors, and the induction G1 phase blocks and apoptosis.Rapamycin and FK-Binding Protein 1 2(FKBP-12) formation of mixture, be considered to relevant to rapamycin growth-inhibiting mechanism.These mixture specific bindings mTOR, suppresses its activity, stops protein translation and Growth of Cells.The cytosis of mTOR inhibitors also shows in the cell of the PTEN that contains the property followed inactivation.Therefore, the antitumour activity of rapamycin obtains approval, and a series of rapamycin homologue, such as temsirolimus and everolimus, is also used for the treatment of the cancer of some types by U.S. food and drugs administration approved.
Just because of PI3K and mTOR play an important role at bioprocess and disease stage; research and develop these kinase whose inhibitor and be very (" Phosphatidylinositol3-kinase isoforms as a novel drug targets. " Current Drug Targets of Worth Expecting; 2011; 12,1056-1081; " Progress in the preclinical discovery and clinical development of class I and dual class I/IVphosphoinositide3-kinase (PI3K) inhibitors. " Current Med Chem2011,18,2686-2714).
Abstract of invention
Below only summarize aspects more of the present invention, be not limited to this.These aspects and other parts have more complete explanation in the back.All reference in this specification sheets are incorporated in this by entirety.When the disclosure of the specification and citing document are when variant, be as the criterion with the disclosure of the specification.
The invention provides a class new compound, can be used for suppressing, control and/or reconcile PI3K and/or mTOR, also can be used for treating human pcna disease, such as cancer.The present invention also provides the method for this compounds of preparation, the method for the treatment of human pcna disease and the pharmaceutical composition that contains this compounds.
On the one hand, the present invention relates to a kind of compound, it is the steric isomer of compound shown in the compound of structure shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Wherein: each Y, R
1, Z, W
1, W
2and W
3there is definition as described in the present invention.
In some embodiments, each W
1, W
2and W
3be N or CR independently
c;
Z is D, CN, N
3or
X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
Y is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
R
1for H, D, Cl, OR
a, NR
ar
b, C
1-6aliphatics or C
3-6cycloalkyl, wherein, described C
1-6aliphatics and C
3-6cycloalkyl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OR
a, SR
aor NR
ar
b;
Each R
aand R
bbe H independently, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprises 1,2,3 or 4 and is independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, C
6-10aryl-C
1-4alkylidene group, (5-10 former molecular heteroaryl)-C
1-4alkylidene group, or R
a, R
btogether with the nitrogen-atoms being connected with them, optionally form replace or non-substituted 3-8 former molecular heterocycle, wherein, described substituting group is not substituted or independently of one another by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkoxyl group or C
1-6alkylamino;
Each R
cbe H independently, D, F, Cl, Br, I, N
3, CN, OH, NH
2, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl group or C
1-6alkylamino.
At other embodiment, W
1for N or CR
c; Each W
2and W
3be CR independently
c.
In other embodiment, Z is CN, N
3or
In other embodiment, X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group or C
3-6heterocyclic radical-C
1-4alkylidene group, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group and C
3-6heterocyclic radical-C
1-4alkylidene group is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4thiazolinyl or C
2-4alkynyl.
In other embodiment, Y is C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4alkynyl, C
6-10aryl or 5-10 former molecular heteroaryl.
At other embodiment, R
1for H, D, Cl, CH
3, CH
2cH
3, CF
3, CH
2cF
3, OCH
3or OCH
2cH
3.
In other embodiment, each R
cbe H independently, D, F, Cl, N
3, CN, NH
2, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl or C
3-6heterocyclic radical, wherein, described C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl and C
3-6heterocyclic radical is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, OH, NH
2, C
1-3alkyl, C
3-6cycloalkyl or C
1-3haloalkyl.
On the other hand, the present invention relates to a kind of pharmaceutical composition, the compound that it comprises the above-mentioned any one of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, or vehicle, or their combination.
In some embodiments, pharmaceutical composition of the present invention, further comprises additional treatment agent, described additional treatment agent is selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, or be used for the treatment of the medicine of pulmonary fibrosis or their combination.
In other embodiment, pharmaceutical composition of the present invention, wherein related 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 (interferonalfa), 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), bosutinib (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), many Weis are for Buddhist nun (dovitinib), Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, Mo Tesaini (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, Aura handkerchief Buddhist nun (olaparib), pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, Telatinib (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 difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), or Herceptin (trastuzumab), or their combination.
On the other hand, can be with the compounds of this invention or pharmaceutical composition of the present invention for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, head and neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to come for the preparation of the purposes that suppresses or regulate the medicine of protein kinase activity in biological sample with the compounds of this invention or pharmaceutical composition of the present invention, described purposes comprises use the compounds of this invention or pharmaceutical composition contacts with described biological sample.
In some embodiments, protein kinase of the present invention is receptor tyrosine kinase.
In other embodiment, receptor tyrosine kinase of the present invention is phosphoinositide 3-kinase (PI3 kinases or PI3K) and/or mTOR.
In some embodiments, the present invention relates to the method for PI3K of inhibition or mTOR a kind of, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described kinases.In some embodiments, the present invention relates to a kind of method of PI3K of inhibition or mTOR signal response, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.Other embodiment is in cell or multicellular organisms, to suppress the activity of PI3K or mTOR signal response.
According to method of the present invention, the method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to described multicellular organisms.In some embodiments, described multicellular organisms refers to Mammals.In other embodiment, described multicellular organisms refers to the mankind.In some embodiments, the method for the invention further comprises additional treatment agent and contacts with described kinases.
On the other hand, the present invention relates to a kind of method that suppresses cell-proliferation activity, described method comprises the effective therapeutic dose and the cells contacting that use the compounds of this invention or its pharmaceutical composition can suppress propagation.In some embodiments, the method for the invention further comprises additional treatment agent and cells contacting.
In some embodiments, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, effective therapeutic dose that described method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
In some embodiments, the present invention relates to a kind of method that suppresses patient tumors growth, effective therapeutic dose that described method comprises use the compounds of this invention or its pharmaceutical composition carries out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) comprises.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.
Circumstantial letter of the present invention
Definition and general terms
Describe now certain embodiments of the present invention in detail, the example is illustrated by the structural formula of enclosing and chemical formula.The invention is intended to contain all substitute, amendment and equivalent technical solutions, they include as the scope of the invention that defines of claim in.Those skilled in the art will appreciate that the similar or method that is equal to many and described herein and material can be used in puts into practice the present invention.The present invention is never limited to method as herein described and material.In one or more different from the application or conflicting situations of document, patent and the analogous material of institute's combination (include but not limited to defined term, term application, described technology, etc.), be as the criterion with the application.
Should further recognize that some feature of the present invention for clearly visible, is described, but also can in single embodiment, provides with array configuration in multiple independently embodiments.Otherwise various features of the present invention for for purpose of brevity, are described in single embodiment, but also can provide separately or with applicable arbitrarily sub-portfolio.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with those skilled in the art of the invention's common understanding.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, should apply the following definition that uses to obtain herein.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can be with reference to " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, and " March ' s Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.
Except as otherwise noted or in context, have an obvious conflict, the article " ", " one (kind) " and " described " that use are herein intended to comprise " at least one " or " one or more ".Therefore these articles that, use herein refer to the article of one or more than one (being at least one) object.For example, " component " refers to one or more components, may have more than one component to be taken into account in the embodiment of described embodiment and adopt or use.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, for example, also refer to primate (for example mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
Term " comprises " for open language, comprises the content that the present invention is specified, but does not get rid of otherwise content.
" steric isomer " refers to have identical chemical constitution, but the spatially different compound of arrangement mode of atom or group.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
" chirality " be have can not overlapping character with its mirror image molecule, and " achirality " refer to can be overlapping with its mirror image molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
" diastereomer " refers to the not steric isomer of mirror image each other of two or more chiral centres and its molecule.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture can operate as electrophoresis and chromatogram by high resolution analysis, and for example HPLC separates.
Stereochemistry definition used in the present invention and rule are generally followed S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of OrganicCompounds ", John Wiley & Sons, Inc., New York, 1994.
Many organic compound exist with optical activity form, and they have the ability that the plane of plane polarized light is rotated.Describing when optically active compound, represent the absolute configuration of molecule or mulitiple chiral centers individual about one with prefix D and L or R and S.Prefix d and l or (+) and (-) are the symbols that is used to specify plane polarized light rotation due to compound, and wherein (-) or l represent that compound is left-handed.Prefix is that the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when there is no stereoselectivity or stereospecificity in chemical reaction or process time, can occur this situation.
Come into the open any asymmetric atom (for example, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, for example (R)-, (S)-or (R, S)-configuration form exist.In certain embodiments, each asymmetric atom (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can be with one in possible isomer or their mixture, and the form of for example racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use the preparation of chiral synthon or chiral reagent, or use routine techniques to split.If compound contains a two key, substituting group may be E or Z configuration; If contain dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis (cis) or trans (trans) configuration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, and diastereomer, for example, by chromatography and/or Steppecd crystallization.
Can the racemic modification of any gained end product or intermediate be split into optical antipode by the familiar method of those skilled in the art by known method, as, by its diastereoisomeric salt obtaining is separated.Racemic product also can separate by chiral chromatography, as, the high performance liquid chromatography (HPLC) of use chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, for example, can be with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2
nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agentsand Optical Resolutions is (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN1972) p.268; ChiralSeparation Techniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer that low energy barrier (low energy barrier) transforms mutually that passes through with different-energy.If tautomerism is possible (as in solution), can reach the chemical equilibrium of tautomer.For example, proton tautomerism body (protontautomer) (also referred to as prototropy tautomer (prototropic tautomer)) comprises the mutual conversion of being undertaken by proton shifting, as keto-enol isomerization and the isomerization of imines-enamine.Valence tautomerism body (valence tautomer) comprises the mutual conversion of being undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is pentane-2, the change of 4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Tautomeric another example is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
" oxynitride " used in the present invention refers in the time that compound contains several amine functional group, can or be greater than the nitrogen-atoms oxidation formation N-oxide compound of 1 by 1.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 example, as hydrogen peroxide or peracid (for example peroxycarboxylic acid) process corresponding amine form N-oxide compound (referring to Advanced Organic Chemistry, WileyInterscience, the 4th edition, Jerry March, pages).Especially, N-oxide compound can, with the method preparation (Syn.Comm.1977,7,509-514) of L.W.Deady, wherein for example at inert solvent, for example, in methylene dichloride, make amine compound react with m-chlorine peroxybenzoic acid (MCPBA).
" solvate " of the present invention refers to the associated complex that one or more solvent molecules and compound of the present invention form.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water forms.
" meta-bolites " refers to the product that concrete compound or its salt obtains by metabolism in vivo.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can characterize by the method that adopts test as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.
" 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 is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. records.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group 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 the additive method recorded on books document as ion exchange method.Other pharmacy acceptable salts comprise adipate, 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 obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The present invention also intends the quaternary ammonium salt that the compound of the group of having conceived any comprised N forms.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C
1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C
1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be 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.
Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Term " optionally ", " optional " or " optionally " refer to subsequently described event or situation can but may not occur, and this description comprises the situation that this event or situation wherein occur, and the situation of this event or situation does not wherein occur, in the present invention, R
a, R
btogether with the nitrogen-atoms being connected with them, optionally form 3-8 former molecular heterocycle that replace or non-substituted, the meaning refers to R
a, R
btogether with the nitrogen-atoms being connected with them, can form 3-8 former molecular heterocycle, also can not form heterocycle, and be other structures well known to those skilled in the art, as N-R
a-R
bor R
a-N-R
bdeng.Generally speaking, term " optionally ", no matter whether be positioned at term " replacement " before, all represents that the one or more hydrogen atoms in given structure are replaced 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.When one or more substituting group that in given structural formula, not only position can be selected from concrete group replaces, substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to D, F, Cl, Br, CN, N
3, NH
2, OH, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl, or 5-10 former molecular heteroaryl, wherein, each R
aand R
bthere is definition as described in the present invention.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different groups, between same-sign, between expressed concrete option, did not affect mutually, also can be illustrated in identical group, between same-sign, between expressed concrete option, not affect mutually.
At the each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, the present invention includes each sub-combinations thereof independently of each member of these radical species and scope.For example, term " C
1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C
3alkyl, C
4alkyl, C
5alkyl and C
6alkyl.
At each several part of the present invention, connection substituting group is described.In the time that this structure clearly needs linking group, the Ma Kushi variable cited for this group is interpreted as linking group.For example, if this structure needs linking group and enumerated " alkyl " or " aryl " for the Ma Kushi group definition of this variable, should be appreciated that, should " alkyl " or " aryl " represent respectively the alkylidene group or the arylene group that connect.
Term " alkyl " or " alkyl group " that the present invention uses, represent to contain 1-20 carbon atom, the univalent hydrocarbyl group of saturated straight chain or side chain, and wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replaces.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom; In other embodiment, alkyl group contains 1-6 carbon atom; In other embodiment, alkyl group contains 1-4 carbon atom; Also in some embodiments, alkyl group contains 1-3 carbon atom.In other embodiment, alkyl group is containing 1-2 carbon atom.
The example of alkyl group 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, i-propyl ,-CH (CH
3)
2), normal-butyl (n-Bu, n-butyl ,-CH
2cH
2cH
2cH
3), isobutyl-(i-Bu, i-butyl ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu, s-butyl ,-CH (CH
3) CH
2cH
3), the tertiary butyl (t-Bu, t-butyl ,-C (CH
3)
3), n-pentyl (n-pentyl ,-CH
2cH
2cH
2cH
2cH
3), 2-amyl group (CH (CH
3) CH
2cH
2cH
3), 3-amyl group (CH (CH
2cH
3)
2), 2-methyl-2-butyl (C (CH
3)
2cH
2cH
3), 3-methyl-2-butyl (CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (CH
2cH
2cH (CH
3)
2), 2-methyl-1-butene base (CH
2cH (CH
3) CH
2cH
3), n-hexyl (CH
2cH
2cH
2cH
2cH
2cH
3), 2-hexyl (CH (CH
3) CH
2cH
2cH
2cH
3), 3-hexyl (CH (CH
2cH
3) (CH
2cH
2cH
3)), 2-methyl-2-amyl group (C (CH
3)
2cH
2cH
2cH
3), 3-methyl-2-amyl group (CH (CH
3) CH (CH
3) CH
2cH
3), 4-methyl-2-amyl group (CH (CH
3) CH
2cH (CH
3)
2), 3-methyl-3-amyl group (C (CH
3) (CH
2cH
3)
2), 2-methyl-3-amyl group (CH (CH
2cH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (C (CH
3)
2cH (CH
3)
2), 3,3-dimethyl-2-butyl (CH (CH
3) C (CH
3)
3), n-heptyl, n-octyl, etc.
Term " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
Term " alkylidene group " represents to remove from the alkane of straight or branched the saturated bivalent hydrocarbon radical group that two hydrogen atoms obtain.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom.In some embodiments, alkylidene group contains 1-6 carbon atom; In other embodiments, alkylidene group contains 1-4 carbon atom; In other embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (CH
2-), ethylidene (CH
2cH
2-), isopropylidene (CH (CH
3) CH
2-) etc.
Term " thiazolinyl " represents the straight or branched monovalence alkyl that contains 2-12 carbon atom, wherein has a unsaturated site at least, has a carbon-to-carbon sp
2two keys, wherein, described alkenyl group can optionally be replaced by one or more substituting groups described in the invention, and it comprises the location of " cis " and " tans ", or the location of " E " and " Z ".In some embodiments, alkenyl group comprises 2-8 carbon atom; In other embodiments, alkenyl group comprises 2-6 carbon atom; In other embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to vinyl (CH=CH
2), allyl group (CH
2cH=CH
2) etc.
Term " alkynyl " represents the straight or branched monovalence alkyl that contains 2-12 carbon atom, wherein has a unsaturated site at least, have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally be replaced by one or more substituting groups described in the invention.In some embodiments, alkynyl group comprises 2-8 carbon atom; In other embodiments, alkynyl group comprises 2-6 carbon atom; In other embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to ethynyl (C ≡ CH), propargyl (CH
2c ≡ CH), 1-proyl (C ≡ C-CH
3) etc.
Term " aliphatics " or " aliphatic group ", represent straight chain (non-side chain) or side chain, substituted or non-substituted group complete saturated or that contain one or more degree of unsaturation hydrocarbon chains.Unless otherwise detailed instructions, aliphatic group is containing 1-20 carbon atom.In some embodiments, aliphatic group is containing 1-10 carbon atom; In other embodiment, aliphatic group is containing 1-8 carbon atom; In other embodiment, aliphatic group is containing 1-6 carbon atom; In other embodiment, aliphatic group is containing 1-4 carbon atom; In other embodiment, aliphatic group is containing 1-3 carbon atom; In other embodiment, aliphatic group is containing 1-2 carbon atom.Aliphatic group includes, but not limited to straight or branched, substituted or non-substituted alkyl, thiazolinyl, or alkynyl.For example, C
1-6aliphatic group, comprises non-side chain or side chain, the C of non-substituted or suitable replacement
1-6alkyl, C
2-6thiazolinyl, or C
2-6alkynyl.Such example comprises, but is not limited to, methyl, and ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, ethene, propylene, butylene, 2-butylene, acetylene, propine, butine, 2-butyne, etc.Described aliphatic group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and thiazolinyl or alkoxy base are replaced by one or more halogen atom, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom.Some of them embodiment is that alkoxy base contains 1-10 carbon atom; Other embodiment is that alkoxy base contains 1-8 carbon atom; Other embodiment is that alkoxy base contains 1-6 carbon atom; Other embodiment is that alkoxy base contains 1-4 carbon atom; Other embodiment is that alkoxy base contains 1-3 carbon atom.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH
3), oxyethyl group (EtO ,-OCH
2cH
3), 1-propoxy-(n-PrO, n-propoxy-,-OCH
2cH
2cH
3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH
3)
2), 1-butoxy (n-BuO, n-butoxy ,-OCH
2cH
2cH
2cH
3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH
2cH (CH
3)
2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH
3) CH
2cH
3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH
3)
3), 1-pentyloxy (n-pentyloxy ,-OCH
2cH
2cH
2cH
2cH
3), 2-pentyloxy (OCH (CH
3) CH
2cH
2cH
3), 3-pentyloxy (OCH (CH
2cH
3)
2), 2-methyl-2-butoxy (OC (CH
3)
2cH
2cH
3), 3-methyl-2-butoxy (OCH (CH
3) CH (CH
3)
2), 3-methyl-l-butoxy (OCH
2cH
2cH (CH
3)
2), 2-methyl-l-butoxy (OCH
2cH (CH
3) CH
2cH
3), etc.Described alkoxy base can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " alkylthio " comprises C
1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and some of them embodiment is that alkylthio is more rudimentary C
1-3alkylthio, such example comprises, but is not limited to methylthio group (CH
3s-).
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C
1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms; Other embodiment is that alkylamino is one or two C
1-3alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.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 " virtue is amino " represents that amino group is replaced by one or two aromatic yl group, and such example comprises, but is not limited to N-phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can further be substituted.
Term " aminoalkyl group " comprises the C being replaced by one or more amino
1-10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced
1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " carbocylic radical " or " carbocyclic ring " expression contain 3-12 carbon atom, nonaromatic saturated or the undersaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence, and this member ring systems has one or more tie points to be connected with the rest part of molecule.Carbon bicyclic group comprises spiral shell carbon bicyclic group and condense carbon bicyclic group, and suitable carbocylic radical group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group further comprises, 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, etc.
Term " cycloalkyl " expression contains 3-12 carbon atom, unit price or multivalence, saturated monocycle, dicyclo or three-ring system, and this member ring systems has one or more tie points to be connected with the rest part of molecule.In some embodiments, cycloalkyl contains 3-12 carbon atom; In other embodiments, cycloalkyl contains 3-8 carbon atom; In other embodiment, cycloalkyl contains 3-6 carbon atom.Described group of naphthene base can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " cycloalkyl alkylidene group " represents that alkyl group can be replaced by one or more group of naphthene base, and wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and group of naphthene base is connected to C
1-6alkyl group on.Other embodiment is that group of naphthene base is connected to C
1-4alkyl group on.Other embodiment is that group of naphthene base is connected to C
1-3alkyl group on.Other embodiment is that group of naphthene base is connected to C
1-2alkyl group on.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.Described cycloalkyl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo or three-ring system, wherein the upper one or more atoms of ring are independent is optionally replaced by heteroatoms, ring can be completely saturated or comprise one or more degrees of unsaturation, but is never the fragrant same clan, has one or more tie points to be connected to other molecules and gets on.One or more ring hydrogen atoms can not be substituted independently or replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical " or " heterocycle " group be 3-7 former molecular monocycle (2-6 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2group, in the time that described ring is three former molecular rings, wherein only has a heteroatoms), other embodiment is, 3-6 former molecular monocycle (2-5 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2group, in the time that described ring is three former molecular rings, wherein only have a heteroatoms), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2group).
Heterocyclic radical can be carbon back or heteroatoms base.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, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, nitrogen heterocyclic heptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl.The example of heterocyclic group also comprises, encircles pyrimidine dione base and 1,1-dioxy thio-morpholinyl that two carbon atoms are replaced by oxygen (=O).Described heterocyclic radical group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heterocyclic radical alkylidene group " represents that alkyl group can be replaced by one or more heterocyclic radical groups, and wherein alkyl and heterocyclic radical group have implication as described in the present invention.Some of them embodiment is, heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and heterocyclic radical group is connected to C
1-6alkyl group on.Other embodiment is that heterocyclic radical group is connected to C
1-4alkyl group on.Such example comprises, but is not limited to 2-tetramethyleneimine ethyl etc.Described heterocyclic radical alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heteroatoms " refers to O, S, N, P and Si, comprises the form of N, S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, is for example connected with Sauerstoffatom, forms oh group.
Term " D " or "
2h " represent single D atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (CDH
2), two D atoms are connected with a methyl, form two-deuterated methyl (CD
2h), and three D atoms are connected with a methyl, form three-deuterated methyl (CD
3).
Term " azido-" or " N
3" a nitrine structure of expression.This group can be connected with other groups, for example, can be connected to form triazonmethane (MeN with a methyl
3), or be connected to form phenylazide (PhN with a phenyl
3).
Term " aryl " represents to contain 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more tie points to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use.The example of aromatic yl group can comprise phenyl, naphthyl and anthryl.Described aromatic yl group can independently optionally be replaced by one or more substituting groups described in the invention.
Term " aryl alkylene " represents that alkyl group can be replaced by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, some of them embodiment is, aryl alkylene group refers to " more rudimentary aryl alkylene " group, and aromatic yl group is connected to C
1-6alkyl group on; Other embodiment is that aryl alkylene group refers to containing C
1-4" the benzene alkylene " of alkyl; Other embodiment is that aryl alkylene group refers to that aromatic yl group is connected to C
1-3alkyl group on; Other embodiment is that aryl alkylene group refers to that aromatic yl group is connected to C
1-2alkyl group on.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Described aryl alkylene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
Term " heteroaryl " represents to contain 5-14 annular atoms, or 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, 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 heteroatomss, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more tie points to be connected with molecule rest part.Term " heteroaryl " can use with term " hetero-aromatic ring " or " heteroaromatics " exchange.Described heteroaryl groups is optionally replaced by one or more substituting groups described in the invention.In some embodiments, 5-10 former molecular heteroaryl comprises 1,2, and 3 or 4 are independently selected from O, the heteroatoms of S and N.In other embodiments, 5-6 former molecular heteroaryl comprises 1,2, and 3 or 4 are independently selected from O, the heteroatoms of S and N.
The monocycle example of heteroaryl groups comprises, but be not limited to, 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, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 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, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 2, 4-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..
Term " heteroaryl alkylidene group " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, heteroaryl alkylidene group refers to " more rudimentary heteroaryl alkylidene group " group, and heteroaryl groups is connected to C
1-6alkyl group on; Other embodiment is that heteroaryl groups is connected to C
1-4alkyl group on; Other embodiment is that heteroaryl groups is connected to C
1-3alkyl group on; Other embodiment is that heteroaryl groups is connected to C
1-2alkyl group on.Wherein specific examples comprises 2-picolyl, 3-furans ethyl etc.Described heteroaryl alkylidene group can not be substituted independently or replaced by one or more substituting groups described in the invention.
No matter term " carboxyl " is to use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO
2h; No matter term " carbonyl ", be to use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " commutative use herein, all refers to the undersaturated bridged-ring system of saturated or part of unit price or multivalence, described bridged-ring system refers to the bicyclic system of non-aromatic.Such system can comprise independently or the unsaturated system of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic group can be used as the substituting group on it).
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo " commutative use herein, refers to that the unsaturated member ring systems of saturated or part of unit price or multivalence, one of them ring originate from the upper specific ring carbon atom of another ring.For example, as described below, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", and ring A and ring B share a carbon atom in two saturated member ring systems, are called as " volution " or " spiral shell dicyclo ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or heterocyclic radical, and each ring is optionally replaced by one or more substituting groups described in the invention.
Term " Heterocyclylalkyl " refers to the unit price that contains 3-12 annular atoms or saturated monocycle, dicyclo or the three-ring system of multivalence, and wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.
Term " n is former molecular ", wherein n is integer, typically describes the number that becomes annular atoms in molecule, the number that becomes annular atoms in described molecule is n.For example, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-tetralyl is 10 former molecular groups of naphthene base.
The term " undersaturated " that used in the present invention represents to contain one or more degrees of unsaturation in group.
When term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), the sub-methoxycarbonyl of carbobenzoxy-(Cbz) (CBZ, Cbz) and 9-fluorenes (Fmoc).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 " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group
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: T.W.Greene for the general description of blocking group, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Any disease of term " treatment " or illness as used in the present invention, some embodiment middle fingers improve disease or illness (slow down or stop or palliate a disease or the development of its at least one clinical symptom) therein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter that may not discover for patient.In other embodiments, " treatment " refer to (for example to stablize perceptible symptom) from health or physiology on (for example stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevention or postpone outbreak, generation or the deterioration of disease or illness.
As described herein, term " pharmaceutically acceptable carrier " comprises any solvent, dispersion medium, dressing dress material, tensio-active agent, antioxidant, sanitas (for example antibacterial agent, anti-mycotic agent), isotonic agent, salt, medicine stablizer, tackiness agent, vehicle, dispersion agent, lubricant, sweeting agent, seasonings, tinting material, or its composition, these carriers are all the known (as Remington ' sPharmaceutical Sciences of affiliated technical field technician, 18th Ed.Mack Printing Company, 1990, described in p1289-1329).Except any conventional carrier and the inconsistent situation of activeconstituents, contain its purposes in treatment or pharmaceutical composition.
" the treatment significant quantity " of term the compounds of this invention refers to and will cause biology or medicinal response, such as reduction or inhibitory enzyme or the protein-active of study subject or improve symptom, relax symptom, slow down or delay the amount of the compounds of this invention that progression of disease or preventing disease etc. are used.In some non-limiting embodiments, term " treatment significant quantity " refers to the amount to the effective the compounds of this invention of the following using in the time being applied to study subject: (1) relax at least partly, suppress, prevent and/or improve (i) by PI3K imbalance mediation or (ii) relevant with PI3K activity or (iii) illness taking PI3K activity as feature or illness or disease; Or (2) alleviate or suppress PI3K activity.In other non-limiting embodiments, term " treatment significant quantity " refers in the time being applied to cell or tissue or non cellular organism material or medium, alleviates at least partly the amount of illness or the effective the compounds of this invention of inhibition PI3K; Or alleviate at least to a certain extent the activity of illness or inhibition PI3K.Term " treatment significant quantity " illustrates the content about the above embodiment of PI3K except being used for, and also can be applied in the same manner any other relevant protein/polypeptide/enzyme.
Term " cancer " and " cancer " refer to or describe the common physiology illness taking Growth of Cells out of control as feature in patient." tumour " comprises one or more cancer cells.The example of cancer includes but not limited to cancer (carcinoma), lymphoma, blastoma, sarcoma and leukemia, or malignant lymph proliferative disease (lymphoid malignancies).The example more specifically of this type of cancer comprises squamous cell carcinoma (as epithelium squamous cell carcinoma), lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer (NSCLC), adenocarcinoma of lung and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma (hepatocellularcancer), cancer of the stomach (gastric or stomach cancer) (comprising gastrointestinal cancer), carcinoma of the pancreas, glioblastoma, cervical cancer, ovarian cancer, liver cancer (livercancer), bladder cancer, hepatoma (hepatoma), mammary cancer, colorectal carcinoma, the rectum cancer, colorectal cancer, carcinoma of endometrium or uterus carcinoma, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma vulvae, thyroid carcinoma, liver cancer (hepatic carcinoma), anus cancer, penile cancer and head and neck cancer.
The description of compound of the present invention
The fragrant heterocyclic compound the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, to protein kinase, the disease that especially PI3K or mTOR regulate or the treatment of illness have potential purposes.
Particularly, on the one hand, the present invention relates to a kind of compound, it is the steric isomer of compound shown in the compound of structure shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Wherein: each Y, R
1, Z, W
1, W
2and W
3there is definition as described in the present invention.
In some embodiments, each W
1, W
2and W
3be N or CR independently
c;
Z is D, CN, N
3or
X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
Y is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
R
1for H, D, Cl, OR
a, NR
ar
b, C
1-6aliphatics or C
3-6cycloalkyl, wherein, described C
1-6aliphatics and C
3-6cycloalkyl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OR
a, SR
aor NR
ar
b;
Each R
aand R
bbe H independently, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprises 1,2,3 or 4 and is independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, C
6-10aryl-C
1-4alkylidene group, (5-10 former molecular heteroaryl)-C
1-4alkylidene group, or R
a, R
btogether with the nitrogen-atoms being connected with them, optionally form replace or non-substituted 3-8 former molecular heterocycle, wherein, described substituting group is not substituted or independently of one another by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkoxyl group or C
1-6alkylamino;
Each R
cbe H independently, D, F, Cl, Br, I, N
3, CN, OH, NH
2, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl group or C
1-6alkylamino.
At other embodiment, W
1for N or CR
c; Each W
2and W
3be CR independently
c.
In other embodiment, Z is CN, N
3or
In other embodiment, X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group or C
3-6heterocyclic radical-C
1-4alkylidene group, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group and C
3-6heterocyclic radical-C
1-4alkylidene group is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4thiazolinyl or C
2-4alkynyl.
In other embodiment, Y is C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4alkynyl, C
6-10aryl or 5-10 former molecular heteroaryl.
At other embodiment, R
1for H, D, Cl, CH
3, CH
2cH
3, CF
3, CH
2cF
3, OCH
3or OCH
2cH
3.
In other embodiment, each R
cbe H independently, D, F, Cl, N
3, CN, NH
2, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl or C
3-6heterocyclic radical, wherein, described C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl and C
3-6heterocyclic radical is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, OH, NH
2, C
1-3alkyl, C
3-6cycloalkyl or C
1-3haloalkyl.
In other embodiment, the present invention relates to following one of them compound or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, but be never limited to these compounds:
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, and the disease of mediation occurs for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprises that those are described in the invention.Compound of the present invention is in the application of producing in cancer therapy drug.Compound of the present invention alleviates for the production of a kind of medical supplies equally, stops, and controls or treat the disease being mediated by PI3K or mTOR.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) representative, the required effective treatment consumption of combination of assistant agent or vehicle.
The present invention comprises treatment patient vessel and occurs the disease of mediation equally, or method to this illness sensitivity, and the treatment significant quantity that the method comprises use formula (I) representative compound is treated patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
In some embodiments, described salt refers to pharmacy acceptable salt.Term " pharmaceutically acceptable " refer to material or composition must with other composition that comprises preparation and/or with the Mammals of its treatment chemically and/or compatible in toxicology.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but pharmacy acceptable salt not necessarily.
Pharmaceutically useful acid salt can form with mineral acid and organic acid, for example acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Can comprise such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. by its derivative mineral acid that obtains salt.
Can comprise for example acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, pyruvic acid, tosic acid, sulphosalicylic acid etc. by its derivative organic acid that obtains salt.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.
Pharmaceutically acceptable base addition salt can form with mineral alkali and organic bases.
Can be comprised by its derivative mineral alkali that obtains salt the metal of the I family of for example ammonium salt and periodictable to XII family.In certain embodiments, this salt is derived from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, aluminium, silver, manganese, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.
Can be comprised by its derivative organic bases that obtains salt amine (comprising the amine of naturally occurring replacement), cyclic amine (as morpholine and piperazine etc.), alkali metal hydroxide, alkaline earth metal hydroxides or the deacidite etc. of primary amine, secondary amine and tertiary amine, replacement.Some organic amine, as, Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.Some amino acid, as glycine and arginine.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety by conventional chemical method.Generally speaking, such salt can be by the free acid form of these compounds is reacted with the suitable alkali of stoichiometry (as the oxyhydroxide of Na, Ca, Mg or K, carbonate, supercarbonate etc.), or by the free alkali form of these compounds and the suitable acid-respons of stoichiometry are prepared.Such reaction is carried out conventionally in water or organic solvent or the mixture of the two.Usually, in suitable situation, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.In for example " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack PublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (Handbook of Pharmaceutical Salts:Properties; Selection; and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in, can find the list of the suitable salt of other.
And, the compounds of this invention, comprise that its salt also can obtain with its hydrate forms, or comprise other solvents for its crystallization.The compounds of this invention can have the acceptable solvent solvate of (comprising water) inherently or by design forming; Therefore that, the invention is intended to comprise solvation and the form of solvation not.
On the other hand, the invention provides the preparation of compound shown in formula (I), the method for separation and purifying.The compounds of this invention may have the form of several asymmetric centers or common described raceme mixture.The present invention further comprises racemic mixture, the enantiomorph that the mixture of partial racemization and separation obtain and diastereomer.
Compound of the present invention can exist with a kind of form in possible isomer, rotational isomer, atropisomer, tautomer or the form of its mixture, the present invention can further comprise the mixture of isomer, rotational isomer, atropisomer, tautomer, or isomer, rotational isomer, atropisomer, the part mixture of tautomer or the isomer of separating, rotational isomer, atropisomer, tautomer.
Any structural formula that the present invention provides is also intended to the form and the isotope-labeled form that represent that these compounds are not labeled.Isotope-labeled compound has the structure that general formula that the present invention provides is described, and the atom except one or more atoms with selected nucleidic mass or total mass number is replaced.Can introduce the isotropic substance that exemplary isotropic substance in the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as
2h,
3h,
11c,
13c,
14c,
15n,
18f,
32p,
36s,
37cl and
125i.
On the other hand, compound of the present invention comprises the defined compound with various isotope-labeled the present invention, for example, wherein has radio isotope, as
3h,
14c and
18those compounds of F, or wherein there is non radioactive isotope, as
2h and
13c.Such isotope-labeled compound can be used for metabolism research and (uses
14c), reaction kinetics research (is for example used
2h or
3h), detection or imaging technique, as positron emission tomography (PET) or comprise medicine or SPECT (single photon emission computed tomography) (SPECT) that substrate tissue distribution is measured, or can be used in patient's radiotherapy.
18the compound of F or mark is desirable especially for PET or SPECT research.Isotope-labeled formula (I) compound can substitute original used unmarked reagent with suitable isotope labeling reagent by the embodiment in familiar routine techniques or the present invention of those skilled in the art and preparation process description to be prepared.
In addition, particularly deuterium is (, for higher isotope
2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.For example, Half-life in vivo increases or dosage demand reduces or therapeutic index improves brings.Should be appreciated that the deuterium in this context regarded as the substituting group of formula (I) compound.Can define the particularly concentration of deuterium of such higher isotope by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to the ratio between specified isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (respectively specifying the deuterium at D atom place 52.5% to mix) to the D atom of each appointment, at least 4000 (60% deuterium mixes), at least 4500 (67.5% deuterium mixes), at least 5000 (75% deuterium mixes), at least 5500 (82.5% deuterium mixes), at least 6000 (90% deuterium mixes), at least 6333.3 (95% deuterium mixes), at least 6466.7 (97% deuterium mixes), the isotopic enrichment factor of at least 6600 (99% deuterium mixes) or at least 6633.3 (99.5% deuterium mixes).The pharmaceutically useful solvate of the present invention comprises that wherein recrystallisation solvent can be for example D that isotropic substance replaces
2o, acetone-d
6, DMSO-d
6those solvates.
The composition of compound of the present invention, preparation and administration
According on the other hand, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound that the present invention is listed, 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 can suppress the protein kinase in biological sample or patient body effectively detectablely.
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 be directly or indirectly according to other any adducts or derivatives of needing administration of patient, the described compound in other aspects of the present invention, its meta-bolites or his residue.
Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, assistant agent, 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 described with 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, the comprehensive content of document herein of New York., 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, the any bad biological effect that for example produced or the interaction producing in the mode being harmful to 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 glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid 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, the derivative of Mierocrystalline cellulose and it is 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, glycols compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleic acid ester and ethyl laurate, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, Deng oozing 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, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, and spraying inhalation, topical, per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of the property implanted medicine box.Term as used herein " through what inject " 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 administration or intravenous injection.The injection system of composition sterile of the present invention can be suspension water or oleaginous.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 nontoxic acceptable thinner or solvent of injection, 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 can be used as solvent or suspension medium by convention.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG synthesizing.Lipid acid, as the glyceride derivative of oleic acid and it 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 thinner or dispersion agent, and as carboxymethyl cellulose or similar dispersion agent, the pharmaceutical preparation that is generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.The tensio-active agent that other are conventional, 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 drug target preparation.
The pharmaceutically acceptable composition of the present invention can be to carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to capsule, tablet, water suspension processed 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.In the time that oral administration is water suspension processed, 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 be with the form rectal administration of suppository.These can be by reagent and suitable non-perfusion adjuvant are mixed with and are formed, this adjuvant be at room temperature solid but next in the temperature of rectum be liquid, thereby in rectum, melt 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 when local application, the therapeutic goal that relates to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable local application's preparation can prepare and be applied to these fields or organ.
Rectal suppository (seeing above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot is medication so also.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 carriers 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 carriers.Suitable carrier comprises, but is not limited to mineral oil, Arlacel-60 (Arlacel-60), Tween-60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Can be prepared into preparation for composition eye use, pharmaceutically acceptable; as waited micronize suspension oozing, 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 use, 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, improve bioavailability with phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent.
The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise known general inert diluent, for example, 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 through acceptable thinner or solvent are made parenterally aseptic parenteral solution, suspension or emulsion, for example, 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 synthetic list or DG.In addition, lipid acid can be applied to injection as oleic acid.
Injection can be aseptic, filters, or mix disinfectant with the form of aseptic solid composite as defended strainer by bacterium, and disinfectant can be dissolved in or be scattered in sterilized water or other aseptic injection media before use.In order to extend the effect of compound of the present invention, conventionally need to slow down by subcutaneous injection or intramuscularly the absorption of compound.Can realize like this problem of utilizing liquid suspension to solve crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on its dissolution rate, depends on successively grain size and crystal shape.In addition, can in oils vehicle, dissolve or disperse the delay of compound injection administration to absorb by compound.
Injection storage form is by biodegradable polymkeric substance, and as many lactic acid-polyglycolide forms, the microcapsule matrix of 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 gather (acid anhydrides).Injection storage form also can embed liposome or the microemulsion compatible with bodily tissue by compound and prepare.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can be by mixing compound of the present invention to prepare with auxiliary material or the carrier of suitable non-perfusion, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid but next for liquid at body temperature in room 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 at least one pharmaceutically acceptable inert excipient 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 using has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can be by dressings, add shell prepares as known coating method on enteric coating and other drug preparation.They can optionally comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the unique activeconstituents in the method release composition postponing.As implant compositions can comprise polymer material and wax.
Active compound can form microcapsule formulations with together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula can or add shell by dressing, 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 the substance except inert diluent as general application, if compressing tablet 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 can optionally comprise tranquilizer, or preferably, in certain part of enteron aisle, with the unique activeconstituents in the method release composition postponing arbitrarily.Applicable implant compositions can comprise, but be not limited to polymer and wax.
Compound of the present invention by part or comprise ointment through the formulation of percutaneous drug delivery, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any essential sanitas or essential buffer reagent under aseptic condition.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 has more advantage aspect control compound is delivered in body, and such formulation can prepare by dissolving or decentralized compound in suitable medium.Absorption enhancer can increase compound through the flow of skin, through-rate control film or compound is scattered in to polymer matrix or gelatin is controlled its speed.
Compound of the present invention is preferably prepared into dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein patient obtains suitably treating the physical dispersion unit of required medicine.But, should be appreciated that compound of the present invention or composition total usage every day will be judged and determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the illness that is treated and the seriousness of illness for any one special patient or organism, the activity of particular compound, concrete composition used, patient's age, 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 that composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition carry out administration by patient.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with one or more other additional treatment (pharmacy) agent, wherein drug combination causes acceptable untoward reaction, and this has special meaning for high proliferative disease as the treatment of cancer.In this case, compound of the present invention can be in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.Picture is used in the present invention, the disease that the normal drug treatment of additional treatment agent is special, known exactly " treating suitably disease "." additional treatment agent " used in the present invention comprises that chemotherapeutic agent or other antiproliferative medicines can be in conjunction with compounds for treating proliferative disease of the present invention or cancers.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and the described compound of those following patents: 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 demethylation reagent, but be not limited to, 5-nitrogen-2 '-the Deoxyribose cytidine (5-aza-dC) of mixing, azacitidine (Vidaza), Decitabine (Decitabine) and with the described compound of 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 that chemotherapeutics or other anti-proliferative drugs can be in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutics comprises, but be not limited to, can combine with cancer therapy drug of the present invention other therapies or the cancer therapy drug of use, operation, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol (Taxol), Docetaxel (Taxotere)), platinum derivatives (cis-platinum (Cisplatin), carboplatin (Carboplatin), oxaliplatin (oxaliplatin), Satraplatin (satraplatin)), biological response modifier (Interferon, rabbit, interleukin), tumour necrosis factor (TNF, TRAIL receptor target thing), overheated and psychrotherapy, alleviate the reagent (as antiemetic) of any untoward reaction, with other approved chemotherapeutics, include, but are not limited to, alkanisation medicine (mustargen (mechlorethamine), Chlorambucil (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (Ifosfamide)), metabolic antagonist (methotrexate (Methotrexate), pemetrexed (Pemetrexed)), purine antagonist and pyrimidine antagonist (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil (5-Fluorouracil), cytosine arabinoside (Cytarabile), gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB) (Vinblastine), vincristine(VCR) (Vincristine), vinorelbine (Vinorelbine)), podophyllotoxin (Etoposide (Etoposide), irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Zorubicin (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (Asparaginase)), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol), dexamethasone (Dexamethasone) etc.).Angiogenesis inhibitor reagent (Avastin (Avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (Belimumab), Brentuximab, Cetuximab (Cetuximab), WAY-CMA 676 (Gemtuzumab), her monoclonal antibody (Ipilimumab), Ofatumumab, Victibix (Panitumumab), Lucentis (Ranibizumab), Rituximab (Rituximab), tositumomab (Tositumomab), Herceptin (Trastuzumab)).Kinase inhibitor (imatinib (Imatinib), Sutent (Sunitinib), Xarelto (Sorafenib), Tarceva (Erlotinib), Gefitinib (Gefitinib), Dasatinib (Dasatinib), AMN107 (Nilotinib), lapatinibditosylate (Lapatinib), gram Zhuo is for Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.).Medicine suppresses or activates the approach of cancer as mTOR, HIF(hypoxia inducible factor) approach and other.Http:// www.nci.nih.gov/ is shown in cancer therapy more widely forum, the oncology list of medications of FDA accreditation is shown in http://www.fda.gov/cder/cancer/druglist-rame.htm and Merck handbook, the 18 edition .2006, all contents are all to combine reference.
Other embodiment is that compound of the present invention can be in conjunction with cytotoxin carcinostatic agent.Such carcinostatic agent can be inner the finding of the 13 edition the Merck index (2001).These carcinostatic agents comprise, but be never limited to, asparaginase, bleomycin, carboplatin, carmustine, Chlorambucil, cis-platinum, L-ASP, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Zorubicin (Dx), epirubicin, Etoposide, 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, Procarbazine, raloxifene, streptozocin, tamoxifen, Tioguanine, Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), and 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-phosphoric acid ethanoyl-L-Aspartic acid (PALA), Plicamycin (plicamycin), Me-CCNU (semustine), teniposide (teniposide), Uniteston, phosphinothioylidynetrisaziridine (thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
Other suitable cytotoxin class carcinostatic agents with compound combined utilization of the present invention comprise newfound cytotoxic substance, comprising, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), capecitabine (capecitabine), Macrolide antitumour drug and natural or synthetic derivative 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 that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is 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 parts separately.Such reagent comprises, but is never limited to, and antibody therapy is as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also comprises, but be never limited to, small molecules kinase inhibitor is as imatinib (imatinib), Sutent (sunitinib), Xarelto (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), lapatinibditosylate (lapatinib), Ke Zhuo is for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, pazopanib, Ah method is for Buddhist nun (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, fork clip is for Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941(Folkes, et al., J.Med.Chem.2008, 51, 5522), BZE235, etc..
Other embodiment is that 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(US 6 abstract3028), 897, 220).
Other embodiment is that compound of the present invention can be in conjunction with other carcinostatic agents as proteasome inhibitor and mTOR inhibitors.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 can also, in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition that comprises 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, thereby obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption of additional treatment agent (those compositions that comprise an additional treatment agent are as described in the invention) 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 comprising is as unique active therapeutic agent.In the composition that comprises 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 the compound shown in formula (I) or the listed compound of the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention the amount of compound effectively detectablely arrestin kinases as the activity of PI3K or mTOR.The compounds of this invention will treat or reduce the deleterious effect of PI3K or mTOR signal response to patient as antitumor drug.
Compound of the present invention will be applied to, but never be limited to, and patient's administration be prevented or treated patient's proliferative disease by the significant quantity of compound of the present invention or composition.Such disease comprises cancer, especially metastatic carcinoma, atherosclerosis and pulmonary fibrosis.
The treatment that is applied to knurl is comprised cancer and metastatic carcinoma by compound of the present invention, further includes, but are not limited to, and cancer is as bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoiesis tumour (comprises leukemia, acute lymphoblastic tumour leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoiesis tumour (comprising acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocyte leukemia); The tumour of mesenchymal cell origin (comprise fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage); Maincenter peripheral nervous system knurl (comprising astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention also can be used for treating such as corneal graft rejection of eye disease, and the new vessel of eye forms, and retinal neovascularization forms and comprises that damage or metainfective new vessel form; Diabetic retinopathy; Terry's sign disease, 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 can be for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathy.The situation that compound of the present invention reduces for cancer patients's volume of blood flow equally.Compound of the present invention shifts to reduce to patient tumors also beneficial effect.
Compound of the present invention, except useful to human treatment, also can be applicable to the animal of veterinary treatment pet, 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 in the situation of salt etc., it also means single compound, salt etc.
The methods for the treatment of that comprises compound of the present invention or composition administration, further comprise the administration to patient's additional treatment agent (combination therapy), wherein additional treatment agent is selected from: chemotherapy, 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 be as single formulation, or the compound separating or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or administration when different.The latter's situation, 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.
The present invention comprises the cytostatic method to expressing PI3K or mTOR equally, 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 the method that suppresses PI3K or mTOR activity in biological sample, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refer to and the sample of live body outside include, but not limited to cell cultures or cell extraction; The examination of living tissue material obtaining from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly PI3K or mTOR activity in biological sample, 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 " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential measuring accurately changes the situation according to patient, and this depends on race, the age, and patient's general condition, 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.For example, vascular stem, has been used to overcome restenosis (after damage, vessel wall shrinks again).But patient uses stem or other implantable devices, and by having, clot forms or the risk of platelet activation.The pharmaceutically acceptable composition precoating device that these disadvantageous effects can comprise compound of the present invention by use stops or alleviates.
The general preparation method of suitable dressing and the dressing of implantable device is at document US 6,099,562; US 5,886,026; With US 5,304, describe to some extent in 121, dressing be typically biocompatible polymer material as hydrogel polymer, poly-methyl two silicon ethers, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, and composition thereof.Dressing can optionally further be covered by suitable dressing, as fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, carry out the feature that the control of performance group compound discharges.Another aspect of the present invention comprises the implantable device that uses compound coating of the present invention.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or " medicine storage institute " is provided with polymkeric substance or other molecular mixing, therefore with the comparison of pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
General building-up process
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiment, only be to provide the method for the present invention of putting into practice.
Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula shown in (I).Reaction scheme below and embodiment are for further illustrating content of the present invention.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; disturb group as suitable protection, by utilizing other known reagent except described in the invention, or reaction conditions is made to 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, are 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, when use all not through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao's purchase obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to reflux to be dried through sodium Metal 99.5 to obtain.Anhydrous methylene chloride and chloroform are to reflux to be dried through hydrolith to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), all suitable soft rubber balls beyond the Great Wall of reaction flask, and substrate is squeezed into by syringe.Glassware was all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.The test condition of proton nmr spectra is: under room temperature condition, the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1
3, DMSO-d
6, CD
3oD or acetone-d
6for solvent (taking ppm as unit), use TMS (0ppm) or chloroform (7.26ppm) as reference standard.In the time there is multiplet, abbreviation by using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).
The test condition of Algorithm (MS) data is: Agilent6120Quadrupole HPLC-MS (pillar model: Zorbax SB-C18,2.1x30mm, 3.5 μ m, 6min, flow velocity is 0.6mL/min, and moving phase: 5%-95% is (containing the CH of 0.1% formic acid
3cN) (containing the H of 0.1% formic acid
2o) ratio in), detect with UV at 210nm/254nm, with electron spray ionisation pattern (ESI).
The characteristic manner of compound purity is: Agilent1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model: NOVASEP, 50/80mm, DAC), detect with UV at 210nm/254nm.
The use of brief word below runs through the present invention:
Ac
2o diacetyl oxide
BBr
3boron tribromide
BINAP 2,2 '-bis-diphenyl phosphine-1,1 '-dinaphthalene
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin
CDC1
3deuterochloroform
CHCl
3chloroform
CH
2cl
2, DCM methylene dichloride
CH
3sO
2cl, MsCl Tosyl chloride
Cs
2cO
3cesium carbonate
Cu copper
CuI cuprous iodide
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
DEAD diethyl azodiformate
DIAD diisopropyl azodiformate
DIBAL diisobutyl aluminium hydride
DIEA, DIPEA diisopropyl ethyl amine
DMAP DMAP
DME glycol dimethyl ether
DMF N, N '-dimethyl formamide
DMSO dimethyl sulfoxide (DMSO)
DMSO-d
6deuterated dimethyl sulfoxide
DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, EA ethyl acetate
Et
2o ether
Et
3n, TEA triethylamine
FBS foetal calf serum
Fe iron
G gram
H hour
HATU O-(7-nitrogen benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester
HBr Hydrogen bromide
HBTU O-benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
HCl hydrochloric acid
H
2hydrogen
H
2o water
H
2o
2hydrogen peroxide
HOAc, AcOH acetic acid
HOBt I-hydroxybenzotriazole
I-Pr
2nH diisopropylamine
K
2cO
3salt of wormwood
KOH potassium hydroxide
LiHMDS LHMDS
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MeCN, CH
3cN acetonitrile
MeI methyl iodide
MeOH, CH
3oH methyl alcohol
2-MeTHF 2-methyltetrahydrofuran
MgSO
4magnesium sulfate
MsCl methylsulfonyl chloride
ML, ml milliliter
N
2nitrogen
NaBH
4sodium borohydride
NaBH
3cN sodium cyanoborohydride
NaCl sodium-chlor
NaClO
2textone
NaH sodium hydride
NaHCO
3sodium bicarbonate
Na
2cO
3sodium carbonate
NaH
2pO
4sODIUM PHOSPHATE, MONOBASIC
NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na
2sO
4sodium sulfate
NBS N-bromo-succinimide
NIS N-N-iodosuccinimide
NH
3ammonia
NH
4c1 ammonia chloride
NMP N-Methyl pyrrolidone
PBS phosphate buffered saline (PBS)
P (t-Bu)
3three (tertiary butyl) phosphine
Pd/C palladium/carbon
Pd
2(dba)
3two (dibenzyl subunit acetone) palladium
Pd (dppf) Cl
21,1 '-bis-(diphenylphosphino) ferrocene palladium chloride
Pd (dppf) Cl
2cH
2cl
2[1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound
Pd (OAc)
2palladium
Pd (OH)
2palladium hydroxide
Pd (PPh
3)
4tetrakis triphenylphosphine palladium
Pd (PPh
3)
2cl
2two (triphenylphosphine) palladium chloride
PE sherwood oil (60-90 DEG C)
POC1
3phosphorus oxychloride
PCl
5phosphorus pentachloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
TBAB Tetrabutyl amonium bromide
TBAF tetrabutyl ammonium fluoride
TBAHSO
44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester
TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
THF tetrahydrofuran (THF)
μ L microlitre
X-Phos 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl
Synthetic schemes 1-3 has listed the experimental procedure of the compound of coming into the open in preparation the present invention.Wherein, each R
1, W
1, W
2, W
3, Y and Z have definition as described in the present invention.X ' is Cl, Br or I.
Synthetic schemes 1
Compound as shown in chemical formula (I) formula can prepare by the method for describing in synthetic schemes 1.First, use go back original reagent by nitropyridine derivative (
1) be reduced into aminopyrazole derivatives (
2), compound (
2) again with SULPHURYL CHLORIDE (
3) under alkaline condition, react, obtain compound (
4), afterwards, compound (
4) and connection boric acid pinacol ester (
5) under the existence of applicable Pd catalyzer, there is coupling, generation boric acid derivatives (
6).
Compound (
12) be also to prepare by the method for description in synthetic schemes 1.First, halogenated compound (
7) in room temperature condition and NIS occur iodide reaction generate compound (
8), next, compound (
8) and compound (
9) (as, acetylene analog derivative, prussiate or triazo-compound, etc.) under alkaline condition, there is linked reaction, generation intermediate (
10).Finally, intermediate (
10) and boric acid derivatives (
6) applicable Pd catalyzer (
11) the lower linked reaction that occurs of effect, obtain final compound (
12).
Synthetic schemes 2
Some compounds in the present invention can prepare by the method for describing in synthetic schemes 2.First, compound (
7) and (chlorine methylene radical) alkyl dimethyl ammonium chloride (
13) reaction obtain aldehyde (
14), aldehyde (
14) again and oxammonium hydrochloride (
15) generation condensation generation oxime (
16).Compound (
16) more further with diacetyl oxide (
17) the generation nitrile compounds that reacts (
18).Finally, nitrile compounds (
18) by with boric acid derivatives (
6) applicable Pd catalyzer (
11) effect lower occur linked reaction change into final compound (
19).
Synthetic schemes 3
Other compounds in the present invention also can prepare by the method for describing in synthetic schemes 3.First, the compound of halo (
7) by with boric acid derivatives (6) applicable Pd catalyzer (
11) effect lower occur linked reaction obtain compound (
20).Next, compound (
20) in room temperature condition and NIS occur iodide reaction generate compound (
21).Finally, compound (
21) and compound (
9) (as, acetylene analog derivative, prussiate or triazo-compound, etc.) under alkaline condition, occur linked reaction change into final compound (
12).
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
embodiment 12, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl third-1-alkynes-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
step 1) the bromo-2-methoxyl group-3-of 5-nitropyridine
Sodium methylate (0.52g, 9.64mmol) is dissolved in 10mL methyl alcohol, to be cooled after 0 DEG C, in reaction solution, add the 5-chloro-3-nitropyridine of bromo-2-(0.57g, 2.41mmol).Reaction solution after 1 hour, rises to room temperature at 0 DEG C of stirring reaction, continues stirring reaction after 18 hours, adds the 20mL shrend reaction of going out, and then adds the HCl aqueous solution of 3M that reaction solution is adjusted to pH=7.Suction filtration, leaves standstill filtrate, separatory, and after organic phase concentrating under reduced pressure, obtaining target compound is light yellow solid (0.4g, 71.4%).
MS(ESI,pos.ion)m/z:233.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm):3.93(s,3H),8.08(s,1H),8.89(s,1H)。
step 2) the bromo-2-methoxypyridine-3-of 5-amine
Bromo-compound 5-2-methoxyl group-3-nitropyridine (0.4g, 1.72mmol) is suspended in the mixed solvent of 5mL ethanol and 5mL water, then in reaction solution, adds iron powder (0.38g, 6.87mmol) and NH
4cl (0.39g, 7.21mmol).After reaction solution stirring and refluxing 1 hour, concentrating under reduced pressure, after residue dilutes by 10mL ethyl acetate, suction filtration, filtrate extracts by ethyl acetate (10mL x3).The salt solution for organic phase (10mL) merging is washed, and with anhydrous sodium sulfate drying, it is yellow solid (0.30g, 86%) that last concentrating under reduced pressure obtains target compound.
MS(ESI,pos.ion)m/z:203.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm):3.92(s,3H),4.86(s,2H),7.03(d,J=2.0Hz,1H),7.41(d,J=2.0Hz,1H)。
step 3) N-(the bromo-2-methoxypyridine-3-of 5-yl)-2,4 difluorobenzene sulphonamide
Bromo-compound 5-2-methoxypyridine-3-amine (10.15g, 50mmol) is dissolved in 50mL pyridine, is cooled to after 0 DEG C, in reaction solution, slowly add 2,4 difluorobenzene-1-SULPHURYL CHLORIDE (11.68g, 60mol).Reaction solution is at room temperature condition stirring reaction after 19 hours, concentrating under reduced pressure, residue is dissolved in 100mL methyl alcohol, then in the methanol solution obtaining, add sodium hydroxide (2.50g, 60mmol), the reaction solution obtaining continues stirring reaction after 12 hours at room temperature condition, concentrating under reduced pressure, residue is dissolved in 50mL water to methylene dichloride for mixed solution (100mL x3) extraction obtaining.The salt solution for organic phase (100mL x3) merging is washed, and with anhydrous sodium sulfate drying, it is brown solid (16.90g, 89.1%) that last concentrating under reduced pressure obtains target compound.
MS(ESI,pos.ion)m/z:379.0[M+H]
+。
step 4) 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide
By compound N-(the bromo-2-methoxypyridine-3-of 5-yl)-2,4-difluorobenzene sulphonamide (16.90g, 44.6mmol) be suspended in 300mL1, in 4-dioxane, then in reaction solution, add successively connection boric acid pinacol ester (13.59g, 53.5mmol), Pd (dppf) Cl
2cH
2cl
2(3.67g, 4.5mmol) and Potassium ethanoate (13.12g, 133.8mmol).Reaction solution is substituted after gas (nitrogen) 3 times, be heated to 90 DEG C and stirring reaction 7 hours, be then cooled to room temperature, add the 100mL shrend reaction of going out, ethyl acetate for mixture (500mL x3) extracts.Salt solution for organic phase (500mL x3) after merging is washed, and with anhydrous sodium sulfate drying, it is faint yellow solid (24.00g, 100%) that last concentrating under reduced pressure obtains target compound.MS(ESI,pos.ion)m/z:427.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm):8.25(d,J=1.0Hz,1H),8.04(s,1H),7.85(m,1H),7.14(s,1H),6.93(m,2H),3.91(s,3H),1.33(s,12H)。
step 5) the chloro-3-iodine of 5-pyrazolo [1,5-a] pyrimidine
By compound 5-chlorine pyrazolo [1, 5-a] pyrimidine (200mg, 1.30mmol) be dissolved in 2mL DMF, then in reaction solution, add NIS (322mg, 1.86mmol), under room temperature condition, stir and spend the night, then add 100mL ethyl acetate dilute reaction solution, the mixed solution obtaining is used 50mL water successively, the aqueous solution of 50mL saturated sodium thiosulfate and the washing of 50mL salt, separatory, concentrating under reduced pressure after anhydrous sodium sulfate drying for the organic phase obtaining, it is faint yellow solid (390mg that residue obtains target compound through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purifying, 100%).
MS(ESI,pos.ion)m/z:279.9[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm):8.57(d,J=7.2Hz,1H),8.16(s,1H),6.86(d,J=7.2Hz,1H)。
step 6) 3-(5-chlorine pyrazolo [1,5-a] pyrimidin-3-yl) third-2-alkynes-1-alcohol
By chloro-compound 5-3-iodine pyrazolo [1,5-a] pyrimidine (363mg, 1.30mmol), Pd (PPh
3)
2cl
2(91mg, 0.13mmol), CuI (25mg, 0.13mmol) and triethylamine (658mg, 6.50mmol) are suspended in 15mL DMF, then in reaction solution, add third-2-alkynes-1-alcohol (73mg, 1.30mmol), reaction solution is substituted after gas (nitrogen) 3 times to stirring reaction 20 hours at ambient temperature, then to adding the 15mL shrend reaction of going out, the ethyl acetate for mixed solution obtaining (50mL x3) extraction in reaction solution.The salt solution for organic phase (50mL x3) merging is washed, with anhydrous sodium sulfate drying, concentrating under reduced pressure, it is yellow solid (220mg, 81.5%) that residue obtains target compound through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying.
MS(ESI,pos.ion)m/z:208.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm):8.58(d,J=7.4Hz,1H),8.23(s,1H),6.90(d,J=7.2Hz,1H),4.58(s,2H)。
step 7) 2, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl third-1-alkynes-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 3-(5-chlorine pyrazolo [1,5-a] pyrimidin-3-yl) third-2-alkynes-1-alcohol (208mg, 1mmol), the fluoro-N-of 2,4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (618mg, 1.5mmol) and Pd (dppf) Cl
2cH
2cl
2(82mg, 0.1mmol) is suspended in 20mL DME, then adds Na to reaction solution
2cO
3(318mg, water (2.5mL) solution 3mmol), substitute after gas (nitrogen) 3 times, reaction solution is heated to 100 DEG C, after stirring reaction 5 hours, be cooled to room temperature, add the 20mL shrend reaction of going out, the ethyl acetate for mixed solution obtaining (500mL x3) extraction.The salt solution for organic phase (50mL x3) merging is washed, with anhydrous sodium sulfate drying, concentrating under reduced pressure, it is yellow solid (80mg, 17%) that residue obtains target compound through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying.
MS(ESI,pos.ion)m/z:472.0[M+H]
+；
1H NMR(400MHz,DMSO-d
6)δ(ppm):10.46(s,1H),9.23(d,J=7.4Hz,1H),8.88(d,J=1.7Hz,1H),8.42(d,J=2.1Hz,1H),8.41(s,1H),7.82(dd,J=8.4,6.2Hz,1H),7.76(d,J=7.5Hz,1H),7.59(td,J=10.0,2.2Hz,1H),7.24(td,J=8.6,2.0Hz,1H),5.38(t,J=5.9Hz,1H),4.41(d,J=5.9Hz,2H),3.72(s,3H)。
embodiment 2 N-(5-(3-cyano pyrazole is [1,5-a] pyrimidine-5-yl also)-2-methoxypyridine-3-yl)-2,4 difluorobenzene sulphonamide
step 1) 5-chlorine pyrazolo [1,5-a] pyrimidine-3-formaldehyde
By compound 5-chlorine pyrazolo [1,5-a] pyrimidine (295mg, 1.92mmol) be dissolved in 10mL methylene dichloride, then in reaction solution, add (chlorine methylene radical) alkyl dimethyl ammonium chloride (1.06g, 6mmol), reaction solution after 45 DEG C of stirrings are spent the night, concentrating under reduced pressure, residue is dissolved in the sodium bicarbonate aqueous solution that 50mL is saturated, ethyl acetate for mixture (50mL x3) extraction obtaining.The organic phase anhydrous sodium sulfate drying merging, it is light yellow solid (380mg, 100%) that concentrating under reduced pressure obtains target compound.
MS(ESI,pos.ion)m/z:182.2[M+H]
+。
step 2) (E)-5-chlorine pyrazolo [1,5-a] pyrimidine-3-formoxime
By compound 5-chlorine pyrazolo [1,5-a] pyrimidine-3-formaldehyde (380mg, 2.1mmol) be suspended in the mixed solvent of 20mL ethanol and 10mL water, then in reaction solution, add oxammonium hydrochloride (220mg, 3.15mmol), reaction solution is at 85 DEG C of stirring reactions after 2 hours, concentrating under reduced pressure, adds saturated sodium bicarbonate aqueous solution that residue is adjusted to pH=7, suction filtration, be yellow solid (280mg, 74.4%) by obtaining target compound after filter cake vacuum-drying.
MS(ESI,pos.ion)m/z:197.1[M+H]
+。
step 3) 5-chlorine pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN
Compound (E)-5-chlorine pyrazolo [1,5-a] pyrimidine-3-formoxime (280mg, 1.42mmol) and the mixture of 20mL diacetyl oxide at 140 DEG C of stirring reactions after 18 hours, be cooled to room temperature, concentrating under reduced pressure, residue is washed with 20mL ether, and after vacuum-drying, obtaining target compound is yellow solid (106mg, 42%).
MS(ESI,pos.ion)m/z:179.1[M+H]
+。
step 4) N-(5-(3-cyano pyrazole is [1,5-a] pyrimidine-5-yl also)-2-methoxypyridine-3-yl)-2,4 difluorobenzene sulphonamide
By compound 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (383mg, 0.9mmol), 5-chlorine pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (106mg, 0.6mmol), Pd (dppf) Cl
2cH
2cl
2(49mg, 0.06mmol) and sodium carbonate (254mg, 2.5mmol) be placed in two-mouth bottle, substitute after gas (nitrogen) 3 times, add successively 12mL1,4-dioxane and 2mL water, again substitute after gas (nitrogen) 3 times, be heated to 90 DEG C, stirring reaction, after 5 hours, is cooled to room temperature, suction filtration, filtrate decompression is concentrated, and it is light yellow solid (200mg, 75.3%) that residue obtains target compound through silica gel column chromatography (PE/EtOAc (v/v)=4/3) purifying.
MS(ESI,pos.ion)m/z:443.2[M+H]
+；HPLC:97%；
1H NMR(400MHz,DMSO-d
6)δ(ppm):10.51(s,1H),9.41(d,J=7.4Hz,1H),8.93(d,J=2.1Hz,1H),8.81(s,1H),8.45(d,J=2.2Hz,1H),7.99(d,J=7.5Hz,1H),7.85-7.78(m,1H),7.61-7.52(m,1H),7.25(t,J=8.4Hz,1H),3.77(s,3H)。
embodiment 3 N-(5-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also)-2-methoxypyridine-3-yl)-2,4 difluorobenzene sulphonamide
step 1) 5-bromine pyrazolo [1,5-a] pyridine
Compound ethyl 5-bromine pyrazolo [1,5-a] Nicotinicum Acidum ester (240mg, 0.89mmol) and 40%H
2sO
4(12mL) mixture is at 100 DEG C of stirring reactions after 4 hours, be cooled to room temperature, under condition of ice bath, in mixture, add the aqueous sodium hydroxide solution of 6M to be adjusted to PH=7, methylene dichloride for mixture (25mL x2) extraction, the organic phase anhydrous sodium sulfate drying merging, it is light yellow solid (175mg, 99.5%) that concentrating under reduced pressure obtains target compound.
MS(ESI,pos.ion)m/z:196.9[M+H]
+。
step 2) 5-bromine pyrazolo [1,5-a] pyridine-3-formaldehyde
By compound 5-bromine pyrazolo [1,5-a] pyridine (175mg, 0.89mmol) be dissolved in 6mL methylene dichloride, then in reactant, add (chlorine methylene radical) alkyl dimethyl ammonium chloride (632mg, 3.56mmol), reaction solution after 44 DEG C of stirrings are spent the night, concentrating under reduced pressure, residue is dissolved in 25mL saturated sodium bicarbonate aqueous solution to ethyl acetate for mixture (25mL x3) extraction obtaining.The organic phase anhydrous sodium sulfate drying merging, after concentrating under reduced pressure, obtaining target compound is light yellow solid (225mg, 100%).
MS(ESI,pos.ion)m/z:225.0[M+H]
+。
step 3) (E)-5-bromine pyrazolo [1,5-a] pyridine-3-formoxime
By compound 5-bromine pyrazolo [1,5-a] pyridine-3-formaldehyde (225mg, 1mmol) is suspended in the mixed solvent of 10mL ethanol and 5mL water, then in reaction solution, adds oxammonium hydrochloride (104mg, 1.5mmol), after 2 hours, be cooled to room temperature, concentrating under reduced pressure at 85 DEG C of stirring reactions, add saturated sodium bicarbonate aqueous solution that residue is adjusted to pH=7, suction filtration, after filter cake vacuum-drying, obtaining target compound is yellow solid (240mg, 99%).
MS(ESI,pos.ion)m/z:240.0[M+H]
+。
step 4) 5-bromine pyrazolo [1,5-a] pyridine-3-formonitrile HCN
Compound (E)-5-bromine pyrazolo [1,5-a] pyridine-3-formoxime (240mg, 1mmol) and the mixture of 6mL diacetyl oxide at 140 DEG C of stirring reactions after 18 hours, be cooled to room temperature, then concentrating under reduced pressure, residue is washed with 1mL ether, and after vacuum-drying, obtaining target compound is yellow solid (44mg, 22.5%).
MS(ESI,pos.ion)m/z:222.0[M+H]
+。
step 5) N-(5-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also)-2-methoxypyridine-3-yl)-2,4 difluorobenzene sulphonamide
By compound 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (612mg, 1.5mmol), 5-bromine pyrazolo [1,5-a] pyridine-3-formonitrile HCN (222mg, 1mmol), Pd (dppf) Cl
2cH
2cl
2(16mg, 0.02mmol) and sodium carbonate (85mg, 0.8mmol) are placed in two-mouth bottle, substitute after gas (nitrogen) 3 times, add 5mL1,4-dioxane and 1mL water, again substitute after gas (nitrogen) 3 times, be heated to 90 DEG C and stirring reaction 5 hours.Reaction solution is cooled to after room temperature, suction filtration, and filtrate decompression is concentrated, and it is light yellow solid (400mg, 81.6%) that residue obtains target compound through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying.
MS(ESI,pos.ion)m/z:442.0[M+H]
+；
1H NMR(400MHz,DMSO-d
6)δ(ppm):10.37(s,1H),9.02(d,J=7.2Hz,1H),8.67(s,1H),8.60(d,J=2.2Hz,1H),8.26-8.16(m,2H),7.82-7.72(m,1H),7.57(dd,J=13.2,5.8Hz,2H),7.21(t,J=8.5Hz,1H),3.67(s,3H)。
embodiment 42, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl third-1-alkynes-1-yl) pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
step 1) 5-bromine pyrazolo [1,5-a] pyridine
Compound ethyl 5-bromine pyrazolo [1,5-a] Nicotinicum Acidum ester (1.2g, 4.46mmol) and 40%H
2sO
4(60mL) mixture after 4 hours, is cooled to room temperature at 100 DEG C of stirring reactions, adds the aqueous sodium hydroxide solution of 6M to be adjusted to pH=7 under condition of ice bath, methylene dichloride for mixture (120mL x2) extraction obtaining.The organic phase anhydrous sodium sulfate drying merging, after concentrating under reduced pressure, obtaining target compound is light yellow solid (900mg, 100%).
MS(ESI,pos.ion)m/z:196.9[M+H]
+。
step 2) the bromo-3-iodine of 5-pyrazolo [1,5-a] pyridine
By compound 5-bromine pyrazolo [1,5-a] pyridine (900mg, 4.46mmol) be dissolved in 100mL methyl alcohol, be cooled to-10 DEG C, then in reaction solution, slowly add NIS (1g, 4.46mmol), reaction solution, after-10 DEG C of stirring reaction half an hour, rises to room temperature, at room temperature condition stirring reaction after 18 hours, concentrating under reduced pressure, is dissolved in residue in 200mL methylene dichloride.The mixture obtaining is washed with the aqueous solution of 200mL saturated sodium thiosulfate, separatory, and after the organic phase concentrating under reduced pressure obtaining, obtaining target compound is lightpink solid (1.4g, 97.5%).
MS(ESI,pos.ion)m/z:322.8[M+H]
+。
step 3) 3-(5-bromine pyrazolo [1,5-a] pyridin-3-yl) third-2-alkynes-1-alcohol
Compound 5-bromo-3-iodine pyrazolo [1,5-a] pyridine (644mg, 2mmol), third-2-alkynes-1-alcohol (112mg, 2mmol), Pd (PPh
3)
2cl
2(140mg; 0.2mmol); CuI (38mg; 0.2mmol), DIPEA (645mg; 5mmol) and the mixture of 32mL DMF under nitrogen protection; after 3 hours, add the dilution of 200mL water in room temperature condition stirring reaction, ethyl acetate for mixture (200mL x3) extraction.The organic phase anhydrous sodium sulfate drying merging, concentrating under reduced pressure, it is yellow solid (200mg, 4%) that residue obtains target compound through silica gel column chromatography (absolute dichloromethane) purifying.
MS(ESI,pos.ion)m/z:251.0[M+H]
+。
step 4) 2, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl third-1-alkynes-1-yl) pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (509mg, 1.2mmol), 3-(5-bromine pyrazolo [1,5-a] pyridin-3-yl) third-2-alkynes-1-alcohol (200mg, 0.8mmol), Pd (dppf) Cl
2cH
2cl
2(65mg, 0.08mmol) and sodium carbonate (339mg, 3.2mmol) be placed in two-mouth bottle, substitute after gas (nitrogen) 3 times, add 15mL1,4-dioxane and 2.5mL water, substitute after gas (nitrogen) 3 times again, is heated to 90 DEG C and stirring reaction 5 hours.Reaction solution is cooled to after room temperature, suction filtration, and filtrate decompression is concentrated, and it is white solid (122mg, 32.5%) that residue obtains target compound through silica gel column chromatography (PE/EtOAc (v/v)=3/1) purifying.
MS(ESI,pos.ion)m/z:471.0[M+H]
+；HPLC:91%；
1H NMR(400MHz,DMSO-d
6)δ(ppm):10.37(s,1H),8.83(d,J=7.2Hz,1H),8.53(d,J=2.3Hz,1H),8.23(s,1H),8.05(d,J=2.3Hz,1H),7.87(s,1H),7.77(dd,J=14.8,8.5Hz,1H),7.59(dd,J=13.9,5.9Hz,1H),7.33(dd,J=7.3,1.9Hz,1H),7.22(t,J=8.4Hz,1H),5.33(t,J=5.9Hz,1H),4.39(d,J=5.8Hz,2H),3.67(s,3H)。
embodiment 52, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl-ethyl acetylene-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
step 1) 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(pyrazolo [1,5-a] pyrimidine-5-yl) pyridin-3-yl) benzsulfamide
Compound 5-chlorine pyrazolo [1,5-a] pyrimidine (0.46g, 3.0mmol) is dissolved in 60mL DME, then adds wherein Pd (dppf)
2cl
2cH
2cl
2water (8mL) solution of (0.25g, 0.3mmol) and sodium carbonate (0.95g, 9.0mmol), mixture is substituted after gas (nitrogen) 3 times, at room temperature stir a moment, and then add the fluoro-N-of 2,4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (1.53g, 3.6mmol).Mixture is substituted after gas (nitrogen) 3 times again, then stirring reaction 6 hours at 100 DEG C, then be cooled to room temperature, concentrating under reduced pressure.It is yellow solid (1.24g, 100%) that gained residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purifying.
MS(ESI,pos.ion)m/z:418.2[M+H]
+。
step 2) 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(pyrazolo [1, 5-a] pyrimidine-5-yl) pyridin-3-yl) benzsulfamide (1.98g, 10.0mmol) be dissolved in methyl alcohol (50mL), at room temperature, in reaction solution, add N-iodosuccinimide (2.47g in batches, 11.0mmol), mixture stirring reaction after 10 hours at 45 DEG C, concentrating under reduced pressure, add water (40mL) that residue is diluted, gained mixture at room temperature stirred after 2 hours, suction filtration, the solid of collecting is diluted in the mixed solvent of PE/EtOAc (40mL/4mL), gained suspension at room temperature stirred after 1 hour, suction filtration, obtaining title compound is faint yellow solid (1.05g, 80.57%).
MS(ESI,pos.ion)m/z:544.0[M+H]
+。
step 3) 2, the fluoro-N-of 4-bis-(5-(3-(3-hydroxyl-ethyl acetylene-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide (2.32g, 4.27mmol), Pd (PPh
3)
2cl
2(0.31g; 0.43mmol) and CuI (82mg; 0.43mmol) be suspended in 15mL DMF; then in reaction solution, add triethylamine (2.15g, 21.3mmol), by mixture substitute gas several times after; add wherein 3-butyne-2-alcohol (1.08g with syringe again; 15.4mmol), mixture after 6 hours, adds water (40mL) cancellation reaction in 50 DEG C of stirring reactions under nitrogen protection.Gained mixture stirred after 1 hour, suction filtration.Filter cake is through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying, obtain crude product, then add the mixed solvent of DCM/MeOH/PE (15mL/3mL/65mL) that crude product is diluted, the mixture obtaining stirred after 2 hours, suction filtration, obtaining title compound is faint yellow solid (1.01g, 48.77%).
MS(ESI,neg.ion)m/z:484.1[M-H]
-；
1H NMR(600MHz,DMSO-d
6)δ(ppm):10.45(s,1H),9.21(d,J=7.4Hz,1H),8.88(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),8.38(s,1H),7.80(dd,J=14.8,8.4Hz,1H),7.75(d,J=7.4Hz,1H),7.58(t,J=8.8Hz,1H),7.23(t,J=7.4Hz,1H),4.69(dd,J=13.1,6.5Hz,1H),3.72(s,3H),1.45(d,J=6.6Hz,3H)。
embodiment 62, the fluoro-N-of 4-bis-(5-(3-(3-hydroxy-3-methyl-ethyl acetylene-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzene sulfonyl
amine
By compound 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide (1.05g, 1.93mmol), Pd (PPh
3)
2cl
2(0.136g, 0.19mmol) and CuI (37mg, 0.19mmol) be dissolved in 5mL DMF, then in reaction solution, add diisopropylethylamine (0.98g, 7.60mmol), by reaction mixture substitute gas (nitrogen) several times after, then add wherein 2-methyl-3-butyne-2-alcohol (0.49g, 5.79mmol) with syringe.Mixture is in 50 DEG C of stirring reactions after 4 hours under nitrogen protection, and concentrating under reduced pressure, then adds water (25mL) cancellation, the mixture obtaining is stirred after 1 hour to suction filtration.Gained solid is through silica gel column chromatography (PE/EtOAc (v/v)=3/1) purifying, and obtaining title compound is yellow solid (520mg, 53.99%).
MS(ESI,neg.ion)m/z:498.0[M-H]
-；HPLC:96.74%；
1H NMR(600MHz,DMSO-d
6)δ(ppm):10.45(s,1H),9.22(d,J=7.4Hz,1H),8.89(d,J=1.8Hz,1H),8.48(d,J=2.1Hz,1H),8.36(s,1H),7.80(dd,J=14.8,8.5Hz,1H),7.76(d,J=7.4Hz,1H),7.65–7.53(m,1H),7.24(td,J=8.5,2.3Hz,1H),5.52(s,1H),3.74(s,3H),1.54(s,6H)。
embodiment 72, the fluoro-N-of 4-bis-(2-methoxyl group-5-(3-(1-propine-1-yl) pyrazolo [1,5-a] pyrimidine-5-yl) pyridin-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyrimidine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide (1.50g, 2.76mmol), Pd (PPh
3)
2cl
2(0.189g, 0.27mmol) and CuI (52mg, 0.27mmol) be dissolved in the DMF of 20mL, then in reaction solution, add diisopropylethylamine (1.78g, 13.8mmol), by mixture substitute gas (nitrogen) several times after, add propine (0.44g with syringe, 11.04mmol), mixture under nitrogen protection in 45 DEG C of stirring reactions after 10 hours, concentrating under reduced pressure, add water (40mL) cancellation reaction, the mixture obtaining was stirred after 1 hour, suction filtration, it is yellow solid (220mg that gained solid obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=300/1) purifying, 17.52%).
MS(ESI,pos.ion)m/z:456.1[M+H]
+；
1H NMR(600MHz,DMSO-d
6)δ(ppm):10.46(s,1H),9.18(d,J=7.3Hz,1H),8.86(s,1H),8.41(s,1H),8.34(s,1H),7.78(dd,J=14.6,8.0Hz,1H),7.72(d,J=7.3Hz,1H),7.58(t,J=9.1Hz,1H),7.21(t,J=7.6Hz,1H),3.71(s,3H),2.14(s,3H)。
embodiment 82, the fluoro-N-of 4-bis-(5-(3-(3-hydroxy-3-methyl-ethyl acetylene-1-yl) pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzene sulfonyl
amine
step 1) 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(pyrazolo [1,5-a] pyridine-5-yl) pyridin-3-yl) benzsulfamide
By compound 5-bromine pyrazolo [1,5-a] pyridine (197mg, 1mmol), 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) benzsulfamide (639mg, 1.5mmol), Na
2cO
3(318mg, 3.0mmol) and Pd (PPh
3)
2cl
2(35mg, 0.05mmol) is dissolved in Isosorbide-5-Nitrae-dioxane/water (5mL/1mL), mixture under nitrogen protection in 90 DEG C of stirring reactions, and with tlc (TLC) monitoring reaction.After having reacted, reaction mixture is cooled to room temperature, and extract with ether (10mL), the salt solution for organic phase (10mL x2) obtaining is washed, then use anhydrous sodium sulfate drying, concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=30/1) purifying, obtaining title chemical combination is white solid (303mg, 73%).
MS(ESI,pos.ion)m/z:416.9[M+H]
+。
step 2) 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(pyrazolo [1,5-a] pyridine-5-yl) pyridin-3-yl) benzsulfamide (2.3g, 5.52mmol) be dissolved in DMF (10mL), then at room temperature, in reaction solution, add N-N-iodosuccinimide (1.3g, 5.8mmol) in batches, reaction mixture at room temperature stirring reaction, after 1 hour, adds saturated Na
2s
2o
3the aqueous solution (10mL) cancellation reaction, by gained mixture suction filtration, obtaining title compound is white solid (2.87g, 96%).
MS(ESI,pos.ion)m/z:542.9[M+H]
+；
1H NMR(600MHz,CDCl
3)δ(ppm):8.52(d,J=7.2Hz,1H),8.19(d,J=2.2,1H),8.03-7.98(m,2H),7.97-7.91(m,1H)7.49(d,J=1.0Hz,1H),7.32(s,1H),7.05-6.91(m,2H),4.00(s,3H),2.80(s,1H)。
step 3) 2, the fluoro-N-of 4-bis-(5-(3-(3-hydroxy-3-methyl-ethyl acetylene-1-yl) pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide
By compound 2, the fluoro-N-of 4-bis-(5-(3-iodine pyrazolo [1,5-a] pyridine-5-yl)-2-methoxypyridine-3-yl) benzsulfamide (1.0g, 1.85mmol), 2-methyl-3-butyne-2-alcohol (0.23g, 2.76mmol), Pd (PPh
3)
2cl
2(0.13g, 0.19mmol), CuI (36mg, 0.19mmol) and diisopropylethylamine (0.74g, 0.57mmol) be dissolved in 20mL DMF, at room temperature stirring reaction after 3 hours of mixture, concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying, and obtaining title compound is faint yellow solid (0.42g, 46%).
MS(ESI,pos.ion)m/z:499.0[M+H]
+；
1H NMR(600MHz,CDCl
3)δ(ppm):8.52(d,J=6.1Hz,1H),8.20(d,J=2.1Hz,1H),8.08(s,1H),8.03(d,J=2.1Hz,1H),7.92(dd,J=14.5,8.3Hz,1H),7.68(s,1H),7.59-7.52(m,1H),7.51-7.42(m,1H),7.05-6.94(m,2H),4.00(s,3H),1.60(s,6H)。
embodiment 9 N-(5-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also)-2-methoxypyridine-3-yl) cyclopropyl-sulfonylamide
Compound 5-bromine pyrazolo [1,5-a] pyridine-3-formonitrile HCN (50mg, 0.225mmol) is dissolved in to 1; in 4-dioxane (5mL) and water (0.5mL); then under nitrogen protection, in reaction solution, add successively N-(2-methoxyl group-5-(4,4; 5; 5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) cyclopropyl-sulfonylamide (96mg; 0.270mmol), Na
2cO
3(48mg, 0.45mmol) and Pd (dppf) Cl
2cH
2cl
2(37mg, 0.045mmol).Reaction solution under nitrogen protection in 90 DEG C of stirring reactions after 3.5 hours, be cooled to room temperature, at room temperature continue to stir to spend the night, then add ethyl acetate (30mL) dilute reaction solution, the mixture obtaining is by diatomite suction filtration, ethyl acetate for filter cake (20mL) is washed, filtrate successively water (30mL) and salt solution (30mL) is washed, separatory, the organic phase anhydrous sodium sulfate drying obtaining, concentrating under reduced pressure, gained residue is through silica gel column chromatography (DCM/EtOAc (v/v)=10/1) purifying, obtaining title compound is white solid (55mg, 66%).
MS(ESI,pos.ion)m/z:370.0[M+H]
+；
1H NMR(300MHz,CDCl
3)δ(ppm):8.61(d,J=7.26Hz,1H),8.27-8.25(m,2H),8.09(d,J=2.07Hz,1H),7.87(s,1H),7.21(dd,J=1.77,7.35Hz,1H),6.80(br s,1H),4.11(s,3H),2.60-2.51(m,1H),1.33-1.22(m,2H),1.07-0.99(m,2H)。
embodiment 10 N-(5-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also)-2-methoxypyridine-3-yl)-2,2,2-trifluoroethyl sulphonamide
step 1) N-(the bromo-2-methoxypyridine-3-of 5-yl)-2,2,2-trifluoroethyl sulphonamide
By bromo-compound 5-2-methoxypyridine-3-amine (500mg, 2.46mmol) be dissolved in pyridine (10mL), then in reaction solution, dropwise add 2, 2, 2-trifluoroethyl SULPHURYL CHLORIDE (898mg, 4.92mmol), at room temperature stirring reaction after 18 hours of reaction solution, concentrating under reduced pressure, then add water (30mL) that residue is diluted, gained is methylene dichloride (20mL x3) extraction for mixture, the organic phase difference water (25mL x2) and the salt solution (25mL) that merge are washed, with anhydrous sodium sulfate drying, it is yellow solid (859mg that concentrating under reduced pressure obtains title compound, 100%), this solid is without being further purified, be directly used in next step reaction.
MS(ESI,pos.ion)m/z:348.9[M+H]
+；
1H NMR(300MHz,CDCl
3)δ(ppm):8.03(d,J=2.19Hz,1H),7.91(d,J=2.22Hz,1H),7.00(br s,1H),4.00(s,3H),3.87(q,J=8.73Hz,2H)。
step 2) 2,2, the fluoro-N-of 2-tri-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) ethyl sulfonamide
By compound N-(the bromo-2-methoxypyridine-3-of 5-yl)-2,2,2-trifluoroethyl sulphonamide (500mg, 1.43mmol), connection boric acid pinacol ester (1.45g, 5.729mmol) and KOAc (562mg, 5.729mmol) be dissolved in 1, in 4-dioxane (10mL), by mixture substitute gas (nitrogen) several times after, add Pd (dppf) Cl
2cH
2cl
2(248mg, 0.304mmol).Reaction solution stirring reaction after 3.5 hours at 80 DEG C, concentrating under reduced pressure, then add methylene dichloride (50mL) dilution residue, the mixture obtaining is by diatomite suction filtration, gained filtrate successively water (25mL x3) and salt solution (35mL) is washed, separatory, the organic phase anhydrous sodium sulfate drying obtaining, concentrating under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, obtaining title compound is yellow oil (395mg, 70%).
MS(ESI,pos.ion)m/z:397.0[M+H]
+；
1H NMR(300MHz,CDCl
3)δ(ppm):8.36(d,J=1.59Hz,1H),8.05(d,J=1.59Hz,1H),6.94(br s,1H),4.04(s,3H),3.85(q,J=7.82Hz,2H),1.33(s,12H)。
step 3) N-(5-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also)-2-methoxypyridine-3-yl)-2,2,2-trifluoroethyl sulphonamide
By compound 5-bromine pyrazolo [1; 5-a] pyridine-3-formonitrile HCN (100mg; 0.450mmol) be dissolved in 1; in 4-dioxane (20mL) and water (4mL); then under nitrogen protection; in reaction solution, add the fluoro-N-of 2,2,2-tri-(2-methoxyl group-5-(4; 4; 5,5-tetramethyl--1,3; 2-dioxane pentaborane-2-yl) pyridin-3-yl) ethyl sulfonamide (196mg; 0.495mmol), KOAc (88mg, 0.900mmol) and Pd (dppf) Cl
2cH
2cl
2(74mg, 0.09mmol).Reaction solution under nitrogen protection in 90 DEG C of stirring reactions after 2.5 hours; be cooled to room temperature and continue to stir and spend the night; by mixture concentrating under reduced pressure; then add ethyl acetate (35mL) dilution residue; gained mixture is through diatomite suction filtration; ethyl acetate for filter cake (35mL) is rinsed, and the filtrate obtaining is water H successively
2o (15mL) and salt solution (20mL) washing, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, the residue obtaining is through silica gel column chromatography (PE/EtOAc (v/v)=2.5/1) purifying, obtaining title compound is yellow solid (94mg, 51%).
MS(ESI,pos.ion)m/z:412.0[M+H]
+；
1H NMR(300MHz,DMSO-d
6)δ(ppm):10.15(s,1H),9.03(d,J=7.32Hz,1H),8.67(s,1H),8.65(d,J=2.25Hz,1H),8.24(d,J=1.05Hz,1H),8.18(d,J=2.28Hz,1H),7.59(dd,J=1.80,7.26Hz,1H),4.63(q,J=9.78Hz,2H),4.00(s,3H)。
embodiment 11 N-(the chloro-5-of 2-(3-cyano pyrazole is [1,5-a] pyridine-5-yl also) pyridin-3-yl)-2,4 difluorobenzene sulphonamide
Compound 5-bromine pyrazolo [1,5-a] pyridine-3-formonitrile HCN (110mg, 0.5mmol) is dissolved in to 1, in 4-dioxane (20mL), then in reaction solution, add successively N-(the chloro-5-(4,4 of 2-, 5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl)-2,4-difluorobenzene sulphonamide (235mg, 0.55mmol), KOAc (98mg, 1mmol), H
2o (2mL) and Pd (dppf) Cl
2cH
2cl
2(81mg; 0.1mmol); reaction solution under nitrogen protection in 93 DEG C of stirring reactions after 2 hours; concentrating under reduced pressure, ethyl acetate for residue (20mL x3) extraction, the organic phase anhydrous sodium sulfate drying of merging; concentrating under reduced pressure; gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4.5/1) purifying, and obtaining title compound is white solid (130mg, 59%).
MS(ESI,pos.ion)m/z:446.0[M+H]
+；
1H NMR(300MHz,DMSO-d
6)δ(ppm):10.98(br s,1H),9.08(d,J=7.29Hz,1H),8.87(d,J=2.67Hz,1H),8.71(s,1H),8.41-8.39(m,2H),7.84-7.76(m,1H),7.63-7.54(m,2H),7.26-7.20(m,1H)。
Biological test
The compounds of this invention can be evaluated by following test as the activity of PI3K and mTOR kinase inhibitor.Result of study shows that the compounds of this invention can suppress PI3K and the kinase whose activity of mTOR effectively.
bioanalytical method
The LC/MS/MS system of analyzing use comprises Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate automatic sampler, post thermostat container, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis is carried out under MRM pattern, and the parameter of MRM conversion is as shown in Table A:
Table A
| Many reaction detection scanning | 490.2→383.1 |
| Cracked voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350℃ |
| Spraying gun | 40psi |
| Moisture eliminator flow velocity | 10L/min |
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μ M posts, inject 5 μ L samples.Analysis condition: the aqueous formic acid (A) that moving phase is 0.1% and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient wash-out is as shown in table B:
Table B
| Time | The gradient of Mobile phase B (0.1% formic acid methanol solution) |
| 0.5min | 5% |
| 1.0min | 95% |
| 2.2min | 95% |
| 2.3min | 5% |
| 5.0min | stop |
In addition G1312A binary syringe pump is equipped with,, for the series of the Agilent6330 in addition LC/MS/MS spectrograph of analyzing,, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrograph adopts ESI radioactive source.Each analyte is carried out to suitable positively charged ion models treated to use reference liquid and best analysis is carried out in MRM conversion.During analyzing, use Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.
embodiment A: the stability of compound in people and rat liver microsomes
People or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), target compound (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and using PBS to be diluted, the concentration that makes its final DMSO solution is 0.05%.And hatch in the water-bath communicating with air at 37 DEG C, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60 minutes), add the ice-cold acetonitrile termination reaction of same volume.Sample is preserved until carry out LC/MS/MS analysis at-80 DEG C.
The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallel microsome of hatching test use sex change is as negative control, and hatching at 37 DEG C, reacts and stop at different time point (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ) is as positive control, and hatching at 37 DEG C, reacts and stop at different time point (0,5,10,15,30 and 60 minutes).In each measuring method, all comprise positive and negative control sample, to ensure the integrity of microsome hatching system.In addition, the stability data of compound of the present invention in people or rat liver microsomes also can be obtained by following test.People or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typical mixtures incubated comprises people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound (ultimate density: 1.5 μ M) and cumulative volume are that the K-buffered soln of 30 μ L (contains 1.0mM EDTA, 100mM, pH7.4).By compound dissolution, in DMSO, and with K-buffered soln dilution, the ultimate density that makes DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density: 2mM) to carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 DEG C.In different time points (0,15,30 and 60 minutes), add 135 μ L acetonitriles (containing IS) termination reaction.With 4000rpm centrifugal 10 minutes, except Deproteinization, collect supernatant liquid, analyze with LC-MS/MS.
In above-mentioned test, ketanserin (1 μ M) is selected as positive control, hatching at 37 DEG C, and reaction stops at different time point (0,15,30 and 60 minutes).In each measuring method, all comprise positive control sample, to ensure the integrity of microsome hatching system.
data analysis
For each reaction, the concentration (representing with per-cent) by compound in people or rat liver microsomes are hatched is mapped by the per-cent of Relative Zero time point, infers CLint CL in body with this
int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, KagayamaA, Sugiyama Y. " Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolicstudies with liver microsomes from animals and humans ", Drug Metabolism and Disposition, 2001,29,1316-1324).
The stability data of table 1 embodiment of the present invention in people and rat liver microsomes
The demonstration of table 1 result, the compounds of this invention is all comparatively stable in the hepatomicrosome of people and rat.
embodiment B: the Pharmacokinetic Evaluation after mouse, rat, dog and monkey injection and oral the compounds of this invention
The present invention to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assess.The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% tween-80, the salt brine solution of 5%DMSO+5%, and 4%MC or capsule form are carried out administration.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.Be 0.25,0.5,1.0,2.0 at time point, 3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and at-20 DEG C or-70 DEG C, preserve until carry out above-mentioned LC/MS/MS analysis.
The pharmacokinetic data of table 2 embodiment of the present invention in rat body
The pharmacokinetic data of table 3 embodiment of the present invention in mouse, dog and monkey body
Table 2,3 results demonstrations, the compounds of this invention absorbs well in mouse, rat, dog and monkey body, and the transformation period is reasonable.
embodiment C: kinase activity test
The compounds of this invention can be evaluated by following test as the activity of PI3K and mTOR kinase inhibitor.
the generality of kinase assay is described
Kinase assay by detection mix γ-
33the myelin basic protein (MBP) of P-ATP completes.Prepare MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS of 20 μ g/mL; 50mM Tris pH8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plates (Greiner) of coated high associativity, every hole 60 μ L.4 DEG C, hatch 24 hours.Wash plate 3 times with 100 μ L TBS afterwards.Kinase reaction is kinase buffer liquid (5mM Hepes pH7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), the 10mM MgCl of 34 μ L at cumulative volume
2, 1mM DTT, 0.02%TritonX-100) in carry out.Compound dissolution, in DMSO, is added in each hole, and the ultimate density of DMSO is 1%.Each data determination twice, the mensuration of each compound is at least carried out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Add do not have markd ATP (10 μ M) and γ-
33aTP (every hole 2 × 10 of P mark
6cpm, 3000Ci/mmole) start to react.Reaction at room temperature concussion is carried out 1 hour.384 orifice plates clean with the PBS of 7x, then add the scintillation solution of every hole 50 μ L.By Wallac Trilux counter detected result.To those of ordinary skill in the art, this is only the one in numerous detection methods, and other method also can.
The IC that above-mentioned test method can be inhibited
50and/or inhibition constant K
i.IC
50be defined as under test conditions the compound concentration while suppressing 50% enzymic activity.Utilize the extension rate of 1/2log to make the curve that comprises 10 concentration point, estimation IC
50value (for example, making a typical curve by following compound concentration: 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M, 0.01 μ M, 0.003 μ M, 0.001 μ M and 0 μ M).
the kinase whose ordinary test scheme of PI3
pI3K (p110 α/p85 α) (h) [cold test]
PI3K (p110 α/p85 α) (h) is containing 10 μ M phosphoric acid acyl inositol-4, in the buffered soln of 5-bisphosphate and MgATP (concentration is determined according to demand), hatches.Add after ATP solution, start reaction.After hatching 30 minutes under room temperature, add wherein and contain EDTA and vitamin H phosphatidylinositols-3, the stop buffer of 4,5-triphosphoric acid carrys out termination reaction.Finally, add detection damping fluid, comprise the anti-GST monoclonal antibody of europium mark, GRP1PH structural domain and the streptavidin-allophycocyanin of GST mark.Orifice plate is reading under time resolved fluorescence pattern, and homogeneous phase time discrimination fluorescence (HTRF) signal is determined by equation HTRF=10000x (Em665nm/Em620nm).
pI3K (p110 β/p85 α) (h) [cold test]
PI3K (p110 β/p85 α) (h) is containing 10 μ M phosphoric acid acyl inositol-4, in the buffered soln of 5-bisphosphate and MgATP (concentration is determined according to demand), hatches.Add after ATP solution, start reaction.After hatching 30 minutes under room temperature, add wherein and contain EDTA and vitamin H phosphatidylinositols-3, the stop buffer of 4,5-triphosphoric acid carrys out termination reaction.Finally, add detection damping fluid, comprise the anti-GST monoclonal antibody of europium mark, GRP1PH structural domain and the streptavidin-allophycocyanin of GST mark.Orifice plate is reading under time resolved fluorescence pattern, and homogeneous phase time discrimination fluorescence (HTRF) signal is determined by equation HTRF=10000x (Em665nm/Em620nm).
pI3K (p110 δ/p85 α) (h) [cold test]
PI3K (p110 δ/p85 α) (h) is containing 10 μ M phosphoric acid acyl inositol-4, in the buffered soln of 5-bisphosphate and MgATP (concentration is determined according to demand), hatches.Add after ATP solution, start reaction.After hatching 30 minutes under room temperature, add wherein and contain EDTA and vitamin H phosphatidylinositols-3, the stop buffer of 4,5-triphosphoric acid carrys out termination reaction.Finally, add detection damping fluid, comprise the anti-GST monoclonal antibody of europium mark, GRP1PH structural domain and the streptavidin-allophycocyanin of GST mark.Orifice plate is reading under time resolved fluorescence pattern, and homogeneous phase time discrimination fluorescence (HTRF) signal is determined by equation HTRF=10000x (Em665nm/Em620nm).
(h) [cold test] of PI3K (p120 γ)
PI3K (p120 γ) (h) is containing 10 μ M phosphoric acid acyl inositol-4, in the buffered soln of 5-bisphosphate and MgATP (concentration is determined according to demand), hatches.Add after ATP solution, start reaction.After hatching 30 minutes under room temperature, add wherein and contain EDTA and vitamin H phosphatidylinositols-3, the stop buffer of 4,5-triphosphoric acid carrys out termination reaction.Finally, add detection damping fluid, comprise the anti-GST monoclonal antibody of europium mark, GRP1PH structural domain and the streptavidin-allophycocyanin of GST mark.Orifice plate is reading under time resolved fluorescence pattern, and homogeneous phase time discrimination fluorescence (HTRF) signal is determined by equation HTRF=10000x (Em665nm/Em620nm).
mTOR(h)
The HEPES that mTOR (h) is 7.0 in 50mM pH value, 1mM EDTA, 0.01% tween 20,2mg/mL substrate, 3mM Manganous chloride tetrahydrate and [γ-
33p-ATP] hatch under (the about 500cpm/pmol of specific activity, concentration according to demand determine) condition of existing.After adding MnATP mixture, start reaction.After hatching 40 minutes under room temperature, add wherein 3% phosphoric acid solution termination reaction.10 μ L reaction solutions are on the mottled P30 of being distributed in strainer, and in 5 minutes, clean 3 times with 75mM phosphoric acid, and before dry and scintillation counting, put at once methanol solution and preserve.
Kinase assay in the present invention completes (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK) by Millipore company of Britain.
The kinase inhibiting activity data of table 4 embodiment of the present invention
Table 4 result shows, the compounds of this invention can suppress PI3K and the kinase whose activity of mTOR effectively, and the different subtype in PI3K kinases family is had to good selectivity, thereby show that the compounds of this invention has different optionally inhibition activity to PI3K and mTOR.
The kinase inhibiting activity of the compounds of this invention also can pass through KINOMEscan
tMtest, it mainly based on quantitative assay sample and fixing, have the part of active-site directed and a test of kinases competitive binding ability.Completing of this test needs in conjunction with following three elements: the kinases of DNA-mark, fixing part and testing sample.The kinase whose ability of competitive binding of testing sample and fixed ligands can be determined by the amount of measuring the PCR in DNA marker.
For great majority tests, the T7 phage strains of kinases-mark is that the escherichia coli host that origin comes from BL21 bacterial strain prepares.First intestinal bacteria are cultivated to logarithmic phase, then infected with T7 phage, and it is being hatched until cracking, by centrifugal lysate, suction filtration, is removed cell debris in 32 DEG C under concussion continuously.And then the remaining kinases producing in HEK-293 cell carrys out mark with DNA, for the detection of qPCR.The magnetic bead that is coated with Streptavidin at room temperature reacts after 30 minutes with biotinylated small molecules part, generates the affine resin for kinase assay.The magnetic bead that coordination is good is stopped up by excessive vitamin H, with sealing buffered soln (SEABLOCK
tM(Pierce), 1%BSA, 0.05% tween 20,1mM DTT) wash and remove free part, to reduce non-specific binding.Association reaction is all at 1x binding buffer liquid (20%SEABLOCK by the magnetic bead of kinases, affinity that coordination is good and testing sample
tM, 0.17x PBS, 0.05% tween 20,6mM DTT) in complete.Carry out in 96 orifice plates of the polystyrene that is all 0.135mL in final volume of responding.The orifice plate of test is all being hatched 1 hour in room temperature condition under concussion continuously, the magnetic bead of affinity is all used lavation buffer solution (1x PBS, 0.05% tween 20) washing, then be resuspended to elution buffer (1x PBS, 0.05% tween 20, the abiotic elementization affinity ligands of 0.5 μ M) in, and under concussion, hatching 30 minutes in room temperature condition continuously.Kinases concentration in elutriant is measured by qPCR.
Kinase assay in the present invention is the KINOMEscan by DiscoveRx company
tM(42501Albrae St.Fremont, CA94538, the USA) that Analysis Service completes.
embodiment D: xenotransplantation tumor model
The drug effect of the compounds of this invention is to evaluate by the standard muroid model of transplantation tumor.Human tumor cells (U87MG glioma cell, ATCC) after cultivating, collecting, (BALB/cA nu/nu, Hunan SLAC Animal Lab.) (for group of solvents and each dosage group: n=6-10) in the female nude mouse body in age in week in rear veutro subcutaneous vaccination in 6-7.When gross tumor volume reaches 100-250mm
3time, animal is divided into solvent control group (5%DMSO+70% randomly
(30%), 7%HCl (pH1), 18%
(30%); Or 7%DMSO, 7%HCl (pH1), 70%
(30%), 16%
) and compound group (30%).Following adopted compound carries out gastric infusion to animal, starting Anywhere in 0 to 15 day from tumor cell inoculation, and conventionally carry out once every day in test.
tumor growth suppresses (TGI) and analyzes
The crystallization growth of tumour is to evaluate by the relation of gross tumor volume and time.Major axis (L) and the minor axis (W) of Subcutaneous tumor measure weekly twice by calipers, and the volume (TV) of tumour is by formula (L × W
2)/2) calculate.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume intermediate value, recently represents with the percentage of solvent control group gross tumor volume intermediate value, calculates by following formula:
Primary statistics is analyzed by repeating variance determination and analysis (RMANOVA) and is completed.Next carry out multiple comparisons by Scheffe psot hoc test method.Separate solvent (5%DMSO+70%
(30%), 7%HCl (pH1), 18%
(30%); Or 7%DMSO, 7%HCl (pH1), 70%
(30%), 16%
(30%)) negative contrast.
Xenotransplantation tumor model (U87MG) data of table 5 embodiment of the present invention
The demonstration of table 5 result, the compounds of this invention can significantly suppress the growth of neurospongioma U87MG xenograft tumor, and presents obvious dose-dependently, and these compounds have good curative effect to neurospongioma.
Finally, it should be noted that other modes are used for implementing the present invention in addition.Correspondingly, embodiments of the invention are to describe as illustration, but are not limited to content described in the invention, may be also the amendment done within the scope of the present invention or the equivalents added in the claims.All publications that the present invention quotes or patent all will be served as reference of the present invention.
Claims (16)
1. a compound, it is the steric isomer of compound shown in the compound of structure shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Wherein:
Each W
1, W
2and W
3be N or CR independently
c;
Z is D, CN, N
3or
X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
Y is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group, C
3-6heterocyclic radical-C
1-4alkylidene group, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, NC-C
1-4alkylidene group, R
ao-C
1-4alkylidene group, R
br
an-C
1-4alkylidene group, C
6-10aryl or 5-10 former molecular heteroaryl;
R
1for H, D, Cl, OR
a, NR
ar
b, C
1-6aliphatics or C
3-6cycloalkyl, wherein, described C
1-6aliphatics and C
3-6cycloalkyl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OR
a, SR
aor NR
ar
b;
Each R
aand R
bbe H independently, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprises 1,2,3 or 4 and is independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, C
6-10aryl-C
1-4alkylidene group, (5-10 former molecular heteroaryl)-C
1-4alkylidene group, or R
a, R
btogether with the nitrogen-atoms being connected with them, optionally form replace or non-substituted 3-8 former molecular heterocycle, wherein, described substituting group is not substituted or independently of one another by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkoxyl group or C
1-6alkylamino;
Each R
cbe H independently, D, F, Cl, Br, I, N
3, CN, OH, NH
2, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, CN, N
3, OH, NH
2, C
1-6alkyl, C
3-6cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl group or C
1-6alkylamino.
2. compound according to claim 1, wherein, W
1for N or CR
c; Each W
2and W
3be CR independently
c.
3. compound according to claim 1, wherein, Z is CN, N
3or
4. compound according to claim 1, wherein, X is H, D, C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group or C
3-6heterocyclic radical-C
1-4alkylidene group, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
3-6cycloalkyl-C
1-4alkylidene group and C
3-6heterocyclic radical-C
1-4alkylidene group is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4thiazolinyl or C
2-4alkynyl.
5. compound according to claim 1, wherein, Y is C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl or comprise 1,2,3 or 4 and be independently selected from O, the heteroatomic 5-10 of a S and N former molecular heteroaryl, wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
6-10aryl and 5-10 former molecular heteroaryl is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, CN, N
3, OR
a, SR
a, NR
ar
b,-C (=O) NR
ar
b, C
1-3alkyl, C
1-3haloalkyl, C
2-4alkynyl, C
6-10aryl or 5-10 former molecular heteroaryl.
6. compound according to claim 1, wherein, R
1for H, D, Cl, CH
3, CH
2cH
3, CF
3, CH
2cF
3, OCH
3or OCH
2cH
3.
7. compound according to claim 1, wherein, each R
cbe H independently, D, F, Cl, N
3, CN, NH
2, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl or C
3-6heterocyclic radical, wherein, described C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, C
3-6cycloalkyl and C
3-6heterocyclic radical is not substituted independently of one another or by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, CN, N
3, OH, NH
2, C
1-3alkyl, C
3-6cycloalkyl or C
1-3haloalkyl.
8. compound according to claim 1, has following one of them structure:
9. a pharmaceutical composition, comprises the compound described in claim 1-8 any one, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, or vehicle, or their combination.
10. pharmaceutical composition according to claim 9, wherein further comprises additional treatment agent, and described additional treatment agent is selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, or be used for the treatment of the medicine of pulmonary fibrosis or their combination.
11. pharmaceutical compositions according to claim 10, 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), bosutinib (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), many Weis are for Buddhist nun (dovitinib), Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, Mo Tesaini (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, Aura handkerchief Buddhist nun (olaparib), pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, Telatinib (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 difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), or Herceptin (trastuzumab), or their combination.
Pharmaceutical composition described in compound or claim 9-11 any one described in 12. claim 1-8 any one is in the purposes for the preparation of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
13. purposes according to claim 12, wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, head and neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
Pharmaceutical composition described in compound or claim 9-11 any one described in 14. claim 1-8 any one is in the purposes of medicine for the preparation of suppress or regulate protein kinase activity in biological sample, and described purposes comprises right to use and requires compound described in 1-8 any one or right to use to require the pharmaceutical composition described in 9-11 any one to contact with described biological sample.
15. purposes according to claim 14, wherein, described protein kinase is receptor tyrosine kinase.
16. purposes according to claim 15, wherein, described receptor tyrosine kinase is PI3K and/or mTOR.
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