CN103387535A - Substituted alkynylpyridine compound, and application method and use thereof - Google Patents
Substituted alkynylpyridine compound, and application method and use thereof Download PDFInfo
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Abstract
The invention provides a substituted alkynylpyridine compound with a structure represented by a formula (I) as described in the specification and a pharmaceutically acceptable salt and a medicinal preparation thereof. The compound is used for adjusting activity of protein kinase and adjusting intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition including the compound provided by the invention and a method of applying the pharmaceutical composition in treating mammals, especially in treating highly proliferative diseases of the mankind.
Description
The application requires to submit on 05 10th, 2012 the Chinese patent application that Patent Office of the People's Republic of China, application number are 201210141993.5, denomination of invention is " the alkynyl pyridine compounds of replacement and using method and purposes " and submitted the right of priority of the Chinese patent application that Patent Office of the People's Republic of China, application number are 201310116652.7, denomination of invention is " the alkynyl pyridine compounds of replacement and using method and purposes " on 04 03rd, 2013 to, and its full content is by reference in conjunction with in this application.
Technical field
The invention belongs to technical field of pharmaceuticals, relate in particular to a kind of alkynyl pyridine compounds and using method and purposes of replacement.
Background technology
Protein kinase, as the important conditioning agent of cell function, is one of member that in gene family, quantity is maximum, function is the widest.They,, by substrate protein is increased to phosphate group, regulate activity, position and the allomeric function of multiple protein, and participate in the many cellular processes of layout.Kinases in the cooperation of signal conduction and sophisticated functions, as: the cell cycle, occupy very outstanding position.In 518 kinds of human kinase proteins, have 478 kinds because the catalytic domain sequence is close, be included into a superfamily, according to the similarity and the biochemical activity that increase sequence, they can be divided into different groups, family or subfamily again.
The list of wherein said kinases part comprises abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes and Zap70.
Receptor tyrosine kinase (RTKs) is one type of abundant transmembrane protein, can be used as the acceptor of cytokine, somatomedin, hormone and other signaling molecules.Receptor tyrosine kinase is expressed in polytype cell, in various cellular processes, plays an important role, and comprises Growth of Cells, differentiation and vasculogenesis.Kinase whose activation starts from extracellular region territory and ligand binding, then causes and conformational change causes receptor dimerization, mutual phosphorylation between the acceptor of dimerization, the outer tyrosine residues of autophosphorylation catalysis region subsequently.This autophosphorylation can the stable activation acceptor conformation, can in the albumen of Cellular Signaling Transduction Mediated, set up again phosphorylation and pile up point.
By receptor activation, suddenly change, gene amplifies, the approach such as growth factor activation, and receptor tyrosine kinase shows as high reactivity in many human entity knurls and malignant hematologic disease.The acceleration of RTKs activates has promoter action to various tumorigenesis factors, and as hyperplasia, survival, intrusion, transfer and vasculogenesis, therefore, the activity that suppresses receptor tyrosine kinase is considered to effective scheme (the Sharma PS of cancer therapy; Et al. " Receptor tyrosine kinase inhibitors as potent weapons in war against cancers. " Curr Pharm Des.2009,15,758).
Receptor tyrosine kinase Nucleophosmin-anaplastic lymphoma kinase (ALK), belong to the insulin receptor superfamily, relevant with the generation of multiple human tumor.In fact; tentatively confirm that the form that ALK merges with constitutively activate and oncogene exists; to be present in nuclear phosphoprotein (NPM) in primary cutaneous type (the lymphadenomatous a kind of independent type of Fei Huojinsen)-ALK-the most common (Morris, S.W.; Et al. " Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin ' s lymphoma. " Science1994,263,1281).
In addition, people have also found the ALK fusion gene in Inflammatory myofibroblastic tumor (IMTs), and, in the subspecies of esophageal squamous cell carcinoma, have also found ALK fusion gene---TPM4-ALK.Studies show that, in familial form and diversity neuroblastoma, all have the sudden change of multiple ALK gene.This sudden change be present in neuroblastoma cell can cause composing type ALK phosphorylation and hypofunction.Contrary, use sRNA and small molecules ALK inhibitor can suppress rapid growth (Palmer, the R.H. of cell strain; Et al. " Anaplastic lymphoma kinase:signalling in development and disease. " Biochem.J.2009,420,345).
Recent years, people confirm in nonsmall-cell lung cancer (NSCLC) cell, exist by part echinoderms microtubule-associated protein sample 4(EML4) the multiple hypotype of the fusion gene of gene and ALK genomic constitution.The NSCLC patient of nearly 3-7% is detected EML4-ALK fusion gene transcript.In body, with external test, confirm, EML4-ALK fusion gene albumen has the oncogenic transformation activity, and the mankind are suffered to NSCLC material impact (Soda, M.; Et al " Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. " Nature2007,448,561).
The fusion gene of ALK demonstrates obvious carinogenicity, and its abnormal tyrosine kinase activity can be strengthened cell proliferation and survival, causes cytoskeleton to be reset, and cell shape is changed.In carcinogenic ALK signal transduction process, ALK and downstream molecules interact, then signal path in activating cells, the same with most of normal and carcinogenic Tyrosylprotein kinases, the ALK fusion gene can activate multiple different path, these paths closely are connected, and overlap, and finally form the Signaling transduction networks of a complexity.According to the literature, the most relevant, and research comparatively clearly path have three: the Ras-ERK(extracellular signal-regulated kinase) path, JAK3(Janus kinases 3)-STAT3 path and PI3K(phosphatidyl-inositol 3-kinase)-the Akt path.Many sites in these three paths can mediate the activation of ALK.In a word, JAK3-STAT3 path and PI3K-Akt path play vital effect (Chiarle, R. to cell survival and phenotypic alternation; Et al. " The anaplastic lymphoma kinase in the pathogenesis of cancer. " Nat.Rev.Cancer2008,8,11; Barreca, A.; Et al. " Anaplastic lymphoma kinase (ALK) in human cancer. " J.Mol.Endocrinol.2011,47, R11).
It is associated that complete, normal ALK acceptor and the generation of other malignancy diseases also exist, such as, glioblastoma multiforme, neuroblastoma, breast cancer, etc.In the collection investigation of a human cancer cell strain, the people such as Dirks confirm, there is the expression of ALK transcript in nervous system cell strain and most of ectoderm entity cancer cell strain, these cell strains comprise retinoblastoma, melanoma and breast cancer (Dirks, P.B. " Cancer ' s source in the peripheral nervous system. " Nature Medicine2008,14,373).
C-Met, i.e. hepatocyte growth factor receptor (HGFR), its main point of application is at endotheliocyte, and has confirmed that it is at endotheliocyte, myogenous cells, all have expression in hematopoietic cell and motor neuron.The natural part of c-Met is pHGF (HGF), and it is a multi-functional somatomedin, i.e. dispersion factor (SF).In fetus and adult, activate the formation that c-Met can promote some form, for example, invasive growth will cause the Fast Growth of cell, intercellular division, and cell moves (Peschard P. on every side to it; Park M. " From Tpr-Met to Met, tumorigenesis and tubes. " Oncogene2007,26,1276; Stellrecht CM; Gandhi V. " Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target. " Cancer Letter2009,280,1).
The human malignancies extensively existed exists lasting c-Met to stimulate, cross and express or variation, comprises mammary cancer, liver cancer, lung cancer, ovarian cancer, kidney, thyroid carcinoma, colorectal carcinoma, glioblastoma, prostate cancer etc.C-Met involves atherosclerosis and pulmonary fibrosis equally.By the interaction of mesenchyma stroma of tumors, comprise the HGF/c-Met approach, the invasive growth speed of these cancer cells has thoroughly been improved.Therefore, a large amount of evidences show that the c-Me signal responses are relevant with certain cancers advancing of disease speed, and improved its with take cancer drug that c-Met is main target spot role status (the Migliore C. in developing; Giordano S. " Molecular cancer therapy:can our expectation be MET. " Eur.J.Cancer2008,44,641; Benedetta Peruzzi; Donald P.Bottaro. " Targeting the c-Met Signaling Pathway in Cancer. " Clinical Cancer Research2006,12,3657).Instantly, the medicine of developing for the c-Met signal path is (Joseph Paul Eder in clinical study just; Et al. " Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer. " Clinical Cancer Research2009,15,2207; " Paolo M.; Et al.Drug development of MET inhibitors:targeting oncogene addiction and expedience. " Nature Review Drug Discovery2008,7,504).
Clinically, there have been many ALK and/or c-Met inhibitor to be used for treating cancer.Ke Zhuo is the competitive ALK inhibitor of a kind of small molecules ATP for Buddhist nun (Crizotinib), simultaneously, also can act on the c-Met receptor tyrosine kinase.On August 26th, 2008, U.S. FDA approval gram is tall and erect for Buddhist nun's (trade(brand)name
code name PF-02341066) be used for the treatment of local late period or metastatic, have the nonsmall-cell lung cancer of Nucleophosmin-anaplastic lymphoma kinase (ALK) gene rearrangement.The rearrangement of ALK (EML4-ALK) gene, cause cell mutation, promoted the malignant phenotype of lung carcinoma cell.Therefore, the kinases ALK of mutation inhibiting is effective for the treatment cancer.
Summary of the invention
In view of this, the invention provides a kind of alkynyl pyridine compounds of new replacement, this compound is inhibited to protein tyrosine kinase, can be for the preparation of the medicine for the treatment of cell proliferation disorders.
Compound of the present invention has restraining effect to protein tyrosine kinase activity, more satisfactory, compound of the present invention can suppress to comprise the ALK fusion gene as ALK(, as: EML4-ALK, or c-Met acceptor (hepatocyte growth factor receptor) signal response NPM-ALK etc.).Correspondingly, the present invention also provides the inhibitor of some new protein tyrosine kinase receptor signal responses, as the response of ALK receptor signal or the response of c-Met receptor signal.
Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can be effective as tyrosine kinase receptor, as the inhibitor of ALK or c-Met.
On the one hand, the present invention relates to a kind of compound as shown in the formula (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein, R
1, R
2, R
3, R
4, R
5, R
6, X and Z have implication as described in the present invention.
In some embodiments, each R
1, R
2, R
3, R
4, R
5and R
6be H independently, D or F;
X is C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N, wherein, described C
6-10aryl and comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N is optionally by 1,2, and 3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3,-OR
a,-SR
a,-NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkenyl, C
2-6alkynyl ,-(C
1-4alkylidene group)-CN ,-(C
1-4alkylidene group)-OR
a,-(C
1-4alkylidene group)-NR
ar
b, C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N;
Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-4alkyl ,-OR
a,-SR
a,-NR
ar
bor-C (=O) NR
ar
b, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently;
Each R
aand R
bbe H independently, C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) or-(C
1-4alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N), and, R worked as
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-8 atom, wherein, described C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) ,-(C
1-4the heterocyclic radical of alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N) and 3-8 atom is optionally by 1,2, and 3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl ,-CN, N
3,-OH ,-NH
2, alkoxyl group or alkylamino;
Special situation, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2.
In the other embodiment, each R
1, R
2, R
3, R
4, R
5and R
6be H or D independently.
In the other embodiment, X is phenyl, and can be optionally by 1,2, and 3 or 4 independently are selected from D, F, Cl, Br, C
1-3alkyl or C
1-3the substituting group of haloalkyl replaces.
In the other embodiment, Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
b, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently.
In the other embodiment, each R
aand R
bbe H independently, C
1-3alkyl, C
3-6cycloalkyl or-(C
1-4alkylidene group)-(C
3-6cycloalkyl), and, R worked as
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-6 atom, wherein, described C
1-3alkyl, C
3-6cycloalkyl ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) and the heterocyclic radical of 3-6 atom optionally by 1,2,3 or 4 substituting groups replace, described substituting group is independently selected from D, F, Cl ,-OH ,-NH
2, C
1-3alkoxyl group or C
1-3alkylamino;
Special situation, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2.
In the other embodiment, Z is selected from any one in minor structure shown in formula (Z1)～(Z42):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each W and W' be independently-O-or-N (H)-;
Minor structure shown in formula (Z1)～(Z42) or its steric isomer be optionally by 1,2, and 3 or 4 independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
bsubstituting group replace, wherein, when Z is the minor structure shown in formula (Z25)～(Z32) or its steric isomer ,-NR
ar
bcan not be-NH
2or-NMe
2.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises the compounds of this invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In some embodiments, pharmaceutical composition of the present invention, further comprise the additional treatment agent, described additional treatment agent is selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis or their combination.
In the 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 (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
On the other hand, can be with the compounds of this invention or pharmaceutical composition 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, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, CNS(central nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to come for the preparation of suppress or regulate the purposes of the medicine of protein kinase activity in biological sample with the compounds of this invention or pharmaceutical composition, described purposes comprises uses the compounds of this invention to contact with described biological sample.
Some embodiments therein, protein kinase of the present invention is receptor tyrosine kinase.
In the other embodiment, receptor tyrosine kinase of the present invention is ALK, c-Met, or their combination.
On the other hand, the invention provides some pharmaceutical compositions, it comprises the compound of the present invention as the tyrosine kinase receptor inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.In some embodiments, pharmaceutical composition provided by the present invention comprises and can be used as ALK receptor signal response, the response of c-Met receptor signal, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.In the other embodiment, pharmaceutical composition of the present invention further comprises the additional treatment agent.
On the other hand, the present invention relates to the method for arrestin tyrosine kinase activity, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described kinases.In some embodiments, the present invention relates to suppress the response of ALK receptor signal, the method for c-Met receptor signal response, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.The other embodiment is that arrestin kinases receptors activity in cell or multicellular organisms, particularly suppress the activity that ALK or c-Met receptor signal respond.According to method of the present invention, the method comprises uses the compounds of this invention or its pharmaceutical composition to carry out administration to described multicellular organisms.In some embodiments, described multicellular organisms refers to Mammals.In the other embodiment, described multicellular organisms refers to the mankind.In some embodiments, the method for the invention further comprises the 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 effective therapeutic dose and the cells contacting of using 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.
On the other hand, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, described method comprises uses effective therapeutic dose of the compounds of this invention or its pharmaceutical composition to carry out administration to the 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 a kind of method that suppresses the patient tumors growth, described method comprises uses effective therapeutic dose of the compounds of this invention or its pharmaceutical composition to carry out administration to the 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.
Experimental result shows, compound provided by the invention shows good transformation period and good pharmacokinetic property, and ALK and c-Met are had to good restraining effect, and the growth of tumour is also had to good restraining effect.
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.
Embodiment
definition and general terms
The present invention will list the corresponding document of specific content of determining in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim is defined.The those skilled in the art will identify many similar or be equal to method described herein and material, and these can be applied to go in practice of the present invention.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but never be limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.
Unless other aspects show, the present invention will apply to give a definition:
According to purpose of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 75,
thed, 1994 define.In addition; the organic chemistry General Principle is shown in " Organic Chemistry; " Thomas Sorrell; University Science Books; Sausalito:1999; and " March ' s Advanced Organic Chemistry, " by Michael B.Smith and Jerry March, John Wiley& Sons, New York:2007, therefore all contents have all merged reference.
Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as top general formula compound, 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." optionally " or " optionally " meaning 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 that this event or situation wherein do not occur.For example: " heterocyclic radical optionally independently is selected from D by 1 or 2; the group of F replaces " meaning refer to this D, F can but may not exist, and this description comprises that wherein heterocyclic radical independently is selected from D by 1 or 2, the situation that the group of F replaces, and the unsubstituted situation of heterocyclic radical.
Generally speaking, term " replacement " or " replacement ", mean that the one or more hydrogen atoms of give in structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to be replaced in each commutable position of group.One or more substituting group that not only position can be selected from concrete group in given structural formula replaces, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " aliphatics " or " aliphatic group " that the present invention uses, mean straight chain (non-side chain) or side chain, the substituted or non-substituted complete saturated or hydrocarbon chain that contains one or more degrees of unsaturation.Unless otherwise detailed instructions, aliphatic group is containing 1-20 carbon atom.Some of them embodiment is, aliphatic group is containing 1-10 carbon atom, and other embodiment is that aliphatic group contains 1-8 carbon atom.Other embodiment is, aliphatic group is containing 1-6 carbon atom, and other embodiment is, aliphatic group is containing 1-4 carbon atom, and other embodiment is that aliphatic group is containing 1-3 carbon atom, other embodiment is that aliphatic group is containing 1-2 carbon atom.Suitable aliphatic group includes, but not limited to straight or branched, substituted or non-substituted alkyl, thiazolinyl, or alkynyl.For example ,-(C
1-C
6) aliphatic group, comprise non-side chain or side chain, non-substituted or suitable replacement-(C
1-C
6) alkyl ,-(C
2-C
6) thiazolinyl, or-(C
2-C
6) alkynyl.Such example comprises, but be not limited to, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, ethene, propylene, butylene, 2-butylene, acetylene, propine, butine, 2-butyne, etc., and aliphatics can be substituted or non-substituted, wherein substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, azido-, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, the cyano group alkyl, hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino, alkylamino, aminoacyl, the alkylamino acyl group, aryl, heteroaryl etc.
Term " alkyl " or " alkyl group " that the present invention uses, mean saturated straight chain or side chain monovalence hydrocarbon polymer atomic group containing 1-20 carbon atom.Wherein said alkyl group can independently optionally be replaced by one or more substituting group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them embodiment is, alkyl group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment is, alkyl group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, other embodiment is, alkyl group is containing 1-3 carbon atom, and other embodiment is that 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.And alkyl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
The term " alkylidene group " that the present invention uses, mean the saturated bivalent hydrocarbon radical obtained from two hydrogen atoms of straight or branched saturated hydrocarbon cancellation.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, some of them embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, other embodiment is, alkylidene group contains 1-3 carbon atom, and other embodiment is that alkylidene group contains 1-2 carbon atom.The example of alkylidene group comprises, but is not limited to methylene radical (CH
2-), ethylidene (CH
2cH
2-), propylidene (CH
2cH
2cH
2-), ethylidine (CH (CH
3)-), inferior sec.-propyl (CH (CH
3) CH
2-) etc.Alkylidene group can be further substituted, and this substituting group is selected from, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " alkenyl " means 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of 2-4 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and a C-C is sp
2two keys, wherein the group of alkenyl can independently optionally be replaced by one or more substituting groups described in the invention, comprises that group has the location of negation " just " or " E " " Z ", and wherein concrete example comprises, but be not limited to vinyl (CH=CH
2), allyl group (CH
2cH=CH
2) etc.
Term " alkynyl " means 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of 2-4 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, a C-C is the sp triple bond, wherein hydrocarbyl group can independently optionally be replaced by one or more substituting groups described in the invention, and concrete example comprises, but is not limited to, ethynyl (C ≡ CH), propargyl (CH
2c ≡ CH) etc.
Term " haloalkyl ", " halogenated alkenyl " or " halogenated alkoxy " means that alkyl, alkenyl or alkoxy base are replaced by one or more halogen atom, wherein alkenyl and alkoxyl group have implication of the present invention, such example comprises, but be not limited to, trifluoromethyl, trifluoromethoxy etc.
Term " carbocyclic ring ", " carbocylic radical " or " carbocyclic ring " refer to monovalence or multivalence, and non-aromatic is saturated or part is unsaturated, containing monocycle, the dicyclo or three of 3-12 carbon atom, encircle.Suitable cyclic aliphatic group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but never is limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, etc.And described " cycloalkyl " refer to monovalence or multivalence, saturated, containing the monocycle of 3-12 carbon atom.And cycloalkyl can be further substituted, this substituting group is selected from, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " cycloalkyl alkylidene group " means 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, the 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.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.The cycloalkyl alkylidene group can be further substituted, and this substituting group can be, but be not limited to deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle or bicyclic system, wherein the upper one or more atoms of ring are independent is optionally replaced by heteroatoms, ring can be fully saturated or comprise one or more degrees of unsaturation, but be never the fragrant same clan, the rest part that only has a tie point to be connected to molecule gets on.One or more ring hydrogen atoms are independent optionally to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical " or " heterocycle " group be the 3-6 ring monocycle (2-5 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain looking like SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain looking like 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, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, the thioxane base, piperazinyl, the homopiperazine base, azelidinyl, the oxa-cyclobutyl, the thia cyclobutyl, homopiperidinyl, epoxypropyl, the nitrogen heterocyclic heptyl, the oxepane base, the thia suberyl, oxygen azatropylidene base, the diazepine base, sulphur azatropylidene base, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranyl, the 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, the dithiane base, the dithiode alkyl, the dihydro-thiophene base, the pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, the 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).And the independent optionally one or more substituting groups described by the present invention of described heterocyclic radical replace, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Term " heterocyclic radical alkylidene group " means 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, the heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and the heterocyclic radical group is connected to C
1-6alkyl group on.Other embodiment is that the heterocyclic radical group is connected to C
1-4alkyl group on.Such example comprises, but is not limited to 2-tetramethyleneimine ethyl etc.The heterocyclic radical alkylidene group can be further substituted, and this substituting group may be, but not limited to,, deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Term " heteroatoms " means one or more O, S, and N, P and Si, comprise N, the form of S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; The perhaps substituted form of the hydrogen on nitrogen-atoms in heterocycle, 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 F, Cl, Br or I.
Term " H " means single hydrogen atom.Such atomic group can be connected with other groups, for example with Sauerstoffatom, is connected, and forms oh group.
Term " D " or "
2h " mean single D atom.Such atomic group is connected with a methyl, forms list-deuterium for methyl (CDH
2), two D atoms are connected with a methyl, form two-deuterium for methyl (CD
2h), and three D atoms are connected with a methyl, form three-deuterium for methyl (CD
3).
Term " N
3" mean a nitrine structure.This group can be connected with other groups, for example, with methyl group, is connected, and can form triazonmethane (triazo-methane, MeN
3); And be connected with phenyl group, form aziminobenzene (PhN
3).
Term " aryl " can be used separately or as most of " aralkyl ", " aralkoxy " or " aryloxy alkyl ", mean to contain altogether the monocycle of 6-14 atom, dicyclo, carbocyclic ring system with three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises the 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, aromatic nucleus can comprise phenyl, naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Term " aryl alkylene " means 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, the 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 the aryl alkylene group refers to containing C
1-4" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Aryl alkylene can be further substituted, and this substituting group can be, but be not limited to deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Term " heteroaryl " can be used separately or as most of " heteroaralkyl ", mean the monocycle containing 5-14 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 the 5-7 ring, and only has an attachment point to be connected with the molecule rest part.Term " heteroaryl " can be used with term " fragrant heterocycle " or " heteroaromatics " exchange.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
Other embodiment is, the virtue heterocycle comprises following monocycle, but be not limited to these monocycles: the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (as the 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (as the 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, pyrazolyl (as the 2-pyrazolyl), isothiazolyl, 1, 2, the 3-oxadiazolyl, 1, 2, the 5-oxadiazolyl, 1, 2, the 4-oxadiazolyl, 1, 2, the 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, the 5-triazinyl, also comprise following dicyclo, but never be limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as the 2-indyl), purine radicals, quinolyl (as the 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as the 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroaryl alkylidene group " means 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, the 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.Wherein specific examples comprises the 2-picolyl, 3-furans ethyl etc.Can further be substituted on the heteroaryl alkylidene group, this substituting group may be, but not limited to,, deuterium, fluorine, chlorine; bromine, iodine, cyano group, nitro, azido-; alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl, hydroxyl; alkoxyl group, sulfydryl, alkylthio, amino, alkylamino; aminoacyl, the alkylamino acyl group, aryl, heteroaryl, etc.
No matter term " carboxyl " is use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO
2h; No matter term " carbonyl ", be use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", mean-(C=O)-.
" alkylthio " comprises C to term
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-).
The term used in the present invention " alkoxyl group ", relate to alkyl, defined as the present invention, by Sauerstoffatom (" alkoxyl group "), is connected on main carbochain, and such example comprises, but is not limited to methoxyl group, oxyethyl group, propoxy-, butoxy etc.
" alkoxyalkyl " means that alkyl group is replaced by one or more alkoxy base to term, wherein alkyl group and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to methoxymethyl, ethoxyl methyl, ethoxyethyl group etc.
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 C
1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " virtue is amino " means that amine groups is replaced by one or two aromatic yl group, and such example comprises, but is not limited to the N-phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can further be substituted.
" hydroxyalkyl " comprises the C replaced by one or more hydroxyl to term
1-10the straight or branched alkyl group.Some of them embodiment is, hydroxyalkyl is by C that one or more oh group replaced
1-6" more rudimentary hydroxyalkyl ", such example comprises, but is not limited to methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl and hydroxyl hexyl.
Term " aminoalkyl group " comprises the C replaced by one or more amino
1-10the straight 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 " cyano group alkyl " comprises the C replaced by one or more cyano group
1-10the straight or branched alkyl group.Some of them embodiment is, the cyano group alkyl is by C that one or more cyano group replaced
1-6" more rudimentary cyano group alkyl ", such example comprises, but is not limited to cyano methyl, cyano ethyl, cyanopropyl, cyano group butyl and cyano group hexyl.
" alkyl amino alkyl " comprises the alkyl group replaced by alkylamino to term.Some of them embodiment is that alkyl amino alkyl is C
1-6more rudimentary alkyl amino alkyl.Other embodiment is that alkyl amino alkyl is C
1-3more rudimentary alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group replace, and such embodiment comprises, but is not limited to N-methylamino methyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc.
The term that used in the present invention " undersaturated " means that part contains one or more degrees of unsaturation.
Term " comprises " for open language, comprises the content that the present invention is specified, but does not get rid of otherwise content.
Term " condensed-bicyclic ", " fused rings ", " condensed-bicyclic base " or " condensing cyclic group ", as scheme as shown in a-c, mean that between two five-rings, (formula a), between two six-rings (formula b), and between five-ring and six-ring, (formula c) shares the bridged-ring system of a C-C key.Unsaturated link(age) isolated or conjugation be can comprise in system, but aromatic nucleus or hetero-aromatic ring (substituting group can be aromaticity) do not comprised in the core ring structure.Each ring in condensed-bicyclic can be carbocyclic ring or heterocycle.
The example of condensed-bicyclic comprises, but be not limited to, hexahydro furyl also [2, 3-b] furans-3-base, 3a-fluorine hexahydro furyl also [2, 3-b] furans-3-base, (3aS, 6aR)-3a, 6a-bis-deuterium hexahydro furyls also [2, 3-b] furans-3-base, 5, 5-difluoro hexahydro furyl also [2, 3-b] furans-3-base, 4, 4-difluoro hexahydro furyl also [2, 3-b] furans-3-base, (3S)-6-hydroxyl hexahydro furyl also [3, 2-b] furans-3-base, (6R)-6-fluorine hexahydro furyl also [3, 2-b] furans-3-base, 3-deuterium hexahydro furyl also [3, 2-b] furans-3-base, 5, 5-bis-deuterium hexahydro furyls also [3, 2-b] furans-3-base, 6, 6-difluoro hexahydro furyl also [3, 2-b] furans-3-base, (3aR, 6aR)-3a, 6a-bis-deuterium hexahydro furyls also [3, 2-b] furans-3-base, the octahydro pentamethylene is [c] pyrroles-5-base also, (3aR, 6aS)-3a, 6a-bis-deuterium octahydro pentamethylene are [c] pyrroles-5-base also, 3a-fluorine two deuterium octahydro pentamethylene are [c] pyrroles-5-base also, 5-deuterium octahydro pentamethylene is [c] pyrroles-5-base also, 1, 1-bis-deuterium octahydro pentamethylene are [c] pyrroles-5-base also, the amino octahydro pentalene of 5--2-base, the amino octahydro pentalene of 5-deuterium-5--2-base, etc..The condensed-bicyclic base can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " condensed-bicyclic base alkylidene group " means that alkyl is replaced by one or more condensed-bicyclic base groups, wherein alkyl group and condensed-bicyclic base group have implication as described in the present invention, such example includes, but are not limited to also [2,3-b] furans-3-ylmethyl of hexahydro furyl, hexahydro furyl also [2,3-b] furans-3-base two deuteriums are for methyl, (3aR, 6aS)-3a, 6a-bis-deuterium hexahydro furyls are [2,3-b] furans-3-ylmethyl etc. also.Condensed-bicyclic base alkylidene group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo ", mean that a ring originates from the upper special ring-type carbon of another ring, for example, described as following formula d, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", otherwise 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 volution is carbocyclic ring or heterocycle independently.Such example comprises, but is not limited to 5-azaspiro [2.4] heptane-5-base, (R)-4-azaspiro [2.4] heptane-6-base etc.The spiral shell bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " spiral shell bicyclic group alkylidene group " means that alkyl is replaced by one or more spiral shell bicyclic group groups, and wherein alkyl group and spiral shell bicyclic group group have implication as described in the present invention.Spiral shell bicyclic group alkylidene group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido-, alkyl, haloalkyl, alkenyl, alkynyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, alkyl amino alkyl, cyano group alkyl; hydroxyl, alkoxyl group, sulfydryl, alkylthio, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Picture is described in the invention, and key of substituting group picture is connected to the member ring systems (as shown below) formed on the ring at center and represents that substituting group can replace any commutable position on ring.For example, formula e represents the substituted position of any possibility on the B ring, shown in f.
Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " expression have the structure isomeride of different-energy can cross low energy barrier, thereby transforms mutually.For example, proton tautomerism body (being prototropy) comprises by proton shifting and carries out change, as the change of keto-enol formula and imines-enamine isomerization.Valence tautomers comprises by some bonding electrons restructuring carries out change.
Unless other aspects show, within all tautomeric forms of compound of the present invention are included in scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.
Term used in the present invention " prodrug ", represent 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) the ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises the OH group, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, as these phosphate compounds are that hydroxyl phosphorylation on parent obtains.About prodrug, complete discussion can be with reference to Publication about Document: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, every piece of document is contained in this by reference.
" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized 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, the 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.
The definition of neutral body chemistry of the present invention and the use of convention be usually with reference to Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley& Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, and enantiomer, atropisomer, and their mixture, as racemic mixture, formed a part of the present invention.A lot of organic compound all exist with the optical activity form, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for meaning the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause in chemical reaction process there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" 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, 66:1-19,1977. put down in writing.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 of putting down in writing on the 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, the 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The present invention also intends having conceived the formed quaternary ammonium salt of compound of the group of any comprised N.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.
" solvate " of the present invention refers to one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the formed associated complex of water.
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), carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes methylene oxygen carbonyl (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 the blocking-up or the 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.But the general description reference for blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley& Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
compound
The heterogeneous ring compound the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, to tyrosine kinase receptor, especially the treatment of the disease of ALK and c-Met regulation or illness has potential purposes.Particularly, the present invention relates to a kind of compound as shown in the formula (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug.
R wherein
1, R
2, R
3, R
4, R
5, R
6, X and Z have implication as described below:
Each R
1, R
2, R
3, R
4, R
5and R
6be H independently, D or F, in some embodiments, can be H or D independently.
X is C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N, wherein, described C
6-10aryl and comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N is optionally by 1,2, and 3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3,-OR
a,-SR
a,-NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkenyl, C
2-6alkynyl ,-(C
1-4alkylidene group)-CN ,-(C
1-4alkylidene group)-OR
a,-(C
1-4alkylidene group)-NR
ar
b, C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N;
In some embodiments, X is phenyl, and can be optionally by 1,2, and 3 or 4 independently are selected from D, F, Cl, Br, C
1-3alkyl or C
1-3the substituting group of haloalkyl replaces.
Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-4alkyl ,-OR
a,-SR
a,-NR
ar
bor-C (=O) NR
ar
b, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently;
In some embodiments, Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
b, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently;
Particularly, Z can be selected from any one in minor structure shown in formula (Z1)～(Z42) or its steric isomer:
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each W and W ' be independently-O-or-N (H)-;
Minor structure shown in formula (Z1)～(Z42) or its steric isomer be optionally by 1,2, and 3 or 4 independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
bsubstituting group replace, wherein, when Z is in the minor structure shown in formula (Z25)～(Z32) or its steric isomer ,-NR
ar
bcan not be-NH
2or-NMe
2.
In above-mentioned each structure of Z, each R
aand R
bbe H independently, C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) or-(C
1-4alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N), and, R worked as
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-8 atom, wherein, described C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) ,-(C
1-4the heterocyclic radical of alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N) and 3-8 atom is optionally by 1,2, and 3 or 4 independently selected from D, F, Cl ,-CN, N
3,-OH ,-NH
2, the substituting group of alkoxyl group or alkylamino replaces;
Special situation, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2, i.e. R
aand R
bcan not be H or simultaneously for methyl simultaneously.
In some embodiments, each R
aand R
bbe H independently, C
1-3alkyl, C
3-6cycloalkyl or-(C
1-4alkylidene group)-(C
3-6cycloalkyl), and, R worked as
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-6 atom, wherein, described C
1-3alkyl, C
3-6cycloalkyl ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) or the heterocyclic radical of 3-6 atom optionally by 1,2,3 or 4 independently selected from D, F, Cl ,-OH ,-NH
2, C
1-3alkoxyl group or C
1-3the substituting group of alkylamino replaces.
Special situation, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2, i.e. R
aand R
bcan not be H or simultaneously for methyl simultaneously.
In the present invention, R
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
btogether with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-8 atom or the heterocyclic radical of 3-6 atom, i.e. R
a, R
btogether with the nitrogen-atoms be connected with them, can form the heterocyclic radical of 3-8 atom or the heterocyclic radical of 3-6 atom, also can not form heterocyclic radical, for other structures well known to those skilled in the art, as N-R
a-R
bor R
a-N-R
bdeng.
The compound of formula of the present invention (I) structure includes but not limited to following particular compound or its steric isomer, geometrical isomer, and tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
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.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be applicable to chemistry or toxicologically, relevant with other components that form preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but pharmacy acceptable salt not necessarily.
If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method provided on document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Perhaps use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; The pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, the organic salt obtained from amino acid, and as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The 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 the application in producing cancer therapy drug that those are described in the invention.Compound of the present invention alleviates for the production of a kind of medical supplies equally, stops, and controls or treat the disease mediated by ALK or c-Met.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) representative, assistant agent or thinner in conjunction with required effective treatment consumption.
The present invention comprises the disease that mediation occurs the treatment patient vessel equally, or, to the method for this illness sensitivity, the treatment significant quantity that the method comprises use formula (I) representative compound is treated the patient.
composition
According on the other hand, the characteristics of pharmaceutical composition of the present invention comprise the compound of formula (I), the compound that the present invention is listed, or the compound in embodiment, 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, other aspects of the present invention described compound, 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, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the comprehensive content of document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produced or the interaction produced in the mode be 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 the 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, the 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, the glycols compound, as propylene glycol and polyoxyethylene glycol, the 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 the spraying inhalation, topical, the 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 synthesized.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, their polyoxyethylene deriv particularly.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 commonly used, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, be 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.About tablet, orally use, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, all typically be added.For the capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension processed, its effective constituent is comprised 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 form, this adjuvant be at room temperature solid but next in the temperature of rectum be liquid, thereby melt and discharge medicine in rectum.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal that relates to zone 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.
Above-mentioned rectal suppository or suitable enema can be applied to the local application of lower intestine.The 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), polysorbate60 (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 oozed, 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 gaseous solvents or the inhalation of nose.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, with phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent, improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except the 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 (cottonseed particularly, 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 as defended strainer by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other aseptic injection media before use.In order to extend the effect of compound of the present invention, usually need to slow down by subcutaneous injection or intramuscularly the absorption of compound.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on its dissolution rate, depends on successively grain size and crystal shape.In addition, can by compound, in the oils vehicle, dissolve or disperse the delay of compound injection administration to absorb.
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 the 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 used 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 postponed.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, as compressing tablet lubricant and other compression aids 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 postponed arbitrarily.Applicable implant compositions can comprise, but be not limited to polymer and wax.
Compound of the present invention by part or comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster through the formulation of percutaneous drug delivery.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 the 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, and through-rate is controlled film or compound is scattered in to polymer matrix or gelatin is controlled its speed.
Compound of the present invention preferably is prepared into the dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein the patient obtains suitably treating the physical dispersion unit of required medicine.Yet, should be appreciated that compound of the present invention or composition total usage every day will be next definite according to reliable medical science scope judgement by the doctor in charge.The patient that concrete effective dose level is special for any one or organism will depend on that many factors comprise the illness that is treated and the seriousness of illness, 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 of consumption that can produce 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 the 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition by the patient and carries out administration.
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, WO2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, with demethylation reagent, comprise, but be not limited to, 5-mix nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the described compound of Publication about Document: US 6, 268137, US 5, 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, US 6, 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, the neutron beam radiotherapy, the electron beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol (Taxol), Docetaxel (Taxotere) etc.), 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) etc.), 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 the 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 is tall and erect for Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.).Medicine suppress or the approach that activates cancer as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer therapy forum more widely is shown in
http:// www.nci.nih.gov/, the oncology list of medications of FAD approval is shown in
http:// www.fda.gov/cder/cancer/druglist-rame.htm, and the 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 the cytotoxin carcinostatic agent.Such carcinostatic agent can be inner the finding of the 13 edition the Merck index (2001).These carcinostatic agents comprise, but never be limited to, asparaginase, bleomycin, carboplatin, carmustine, Chlorambucil, cis-platinum, L-ASP, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Zorubicin (Dx), epirubicin, Etoposide, 5-fluor-uracil, the 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.
With other suitable cytotoxic drugs of compound drug combination of the present invention, comprise, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman ' s The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but never be 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, the 5 FU 5 fluorouracil deoxynucleoside, the 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), the trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
Other suitable and cytotoxin class carcinostatic agents 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 Clinical Oncology, 2004, 23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377).
Other embodiment is 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) with their parts separately.Such reagent comprises, but never is limited to, and antibody therapy is as Herceptin (Trastuzumab), Cetuximab (Cetuximab), her monoclonal antibody (Ipilimumab) and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but never be limited to, the 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 the bonding histone deacetylase inhibitors.Such reagent comprises, but never be limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3028) and MGCDOI03 (US6, 897, 220).
Other embodiment is that compound of the present invention can be in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but never be limited to Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract3849).Compound of the present invention 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 the part of many dosage regimens.Perhaps, those therapeutical agents can be the parts of one-pack type, form single composition together with compound of the present invention.If administration is as the part of many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thereby obtain the 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 will be no more than composition and comprise the amount of therapeutical agent as the normal administration of unique promoting agent.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as unique active therapeutic agent.In the composition that comprises the additional treatment agent at those, the additional treatment agent will play synergy with compound of the present invention.
the application of compound and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for for the preparation of the medicine that protects, processes, treats or alleviate proliferative disease, also can be for the preparation of the medicine for inhibition or adjusting protein kinase activity.
Particularly, in composition of the present invention the amount of compound effectively detectablely the arrestin kinases as the activity of ALK or c-Met.The deleterious effect of ALK and c-Met signal response will be treated or be reduced as antitumor drug to the compounds of this invention to the patient.
Compound of the present invention can be applied to, but never is limited to, and by the significant quantity of compound of the present invention or composition, patient's administration is prevented or treats patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma, atherosclerosis and pulmonary fibrosis.
Compound of the present invention can be applied to the treatment of knurl, comprises cancer and metastatic carcinoma, further includes, but are not limited to, 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 the 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, xenoderoma pigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention and pharmaceutical composition also can be used for treating for example 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 equally also are used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention and pharmaceutical composition can also be for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathies.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 and pharmaceutical composition, except useful to the human treatment, also can be applicable to the animal of veterinary treatment pet, introduced variety and the animal on farm, comprise 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 the additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein the additional treatment agent is applicable to treated disease, and the 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 separated or composition are as the part of multi-form.The 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 equally to expressing the cytostatic method of ALK or c-Met, 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, the 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 in biological sample the method that suppresses ALK or c-Met kinase activity, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of live body outside, include, but not limited to cell cultures or cell extraction; The examination of living tissue material obtained 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 ALK or c-Met kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but never is 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 amount accurately will change according to patient's situation, and this depends on the 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 the present invention discusses.
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, the vascular stem, be used to overcome restenosis (after damage, vessel wall shrinks again).Yet the patient uses stem or other implantable devices will have the risk of clot formation or 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 in document US6,099,562; US 5,886, and 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 the fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, come the performance group compound to control the feature discharged.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, and therefore with the pharmaceutical aqueous solution administering mode, compare, allow drug release that longer time limit is arranged.
the synthetic method of compound
For describing the present invention, below listed 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 further instruction arranged, wherein substituent definition is suc as formula shown in (I).Following reaction scheme 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 all is 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 the 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 modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions also are applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, be decided to be degree centigrade unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company does not have during use 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, the Tianjin space chemical company limited of residing well, Tianjin good fortune chemical reagent factory in morning, the prosperous China in Wuhan development in science and technology far away company limited, imperial chemical reagent company limited is risen in Qingdao, and Haiyang Chemical Plant, Qingdao buys and obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to obtain through sodium Metal 99.5 backflow drying.Anhydrous methylene chloride and chloroform are to obtain through hydrolith backflow drying.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction be generally nitrogen or argon gas direct draught or on anhydrous solvent cover one drying tube (unless showing aspect other), reaction flask is suitable soft rubber ball beyond the Great Wall all, substrate is squeezed into by syringe.Glassware is all dry the mistake.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1
3, d
6-DMSO, CD
3oD or d
6-acetone is solvent (report be take ppm as unit), uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.When multiplet occurring, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplets).Coupling constant, mean with hertz (Hz).
The condition of Algorithm (MS) data is: and Agilent1200 or Agilent6120Series LCMS (the pillar model: Zorbax SB-C18,2.1 * 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Moving phase: 5-95%(is containing the CH of 0.1% formic acid
3cN) at (H that contains 0.1% formic acid
2o) ratio in, detect with UV at 210/254nm, by low-response EFI pattern (ESI); Agilent7890A-5975C Series GCMS (pillar model: DB-624,30mm * 0.32mm, 1.8 microns), substance level Four bar mass analyzer.
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detect with UV at 210nm and 254nm.Pillar operation under 40 ℃ usually.
The use of following brief word runs through the present invention:
BBr
3boron tribromide
BINAP 2,2 '-bis-diphenyl phosphines-1,1 '-dinaphthalene
BOC, the Boc tert-butoxycarbonyl
The BSA bovine serum albumin
CDC1
3deuterochloroform
CHCl
3chloroform
CH
2cl
2, the DCM methylene dichloride
CH
3sO
2cl, the MsCl Tosyl chloride
Cs
2cO
3cesium carbonate
Cu copper
The CuI cuprous iodide
The DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
The DEAD diethyl azodiformate
The DEAD diethyl azodiformate
The DIAD diisopropyl azodiformate
The DIBAL diisobutyl aluminium hydride
DIEA, the DIPEA diisopropyl ethyl amine
The DMAP DMAP
The DMF DMF
The DMSO dimethyl sulfoxide (DMSO)
The DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, the EA ethyl acetate
Et
2the O ether
Et
3n, the TEA triethylamine
The FBS foetal calf serum
Fe iron
The g gram
H hour
HATU O-(7-pyridine triazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester
The 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
The HOBt I-hydroxybenzotriazole
K
2cO
3salt of wormwood
KOH potassium hydroxide
The LiHMDS LHMDS
The LDA lithium diisopropyl amido
The MCPBA metachloroperbenzoic acid
MeCN, CH
3the CN acetonitrile
The MeI methyl iodide
MeOH, CH
3oH methyl alcohol
2-MeTHF 2-methyltetrahydrofuran
MgSO
4sal epsom
ML, the ml milliliter
N
2nitrogen
NaBH
4sodium borohydride
NaBH
3the CN sodium cyanoborohydride
NaCl sodium-chlor
NaClO
2textone
The NaH sodium hydride
NaHCO
3sodium bicarbonate
NaH
2pO
4sODIUM PHOSPHATE, MONOBASIC
The NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na
2sO
4sodium sulfate
NBS N-bromo-succinimide
NH
3ammonia
NH
4the C1 ammonia chloride
The NMP N-Methyl pyrrolidone
The 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
2two (diphenylphosphino) ferrocene palladium chlorides of 1,1-
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 ℃)
POC1
3phosphorus oxychloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
The Rt retention time
The TBAB Tetrabutyl amonium bromide
TBAHSO
44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester
The TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
The THF tetrahydrofuran (THF)
μ L microlitre
Following synthetic schemes has been described the come into the open step of compound of preparation the present invention.Unless otherwise indicated, each X, Z, R
5, R
6have definition as described in the present invention, V is optional heterocycle or the spiral shell dicyclo replaced, R
7h or methyl.
Synthetic method 1
The part of compounds of formula (I) definition can prepare by synthetic method 1:
(R)-aryl alcohol (
1) with the fluorinated pyridine replaced (
2) take NaH as alkali, at aprotic solvent, react in as THF, obtain coupled product (
3).Compound (
3) in nitro on pyridine ring under the acidic reduction condition, use reductive agent as the Fe powder convert to aminocompound (
4).Then under the NBS effect, by the regioselectivity bromination on pyridine ring, obtain compound (
5).Finally, compound (
5) and alkynes (
6), as 2-methyl fourth-3-alkynes-2 alcohol, under suitable Pd catalyst action, coupling generation kinase inhibitor (
7), i.e. the compound of formula (I) definition.
Synthetic method 2
Other compounds in the present invention can prepare by synthetic method 2:
According to the method in synthetic method 1 or additive method prepare formula (
5) shown in compound, compound (
5) with the Boc acid anhydrides at alkali, under the effect as triethylamine, generate compound (
8).Compound (
8) and alkynol (
9) under suitable Pd catalyzer exists as: two (triphenylphosphine) palladium chloride, the Sonogashira coupling occurs, obtain compound (
10).Afterwards, compound (
10) under alkaline condition, change into compound (
11).The compound obtained (
11) with nitrogen heterocyclic ring or azaspiro dicyclic compound (
12) the generation nucleophilic substitution, the generation compound (
13).Finally, under acidic conditions, as the dichloromethane solution of trifluoroacetic acid, the ethyl acetate solution of hydrogenchloride, remove amino protecting group (Boc), obtain target product (
14), i.e. the compound of formula (I) definition.
The present invention adopts following methods to carry out biological test to the compound shown in formula (I):
1, 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 the 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 |
| The 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 that moving phase is 0.1% (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is as shown in table B:
Table B
| Time | The gradient of Mobile phase B |
| 0.5min | 5% |
| 1.0min | 95% |
| 2.2min | 95% |
| 2.3min | 5% |
| 5.0min | stop |
In addition, the series of the Agilent6330 in addition LC/MS/MS spectrograph for analyzing, be equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; The LC/MS/MS spectrograph adopts the ESI radioactive source.Each analyte is carried out to suitable positively charged ion models treated to Application standard liquid and best analysis is carried out in the MRM conversion.Use Capcell MP-C18 post during analyzing, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is the 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.
2, the stability of compound in people and rat liver microsomes
(1) people or rat liver microsomes are placed in to the 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), NADPH (1.0mM) potassium phosphate buffer (PBS that target compound (5 μ M) and cumulative volume are 200 μ L, 100mM, the pH value is 7.4), by compound dissolution in DMSO, and use PBS that it is diluted, the concentration that makes its final DMSO solution is 0.05%.And hatched in the water-bath communicated with air under 37 ℃, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60min), add the cold acetonitrile termination reaction of consubstantiality accumulated ice.Sample is preserved until carry out the LC/MS/MS analysis under-80 ℃.
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 under 37 ℃, react and stop at different time point (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ) is as positive control, and hatching under 37 ℃, react and stop at different time point (0,5,10,15,30 and 60 minutes).All comprise positive and negative control sample in each measuring method, to guarantee the integrity of microsome hatching system.
(2) 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 the polypropylene test tube and hatch, and guide it to copy.Typical mixtures incubated comprise people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), 1.5 μ M) and the cumulative volume K-buffered soln (containing 1.0mM EDTA, 100mM, pH7.4) that is 30 μ L compound (ultimate density:.By compound dissolution, in DMSO, and with K-buffered soln dilution, the ultimate density that makes DMSO is 0.2%.After preincubate 10 minutes, (ultimate density: 2mM) carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 ℃ to add 15 μ L NADPH.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, with LC-MS/MS, analyze.
In above-mentioned test, ketanserin (1 μ M) is selected as positive control, hatching under 37 ℃, and reaction stops at different time point (0,15,30 and 60 minutes).All comprise positive control sample in each measuring method, to guarantee the integrity of microsome hatching system.
The present invention adopts following methods to carry out data analysis, to obtain the stability analysis result:
For each reaction, the concentration (meaning with per-cent) by compound in people or rat liver microsomes are hatched, by the per-cent mapping of Relative Zero time point, is inferred CLint CL in body with this
int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.)
3, the compounds of this invention Pharmacokinetic Evaluation in animal body
The present invention adopt following methods to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assessed:
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.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and preserve under-20 ℃ or-70 ℃ until carry out above-mentioned LC/MS/MS analysis.
4, kinase assay
Kinase assay by detection mix γ-
33the myelin basic protein of P-ATP (MBP) completes.MBP (Sigma#M-1891) Tutofusin tris buffer salt solution (TBS for preparing 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 ℃, hatch 24h.Wash plate 3 times with 100 μ L TBS afterwards.The kinase buffer liquid that kinase reaction is 34 μ L at cumulative volume (5mM Hepes pH7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl
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-
33the ATP of P mark (every hole 2x10
6cpm, 3000Ci/mmol) start to react.Reflection 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 a kind of 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, by following compound concentration, making a typical curve: 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, 0 μ M).
Kinase assay in the present invention completes (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK) by Britain Millipore company.
4.1ALK (h) kinase assays
The MOPS that people ALK is 7.0 in 8mM pH value, 0.2mM EDTA, 250 μ M KKKSPGEYVNIEFG, hatched under the condition that 10mM magnesium acetate and [γ-33P-ATP] (the about 500cpm/pmol of specific activity, concentration is determined according to demand) exist.Start reaction after adding the MgATP mixture.After hatching 40 minutes under room temperature, add wherein 3% phosphoric acid solution to carry out termination reaction.The reaction solution of 10 μ L is on the mottled P30 of being distributed in strainer, and cleans 3 times in 5 minutes with 75mM phosphoric acid, and put at once methanol solution and preserve before dry and scintillation counting.
4.2c-Met (h) kinase assays
The MOPS that people c-Met is 7.0 in 8mM pH value, 0.2mM EDTA, 250 μ M KKKSPGEYVNIEFG, the 10mM magnesium acetate and [γ-
33p-ATP] hatched under (the about 500cpm/pmol of specific activity, concentration according to demand determine) condition of existing.Start reaction after adding the MgATP mixture.After hatching 40 minutes under room temperature, add wherein 3% phosphoric acid solution to carry out termination reaction.The reaction solution of 10 μ L is on the mottled P30 of being distributed in strainer, and cleans 3 times in 5 minutes with 75mM phosphoric acid, and put at once methanol solution and preserve before dry and scintillation counting.
5, cells phosphorylation test
Usually, cell and testing compound preincubate, make it reach sufficient target combination.Utilize sandwich ELISA (Sandwich-ELISA) technology for detection autophosphorylation level.Utilize the extension rate of 1/1log to make the curve that comprises 8 concentration point, estimation IC
50value (each concentration determination 2 times).In the present invention, the cells phosphorylation test is to complete by ProQinase GmbH company (ProQinase GmbH, Breisacher Stra β e117D-79106, Freiburg, Germany).
5.1c-Met phosphorylation test
As everyone knows, people's gastric adenocarcinoma cells strain MKN45 crosses expression c-Met.C-Met crosses to express and causes composing type, the kinases autophosphorylation of the non-dependence of part.Add SU11274, phosphorylation Met level significantly reduces, and therefore can determine the inhibition ability of the compounds of this invention.By sandwich ELISA (Sandwich-ELISA) technology, can carry out quantitatively phosphorylation Met signal.Known Met inhibitor group is established in test, with the reliability of checking test method.
6, xenotransplantation tumor model
The drug effect of the compounds of this invention is estimated by the standard muroid model of transplantation tumor, and method is as follows:
Human tumor cells (for example, the U87MG neuroblastoma cell, the MKN45 gastric adenocarcinoma cells, the MDA-MB-231 breast cancer cell, or the Caki-1 kidney cancer cell, cell derived is in ATCC company) cultivate, collect after, (the BALB/cA nu/nu in the female nude mouse body in age in week in rear veutro subcutaneous vaccination in 6-7, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8).When gross tumor volume reaches 100-250mm
3the time, animal is divided into solvent control group (aqueous solution of 2%HPMC+1% twen-80) and compound group randomly.The following adopted compound carries out gastric infusion (3-50mpk/dose is dissolved in the aqueous solution of 2%HPMC+1% twen-80) to animal, starting Anywhere in 0 to 15 day from tumor cell inoculation, and usually carry out once every day in test.
6.1 suppressing (TGI), tumor growth analyzes
The crystallization growth of tumour is estimated by the relation of gross tumor volume and time.The major axis of Subcutaneous tumor (L) and minor axis (W) measure weekly twice by calipers, and the volume of tumour (TV) is by formula (L * W
2)/2) calculated.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, with the percentage of solvent control group gross tumor volume intermediate value, recently means, by following formula, is calculated:
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 (the 2%HPMC+1% twen-80, etc.) negative contrast.
Result shows, compound provided by the invention shows good transformation period and good pharmacokinetic property, and ALK and c-Met are had to good restraining effect, and the growth of tumour is also had to good restraining effect.
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
embodiment 1:4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-
alkynes-2-alcohol
step 1) (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-2-nitropyridine
(R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethanol (10g, 47.81mmol) is dissolved in tetrahydrofuran (THF) (10mL), is cooled to 0 ℃, in 30 minutes, add wherein sodium hydride (1.4g, 57.42mmol) in batches.After stirring at room 2 hours, again be cooled to 0 ℃, in 20 minutes, to dripping tetrahydrofuran (THF) (80mL) solution of the fluoro-2-nitropyridine of 3-(8.2g, 57.43mmol) in reaction system.Return to room temperature, continue to stir 3 hours.Reaction is finished, with frozen water (10mL) cancellation reaction, and concentrating under reduced pressure.Residue water (150mL) dilution, and extract by ethyl acetate (150mL x3).The organic phase merged is used saturated NaHCO successively
3(400mL) wash, saturated aqueous common salt (400mL) is washed, anhydrous Na
2sO
4dry.Concentrating under reduced pressure, the gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=6:1 to 4:1) purifying, and obtaining title compound is white solid (13.4g, 84.8%).
LC-MS(ESI,pos.ion)m/z:331[M+H]
+。
step 2) (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine
(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-2-nitropyridine (13.4g, 39.3mmol) is suspended in ethanol (250mL), and adds wherein iron powder (11g, 197mmol).Mixture after 20 minutes, adds 1N HCl (4mL) 90 ℃ of stirrings in reaction mixture, continues to stir 15 minutes, again adds 1N HCl (4mL).Reaction solution stirs 2 hours at 90 ℃.Reaction is finished, and is down to room temperature, and by the mixture diatomite filtration, ethanol for filter cake (80mL x3) is washed.Filtrate decompression is concentrated, and obtaining title compound is light brown solid (12g, 100%).
LC-MS(ESI,pos.ion)m/z:301[M+H]
+；
1H?NMR(400MHz,d
6-DMSO)δ(ppm):1.75(d,J=6.6Hz,3H),5.67(brs,2H),5.97-5.92(q,J=6.6Hz,1H),6.38-6.35(dd,J=7.7Hz,5.0Hz,1H),6.61(d,J=7.1Hz,1H),7.47-7.42(m,2H),7.56-7.52(dd,J=7.7Hz,5.0Hz,1H)。
step 3) (R) the bromo-3-of-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine
(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine (12g, 39.3mmol) is dissolved in acetonitrile (250mL), be cooled to 0 ℃, in 20 minutes, add wherein NBS (9.4g, 52.3mmol) in batches.Reaction solution 0 ℃ stir 1 hour after, concentrating under reduced pressure, the gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1 is to 3/1) purifying, obtaining title compound is light brown solid (10g, 68%).
LC-MS(ESI,pos.ion)m/z:379[M+H]
+；
1H?NMR(400MHz,d
6-DMSO)δ(ppm):1.82(d,J=6.6Hz,3H),4.82(brs,2H),6.01-5.96(q,J=6.6Hz,1H),6.83(d,J=1.8Hz,1H),7.10(t,J=8.0Hz,1H),7.33-7.30(dd,J=8.9Hz,4.8Hz,2H),7.66(dd,J=5.0Hz,1.8Hz,1H)。
step 4) 4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes
-2-alcohol
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (0.19g, 0.5mmol), two (triphenyl phosphorus) palladium chloride (35mg, 0.05mmol) and cuprous iodide (9.5mg, 0.05mmol) be suspended in triethylamine (2.5mL), and add wherein 3-butyne-2-alcohol (53mg, 0.75mmol).Reaction solution after 80 minutes, is cooled to room temperature at 90 ℃ of microwave reactions, and concentrating under reduced pressure.After methylene dichloride for residue (10mL) dilution, filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purifying, and obtaining title compound is yellow solid (0.1g, 54%).
LC-MS(ESI,pos.ion)m/z:369[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.50-1.52(m,3H),1.81(d,J=6.7Hz,3H),4.68-4.73(m,1H),5.02(s,2H),5.98-6.03(q,J=6.6Hz,1H),6.74(d,J=1.4Hz,1H),7.05-7.09(m,1H),7.26-7.32(m,1H),7.77(d,J=1.0Hz,1H)。
embodiment 2:(R)-4-(6-amino-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-2-
methyl fourth-3-alkynes-2-alcohol
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (0.19g, 0.5mmol), two (triphenylphosphine) palladium chloride (35mg, 0.05mmol) and cuprous iodide (9.5mg, 0.05mmol) be suspended in triethylamine (2.5mL), and add wherein 2-methyl fourth-3-alkynes-2-alcohol (63mg, 0.75mmol).Reaction solution after 1 hour, is cooled to room temperature at 90 ℃ of microwave reactions, and concentrating under reduced pressure.After methylene dichloride for residue (10mL) dilution, filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH/Et
3n (v/v/v)=1000/50/1) purifying, obtaining title compound is white solid (115mg, 81%).
LC-MS(ESI,pos.ion)m/z:384[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.63(s,6H),1.80(d,J=6.4Hz,3H),2.46(1H),4.97(s,2H),6.01(q,J=6.4Hz,1H),6.74(d,J=1.56Hz,1H),7.07(m,1H),7.29(m,1H),7.74(s,1H);
13C?NMR(100MHz,CDCl
3)δ(ppm):18.8,29.7,31.5,65.5,76.7,93.8,108.7,116.8,119.3,128.9,130.0,136.8,138.8,143.0,150.2。
embodiment 3:(R)-5-((1H-pyrazoles-4-yl) ethynyl)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)
pyridine-2-amine
step 1) 4-((trimethyl silicon based) ethynyl)-1H-pyrazoles
By the iodo-1H-pyrazoles of 4-(2.91g, 15mmol), two (triphenylphosphine) palladium chloride (1g, 1.5mmol), cuprous iodide (286mg, 1.5mmol) and triethylamine (6mL) be dissolved in ethanol (20mL), and add wherein trimethyl silicane ethyl-acetylene (3.2mL, 22.5mmol).Reaction solution after 4 hours, is cooled to room temperature 70 ℃ of stirrings, and concentrating under reduced pressure.By ethyl acetate for residue (20mL) dilution, to filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure, residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (1.3g, 53%).
LC-MS(ESI,pos.ion)m/z:165[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.24(s,9H),7.76(s,2H),11.43(br,1H)。
step 2) 4-ethynyl-1H-pyrazoles
4-((trimethyl silicon based) ethynyl)-1H-pyrazoles (1g, 6.1mmol) is dissolved in tetrahydrofuran (THF) (12mL) and water (2mL), and adds wherein salt of wormwood (1g, 12.2mmol).After reaction solution stirring at room 2 hours, concentrating under reduced pressure, obtain title compound, and product is not purified directly as next step.
LC-MS(ESI,pos.ion)m/z:93[M+H]
+;
1H?NMR(400MHz,CDCl
3)δ(ppm):3.04(s,1H),7.75(s,2H),10.85(br,1H).
step 3) (R)-5-((1H-pyrazoles-4-yl) ethynyl)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyrrole
pyridine-2-amine
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (695mg, 1.83mmol), two (triphenylphosphine) palladium chloride (128mg, 0.18mmol) and cuprous iodide (35mg, 0.18mmol) be dissolved in ethanol (12mL) and dioxane (12mL), and add wherein N, N-diisopropylethylamine (4mL) and 4-ethynyl-1H-pyrazoles (168mg, 1.83mmol).Reaction solution after 16 hours, is cooled to room temperature 80 ℃ of stirrings, and concentrating under reduced pressure.By methylene dichloride for residue (25mL) dilution, to filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH/Et
3n (v/v/v)=1000/50/1) purifying, obtaining title compound is white solid (0.25,35%).
LC-MS(ESI,pos.ion)m/z:393[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.84(d,J=6.8Hz,1H),6.09(q,J=6.8Hz,1H),6.73(d,J=1.6Hz,1H),7.25(m,1H),7.46(m,1H),7.60(d,J=1.68Hz,1H),7.62(s,1H),7.83(s,1H)；
13C?NMR(100MHz,d
6-DMSO)δ(ppm):18.7,72.2,80.8,87.3,101.2,106.8,117.4,118.1,120.8,128.5,130.5,136.5,137.8,142.5,150.8,155.5,158.0。
embodiment 4:5-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-3-
base)-1,1, the fluoro-2-methylpent of 1-tri--4-alkynes-2-alcohol
step 1) 1,1, the fluoro-2-methylpent of 1-tri--4-alkynes-2-alcohol
Aluminium foil (0.34g, 12.6mmol) is suspended in tetrahydrofuran (THF) (6mL), and adds wherein a small amount of mercury chloride (5mg, 0.02mmol).Mixture after 1 hour, in 30 minutes, drips propargyl bromide (1.5g, 12.6mmol) in the room temperature vigorous stirring wherein.Reaction solution after 2 hours, is cooled to room temperature 40 ℃ of stirrings, continues to stir 3 hours, standby;
TFK (0.24g, 2.09mmol) is dissolved in ether (20mL), is cooled to-78 ℃, add wherein above-mentioned standby suspension liquid.Reaction solution is returned to room temperature, and in stirring at room 16 hours, water (30mL) cancellation afterwards.Separate organic phase, ether for water (40mL x3) extraction, the organic phase of merging is washed through saturated aqueous common salt (100mL x2), anhydrous sodium sulfate drying, and concentrating under reduced pressure (thickening temperature<5 ℃), obtaining title compound is light yellow solid (0.46g, > 100%).Thick product is not purified, is directly used in next step reaction.
GC-MS(EI):152.0,137.0,126.8,113.0.
step 2) 5-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-1,1,1-
three fluoro-2-methylpent-4-alkynes-2-alcohol
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (0.3g, 0.79mmol), two (triphenylphosphine) palladium chloride (27mg, 0.04mmol) and cuprous iodide (7mg, 0.04mmol) be suspended in N, in dinethylformamide (5mL), and add wherein 1, the N of the fluoro-2-methylpent of 1,1-tri--4-alkynes-2-alcohol (0.32g, 2.1mmol), dinethylformamide (5mL) solution and triethylamine (2.2mL, 15.8mmol).Reaction solution after 16 hours, is cooled to room temperature 75 ℃ of reacting by heating, and dilutes (150mL) with methylene dichloride.The gained mixture is water (100mL x2) successively, and saturated aqueous common salt (100mL x2) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is successively through silica gel column chromatography (PE/EtOAc (v/v)=2/1) with prepare silica-gel plate (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is light yellow solid (0.16g, 45%).
LC-MS(ESI,pos.ion)m/z:451.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.49(s,3H),1.81(d,J=6.68Hz,3H),2.72(d,J=17.00Hz,1H),2.89(d,J=17.02Hz,1H),5.01(s,2H),5.97-6.03(q,J=6.68Hz,1H),6.72(m,1H),7.10(t,J=8.48Hz,1H),7.27-7.52(dd,J=8.92Hz,4.84Hz,1H),7.72(m,1H)。
embodiment 5:4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-3-
base)-1,1, the fluoro-2-methyl fourth of 1-tri--3-alkynes-2-alcohol
step 1) 1,1, the fluoro-2-methyl-4-of 1-tri-(trimethyl silicon based) fourth-3-alkynes-2-alcohol
Trimethylsilyl acetylene (1g, 10.2mmol) is dissolved in ether (10mL), is cooled to-78 ℃, and, in 30 minutes, with syringe, add wherein n-Butyl Lithium (4.11mL, 10.3mmol).Mixture after 30 minutes, continues at ether (10mL) solution that adds wherein TFK (1.37mL, 10.2mmol) in 30 minutes-78 ℃ of stirrings.Reaction solution stirring at room 50 minutes, use saturated aqueous ammonium chloride solution (20mL) cancellation afterwards, separates and obtain organic phase, extracted with diethyl ether for water (30mL x4).The organic phase merged is washed through saturated aqueous common salt (50mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure (<10 ℃), and obtaining title compound is light yellow oil (2.1g, 98%).
GC-MS(EI):209.0,137.0,113.0。
step 2) 1,1, the fluoro-2-methyl fourth of 1-tri--3-alkynes-2-alcohol
The fluoro-2-methyl-4-of 1,1,1-tri-(trimethyl silicon based) fourth-3-alkynes-2-alcohol (0.8g, 3.8mmol) is dissolved in methyl alcohol (10mL), and adds wherein potassium hydroxide (1.28g, 22.8mmol).After reaction solution stirring at room 16 hours, add water (30mL) cancellation, and with extracted with diethyl ether (40mLx3).The saturated aqueous common salt for organic phase (100mL x2) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure (<10 ℃), and residue is 5 ℃ of vacuum-dryings, and obtaining title compound is colorless oil (0.31g, 59%).
GC-MS(EI):137.0,113.0。
step 3) 4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-1,1,1-
three fluoro-2-methyl fourths-3-alkynes-2-alcohol
The bromo-3-of (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine (0.2g, 0.53mmol) is dissolved in methylene dichloride, at N
2under protection, add successively wherein two (triphenylphosphine) palladium chlorides (18mg, 0.03mmol), cuprous iodide (5mg; 0.03mmol), 1,1; the fluoro-2-methyl fourth of 1-tri--3-alkynes-2-alcohol (0.31g, 2.37mmol) and triethylamine (1.47mL, 10.5mmol).Reaction solution, is cooled to room temperature, and dilutes with methylene dichloride (150mL) after 2.5 hours 75 ℃ of stirrings.Saturated common salt washing (200mL x3) for the gained mixture, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through preparing the silica-gel plate purifying, and obtaining title compound is yellow solid (30mg, 13%).
LC-MS(ESI,pos.ion)m/z:437.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.22(s,3H),1.75(d,J=6.56Hz,3H),5.96-6.02(q,J=6.68Hz,1H),6.29(s,2H),6.59(s,1H),7.50(t,J=8.60Hz,1H),7.54-7.59(dd,J=8.92Hz,5.00Hz,1H),7.62(s,1H)。
embodiment 6:(R)-4-((6-amino-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) acetylene
base) piperidines-4-alcohol
step 1) 1-(tertbutyloxycarbonyl)-4-((trimethyl silicon based) ethynyl) piperidines-4-alcohol
Under nitrogen protection; by trimethyl silicane ethyl-acetylene (1.7mL; 12mmol) be dissolved in anhydrous tetrahydro furan (20mL); be cooled to-40 ℃, in solution, slowly add n-butyllithium solution (4.8mL, 12mmol); mixture-40 ℃ stir 1 hour after; be cooled to-78 ℃, and by double-ended needle to anhydrous tetrahydro furan (10mL) solution that adds 1-(tertbutyloxycarbonyl) piperidin-4-one-(2g, 10mmol) in system.Reaction solution after 1 hour, returns to room temperature-78 ℃ of stirrings, and under room temperature, continues to stir 72 hours.Reaction is finished, add saturated aqueous ammonium chloride (15mL) and water (50mL) cancellation, and with ethyl acetate (50mL x3) extraction, the organic phase of merging water (50mL) and saturated aqueous common salt (50mL) is successively washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (1.93g, 65%).
1H?NMR(400MHz,CDCl
3)δ(ppm):0.17(s,9H),1.46(s,9H),1.68(m,2H),1.87(m,2H),2.19(s,1H),3.22(m,2H),3.79(br,2H)；
13C?NMR(100MHz,CDCl
3)δ(ppm):28.5,39.0,67.2,79.6,89.9,107.7,154.7。
step 2) 1-(tertbutyloxycarbonyl)-4-ethynyl piperidines-4-alcohol
By 1-(tertbutyloxycarbonyl)-4-((trimethyl silicon based) ethynyl) piperidines-4-alcohol (1.4g, 6.22mmol) be dissolved in methyl alcohol (12mL) and water (2mL), and add wherein salt of wormwood (3.4g, 24.88mmol).After reaction solution stirring at room 2 hours, concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifying, and obtaining title compound is white solid (0.95g, 90%).
1H?NMR(400MHz,CDCl
3)δ(ppm):1.46(s,9H),1.68(m,2H),1.87(m,2H),2.53(s,1H),3.27(m,2H),3.50(s,1H),3.75(br,2H);
13C?NMR(100MHz,CDCl
3)δ(ppm):28.6,38.9,40.8,66.5,73.1,79.9,86.5,154.8。
step 3) (R)-4-((6-amino-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) acetylene
base)-1-(tertbutyloxycarbonyl) piperidines-4-alcohol
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (695mg, 1.83mmol), two (triphenylphosphine) palladium chloride (128mg, 0.18mmol), cuprous iodide (35mg, 0.18mmol) and salt of wormwood (505mg, 3.66mmol) be suspended in dioxane (12mL), and add wherein N, N-diisopropylethylamine (4mL) and 1-(tertbutyloxycarbonyl)-4-ethynyl piperidines-4-alcohol (412mg, 1.83mmol).Reaction solution after 16 hours, is cooled to room temperature 90 ℃ of stirrings, and concentrating under reduced pressure.Methylene dichloride for residue (20mL) dilution, and filter.Filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is light yellow solid (0.15g, 16%).
LC-MS(ESI,pos.ion)m/z:524[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.48(s,9H),1.76(m,2H),1.81(d,J=6.8Hz,1H),1.92(m,2H),3.25(m,2H),3.82(br,2H),5.04(br,2H),6.73(s,1H),6.99(q,J=6.8Hz,1H),7.30(m,1H),7.74(m,1H),7.79(br,1H)；
13C?NMR(100MHz,CDCl
3)δ(ppm):14.1,28.6,39.1,67.1,72.6,82.9,91.5,116.8,119.2,122.0,128.9,130.0,136.6,154.8。
step 4) (R)-4-((6-amino-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) ethynyl)
piperidines-4-alcohol
By (R)-4-, (((1-(2 for 6-amino-5-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) ethynyl)-1-(tertbutyloxycarbonyl) piperidines-4-alcohol (150mgm, 0.29mmol) be dissolved in methylene dichloride (4mL), be cooled to 0 ℃, to the ethyl acetate solution (3M, 10mL) that adds hydrogenchloride in solution.Reaction solution is in stirring at room after 4 hours, and product is separated out, and filters.Add water (10mL) in the gained solid, and be 10 by 4M aqueous sodium hydroxide solution adjusting pH value.The gained mixture is extracted with ethyl acetate (10mL x3), the organic phase anhydrous sodium sulfate drying of merging, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH/Et
3n (v/v/v)=1000/50/1) purifying, obtaining title compound is white solid (70mg, 56%).
LC-MS(ESI,pos.ion)m/z:424[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.76(m,2H),1.81(d,J=6.8Hz,1H),1.92(m,2H),2.86(m,2H),3.12(br,2H),4.96(br,2H),5.99(q,J=6.8Hz,1H),6.73(s,1H),7.30(m,1H),7.74(m,1H),7.76(s,1H);
13C?NMR(100MHz,CDCl
3)δ(ppm):11.5,40.7,43.7,67.6,72.6,82.7,91.9,116.8,119.3,120.2,128.9,136.8,138.8,142.9,150.2。
embodiment 7:3-((6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) acetylene
base) tetrahydrofuran (THF)-3-alcohol
step 1) 3-((trimethyl silicon based) ethynyl) tetrahydrofuran (THF)-3-alcohol
Trimethylsilyl acetylene (1g, 10.2mmol) is dissolved in THF (20mL), is cooled to-78 ℃, and add wherein n-Butyl Lithium (4.11mL, 10.3mmol).Mixture after 30 minutes, continues to add tetrahydrofuran (THF) (20mL) solution of dihydrofuran-3 (2H)-one (0.87g, 10.2mmol)-78 ℃ of stirrings in system.Reaction solution continues to stir 30 minutes at-78 ℃, returns to room temperature, continues to stir 50 minutes.Reaction is finished, and adds the cancellation of saturated ammonium chloride (20mL) aqueous solution, and extracts by ethyl acetate (50mL x4).The organic phase merged is washed through saturated aqueous common salt (100mL x2), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is white solid (1.67g, 89%).Product is not purified, is directly used in next step reaction.
1H?NMR(400MHz,d
6-DMSO)δ(ppm):0.14(s,9H),2.05-2.08(m,2H),3.62-3.70(m,2H),3.79-3.83(m,2H),5.72(s,1H)。
step 2) 3-ethynyl tetrahydrofuran (THF)-3-alcohol
3-((trimethyl silicon based) ethynyl) tetrahydrofuran (THF)-3-alcohol (1.67g, 9.06mmol) is dissolved in methyl alcohol (50mL), and adds wherein potassium hydroxide (1.01g, 18.12mmol).Reaction solution is in stirring at room after 2 hours, and water (100mL x2) and saturated aqueous common salt (100mLx2) are washed successively.Mixed solution is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow oil (0.77g, 75.9%).
LC-MS(ESI,pos.ion)m/z:113.05[M+H]
+；
1H?NMR(400MHz,d
6-DMSO)δ(ppm):2.06-2.10(m,2H),3.41-3.42(m,1H),3.63-3.70(m,2H),3.80-3.83(m,2H),5.72(s,1H)。
step 3) 3-((6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) ethynyl)
tetrahydrofuran (THF)-3-alcohol
Under nitrogen protection; by 3-ethynyl tetrahydrofuran (THF)-3-alcohol (0.72g, 6.43mmol), (1-(2 for the bromo-3-of (R)-5-; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (1.88g; 4.95mmol), two (triphenylphosphine) palladium chlorides (0.17g, 0.25mmol); cuprous iodide (47mg; 0.25mmol) be dissolved in DMF (20mL), and add wherein triethylamine (9.99g).Reaction solution 100 ℃ stir 12 hours after, concentrating under reduced pressure.By methylene dichloride for residue (100mL) dilution, and water (100mL x2) and saturated aqueous common salt (100mL x2) are washed successively.Gained mixture anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue after silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, recrystallization in the mixed solution ((v/v)=10/1) of sherwood oil and ethyl acetate, obtaining title compound is light yellow solid (0.3g, 15%).
LC-MS(ESI,pos.ion)m/z:412.00[M+H]
+；
1H?NMR(400MHz,d
6-DMSO)δ(ppm):1.74-1.76(d,3H),2.10-2.13(m,2H),3.66-3.74(m,2H),3.82-3.86(m,2H),5.74(s,1H),5.96-6.00(m,1H),6.16(s,2H),6.60-6.61(m,1H),7.44-7.49(m,1H),7.56-7.57(m,1H),7.59-7.60(m,1H)。
embodiment 8:3-((6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) acetylene
base) tetramethyleneimine-3-alcohol
step 1) 1-(tertbutyloxycarbonyl)-3-((trimethyl silicon based) ethynyl) tetramethyleneimine-3-alcohol
Trimethylsilyl acetylene (1g, 10.2mmol) is dissolved in tetrahydrofuran (THF) (20mL), is cooled to-78 ℃, and, in 30 minutes, in solution, add n-Butyl Lithium (4.11mL, 10.3mmol, the hexane solution of 2.5M).Mixture after 30 minutes, in 30 minutes, continues to add wherein the tetrahydrofuran solution of N-Boc-3-pyrrolidone (1.89g, 10.2mmol)-78 ℃ of stirrings.After reaction solution stirring at room 50 minutes, add saturated aqueous ammonium chloride solution (8mL) cancellation, and extract by ethyl acetate (50mL x4).The organic phase merged is washed through saturated aqueous common salt (100ml x2), anhydrous sodium sulfate drying, and concentrating under reduced pressure to obtain title compound be light yellow solid (2.6g, 90%).
1H?NMR(400MHz,CDCl
3)δ(ppm):0.17(s,9H),1.45(s,9H),2.10-2.24(m,2H),3.44-3.67(m,4H)。
step 2) 1-(tertbutyloxycarbonyl)-3-ethynyl tetramethyleneimine-3-alcohol
1-(tertbutyloxycarbonyl)-3-((trimethyl silicon based) ethynyl) tetramethyleneimine-3-alcohol is dissolved in methyl alcohol (30mL), and adds wherein potassium hydroxide (0.59g, 10.6mmol).After reaction solution stirring at room 2 hours, add water (50mL) dilution, and extract by ethyl acetate (60mL x5).The saturated aqueous common salt for organic phase (100mL x2) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=3/1) purifying, and obtaining title compound is white solid (0.86g, 76%).
LC-MS(ESI,pos.ion)m/z:156.2[M+H-56]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.45(s,9H),2.18(m,2H),2.58(m,1H),2.54(s,1H),3.47-3.72(m,4H)。
step 3) 3-((6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) acetylene
base)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-alcohol
N
2under protection; by the bromo-3-of (R)-5-, (1-(2; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (0.3g; 0.79mmol) be dissolved in N; in dinethylformamide (30mL); and add successively wherein two (triphenylphosphine) palladium chloride (28mg; 0.04mmol); CuI (7mg; 0.04mmol); 1-(tertbutyloxycarbonyl)-3-ethynyl tetramethyleneimine-3-alcohol (0.17g, 0.79mmol) and triethylamine (2.2mL, 15.8mmol).Reaction solution after 16 hours, is cooled to room temperature 75 ℃ of stirrings, and adds methylene dichloride (300mL) dilution.Gained for mixture saturated aqueous common salt (100mL x3) wash, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1to1/1) purifying, and obtaining title compound is red-brown oily matter (0.25g, 62%).
step 4) 3-((6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) ethynyl)
tetramethyleneimine-3-alcohol
By 3-((6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) ethynyl)-1-(tertbutyloxycarbonyl) tetramethyleneimine-3-alcohol (0.25g, 0.49mmol) be dissolved in methylene dichloride (20mL), and add wherein saturated hydrogenchloride ethyl acetate solution (5mL).After reaction solution stirring at room 16 hours, concentrating under reduced pressure.Residue water (5mL) dilution, regulate pH=12 with saturated aqueous sodium carbonate, and extract with the mixed solution (40mL x5) of DCM/MeOH (v/v=10:1).The saturated aqueous common salt for organic phase (100mL x2) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is yellow solid (0.11g, 54%) through preparing silica-gel plate (DCM/MeOH (v/v)=10/1) purifying, obtaining title compound.
LC-MS(ESI,pos.ion)m/z:410.0[M+H]
+；
1H?NMR(400MHz,CDCl
3+CD
3OD)δ(ppm):1.83(d,J=6.68Hz,3H),2.25-2.48(m,2H),3.43-3.58(m,4H),5.88-6.06(q,J=6.68Hz,1H),6.72(d,J=1.52Hz,1H),7.17(t,J=8.80Hz,1H),7.32-7.38(dd,J=8.92Hz,4.80Hz,1H),7.65(d,J=1.56Hz,1H)。
embodiment 9:3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(morpholinyl fourth-1-alkynes-1-yl)
pyridine-2-amine
step 1) (R) the bromo-N of-5-, two (tertbutyloxycarbonyl)-3-(1-(the chloro-3-fluorophenyl of 2, the 6-bis-) oxyethyl group) pyrroles of N-
pyridine-2-amine
By the bromo-3-of (R)-5-, (1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (2.52g, 6.63mmol), DMAP (809mg, 6.63mmol) be dissolved in tetrahydrofuran (THF) (66mL), and add wherein Boc acid anhydrides (4.7mL, 19.89mmol) and triethylamine (2.8mL, 19.89mmol).Reaction solution, adds saturated sodium bicarbonate aqueous solution (50mL) cancellation, and extracts by ethyl acetate (50mL x3) after 11 hours 68 ℃ of stirrings.The organic phase merged is water (50mL) successively, and saturated sodium bicarbonate aqueous solution (50mL) and saturated aqueous common salt (50mL) are washed.Gained solution anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through column chromatography (PE/EtOAc (v/v)=4/1) purifying, and obtaining title compound is yellow solid (4.4g, 114%).
LC-MS(ESI,pos.ion)m/z:603[M+Na]
+。
step 2) 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)
pyridin-3-yl) fourth-3-alkynes-2-alcohol
By the bromo-N of (R)-5-, (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (0.25g, 0.43mmol), two (triphenylphosphine) palladium chlorides (30mg, 0.04mmol) and cuprous iodide (8.1mg, 0.04mmol) are suspended in triethylamine (2.5mL), and add wherein 3-butyne-2-alcohol (0.05mL, 0.65mmol).Reaction solution after 80 minutes, is cooled to room temperature at 90 ℃ of microwave reactions, and concentrating under reduced pressure.By methylene dichloride for residue (10mL) dilution, to filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through purification by silica gel column chromatography (PE/EtOAc (v/v)=2/1), and obtaining title compound is yellow solid (201mg, 82%).
1H?NMR(400MHz,CDCl
3)δ(ppm):1.37-1.41(m,18H),1.55(d,J=6.6Hz,3H),1.78(d,J=6.6Hz,3H),4.72-4.78(m,1H),5.97-5.02(q,J=6.7Hz,1H),7.06-7.12(m,2H),7.27-7.32(m,1H),8.12-8.13(m,1H)。
step 3) 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)
pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates
Under nitrogen protection; by 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-alcohol (244mg; 0.43mmol) be dissolved in methylene dichloride (2.4mL); be cooled to-20 ℃; and add wherein triethylamine (0.14g, 1.38mmol) and Methanesulfonyl chloride (0.05mL, 0.65mmol).Reaction solution after 3 hours, returns to room temperature-20 ℃ of stirrings, continues to stir 3 hours.Add saturated sodium bicarbonate aqueous solution (10mL) cancellation reaction, gained is methylene dichloride (10mL x3) extraction for mixture, the organic phase merged is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtaining title compound is yellow oil (243mg, 99%), product is not purified, is directly used in next step reaction.
LC-MS(ESI,pos.ion)m/z:647[M+H]
+。
step 4) N, two (the tertbutyloxycarbonyl)-3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) of N--5-(3-
quinoline Ji Ding-1-alkynes-1-yl) pyridine-2-amine
By 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates (0.28g, 0.43mmol) be dissolved in acetonitrile (5mL), and add wherein morpholine (0.13g, 1.5mmol).Reaction solution after 16 hours, is cooled to room temperature 60 ℃ of stirrings, and concentrating under reduced pressure.By methylene dichloride for residue (50mL) dilution, gained mixture water (50mL) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is yellow solid (219mg, 80%).
LC-MS(ESI,pos.ion)m/z:638[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.35-1.42(m,18H),1.41-1.44(m,3H),1.81(d,J=6.7Hz,3H),2.54-2.56(m,2H),2.71-2.74(m,2H),3.63-3.69(m,1H),3.78-3.80(m,4H),5.98-6.03(q,J=6.7Hz,1H),7.06-7.12(m,2H),7.29-7.34(m,1H),8.09(s,1H)。
step 5) 3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(morpholinyl fourth-1-alkynes-1-yl) pyrrole
pyridine-2-amine
By N, two (tertbutyloxycarbonyl)-3-((the R)-1-(2 of N-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(morpholinyl fourth-1-alkynes-1-yl) pyridine-2-amine (219mg, 0.34mmol) be dissolved in methylene dichloride (5mL), and add wherein hydrogenchloride ethyl acetate solution (3M, 1mL).After reaction solution stirring at room 18 hours, add unsaturated carbonate aqueous solutions of potassium (30mL) cancellation, and extract by ethyl acetate (50mL x3).The organic phase merged water (50mL) and saturated aqueous common salt (50mL) is successively washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is yellow solid (134mg, 90%).
LC-MS(ESI,pos.ion)m/z:439[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.37-1.39(m,3H),1.82(d,J=6.7Hz,3H),2.51-2.54(m,2H),2.67-2.72(m,2H),3.58-3.64(m,1H),3.71-3.80(m,4H),5.03(s,2H),5.99-6.04(q,J=6.6Hz,1H),6.76(s,1H),7.04-7.08(m,1H),7.28-7.32(m,1H),7.72(d,J=1.0Hz,1H)。
embodiment 10:3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(3-(piperazine-1-yl) fourth-1-alkynes
-1-yl) pyridine-2-amine
step 1) N, two (tertbutyloxycarbonyl)-3-((R)-1-(the chloro-3-fluorophenyl of 2, the 6-bis-) ethoxies of N-
base)-5-(3-(piperazine-1-yl) fourth-1-alkynes-1-yl) pyridine-2-amine
By 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates (0.39g, 0.6mmol) be dissolved in acetonitrile (7mL), and add wherein piperazine (0.52g, 6mmol).Reaction solution after 16 hours, is cooled to room temperature 60 ℃ of stirrings, and concentrating under reduced pressure.Methylene dichloride for residue (50mL) dilution.The gained mixture is washed through water (50mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, and obtaining title compound is yellow solid (0.23g, 61%).Product is not purified, directly as next step reaction.
LC-MS(ESI,pos.ion)m/z:637[M+H]
+。
step 2) 3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(3-(piperazine-1-yl) fourth-1-alkynes-1-
base) pyridine-2-amine
By N, two (tertbutyloxycarbonyl)-3-((the R)-1-(2 of N-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(3-(piperazine-1-yl) fourth-1-alkynes-1-yl) pyridine-2-amine (0.2g, 0.3mmol) be dissolved in methylene dichloride (5mL), and add wherein the ethyl acetate solution (3M, 1mL) of hydrogenchloride.After reaction solution stirring at room 18 hours, add unsaturated carbonate aqueous solutions of potassium (30mL) cancellation, and extract by ethyl acetate (50mL x3).The organic phase merged water (50mL) and saturated aqueous common salt (50mL) is successively washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DMC/MeOH/Et
3n (v/v/v)=200/20/1) purifying, obtaining title compound is yellow solid (123mg, 90%).
LC-MS(ESI,pos.ion)m/z:219[M/2+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.37-1.39(m,3H),1.81(d,J=6.64Hz,3H),2.50-2.53(m,2H),2.67-2.71(m,2H),2.91-2.98(m,4H),3.60-3.64(m,1H),4.96(s,2H),5.99-6.04(q,J=6.64Hz,1H),6.77(d,J=1.5Hz,1H),7.09-7.05(m,1H),7.32-7.26(m,1H),7.73(d,J=1.6Hz,1H)。
embodiment 11:3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(3-(4-methylpiperazine-1-yl)
fourth-1-alkynes-1-yl) pyridine-2-amine
step 1) N, two (the tertbutyloxycarbonyl)-3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) of N--5-(3-(4-
methylpiperazine-1-yl) fourth-1-alkynes-1-yl) pyridine-2-amine
By 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates (0.35g, 0.55mmol) be dissolved in acetonitrile (4mL), and add wherein 1-methylpiperazine (0.22g, 2.18mmol).Reaction solution after 16 hours, is cooled to room temperature 60 ℃ of stirrings, and concentrating under reduced pressure.By methylene dichloride for residue (50mL) dilution, gained mixture water (50mL) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtAOc (v/v)=2/1) purifying, and obtaining title compound is yellow solid (0.31g, 94%).
LC-MS(ESI,pos.ion)m/z:651[M+H]
+。
step 2) 3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(3-(4-methylpiperazine-1-yl) fourth-1-
alkynes-1-yl) pyridine-2-amine
By N, two (tertbutyloxycarbonyl)-3-((the R)-1-(2 of N-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(3-(4-methylpiperazine-1-yl) fourth-1-alkynes-1-yl) pyridine-2-amine (0.31g, 0.47mmol) be dissolved in methylene dichloride (5mL), and add wherein the ethyl acetate solution (3M, 1mL) of hydrogenchloride.After reaction solution stirring at room 18 hours, add unsaturated carbonate aqueous solutions of potassium (30mL) cancellation, and extract by ethyl acetate (50mL x3).The organic phase merged water (50mL) and salt solution (50mL) is successively washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and obtaining title compound is yellow solid (182mg, 91%).
LC-MS(ESI,pos.ion)m/z:451[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):1.38-1.40(dd,J=7.0Hz,1.0Hz,3H),1.80(d,J=6.7Hz,3H),2.30(s,3H),2.50-2.58(m,6H),2.74-2.78(m,2H),3.62-3.67(q,J=7.0Hz,1H),4.91(s,2H),5.98-6.03(q,J=6.64Hz,1H),6.77(s,1H),7.08-7.04(m,1H),7.32-7.26(m,1H),7.72(d,J=1.6Hz,1H)。
embodiment 12:5-(4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)
fourth-3-alkynes-2-yl)-5-azaspiro [2.4] heptane-7-amine
step 1) (E)-5-benzyl-7-(oximido)-5-azaspiro [2.4] heptane-4-ketone
By 5-benzyl-5-azaspiro [2.4] heptane-4,7-diketone (6g, 28mmol) and triethylamine (6mL, 42mmol) are dissolved in ethanol (144mL), and add wherein oxammonium hydrochloride (2.92g, 42mmol).Reaction solution is in stirring at room after 24 hours, concentrating under reduced pressure.By residue water (140mL) dilution, the gained mixture, filters after 2 hours in stirring at room.Filter cake was 45 ℃ of lower drying under reduced pressure 24 hours, and obtaining title compound is faint yellow solid (5.9g, 91%).
LC-MS(ESI,pos.ion)m/z:231.0[M+H]
+；
1H?NMR(400MHz,d
6-DMSO)δ(ppm):1.22(d,J=3.6Hz,2H),1.35(d,J=3.6Hz,2H),4.02(s,2H),4.52(s,2H),7.24-7.32(m,3H),7.35-7.39(m,2H)。
step 2) 5-benzyl-5-azaspiro [2.4] heptane-7-amine
By lithium aluminum hydride (0.87g, 22.8mmol) be dissolved in tetrahydrofuran (THF) (10mL), be cooled to 0 ℃, tetrahydrofuran (THF) (20mL) solution that adds down wherein (E)-5-benzyl-7-(oxyimino)-5-azaspiro [2.4] heptane-4-ketone (1.31g, 5.7mmol).After reaction solution stirring at room 30 minutes, be heated to 60 ℃, continue to stir 5 hours.Reaction is finished, and is cooled to room temperature, slowly adds ethyl acetate (40mL) and water (20mL) cancellation reaction.Mixture is filtered, and filtrate decompression is concentrated, ethyl acetate for residue (40mL) dilution, and the gained mixture is washed through water (20mL), anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtaining title compound is orange liquid (1.24g, 99%).
LC-MS(ESI,pos.ion)m/z:203.1[M+H]
+；
step 3) 5-benzyl-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine
By 5-benzyl-5-azaspiro [2.4] heptane-7-amine (1.2g, 6.0mmol), triethylamine (2.1mL, 15mmol) is dissolved in tetrahydrofuran (THF) (20mL), and adds wherein Boc acid anhydrides (2.1mL, 9.0mmol).After reaction solution stirring at room 2 hours, concentrating under reduced pressure.By methylene dichloride for residue (60mL x2) dilution, gained for mixture saturated aqueous common salt (30mL x2) wash, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (sherwood oil) purifying, and obtaining title compound is white solid (1.85g, 100%).
LC-MS(ESI,pos.ion)m/z:303.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.43-0.45(m,2H),0.58-0.80(m,2H),1.35(s,9H),2.34(d,J=8.8Hz,1H),2.66-2.69(m,2H),2.88-2.95(m,1H),3.60(dd,J=28.4Hz,12.8Hz,2H),3.88(s,1H),4.97(d,J=7.6Hz,1H),7.26(s,2H),7.30(s,3H)。
step 4) N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine
By 5-benzyl-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine (0.93g, 3mmol) be dissolved in methyl alcohol (20mL), and add catalyst P d/C (10%, 54.5%water), reaction passes into hydrogen, and stirring at room is after 24 hours, filter, filtrate decompression is concentrated, and obtaining title compound is yellow liquid (0.6g, 100%).
LC-MS(ESI,pos.ion)m/z:213.1[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.56(dd,J=33.2Hz,9.6Hz,2H),0.77(s,2H),1.37(s,9H),2.73(d,J=10.8Hz,1H),2.93(dd,J=11.6Hz,3.2Hz,1H),2.99(d,J=10.8Hz,1H),3.33(dd,J=11.6Hz,5.6Hz,1H),3.47(s,1H),3.66(s,1H),7.26(s,2H),4.75(s,1H)。
step 5) 5-(4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethoxy
base) pyridin-3-yl) fourth-3-alkynes-2-yl)-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine
By 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates (0.16g, 0.25mmol) be dissolved in acetonitrile (5mL), add N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine (78.5mg under room temperature, 0.38mmol) and triethylamine (0.35mL, 2.5mmol).Reaction solution after 16 hours, is cooled to room temperature, concentrating under reduced pressure 69 ℃ of stirrings.Ethyl acetate for residue (50mL) dilution, gained mixture water (50mL) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purifying, and obtaining title compound is yellow solid (0.11g, 58%).
LC-MS(ESI,pos.ion)m/z:764[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.50-0.70(m,2H),0.73-0.92(m,2H),1.30-1.41(m,3H),1.41-1.46(m,27H),1.79(d,J=6.6Hz,3H),2.54-2.64(m,1H),2.69-2.86(m,2H),3.01-3.16(m,1H),3.75-3.76(m,1H),3.84-3.89(m,1H),4.91-4.95(m,1H),5.97-6.02(q,J=6.45Hz,1H),7.06-7.10(m,2H),7.30-7.32(m,1H),8.10(d,J=1.5Hz,1H)。
step 6) 5-(4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-
alkynes-2-yl)-5-azaspiro [2.4] heptane-7-amine
By 5-(4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-yl)-N-(tertbutyloxycarbonyl)-5-azaspiro [2.4] heptane-7-amine (0.4g, 0.52mmol) be dissolved in methylene dichloride (15mL), be cooled to 0 ℃, the ethyl acetate solution (3M, 5mL) that adds wherein hydrogenchloride.After reaction solution stirring at room 16 hours, concentrating under reduced pressure.By residue water (50mL) dilution, add saturated aqueous sodium carbonate to regulate pH=10, and extract with methylene dichloride (80mL x3).The saturated aqueous common salt for organic phase (50mL) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH/Et
3n (v/v/v)=200/20/1) purifying, obtaining title compound is yellow solid (294mg, 90%).
LC-MS(ESI,pos.ion)m/z:464[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.41-0.49(m,1H),0.59-0.67(m,2H),0.75-0.78(m,1H),1.40(d,J=6.9Hz,3H),1.81(d,J=6.7Hz,3H),2.56-2.64(m,2H),2.89-2.80(m,1H),3.07-3.14(m,1H),3.20-3.25(m,1H),3.70-3.73(m,1H),4.95(s,2H),6.00-6.02(q,J=6.5Hz,1H),6.75(s,1H),7.10(t,J=8.6Hz,1H),7.28-7.32(m,1H),7.73(d,J=1.5Hz,1H)。
embodiment 13:5-(4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)
fourth-3-alkynes-2-yl)-5-azaspiro [2.4] heptane-7-alcohol
step 1) 5-(4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethoxy
base) pyridin-3-yl) fourth-3-alkynes-2-yl)-5-azaspiro [2.4] heptane-7-alcohol
By 4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-methanesulfonates (0.99g, 1.53mmol) be dissolved in acetonitrile (13mL), under room temperature, add wherein 5-azaspiro [2.4] heptane-7-alcohol (259mg, 1.95mmol) and triethylamine (2mmol).Reaction solution after 16 hours, is cooled to room temperature 69 ℃ of stirrings, and concentrating under reduced pressure.By ethyl acetate for residue (50mL) dilution, gained mixture water (50mL) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1 is to 1/2) purifying, and obtaining title compound is yellow solid (0.74g, 74%).
LC-MS(ESI,pos.ion)m/z:664[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.60-0.72(m,2H),0.73-0.80(m,1H),0.90-0.98(m,1H),1.41-1.48(m,21H),1.79(d,J=6.8Hz,3H),2.92-3.10(m,2H),3.72-3.88(m,2H),5.99(m,1H),7.08-7.105(m,3H),8.10(d,J=1.7Hz,1H)。
step 2) 5-(4-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-
alkynes-2-yl)-5-azaspiro [2.4] heptane-7-alcohol
By 5-(4-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) fourth-3-alkynes-2-yl)-5-azaspiro [2.4] heptane-7-alcohol (0.42g, 0.6mmol) be dissolved in methylene dichloride (15mL), be cooled to 0 ℃, the ethyl acetate solution (3M, 8mL) that adds wherein hydrogenchloride.Reaction solution is in stirring at room after 16 hours, concentrating under reduced pressure.By residue water (50mL) dilution, add saturated aqueous sodium carbonate to regulate pH=10, and extract with methylene dichloride (50mL x3).The saturated aqueous common salt for organic phase (50mL) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (EtOAc/MeOH/Et
3n (v/v/v)=250/10/1) purifying, obtaining title compound is yellow solid (0.16g, 60%).
LC-MS(ESI,pos.ion)m/z:464[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.57-0.58(m,1H),0.63-0.65(m,1H),0.72-0.75(m,1H),0.92-0.94(m,1H),1.39-1.42(m,3H),1.81(d,J=6.7Hz,3H),2.57-2.64(m,1H),2.84-3.00(m,3H),3.71-3.77(m,2H),5.01(s,2H),6.01(m,1H),6.75(d,J=1.4Hz,1H),7.05-7.09(m,1H),7.29-7.31(m,1H),7.72(s,1H)。
embodiment 14:5-(3-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)
third-2-alkynes-1-yl)-5-azaspiro [2.4] heptane-7-alcohol
step 1) (R)-3-(6-(two (tertbutyloxycarbonyl) amino)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)
pyridin-3-yl) third-2-alkynes-1-alcohol
By the bromo-N of (R)-5-, (1-(2 for two (the tertbutyloxycarbonyl)-3-of N-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine (2g, 3.5mmol), two (triphenylphosphine) palladium chlorides (246mg, 0.35mmol) and cuprous iodide (67mg, 0.35mmol) are suspended in triethylamine (18mL), and add wherein 2-propine-1-alcohol (0.42mL, 7mmol).Reaction solution after 80 minutes, is cooled to room temperature at 90 ℃ of microwave reactions, and concentrating under reduced pressure.By methylene dichloride for residue (100mL) dilution, to filter, filtrate is used anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purifying, and obtaining title compound is yellow solid (1.52g, 80%).
1H?NMR(400MHz,CDCl
3)δ(ppm):1.37-1.41(m,18H),1.55(d,J=6.6Hz,3H),1.78(d,J=6.6Hz,3H),4.72-4.78(m,1H),5.97-5.02(q,J=6.7Hz,1H),7.06-7.12(m,2H),7.27-7.32(m,1H),8.12-8.13(m,1H)。
step 2) (R)-3-(6-(two (tertbutyloxycarbonyl) amino)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)
pyridin-3-yl) third-2-alkynes-1-methanesulfonates
Under nitrogen protection; by (R)-3-, (6-(two (tertbutyloxycarbonyl) amino)-(1-(2 for 5-; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) third-2-alkynes-1-alcohol (300mg; 0.54mmol) be dissolved in methylene dichloride (2.5mL); be cooled to 0 ℃; add wherein triethylamine (0.22mL, 1.6mmol) and Methanesulfonyl chloride (63 μ L, 0.81mmol).Reaction solution, adds saturated sodium bicarbonate aqueous solution (10mL) cancellation, and extracts with methylene dichloride (10mL x3) after 1 hour in the stirring at room reaction.The organic phase merged is through anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtains title compound.Product is not purified, is directly used in next step reaction.
LC-MS(ESI,pos.ion)m/z:633[M+H]
+。
step 3) 5-(3-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethoxy
base) pyridin-3-yl) third-2-alkynes-1-yl)-5-azaspiro [2.4] heptane-7-alcohol
By (R)-3-, (6-(two (tertbutyloxycarbonyl) amino)-(1-(2 for 5-, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) third-2-alkynes-1-methanesulfonates (341mg, 0.54mmol) be dissolved in acetonitrile (5mL), add wherein 5-azaspiro [2.4] heptane-7-alcohol (92mg, 1.08mmol) and triethylamine (1mL) under room temperature.Reaction solution after 16 hours, is cooled to room temperature 69 ℃ of stirrings, and concentrating under reduced pressure.By ethyl acetate for residue (50mL) dilution, gained mixture water (50mL) is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through column chromatography purification (PE/EtOAc (v/v)=2/1), and obtaining title compound is yellow solid (0.14g, 40%).
LC-MS(ESI,pos.ion)m/z:650[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.61-0.69(m,2H),0.77-0.78(m,1H),0.93-0.96(m,1H),1.38-1.43(m,18H),1.78(d,J=6.6Hz,3H),2.57-2.60(dd,J=8.8Hz,4.8Hz,1H),2.92-2.95(m,2H),3.04-3.07(dd,J=10.0Hz,1.6Hz,1H),3.65(s,2H),3.77-3.79(m,1H),5.99(m,1H),7.05-7.10(m,2H),7.27-7.32(m,1H),8.10(d,J=1.7Hz,1H)。
step 4) 5-(3-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl) third-2-
alkynes-1-yl)-5-azaspiro [2.4] heptane-7-alcohol
By 5-(3-(6-(two (tertbutyloxycarbonyl) amino)-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl) third-2-alkynes-1-yl)-5-azaspiro [2.4] heptane-7-alcohol (0.14g, 0.22mmol) be dissolved in methylene dichloride (6mL), be cooled to 0 ℃, the ethyl acetate solution (3M, 2mL) that adds wherein hydrogenchloride.After reaction solution at room temperature stirs 16 hours, concentrating under reduced pressure.By residue water (50mL) dilution, add saturated aqueous sodium carbonate to regulate pH=10, and extract with methylene dichloride (50mL x3).The saturated aqueous common salt for organic phase (50mL) merged is washed, anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residue is through silica gel column chromatography (EtOAc/MeOH/Et
3n (v/v/v)=300/30/1) purifying, obtaining title compound is yellow solid (85mg, 88%).
LC-MS(ESI,pos.ion)m/z:450[M+H]
+；
1H?NMR(400MHz,CDCl
3)δ(ppm):0.69-0.78(m,3H),0.91-0.95(m,1H),1.81(d,J=6.7Hz,3H),2.58(d,J=8.6Hz,1H),2.92(t,J=8.6Hz,2H),3.02-3.05(dd,J=10.1Hz,4.9Hz,1H),3.61(s,2H),3.75-3.76(m,1H),4.96(s,2H),5.98-6.03(q,J=6.7Hz,1H),6.74(d,J=1.3Hz,1H),7.05-7.09(m,1H),7.29-7.32(m,1H),7.73(s,1H)。
Biological test
The compound that adopts method and apparatus mentioned above to prepare the embodiment of the present invention carries out bioanalysis.
The stability of embodiment A in people and rat liver microsomes
People or rat liver microsomes are placed in to the 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), NADPH (1.0mM) potassium phosphate buffer (PBS that target compound (5 μ M) and cumulative volume are 200 μ L, 100mM, the pH value is 7.4), by compound dissolution in DMSO, and use PBS that it is diluted, the concentration that makes its final DMSO solution is 0.05%.And hatched in the water-bath communicated with air under 37 ℃, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60min), add the cold acetonitrile termination reaction of consubstantiality accumulated ice.Sample is preserved until carry out the LC/MS/MS analysis under-80 ℃.
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 under 37 ℃, react and stop at different time point (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ) is as positive control, and hatching under 37 ℃, react and stop at different time point (0,5,10,15,30 and 60 minutes).All comprise positive and negative control sample in each measuring method, to guarantee the integrity of microsome hatching system.
For each reaction, the concentration (meaning with per-cent) by compound in people or rat liver microsomes are hatched, by the per-cent mapping of Relative Zero time point, is inferred CLint CL in body with this
int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001, 29:1316-1324.), through overtesting, detect, result shows when the compound that the embodiment of the present invention is provided is incubated in respectively in people and rat liver microsomes, compound of the present invention all shows good transformation period (T
1/2) and CL
int.
The stability of the compound that table 1 embodiment of the present invention provides in people and rat liver microsomes is real
Test result
Embodiment B the compounds of this invention Pharmacokinetic Evaluation in animal body
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, the aqueous solution of 2%HPMC+1% tween-80, and the salt brine solution form of 5%DMSO+5% is carried out administration.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and preserve under-20 ℃ or-70 ℃ until carry out above-mentioned LC/MS/MS analysis.Result is referring to table 2, and the medicine of compound in the rat body that table 2 provides for the embodiment of the present invention is for the experimental result of feature.
The medicine of the compound that table 2 embodiment of the present invention provides in the rat body is for the feature experimental result
Result shows, during by the compound Bolos intravenous administration, compound of the present invention shows good pharmacokinetic property, comprises desirable clearance rate (Cl), transformation period (T
1/2) oral administration biaavailability of becoming reconciled.
The Embodiment C kinase assay
The compound embodiment of the present invention provided according to method mentioned above carries out ALK (h) kinase assays and c-Met (h) kinase assays, and result is referring to table 3, the kinase assay result that table 3 provides for the embodiment of the present invention.
The kinase assay result of the compound that table 3 embodiment of the present invention provides
As shown in Table 3, compound of the present invention generally demonstrates very high activity in the test of ALK and c-Met (h).
Embodiment D cells phosphorylation
According to method mentioned above, the compound that the embodiment of the present invention is provided carries out the cells phosphorylation level detection, estimation IC
50value (each concentration determination 2 times).The test-results demonstration, the compounds of this invention generally demonstrates very high activity in the cells phosphorylation test of ALK and c-Met.
Embodiment E xenotransplantation tumor model
Adopt method mentioned above to set up U87MG transplanted tumor model, and adopt method mentioned above to be analyzed.In U87MG transplanted tumor model, by (QD) oral administration compound every day (p.o.) of embodiment 1 to embodiment 14, and lasting 13-21 days.Under 60mg/kg dosage, the compound of embodiment 1 to embodiment 14 all has meaning statistically, can suppress the growth of nude mice by subcutaneous tumour.
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 modification 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 as reference of the present invention.
Claims (15)
1. a compound as shown in the formula (I):
Or its steric isomer, geometrical isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, wherein:
Each R
1, R
2, R
3, R
4, R
5and R
6be H independently, D or F;
X is C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N, wherein, described C
6-10aryl and comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N is optionally by 1,2, and 3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3,-OR
a,-SR
a,-NR
ar
b,-C (=O) NR
ar
b, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkenyl, C
2-6alkynyl ,-(C
1-4alkylidene group)-CN ,-(C
1-4alkylidene group)-OR
a,-(C
1-4alkylidene group)-NR
ar
b, C
6-10aryl or comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N;
Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-4alkyl ,-OR
a,-SR
a,-NR
ar
bor-C (=O) NR
ar
b, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently;
Each R
aand R
bbe H independently, C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) or-(C
1-4alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N), and, R worked as
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-8 atom, wherein, described C
1-6aliphatics, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
6-10aryl, comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
6-10aryl) ,-(C
1-4the heterocyclic radical of alkylidene group)-(comprise 1,2,3 or 4 and independently be selected from O, the heteroaryl of heteroatomic 5-10 the atom of S or N) and 3-8 atom is optionally by 1,2, and 3 or 4 substituting groups replace, and described substituting group is independently selected from D, F, Cl ,-CN, N
3,-OH ,-NH
2, alkoxyl group or alkylamino;
Situation distinguishingly, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2.
2. compound according to claim 1, wherein, each R
1, R
2, R
3, R
4, R
5and R
6be H or D independently.
3. compound according to claim 1, wherein, X is phenyl, and can be optionally by 1,2,3 or 4 independently are selected from D, F, Cl, Br, C
1-3alkyl or C
1-3the substituting group of haloalkyl replaces.
4. compound according to claim 1, wherein, Z is C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), wherein, described C
1-6alkyl, C
3-6cycloalkyl, C
3-6heterocyclic radical, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
3-6cycloalkyl) ,-(C
1-4alkylidene group)-(C
3-6heterocyclic radical) ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) and-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group), optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
bsubstituting group replace, and, C
5-12the condensed-bicyclic base, C
5-12the spiral shell bicyclic group ,-(C
1-4alkylidene group)-(C
5-12the condensed-bicyclic base) or-(C
1-4alkylidene group)-(C
5-12the spiral shell bicyclic group) each ring in is carbocyclic ring or heterocycle independently.
5. compound according to claim 1, wherein, each R
aand R
bbe H independently, C
1-3alkyl, C
3-6cycloalkyl or-(C
1-4alkylidene group)-(C
3-6and work as R cycloalkyl),
aand R
bwhile being connected with same nitrogen-atoms, R
a, R
b, together with the nitrogen-atoms be connected with them, can also optionally form the heterocyclic radical of 3-6 atom, wherein, described C
1-3alkyl, C
3-6cycloalkyl or-(C
1-4alkylidene group)-(C
3-6cycloalkyl) and the heterocyclic radical of 3-6 atom optionally by 1,2,3 or 4 substituting groups replace, described substituting group is independently selected from D, F, Cl ,-OH ,-NH
2, C
1-3alkoxyl group or C
1-3alkylamino;
Special situation, when Z is C
1-6during alkyl ,-NR
ar
bcan not be-NH
2or-NMe
2.
6. compound according to claim 1, wherein, Z is selected from any one in minor structure shown in formula (Z1)～(Z42):
Or its steric isomer, wherein:
N is 0,1,2 or 3;
Each W and W ' be independently-O-or-N (H)-;
Minor structure shown in formula (Z1)～(Z42) or its steric isomer be optionally by 1,2, and 3 or 4 independently selected from D, F, Cl, Br, I ,-CN ,-NO
2, N
3, C
1-3alkyl ,-OR
a,-NR
ar
bsubstituting group replace, wherein, when Z is the minor structure shown in formula (Z25)～(Z32) or its steric isomer ,-NR
ar
bcan not be-NH
2or-NMe
2.
7. compound according to claim 1 has following one of them structure:
8. a pharmaceutical composition, comprise the described compound of claim 1-7 any one and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
9. pharmaceutical composition according to claim 8, also comprise the additional treatment agent, and described additional treatment agent is selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, is used for the treatment of the medicine of pulmonary fibrosis or their combination.
10. pharmaceutical composition according to claim 9, described additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
11. a right to use requires the described compound of 1-7 any one or the described pharmaceutical composition of claim 8-10 any one for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
12. the purposes according to the described compound of claim 11 or pharmaceutical composition, is characterized in that, described proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
13. a right to use requires the described compound of 1-7 any one or the described pharmaceutical composition of claim 8-10 any one to come for the preparation of suppress or regulate the purposes of the medicine of protein kinase activity in biological sample, described purposes comprises right to use and requires the described compound of 1-7 any one or right to use to require the described pharmaceutical composition of 8-10 any one to contact with described biological sample.
14. purposes according to claim 13, is characterized in that, described protein kinase is receptor tyrosine kinase.
15. purposes according to claim 14, is characterized in that, described receptor tyrosine kinase is ALK, c-Met, or their combination.
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| Title |
|---|
| 凌保东: "《药理学》", 31 December 2009 * |
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|---|---|
| CN103387535B (en) | 2016-06-01 |
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