CN104513252B - Substituted urea derivative and its application in medicine - Google Patents

Substituted urea derivative and its application in medicine Download PDF

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CN104513252B
CN104513252B CN201410499464.1A CN201410499464A CN104513252B CN 104513252 B CN104513252 B CN 104513252B CN 201410499464 A CN201410499464 A CN 201410499464A CN 104513252 B CN104513252 B CN 104513252B
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alkyl
base
alkoxy
compound
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CN104513252A (en
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郑常春
刘兵
张英俊
龙伯华
章维红
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Guangdong HEC Pharmaceutical
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Abstract

The invention provides substituted carbamide derivative or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, and its pharmaceutical composition.Such compound can be used in adjusting Flt3 kinase activities and for suppressing FLT3 ITD kinases, while can be used for the purposes for treating disease caused by flt3 mediations or flt3 ITD.

Description

Substituted urea derivative and its application in medicine
Invention field
The invention belongs to pharmaceutical field.The invention provides a kind of new substituted urea derivative and combinations thereof and for controlling Treat the purposes of disease caused by flt3 mediations or flt3-ITD.Such compound is a kind for the treatment of, alleviation or prevention and tyrosine Kinase activity relevant disease or illness, or the new substituted carbamide compounds of the purposes of one or more symptom.
Background of invention
Protein kinase (PKs) is the oh group phosphoric acid on the tyrosine, serine and threonine residues of catalytic proteins The enzyme of change effect.Receptor protein tyrosine kinase (RTK) race of protein kinase, especially protein kinase, mainly as growth because Sub- acceptor, played an important role in the signal transduction pathway control aspect of many cell functions, such as cell cycle, cell life Long, cell differentiation and cell death.The imbalance of receptor protein tyrosine kinase (RPTK) activity or excessive, irregular activity are Through being observed under many disease conditions, including benign and pernicious Proliferative Disorders, inflammatory conditions, immune system disorder, It is as caused by the unsuitable activation of immune system, can cause such as autoimmune disease.
For the irregular activity of the receptor tyrosine kinase of platelet growth factor acceptor (PDGFR) race, as wherein One, it has been found that it is relevant with various Proliferative Disorders.PDGFR gene magnification or up-regulation is with glioma or meat Occur in the patient of knurl (referring to Kumabe etc., Oncogene, (1992) 7:627-633；Ostman and Heldin Cancer Res.(2001)80:1-38).One member of PDGFR races, Flt3 (also referred to as Flk-2), propagation and change in candidate stem cell Played an important role in different, the activated mutant or overexpression of this receptor are found (ginseng in AML (acute myelogenous cell leukemia) See Heinrich Mini-Reviews, pharmaceutical chemistry (2004) 4 (3):255-271；Kiyoi etc., lnt JHematol (2005) 82:85-92).Many known Flt3 inhibitor just conduct a research, some be expected to obtain anti-AML clinical effectiveness (referring to Levis etc., lnt J Hematol. (2005) 82:100-107).Flt3 acceptors are also expressed in large quantities of dendritic cell precursors, And stimulating this receptor to cause, these precursors are bred and differentiation turns into dendritic cells (DC).Because dendritic cells are T- cells The main initiators of the immune response (including spontaneous immune response) of mediation, Flt3 inhibitory action are to lower the inflammation of DC- mediations Disease and the mechanism of autoimmune response.Research shows that Flt3 inhibitor Cs EP-701 can be effectively reduced Autoimmune Encephalomyelitis (EAE) test, the myelin in multiple cerebral sclerosis mouse models is lost (referring to Whartenby etc., PNAS (2005) 102: 16741-16746).Gao Shui is found in the patients serum with langerhans cell histiocytosis and systemic loupus erythematosus Flat Flt3 parts, this is further imply, and Flt3 is carried out in the dendritic cell precursor imbalance of those autoimmune diseases Signal transduction is (referring to Rolland etc., J Immunol. (2005) 174:3067-3071).
It is reported that some small molecules for suppressing kinases FLT3 the cell of FLT3 kinase mutants can wither effectively in inducible cell line Die, and the life cycle of the mouse with bone marrow cell FLT3 mutation can be extended (referring to Levis etc., Blood (2002) 99:3885- 3891；Kelly etc., Cancer Cell 1 (2002):421-432；(2002) 433- of Weisberg etc., Cancer Cell 1 443；Yee etc., Blood (2002) 100:2941-2949).
The ITD that FLT3 internal series-connections repeat is activated (flt3-ITD), in about 20% acute myelocytic leukemia Found in people, and it is associated with some poor prognosis.Substantial amounts of experimental data and clinical data, including early stage FLT3 inhibitor The shortage of clinical event, it was demonstrated that make cancer when FLT3-ITD plays, when and make the angle for the body lesion that cancer maintains Color.It has been reported that in some patients, especially there is the trend of recurrence after the treatment, it may be possible to because flt3 kinase mutants (referring to The .Blood such as Heidel, F. (2006) 107:293–300.).There are some researches show FLT3-ITD inhibitor plays obstruction and induces evil The role of property tumor pathogenesis and in patient AML effective therapeutic purpose effect (referring to Catherine etc., Nature (2012)485:260-263)。
Flt3 mutation frequently occur in AML patient and comprising the coding region of the repetition (ITD) of internal series-connection by film or The tyrosine kinase domain (TKD) of the mutation of point.Dimerization and work of the FLT3-ITD and FLT3-TKD mutation due to flt3 acceptors Property causes part independently to spread.The ratio and the poor prognosis of adult and child of FLT3-ITD high variation wild-type allele Correlation is (referring to AS Moore etc., Leukemia (2012) 26:1462-1470).
The treatment that researchers are used for cancer for exploitation kinase inhibitor has sizable interest, wherein having had been reported that Urea derivative can alternatively property Flt3 inhibitor.
Abstract of invention
The invention provides the substituted carbamide derivative for drug therapy and its pharmaceutical composition and for adjusting Flt3 Kinase activity and for suppress FLT3-ITD a series of substitute urea compounds and for treat flt3 mediation or flt3-ITD The purposes of caused disease.
On the one hand, the present invention provides a kind of compound, and it is compound shown in the shown compound or formula (I) of formula (I) Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmacy Upper acceptable salt or its prodrug,
Wherein：
Q and W is each independently CH or N；
G is-O- ,-S (=O)t- ,-S- ,-C (=O)-or five yuan of inferior heteroaryls；
R is-NR3R2, alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkyl-S (=O)t-, alkoxyalkyl, hydroxyl Alkyl, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkoxy alkane Epoxide, cycloalkyl, cycloalkyl-alkyl, cycloalkyl oxy, cycloalkyl amino, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, Heterocyclylalkoxy, heterocyclic radical epoxide alkoxy, heterocyclic radical epoxide, carbocylic radical epoxide alkoxy, carbocyclylalkoxy, carbocylic radical Alkylamino, aryl, aryl alkyl, aryloxy group alkyl epoxide, aryloxy group, alkoxy aryl, aryl alkane amino, heteroaryl alkyl are miscellaneous Aryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryl epoxide, heteroaryl epoxide alkoxy, condensed-bicyclic base epoxide are thick Bicyclic group alkyl is closed, miscellaneous bicyclic group alkyl is condensed, condenses miscellaneous bicyclic group epoxide, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group Alkoxy, miscellaneous bicyclic group alkylamino is condensed, condense miscellaneous bicyclic group epoxide alkoxy, condense miscellaneous bicyclic group epoxide alkylamino, spiral shell is miscellaneous Bicyclic group alkyl, the miscellaneous bicyclic group alkoxy of spiral shell, the miscellaneous bicyclic group alkyl of bridge, the miscellaneous bicyclic group epoxide of bridge, the miscellaneous bicyclic group alkoxy of bridge, bridge Miscellaneous bicyclic group alkylamino, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell or the miscellaneous bicyclic group of fusion；
K is the heteroaryl groups of 5-6 members；At least 2 hetero atoms, each hetero atom are only in wherein described heteroaryl groups It is on the spot O, S, NR4Or N；
Each L independently is amino, nitro, C1-4Alkylthio group, C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-4Alkyl halide Base, C1-4Alkyl amino, hydroxyl, fluorine, chlorine, bromine, iodine, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkyl or cyanogen Base；
E is bicyclic heteroaryl group；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
Each R3And R2It independently is hydrogen, C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-6Alkoxy C1-6Alkyl or hydroxyl Base C1-4Alkyl；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each d independently is 1,2,3 or 4；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each a independently is 0,1,2,3 or 4；
Wherein, described aryl, bicyclic heteroaryl group, heteroaryl groups ,-(CH2)n- C (=O)-, alkoxy, alkyl- S (=O)t- ,-G- (CH2)n- R, alkoxyalkyl, hydroxy alkyl, aryl alkyl, heteroaryl alkyl, heteroaryl, heterocyclic radical, bridge Miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell, condense miscellaneous bicyclic group, alkyl, haloalkyl, alkyl amino, hydroxy alkoxy base, Aminoalkoxy Base, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, alkoxyalkyl, hydroxy alkyl, alkylamino halo Alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl oxy, alkoxy aryl, aryl alkane amino, heteroarylalkoxy Base, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclylalkoxy, Carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxy, heterocyclic radical epoxide alcoxyl Base, carbocylic radical epoxide alkoxy, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl, condense miscellaneous bicyclic group alkane Base, miscellaneous bicyclic group epoxide is condensed, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group alkoxy, condense miscellaneous bicyclic group alkylamino, it is thick Miscellaneous bicyclic group epoxide alkoxy is closed, condenses miscellaneous bicyclic group epoxide alkylamino, the miscellaneous bicyclic group alkyl of spiral shell, the miscellaneous bicyclic group alkoxy of spiral shell, The miscellaneous bicyclic group alkyl of bridge, the miscellaneous bicyclic group epoxide of bridge, the miscellaneous bicyclic group alkoxy of bridge, the miscellaneous bicyclic group alkylamino of bridge, alkyl-C (=O)- NH-, alkylthio group and cycloalkyl, can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, the X, Y, Z, T, T on the E rings1, Z1, Z2, Z3And Z4It is hetero atom at least while to have two；
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10Heterocyclic radical C1-4Alkane Base, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, Halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C3-10Cycloalkyl oxy, C6-10Aryl C1-4Alkoxy, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alkoxy, C1-9Heteroaryl Base C1-4Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl oxy, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkane Epoxide, C3-10Carbocylic radical C1-4Alkoxy, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxy, C6-10Aryloxy group, C1-9Heteroaryl epoxide, C1-9Heteroaryl epoxide C1-4Alkoxy, C2-10Heterocyclic radical epoxide C1-4Alkoxy, C3-10Carbocylic radical epoxide C1-4 Alkoxy, C2-10Heterocyclic radical epoxide, C1-4Alkoxy, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C1-9Heteroaryl,
Or R is following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)- NH-, oxo (=O), C1-4Alkyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In other embodiments, wherein described E is one of heteroaryl groups that following subformula is formed：
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl halide Base, C1-9Heteroaryl C1-6Alkyl or
R is following subformula：
Each R3And R2It independently is methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, n-pentyl, isopentyl, cyclopropyl, ring Amyl group, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methyl Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl-C (=O)-, N-propyl-C (=O)-, isopropyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In some embodiments, wherein described G is-O- or furylidene.
In some embodiments, wherein one of heteroaryl groups that the subformula that described K is as follows is formed：
Each L independently is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, C3-6Heterocyclylalkyl, amino, cyano group, nitro, fluorine, Chlorine, bromine, iodine, C1-4Haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, the tert-butyl group, C1-4Alkyl amino, hydroxyl, cyanogen Base, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkyl or C1-4Alkylthio group.
In some embodiments, the present invention provides a kind of substituted carbamide derivative, and it is the compound shown in formula (II) Or the stereoisomer of compound shown in formula (II), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvation Thing, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
Q and W is each independently CH or N；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
Each L independently is the tert-butyl group；
D is 1；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each a independently is 0,1,2,3 or 4；
E is one of heteroaryl groups that following subformula is formed：
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl halide Base, C1-9Heteroaryl C1-6Alkyl or R are following subformula：
Each R3And R2It independently is methyl, ethyl, propyl group, isopropyl, the tert-butyl group, amyl group, isopentyl, cyclopropyl, ring penta Base, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methyl Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl-C (=O)-, N-propyl-C (=O)-, isopropyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In some embodiments, the present invention provides a kind of substituted carbamide derivative, and it is the compound shown in formula (III) Or the stereoisomer of compound shown in formula (III), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvation Thing, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
Wherein, described X, Y, Z, Z1, Z2, Z3And Z4It is hetero atom at least while to have two；
Described R1, a, n and R have implication as described in the present invention.
On the other hand, present invention also offers a kind of pharmaceutical composition, the pharmaceutical composition to include of the present inventionization Compound.
In some embodiments, pharmaceutical composition of the present invention, it is further comprising pharmaceutically acceptable Carrier, excipient, diluent, at least one of assistant agent and medium.
In some embodiments, pharmaceutical composition of the present invention, it further includes additional therapeutic agent, institute It is chemotherapeutic agent to state additional therapeutic agent, antiproliferative, anti-inflammatory reagent, immunodepressant, immunostimulant, for treating The medicine of atherosclerosis, for treating the medicine or combinations thereof of pulmonary fibrosis.
In other embodiments, pharmaceutical composition of the present invention, wherein the additional therapeutic agent is benzene fourth Sour mustargen (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea assistant Rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), reach Carbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), TPT (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), TAM (tamoxifen), Flutamide (flutamide), Gonadorelin analog (gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib angstrom gram are replaced Buddhist nun (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), come that For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relax Buddhist nun replaces Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or combinations thereof.
On the other hand, the purposes the present invention relates to described compound or pharmaceutical composition in medicine is prepared, wherein institute Medicine is stated to be used to preventing, handle, mitigate or treating proliferative diseases, autoimmune disease or inflammatory disease.
In some embodiments, the proliferative diseases are that acute myeloid leukaemia, chronic myelogenous leukemia, gastrointestinal stromal swell Knurl, acute myelocytic leukemia (AML), mutation chronic myelogenous leukemia (CML), ALL (ALL), Colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, CNS (in Pivot nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, Rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic are white Blood disease, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases Benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, NHL, Sezary syndromes, biography Metachromia monocytosis,mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, rectum Cancer, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, medullary thyroid sample Cancer, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha, malignant tumor of digestive tract, non-small cell lung Cancer, cervical carcinoma, orchioncus, carcinoma of urinary bladder or myeloma.
In some embodiments, the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, Type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, and liver is hard Change, cholecystitis or chronic inflammation.
In some embodiments, the disease is disease caused by FLT3 mediations or FLT3-ITD.
On the other hand, the present invention relates to described compound or pharmaceutical composition to be used to preventing, handle, treat or mitigating trouble The method of person's proliferative diseases, autoimmune disease or inflammatory disease, its method include the patient for giving the infection or disease Effective therapeutic dose of compound as described in the present invention or pharmaceutical composition of the present invention.
In some embodiments, the disease be that FLT3 is kinase mediated or FLT3-ITD kinases caused by disease.
On the other hand, the present invention relates to described compound or pharmaceutical composition to be used to preventing, handle, treat or mitigating trouble Person's proliferative diseases, autoimmune disease or inflammatory disease.
Another aspect of the present invention is related to prevention, processing, treatment or mitigates patient's proliferative diseases, autoimmune disease or inflammation Property disease method, methods described include using the present invention compound pharmaceutically acceptable effective dose patient is carried out to Medicine.
Another aspect of the present invention is related to prevention, processing, treatment or mitigates patient's proliferative diseases, autoimmune disease or inflammation Property disease method, methods described includes to be had using the pharmaceutically acceptable of pharmaceutical composition of compound containing the present invention Effect dosage is administered to patient.
Another aspect of the present invention is directed to use with a kind of compound of the invention and is used to preventing, handle or treating patient to produce Proliferative diseases, autoimmune disease or inflammatory disease, and mitigate the purposes of the medicine of its order of severity.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will in detail list the document corresponding to the content of the materialization of determination, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, and these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to Method and material described by this, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.There is many documents and similar material to distinguish or contradict with the present patent application, including but be not limited to term Definition, the usage of term, the technology of description or the scope controlled as the present patent application.
The present invention will apply defined below unless other aspects show.According to the purpose of the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999, and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March, John Wiley&Sons,New York:2007, therefore all contents have all merged bibliography.
As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".In general, art Language " optionally " is whether located at before term " substituted ", and expression gives one or more of structure hydrogen atom can be by Specific substituent is substituted.Unless otherwise indicated, an optional substituted radical can have a substituent in group Each commutable position is substituted.When more than one position can be by one selected from specific group in given structural formula Or multiple substituents are substituted, then substituent with identical or different can substitute in each position.Wherein described substituent It can be, but be not limited to：Hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, Alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, virtue Base, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, ring third Base, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base with individually optional can be substituted by one or more substituents described in the invention.Some of embodiments are alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom.The further example of alkyl group includes, but is not limited to, methyl, Ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyls or isobutyl group, 1- methyl-propyls or sec-butyl, the tert-butyl group, positive penta Base, 2- amyl groups, 3- amyl groups, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acids-butyl, 2-methyl-1-butene base, just oneself Base, 2- hexyls, 3- hexyls, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 3- methyl -3- amyl groups, 2- first Base -3- amyl groups, 2,3- dimethyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl etc..Term " alkyl " and Its prefix " alkane " uses here, the saturated carbon chains all comprising straight chain and side chain.
Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is insatiable hunger And state, i.e. a C-C is the keys of sp tri-, and wherein alkynyl group can be with individually optional by one or more described in the invention Substituent is substituted, and specific example includes, but is not limited to, acetenylPropargylEtc..
Term " alkenyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is insatiable hunger And state, i.e. a C-C is sp2The group of double bond, wherein alkenyl with individually optional can be retouched by one or more present invention The substituent stated is substituted, including group has negation " just " or " E " " Z " positioning, wherein specific example includes, but it is and unlimited In vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2) etc..
Divalent hydrocarbon that term " alkylidene " and " alkylidene chain " refer to straight or branched, being only made up of carbon and hydrogen atom Chain, without unsaturated bond, there are 1 to 8 carbon atoms, for example, methylene, ethylidene, propylidene, positive butylidene etc..Alkylidene Chain can be connected on the remainder of molecule by any two carbon atom in chain.
Term " alkenylene " or " alkenylene chain " refer to straight or branched, the unsaturation two that is only made up of carbon and hydrogen atom Valency group, there are 1 to 8 carbon atoms, wherein unsaturated bond only exists as double bond, and double bond may reside in any two in chain Between individual carbon atom, for example, ethenylidene, 1,3- allylidenes, 2- butenylidenes etc..Alkenylene chain can be by any in chain Two carbon atoms are connected on the remainder of molecule.
Term " alkynylene " or " sub- alkynes chain " refers to straight or branched, the unsaturated divalence that is only made up of carbon and hydrogen atom Group, there are 1 to 8 carbon atoms, wherein unsaturated bond only exists with three key-shaped formulas, and three keys may reside in any the two of carbochain Between individual carbon atom, for example, sub- acetylene, 1- Asias propine, 2- Aden alkynes, 1- Asias pentyne, 3- Asias pentyne etc..The sub- alkynes chain can lead to Any two carbon atom in chain is crossed to be connected on the remainder of molecule.
Terminology used in the present invention " halogen ", " halogen atom " or " halogen atom " include fluorine, chlorine, bromine, iodine.
Term " amino " refers to formula-NH2。
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino Group is separately substituted by one or two alkyl group, and wherein alkyl group has implication as described in the present invention. Some of embodiments are that alkyl amino is one or two C1-6Alkyl is connected to the alkyl amino of the lower level on nitrogen-atoms Group.Other embodiment is that alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group Can be alkyl monosubstituted amino or dialkyl amido, such example includes, but is not limited to, N- methylaminos, N- ethylaminos, N, N- Dimethylamino, N, N- lignocaines etc..
Term " alkoxy " used in the present invention, is related to alkyl, as defined in the present invention, is connected by oxygen atom It is connected in main carbochain.Such embodiment includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..
Term " alkoxyalkyl " or " alkyloxy-alkoxy ", represent that alkyl or alkoxy can be by one or more identical Or the situation of different alkoxy substitutions, wherein alkyl and alkoxy have implication as described in the present invention.Such embodiment Include, but is not limited to, methoxy methyl alkyl, (ethoxymethyl) alkyl, methoxy propoxy, methoxymethoxy etc..
Term " alkyl-S (=O)t- ", expression-S (=O)t- situation about can be connected with an alkyl, wherein alkyl have Implication as described in the present invention.Wherein, t 0,1 or 2.Such embodiment includes, but is not limited to, methyl-S (=O )2-, ethyl group-S (=O)2-, propyl-S (=O)2-, methyl-S (=O)-, ethyl group-S (=O)-, propyl-S (= O)-, methyl-S-, ethyl group-S-, propyl-S-, etc..
Term " alkyl-C (=O)-", represent the situation that acyl group (- C (=O) -) can be connected with an alkyl, wherein alkane Base has implication as described in the present invention.Such embodiment includes, but is not limited to, acetyl group (CH3- C (=O) -), propionyl Base (C2H5- C (=O) -) etc..
Term " haloalkyl " or " halogenated alkoxy " represent that alkyl or alkoxy can be by one or more identical or not Situation about being substituted with halogen atom.Wherein alkyl and alkoxy base have implication as described in the present invention, such example Include, but is not limited to trifluoromethyl, trifluoromethoxy etc..
Term " alkylamino halogenated alkoxy " represents that halogenated alkoxy can be by one or more identical or different alkylaminos Situation about being substituted.Wherein alkylamino and halo alkoxy group have implication as described in the present invention, and such example includes, But it is not limited to methylamino difluoro-methoxy etc..
Term " hydroxy alkyl " or " hydroxy alkoxy base " represent that alkyl or alkoxy can be taken by one or more hydroxyls The situation in generation.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to Methylol, 1- ethoxys, hydroxypropyl, 1,2- dihydroxypropyl, hydroxyl methoxyl group, 1- hydroxy ethoxies etc..
Term " aminoalkoxy " or " alkylaminoalkoxy " represent that alkoxy can be by one or more amino or alkane ammonia The situation that base is substituted.Wherein alkylamino or alkoxy base have implication as described in the present invention, and such example includes, but It is not limited to aminomethoxy, 1- amino ethoxies, methylamino methoxyl group, ethylamino ethyoxyl etc..
Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, can be it is monocyclic, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are aromatic, each of which Member ring systems include 3-7 atom.Term " aryl " can be exchanged with term " aromatic rings " and used, as aromatic rings can include benzene Base, naphthyl and anthracene.And the aryl can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, Aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, halogen Substituted alkyl, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl are miscellaneous Ring group, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- Or alkoxyalkyl etc..Depending on structure, aryl can be monoradical or divalent group (that is, arlydene).
Term " heteroaryl ", " hetero-aromatic ring " are used interchangeably here, can be used alone or as " heteroaryl alkyl " Or the part of " heteroarylalkoxy ", all referring to monocyclic, bicyclic, three rings or tetracyclic ring system, wherein, Bicyclic heteroaromatic rings, three Ring hetero-aromatic ring or Fourth Ring heteroaromatic ring systems are cyclic in the form of condensing.Wherein, heteroaromatic ring systems are armaticity, one on ring Or multiple atoms are substituted that (hetero atom is selected from N, O, P, S, in this S or P optionally by one or more by hetero atom individually optionally Individual oxygen atom substitutes to obtain as SO, SO2, PO, PO2Group).Heteroaryl system can be on any hetero atom or carbon atom It is connected in main structure so as to form stable compound.Heteroaryl system group can be 3-7 former molecular monocyclic, or 7- 10 originals are molecular bicyclic, or 10-15 former molecular three ring.Bicyclic with 7-10 atom can be two rings [4, 5], [5,5], [5,6] or [6,6] system, three rings with 10-15 atom can be three rings [5,5,6], [5,7,6] or [6, 5,6] system.And the heteroaryl or hetero-aromatic ring can be substituted or non-substituted, and wherein substituent can be, but and unlimited In, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (= O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, Alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C =O) NH- or alkoxyalkyl etc..Depending on structure, hetero-aromatic ring can be monoradical or divalent group (that is, inferior heteroaryl).
Other embodiment is that heteroaryl system (including heteroaryl, hetero-aromatic ring) includes example below, but is not limited to this A little examples：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- are different Oxazolyl, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrroles Cough up base, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls With 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyl, 1,2, 5- oxadiazolyls, 1,2,4- oxadiazolyl, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2, 5- thio biphosphole bases, 1,3,4- thiadiazoles -2- bases, pyrazinyl, pyrazine -2- bases, 1,3,5-triazines base, benzo [d] thiazole -2- Base, imidazo [1,5-a] pyridine -6- bases, benzimidazolyl, benzoxazolyl, 1,8- phthalazinyl, benzothienyl, Yin Diindyl base (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinoline), tetralyl, benzopyrazoles Base, acridinyl, benzimidazolyl, benzindole base, Ben Bing Yi oxazinyls, benzo [4,6] imidazo [1,2-a] pyridine radicals, benzene And [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, aphthofurans base, diazosulfide base, benzo thio-phenyl, benzo three Oxazolyl, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, B-carboline base, carbazyl, adjacent diaza Naphthyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizine base, indyl, different benzo thianthrene Base, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridines base, oxazolidinedione base, oxazolidine base, Evil Azoles and pyridine radicals, oxazolyl, Oxyranyle, embedding two pyridyl of tea, phenanthridinyl, phenanthroline base, phenarsazine base, phenazinyl, fen Thiazinyl , phenoxazine groups, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl , quinoxalinyls, thio-phenyl, triazine radical, 2H- pyrrolo-es [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2,3] oxazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] Thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyridine radicals, imidazo [2 ', 1 ':2,3] thiophene Azoles simultaneously [5,4-b] pyridine radicals, pyrazolo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzos [4,5] thieno [2, 3-d] imidazole radicals, 1- methyl isophthalic acid H- benzos [4,5] thieno [2,3-d] imidazole radicals, imidazo [2', 1':2,3] thiazole simultaneously [4, 5-b] pyrazinyl, 1H- benzos [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] sulphur azatropylidene base etc..
Term " Bicyclic heteroaromatic rings " " Bicyclic heteroaromatic rings base " is cyclic in the form of fusion.Wherein, heteroaromatic ring systems are fragrance Property, one or more atoms are substituted that (hetero atom is selected from N, O, P, S, appoints in this S or P by hetero atom individually optionally on ring Selection of land substitutes to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group).Heteroaryl system can be in any miscellaneous original It is connected on son or carbon atom in main structure so as to form stable compound.Heteroaryl system is 7-10 former molecular double Ring, the bicyclic of 7-10 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system.And the heteroaryl is miscellaneous Aromatic ring can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, oxygen Generation (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alcoxyl Base, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, fragrant oxygen Base, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..Depending on knot Depending on structure, Bicyclic heteroaromatic rings can be monoradical or divalent group (that is, sub- bicyclic heteroaryl).
Other embodiment is benzo [d] thiazol-2-yl, imidazo [1,5-a] pyridine -6- bases, benzimidazolyl, Benzoxazolyl, 1,8- phthalazinyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolines Quinoline base, 3- quinolyls, 4- quinoline), tetralyl, benzopyrazoles base, benzimidazolyl, benzindole base, Ben Bing Yi oxazinyls, Benzofuranyl, aphthofurans base, diazosulfide base, benzo thio-phenyl, BTA base, benzo thiopyranyl, benzene Bing oxazinyls, benzoxazolyl, benzothiazolyl, B-carboline base, carbazyl, cinnoline base, dibenzofuran group, imidazoles And pyridine radicals, Imidazothiazole base, indazolyl, indolizine base, indyl, different benzo thienyl, iso-dihydro-indole-group, isoquinolin Base, naphthyridines base, oxazole and pyridine radicals, embedding two pyridyl of tea, phenanthridinyl, phenanthroline base, phenarsazine base, phenazinyl, phenothiazinyl, Phenoxazine group, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl , quinoxalinyls etc..
Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " cycloalkyl " refer to monovalence or multivalence, non-aromatic, satisfied And/or part unsaturation ring, and do not include hetero atom, including 3-12 carbon atom monocyclic or 7-12 carbon atom two Ring or three rings.Bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, have simultaneously The bicyclic carbocyclic ring for having 9 or 10 atoms can be two rings [5,6] or [6,6] system.Depending on structure, " carbocylic radical " or " ring-type fat Fat race ", " carbocyclic ring ", " cycloalkyl " can be monoradical or divalent group, i.e., in certain embodiments of the present invention, can substitute Or used as sub- carbocylic radical, cycloalkylidene.The example of cyclic aliphatic group further comprises, but is not limited to, cyclopropyl, Cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- hexamethylenes Base -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, ring Decyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocylic radical " or " annular aliphatic ", " carbocyclic ring " Can be substituted or non-substituted, wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (= O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkane Amino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl Base alkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " heterocyclic radical ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably here, All referring to monocyclic, bicyclic, three rings or tetracyclic ring system, one or more atoms are taken by hetero atom individually optionally in its middle ring Generation, ring can be fully saturated or comprising one or more degrees of unsaturation, but the definitely not fragrant same clan.It is " miscellaneous depending on structure Ring group ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " can be monoradical or divalent group, i.e. some implementations in the present invention In example, it can substitute or be used as sub- heterocyclic radical.Heterocyclic system can be connected to master on any hetero atom or carbon atom So as to forming stable compound in structure.One or more ring hydrogen atoms are individually optionally by one or more present invention Described substituent is substituted.Some of embodiments are " heterocyclic radicals ", " Heterocyclylalkyl ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " group is that (1-6 carbon atom and selected from N, O, P, is appointed at S 1-3 hetero atom in this S or P for 3-7 yuan of rings monocyclic Selection of land substitutes to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group；In addition, carbon atom can be by oxo, shape Into-C=O-；When described ring is three-membered ring, only one of which hetero atom), or 7-10 former molecular bicyclic (4-9 Individual carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain by one or more oxygen atoms in this S or P As SO, SO2, PO, PO2Group).
" heterocyclic radical " can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part not Saturated rings or heterocycle simultaneously close formed group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thia suberyl, N- morpholinyls, 2- morpholinyls, morpholinyl, thio-morpholinyl, homopiperazine base, 4- methoxyl groups-piperazine Pyridine -1- bases, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrrolin -1- bases, 2- pyrrolinyls, 3- pyrrolinyls, two Hydrogen indoles base, 2- indolines base, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxies amyl group, dithiane base, two Thiophene cyclopentadienyl alkyl, dihydro-thiophene base, 1,2,6- thiadiazine alkane 1,1- dioxy -2- bases, hexahydro -2H- [1,4] dioxin [2,3-c] pyrrole Cough up base, 1,1- titanium dioxide thio-morpholinyls, 2,3,3a, 7a- tetrahydrochysene -1H- isoindolyls, 1,2,3,4- tetrahydric quinoline groups, N- pyrroles Piperidinyl urea, dioxolanyl, dihydro pyrazine base, dihydropyridine base, pyrazoline base, dihydro-pyrimidin base, pyrrolin base, 1, 4- dithiane base, morpholinyl, decahydro indyl, decahydro isoindolyl, piperazinyl, piperidyl, pteridyl and purine radicals.And The heterocyclic radical can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl Base, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, Alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, Aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc.. Such as 1- picolines -2 (1H) -one, hexamethylene -2,4- diene ketone group, 2,6- dimethyl-purine base etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represent saturation or undersaturated condensed ring body System, is related to the bicyclic system of non-aromatic, at least one ring is nonaromatic.Depending on structure, " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " can be unit price or divalent group, i.e., in certain embodiments of the present invention, can be with Substitute or used as sub- condensed-bicyclic base.Such system can include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).Each in condensed-bicyclic Ring is either carbocyclic ring or is miscellaneous alicyclic, and such example includes, but is not limited to, hexahydro-furans [3,2-b] furyl, 2,3,3a, 4,7,7a- hexahydro -1H- indenyls, 7- azabicyclos [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl, fusion Bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a- octahydro naphthyls, these are included within the system of condensed-bicyclic. And the condensed-bicyclic base can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, amino alkane Base, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, Hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, mercapto Base, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alcoxyl Base alkyl etc..
Term " condensing miscellaneous bicyclic group " represents saturation or undersaturated fused ring system, is related to the bicyclic body of non-aromatic System, at least one ring is nonaromatic.Such system can include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).Depending on structure, " fusion is miscellaneous Bicyclic group " can be unit price or divalent group, i.e., in certain embodiments of the present invention, can substitute or miscellaneous bicyclic as Asia fusion Base uses.And at least one member ring systems include one or more hetero atoms, each of which member ring systems include 3-7 atom and formed Ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, in this S or P optionally by one or more oxygen Atom substitutes to obtain as SO, SO2, PO, PO2Group, in addition, carbon atom can also form-C=O- by oxo；Such reality Example includes, but is not limited to, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, 3- azabicyclos [3.3.0] octyl, 3- Methyl -3,7- diazabicyclo [3.3.0] octyl, 8- azabicyclos [4.3.0] nonyl, 8- azabicyclos [4.3.0] nonyl Alkane 3- bases, 3- azabicyclos [4.3.0] nonane -3- bases, 1,5- dioxy -8- azabicyclos [4.3.0] nonyl, (1R, 6S) -2, 5- dioxy -8- azabicyclos [4.3.0] nonyl, (1R, 6R) -2,5- dioxy -8- azabicyclos [4.3.0] nonyl, different Yin Diindyl quinoline base, 1,2,3,4- tetrahydric quinoline group, (1S, 5S) -1- hydroxyl -3- azabicyclos [3.1.0] hexyl, (1R, 5S) -1- hydroxyls Base -3- azabicyclos [3.1.0] hexyl, (1R, 5S) -1-N, N- dimethylamino -3- azabicyclos [3.1.0] hexyl, (1S, 5R, 6R) -1- methyl -6- alcohol -3- azabicyclos [3.2.0] heptane base, 3- nitrogen -7- oxabicyclos [3.3.0] octyl, 3,7- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 3- ethyl -3,7- diazabicyclos [3.3.0] octyl, 2,7- diazabicyclos [3.3.0] octyl, 7- acetyl group -2,7- diazabicyclo [3.3.0] octane Base, 2,8- diazabicyclos [4.3.0] nonyl, 2- methyl -2,8- diazabicyclo [4.3.0] nonyl, 3- oxygen -8- azepines Bicyclic [4.3.0] nonyl, 2- oxygen -8- azabicyclos [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclos [4.3.0] nonanes Base, (1S, 6R) -2- methyl -2,8- phenodiazine -5- oxabicyclos [4.3.0] nonyl, 3- ethyl -3,9- diazabicyclos [4.3.0] nonyl, 4,9- diazabicyclos [4.3.0] nonyl, 2,9- diazabicyclos [4.3.0] nonyl, 3- methyl- 3,9- diazabicyclos [4.3.0] nonyl, 3- ethyls -3,7- diazabicyclo [4.3.0] nonyl, 3- methyl -3,7- bis- Azabicyclo [4.3.0] nonyl, 2- ethyls -2,8- diazabicyclo [4.3.0] nonyl, 3- oxos -2,4, the azepines of 8- tri- Bicyclic [4.3.0] nonyl, 3- oxos -4- oxygen -2,8- diazabicyclo [4.3.0] nonyl, 3- oxos -2,8- diaza are double Ring [4.3.0] nonyl, 3,8- diazabicyclos [4.3.0] nonyl, 8- methyl -2,8- diazabicyclo [4.3.0] nonane Base, 3,7- diazabicyclos [4.3.0] nonyl, 3,9- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclos [4.3.0] nonyl, 3- sulphur -8- azabicyclos [4.3.0] nonyl, 9- methyl -3,9- diazabicyclo [4.3.0] nonane Base, 7- methyl -3,7- diazabicyclo [4.3.0] nonyl, 9- ethyls -3,9- diazabicyclo [4.3.0] nonyl, 7- second Base -3,7- diazabicyclo [4.3.0] nonyl, 8- ethyls -2,8- diazabicyclo [4.3.0] nonyl, 5,6- dihydros - 4H- pyrrolo-es [3,4-c] isoxazolyl, 3- ethyls-[1,2,4] triazole [4,3-a] and piperidyl, [1,2,4] triazole [4, 3-a] and piperidyl, simultaneously [4,3-c] piperidyl, 3- methyl -5,6- dihydro -4H- pyrrolo-es [3,4-c] are different for 3- methyl-isoxazole Oxazolyl, 2- methyl -4,5,6,7- tetrahydrochysene -1H- imidazos [4,5-c] pyridine radicals, 2- methyl -4,5,6,7- tetrahydrochysene oxazoles are simultaneously [4,5-c] pyridine radicals, 2- methyl -4,5,6,7- tetrahydrochysene -1H- thiazoles simultaneously [4,5-c] pyridine radicals, isoxazole simultaneously [4,3-c] piperidines Base, 4,5,6,7- tetrahydrochysene isoxazoles simultaneously [3,4-c] pyridine radicals, [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 3- trifluoromethyls- [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 3- methyl-[1,2,4] triazole simultaneously [4,3-a] piperazinyl, 2- oxo -3- oxygen - 8- azabicyclos [4.3.0] nonyl, 1,3- dimethyl -4,5,6,7- tetrahydrochysene -1H- pyrazolos [4,3-c] pyridin-2-yls, 2- oxygen - 7- azabicyclos [4.4.0] decyl, 1,5- dioxy -9- azabicyclos [4.4.0] decyl, 2,3- dimethyl -4,5,6,7- Tetrahydrochysene -2H- pyrazolos [4,3-c] pyridin-2-yl, 3- azabicyclos [4.4.0] decyl, 5- benzyl -2- oxygen -5,8- diaza are double Ring [4.3.0] nonyl, 2,7- diaza decahydro naphthyls or 2- oxygen -8- azabicyclos [4.4.0] decyl etc..It is and described thick It can be substituted or non-substituted to close miscellaneous bicyclic group, and wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl Base, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, Alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, Aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " bridge bicyclic group " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic.This The system of sample can include independent or conjugation undersaturated condition, but its core texture do not include aromatic rings or hetero-aromatic ring (but It is that aromatic series can be as substituent thereon).Each of which member ring systems include 3-7 atom, and such example includes, but It is not limited to, bicyclic [2.2.1] heptane base, 2- methyl-miscellaneous two ring [2.2.1] heptane base etc..And the bridge bicyclic group can be with It is substituted or non-substituted, wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), Fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkane ammonia Base, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl Alkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " the miscellaneous bicyclic group of bridge " represents saturation or undersaturated bridged-ring system, is related to the bicyclic system of non-aromatic. Depending on structure, " the miscellaneous bicyclic group of bridge " can be monoradical or divalent group, i.e., in certain embodiments of the present invention, can replace In generation, uses as the miscellaneous bicyclic group of sub- bridge.Such system can include independent or conjugation undersaturated condition, but its core Structure does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).And at least one member ring systems include One or more hetero atoms, each of which member ring systems include 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain as SO, SO by one or more oxygen atoms in this S or P2, PO, PO2Group, In addition, carbon atom can also form-C=O- by oxo；Such example includes, but is not limited to 2- oxygen -5- azabicyclos [2.2.1] heptane base, thio -5- azabicyclos [2.2.1] the heptane bases of 2-, 2- oxo -5- azabicyclos [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, 2- methyl -2,5- diazabicylo [2.2.1] heptane base etc..And the bridge is miscellaneous Bicyclic group can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, Oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkane Epoxide, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, virtue Epoxide, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " cycloalkyl-alkyl " refers to that alkyl is substituted by one or more cycloalkyl, wherein, alkyl and group of naphthene base With implication as described in the present invention, wherein embodiment may be, but not limited to, Cvclopropvlmethvl, cyclohexyl methyl, cyclohexyl Ethyl etc..
Term " cycloheteroalkylalkyl " refers to that alkyl is substituted by one or more heterocyclic radicals, wherein, alkyl and heterocyclyl groups With implication as described in the present invention, wherein embodiment may be, but not limited to, ring propoxy methyl, morpholinyl methyl, piperidines Base ethyl etc..
Term " cycloalkyl oxy " or " carbocylic radical epoxide " include cycloalkyl or the carbocylic radical optionally substituted, such as institute of the present invention Definition, it is connected on oxygen atom, and be connected by oxygen atom with remaining molecule, such example includes, but is not limited to ring Propyl group epoxide, cyclopentyloxy, cyclohexyl epoxide, cyclopropyl epoxide of hydroxyl substitution etc..
Term " cycloalkyl amino " represents that amino group is substituted by one or two group of naphthene base, and wherein cycloalkyl has There is implication as described in the present invention, such example includes, but is not limited to cyclopropylamino, clopentylamino, cyclohexyl ammonia Base, the cyclopropylamino of hydroxyl substitution, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " alkoxy aryl " represents that alkoxy base is substituted by one or more aryl, wherein aryl and alkoxy With implication of the present invention, such example includes, but is not limited to, Phenylmethoxy, phenyl ethoxy, p-methylphenyl Methoxyl group, phenyl-propoxy etc..
Term " aryl alkane amino " represents that alkylamino radicals are substituted by one or more aromatic yl groups, wherein aryl and alkane Epoxide has implication of the present invention, and such example includes, but is not limited to, phenyl methylamino, phenylethylamino, phenyl Third amino, p-methylphenyl methylamino etc..
Term " heteroarylalkoxy " represent alkoxy base substituted by one or more heteroaryls, wherein heteroaryl and Alkoxy has implication of the present invention, and such example includes, but is not limited to, pyridine -2- ylmethoxies, thiazole -2- Base oxethyl, imidazoles -2- base oxethyls, pyrimidine -2-base propoxyl group, pyrimidine -2-base methoxyl group etc.
Term " heteroarylalkylamino " is connected in other groups including heteroarylalkyl group by nitrogen-atoms, wherein miscellaneous Aryl alkyl has implication as described in the present invention, and such example includes, but is not limited to, pyridine -2- base methylaminos, thiophene Azoles -2- base ethylaminos, imidazoles -2- base ethylaminos, the amino of pyrimidine -2-base third, pyrimidine -2-base methylamino etc..
Term " heterocyclylalkoxy " includes the remainder phase of the alkoxy, wherein oxygen atom and molecule of heterocyclic radical substitution Even；Term " heterocyclic radical alkylamino " includes the alkylamino of heterocyclic radical substitution, and wherein nitrogen-atoms is connected with the remainder of molecule.Its Middle heterocyclic radical, alkoxy and alkylamino have implication as described in the present invention, and such example includes, but is not limited to, and morpholine- 4- base oxethyls, piperazine -4- base oxethyls, piperidin-4-yl ethylamino etc..
Term " cycloalkyl alkoxy ", or " carbocyclylalkoxy " represent alkoxy base by one or more cycloalkyl bases Group or carbocylic radical group are substituted, and wherein group of naphthene base or carbocylic radical group and alkoxy base have as described in the present invention Implication, such example include, but is not limited to, cyclo propyl methoxy, cyclopropylethoxy, cyclopenta ethyoxyl, cyclohexyl Ethyoxyl, cyclohexyl methoxy, cyclopropyl propoxyl group etc..
Term " amino-n-cycloalkyl " or " carbocylic radical alkylamino " represent alkylamino radicals by one or more cycloalkyl bases Group or carbocylic radical group are substituted, and wherein group of naphthene base or carbocylic radical group and alkylamino radicals have as described in the present invention Implication, such example include, but is not limited to, cyclopropyl methylamino, cyclopropyl ethylamino, cyclopenta ethylamino, cyclohexyl Ethylamino, cyclohexyl-methyl-amino, cyclopropyl propylamino etc..
Term " aryloxy group alkyl epoxide " represent alkoxy substituted by one or more aryloxy groups, wherein alkoxy and Aryloxy group has implication as described in the present invention, and such example includes, but is not limited to, phenoxy group methoxyl group, benzene oxygen Base oxethyl, Phenoxypropoxy etc..
Term " heteroaryl epoxide alkoxy " represents that alkoxy is substituted by one or more heteroaryl epoxide groups, wherein Alkoxy and heteroaryl epoxide group have implication as described in the present invention, and such example includes, but is not limited to, pyridine radicals Oxymethoxy, pyrimidine radicals epoxide ethyoxyl, thiazolyl epoxide propoxyl group etc..
Term " aryloxy group " or " aryloxy " include the aryl optionally substituted, as defined herein, are connected to oxygen On atom, and it is connected by oxygen atom with molecule remainder, wherein aromatic yl group has implication as described in the present invention, so Example include, but is not limited to, phenoxy group, toloxyl, ethylbenzene epoxide etc..
Term " heteroaryl epoxide " includes the heteroaryl optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein heteroaryl groups have implication as described in the present invention, such reality Example includes, but is not limited to, pyridine -2- epoxides, thiazole -2- epoxides, imidazoles -2- epoxides, pyrimidine -2- epoxides etc..
Term " heterocyclic radical epoxide alkoxy " represents that alkoxy is substituted by one or more heterocyclic radical epoxide groups, wherein Alkoxy and heterocyclic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to, and pyrroles- 2- Oxymethoxies, pyrroles's -3- epoxide ethyoxyls, piperidines -2- epoxide ethyoxyls, piperidines -3- epoxide ethyoxyls, piperazine -2- oxygen Ylmethoxy, piperidines -4- epoxide ethyoxyls etc..
Term " carbocylic radical epoxide alkoxy " represents that alkoxy is substituted by one or more carbocylic radical epoxide groups, wherein Alkoxy and carbocylic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to, cyclopropyl Oxymethoxy, cyclopropyl epoxide ethyoxyl, cyclopentyloxy ethyoxyl, cyclohexyl epoxide ethyoxyl, cyclohexenyl group -3- epoxides Ethyoxyl etc..
Term " heterocyclic radical epoxide " includes the heterocyclic radical optionally substituted, as defined herein, is connected on oxygen atom, Wherein oxygen atom is connected with the remainder of molecule, and such example includes, but is not limited to, pyrroles's -2- epoxides, pyrroles -3- Epoxide, piperidines -2- epoxides, piperidines -3- epoxides, piperazine -2- epoxides, piperidines -4- epoxides etc..
Term " condensed-bicyclic base epoxide " includes the condensed-bicyclic base optionally substituted, as defined in the present invention, is connected to On oxygen atom, and it is connected by oxygen atom with molecule remainder, such example includes, but is not limited to, and 1,2,3,4,4a, 5,8,8a- octahydro naphthyl epoxides, condensed-bicyclic [3.3.0] octane -2- epoxides, condensed-bicyclic [3.1.0] hexane -2- epoxides etc..
Term " condensing miscellaneous bicyclic group epoxide " includes the miscellaneous bicyclic group of fusion optionally substituted, as defined in the present invention, even It is connected on oxygen atom, and is connected by oxygen atom with molecule remainder, such example includes, but is not limited to, hexahydro- Furo [3,2-b] furans -2- base epoxides, 7- azabicyclos [2.3.0] heptane -2- base epoxides, 7- azabicyclos [2.3.0] heptan Alkane -4- base epoxides etc..
Term " condensed-bicyclic base amino " represents that amino group is substituted by one or two condensed-bicyclic base, wherein condensing Bicyclic group has implication as described in the present invention, and such example includes, but is not limited to, 1,2,3,4,4a, 5,8,8a- octahydros Naphthyl-amino, two (1,2,3,4,4a, 5,8,8a- octahydro naphthyl) amino, condensed-bicyclic [3.3.0] octyl amino, fusion are double Ring [3.1.0] hexyl amino etc..
Term " condensing miscellaneous bicyclic group amino " represents that amino group is substituted by one or two miscellaneous bicyclic group of fusion, wherein Condensing miscellaneous bicyclic group has implication as described in the present invention, and such example includes, but is not limited to, hexahydro-furo [3,2-b] Furans -2- base amino, 7- azabicyclos [2.3.0] heptane -2- base amino, 7- azabicyclos [2.3.0] heptane -4- base amino Deng.
Term " condensed-bicyclic base alkylamino " represents that alkylamino radicals are substituted by one or two condensed-bicyclic base, wherein Condensed-bicyclic base has implication as described in the present invention, and such example includes, but is not limited to, and 1,2,3,4,4a, 5,8,8a- Octahydro napthylmethylamino, two (1,2,3,4,4a, 5,8,8a- octahydro naphthyl) methylaminos, condensed-bicyclic [3.3.0] octyl first ammonia Base, condensed-bicyclic [3.1.0] hexyl methylamino etc..
Term " condensing miscellaneous bicyclic group alkylamino " represents that alkylamino radicals are substituted by one or two miscellaneous bicyclic group of fusion, Wherein condensing miscellaneous bicyclic group has implication as described in the present invention, and such example includes, but is not limited to, hexahydro-furo [3, 2-b] furans -2- base methylaminos, 7- azabicyclos [2.3.0] heptane -2- base methylaminos, 7- azabicyclos [2.3.0] heptane -4- Base methylamino etc..
Term " condensed-bicyclic base alkoxy " represents that alkoxy is substituted by one or more condensed-bicyclic base groups, wherein Alkoxy and condensed-bicyclic base have implication as described in the present invention, and such example includes, but is not limited to, and 1,2,3,4, 4a, 5,8,8a- octahydro naphthylmethoxies, 1,2,3,4,4a, 5,8,8a- octahydro naphthyl ethyoxyls, condensed-bicyclic [3.3.0] are pungent Alkane-ethyoxyl, condensed-bicyclic [3.1.0] hexane-propoxyl group etc..
Term " condensing miscellaneous bicyclic group alkoxy " represents that alkoxy condenses miscellaneous bicyclic group group by one or more and substituted, Wherein alkoxy and the miscellaneous bicyclic group of fusion has implication as described in the present invention, and such example includes, but is not limited to, and six Hydrogen-furo [3,2-b] furans -2- base propoxyl group, 7- azabicyclos [2.2.1] heptane -2- base oxethyls, 7- azabicyclos [2.3.0] heptane -4- base propoxyl group, hexahydro-furo [3,2-b] furans -2- base oxethyls, 7- azabicyclos [2.3.0] heptane - 2- base propoxyl group, 7- azabicyclos [2.3.0] heptane -4- base oxethyls etc..
Term " condensed-bicyclic base alkyl " represents that alkyl is substituted by one or more condensed-bicyclic base groups, wherein alkyl There is implication as described in the present invention with condensed-bicyclic base, such example includes, but is not limited to, and 1,2,3,4,4a, 5,8, 8a- octahydro naphthyl methyls, 1,2,3,4,4a, 5,8,8a- octahydro naphtylethyl groups, condensed-bicyclic [3.3.0] octane-ethyl, fusion Bicyclic [3.1.0] hexane-propyl group etc..
Term " condensing miscellaneous bicyclic group alkyl " represents that alkyl condenses miscellaneous bicyclic group group by one or more and substituted, wherein Alkyl and the miscellaneous bicyclic group of fusion have implication as described in the present invention, and such example includes, but is not limited to, hexahydro-furo [3,2-b] furans -2- base propyl group, 7- azabicyclos [2.2.1] heptane -2- base ethyls, 7- azabicyclos [2.3.0] heptane -4- Base propyl group, hexahydro-furo [3,2-b] furans -2- base ethyls, 7- azabicyclos [2.3.0] heptane -2- base propyl group, 7- azepines are double Ring [2.3.0] heptane -4- base ethyls etc..
Term " condensing miscellaneous bicyclic group epoxide alkoxy " represents that alkoxy condenses miscellaneous bicyclic group epoxide base by one or more Group is substituted, and wherein alkoxy and the miscellaneous bicyclic group epoxide of fusion has implication as described in the present invention, and such example includes, but It is not limited to, hexahydro-furo [3,2-b] furans -2- base epoxide propoxyl group, 7- azabicyclos [2.2.1] heptane -2- base epoxide second Epoxide, 7- azabicyclos [2.3.0] heptane -4- base epoxide propoxyl group, hexahydro-furo [3,2-b] furans -2- base epoxide ethoxies Base, 7- azabicyclos [2.3.0] heptane -2- base epoxide propoxyl group, 7- azabicyclos [2.3.0] heptane -4- base epoxide ethyoxyls Deng.
Term " condensing miscellaneous bicyclic group epoxide alkylamino " represents that alkylamino condenses miscellaneous bicyclic group epoxide base by one or more Group is substituted, and wherein alkylamino and the miscellaneous bicyclic group epoxide of fusion has implication as described in the present invention, and such example includes, but It is not limited to, hexahydro-furo [3,2-b] furans -2- bases the third amino of epoxide, 7- azabicyclos [2.2.1] heptane -2- base epoxide second Amino, 7- azabicyclos [2.3.0] heptane -4- bases the third amino of epoxide, hexahydro-furo [3,2-b] furans -2- base epoxide second ammonia Base, 7- azabicyclos [2.3.0] heptane -2- bases the third amino of epoxide, 7- azabicyclos [2.3.0] heptane -4- base epoxide ethylaminos Deng.
Term " the miscellaneous bicyclic group alkoxy of bridge " represents that alkoxy base is substituted by the miscellaneous bicyclic group of one or more bridges, wherein The miscellaneous bicyclic group of bridge and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to, and 2- oxygen- 5- azabicyclos [2.2.1] heptane ylmethoxy, 2,5- diazabicylos [2.2.1] heptane base oxethyl, 2- methyl -2,5- bis- Azabicyclic [2.2.1] heptane base propoxyl group etc..
Term " the miscellaneous bicyclic group alkyl of bridge " represents that alkyl group is substituted by the miscellaneous bicyclic group of one or more bridges, and its jackshaft is miscellaneous Bicyclic group and alkyl group have implication as described in the present invention, and such example includes, but is not limited to, 2- oxygen -5- azepines Bicyclic [2.2.1] heptane ylmethyl, 2,5- diazabicylos [2.2.1] heptane base ethyl, 2- methyl -2,5- diazabicylos [2.2.1] heptane base propyl group etc..
Term " the miscellaneous bicyclic group alkylamino of bridge " represents that alkylamino radicals are substituted by the miscellaneous bicyclic group of one or more bridges, wherein The miscellaneous bicyclic group of bridge and alkylamino radicals have implication as described in the present invention, and such example includes, but is not limited to, and 2- oxygen- 5- azabicyclos [2.2.1] heptane base methylamino, 2,5- diazabicylos [2.2.1] heptane base ethylamino, 2- methyl -2,5- bis- Azabicyclic [2.2.1] heptane third amino of base etc..
Term " the miscellaneous bicyclic group epoxide of bridge " includes the miscellaneous bicyclic group of bridge optionally substituted, as defined in the present invention, is connected to On oxygen atom, and it is connected by oxygen atom with molecule remainder, such example includes, but is not limited to, 2- methyl -2,5- Diazabicylo [2.2.1] alkyl oxy in heptan, 2,5- diazabicylos [2.2.1] alkyl oxy in heptan etc..
Term " aryl alkyl " represents that alkyl group is substituted by one or more aromatic yl groups, wherein alkyl group and virtue Base group has implication as described in the present invention, and such example includes, but is not limited to phenethyl, benzyl, to toluene second Base etc..
Term " heteroaryl alkyl " represents that alkyl group is substituted by one or more heteroaryl groups, wherein alkyl group There is implication as described in the present invention with heteroaryl groups, such example includes, but is not limited to, pyridine -2- ethyls, thiophene Azoles -2- methyl, imidazoles -2- ethyls, pyrimidine -2- propyl group etc..
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of divalence, wherein alkyl group With implication as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level1-3Alkylthio group, such example Include, but is not limited to, methyl mercapto (CH3S-), ethylmercapto group etc..
Term " aminoacyl " refers to-C (=O) NH2。
" alkyl-C (=O) NH- " includes C to term1-10The alkyl of straight or branched is connected on-C (=O) NH-, wherein alkane Base group has implication as described in the present invention.Such example includes, but is not limited to, acetamido (CH3C (=O) NH-), propionamido- (C2H5C (=O) NH-) etc..
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " represent a ring originating from special on another ring Ring-type carbon.For example, as disclosed below, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", on the contrary Ring A and ring B shares a carbon atom in the member ring systems of two saturations, then is referred to as " loop coil ".Each ring inside loop coil It is or that carbocyclic ring is miscellaneous alicyclic.Such example includes, but is not limited to, 4- azaspiros [2.4] heptane -5- bases, 4- Oxaspiro [2.4] heptane -5- bases, 5- azaspiros [2.4] heptane -5- bases, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyls Base -5- azaspiros [2.4] heptane -5- bases etc..And the spiral shell bicyclic group can be substituted or non-substituted, and wherein substituent can To be, but it is not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkane Base, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano group, aryl, Heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, Phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " the miscellaneous bicyclic group of spiral shell " represents a ring originating from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", otherwise ring A and ring B is in the ring of two saturations A carbon atom is shared in system, then is referred to as " loop coil ".And at least one member ring systems include one or more hetero atoms, wherein Each member ring systems includes 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, in this S or P optionally substitutes to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group, such example includes, but not It is limited to 4- azaspiros [2.4] heptane base, 4- oxaspiros [2.4] heptane base, 5- azaspiros [2.4] heptane base, 7- hydroxyl -5- azepines Spiral shell [2.4] heptane base, 2- azaspiros [4.5] decyl, 2- azepine spiroheptane bases, 2- azaspiros [4.4] nonyl, 2- Methyl -2,6- diaza spiro [4.5] decyl, 3- azaspiros [5.4] decyl, 2- methyl -2- azepine spiroheptane bases, 2- oxygen -6- azepine spiroheptane bases, 2,6- diaza spiroheptane bases, 2- sulphur -6- azepine spiroheptane bases 2- mono- Oxide, 2- sulphur -6- azepine spiroheptanes base 2,2- dioxide etc..And the miscellaneous bicyclic group of spiral shell can be substitution or Non-substituted, wherein substituent can be, but be not limited to, hydrogen, aminoalkyl, aminoacyl, oxo (=O), fluorine, chlorine, bromine, Iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t-, haloalkyl, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, Halogenated alkoxy, cyano group, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkane Base-(C=O)-, benzyl, cyclopropyl, phenyl, methyl-(C=O) NH- or alkoxyalkyl etc..
Term " the miscellaneous bicyclic group alkoxy of spiral shell " represents that alkoxy base is substituted by the miscellaneous bicyclic group of one or more spiral shells, wherein The miscellaneous bicyclic group of spiral shell and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to, 4- azepines Spiral shell [2.4] heptane -5- ylmethoxies, 4- azaspiros [2.4] heptane -2- base oxethyls, 4- oxaspiros [2.4] heptane -5- base second Epoxide, 5- azaspiros [2.4] heptane -5- base propoxyl group etc..
Term " the miscellaneous bicyclic group alkyl of spiral shell " represents that alkyl group is substituted by the miscellaneous bicyclic group of one or more spiral shells, and wherein spiral shell is miscellaneous Bicyclic group and alkyl group have implication as described in the present invention, and such example includes, but is not limited to, 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -2- base ethyls, 4- oxaspiros [2.4] heptane -5- base ethyls, 5- nitrogen Miscellaneous spiral shell [2.4] heptane -5- base propyl group etc..
" antiproliferative " refers to antimetabolite (for example, 5- fluoro-uracil, methotrexate, fludarabine), anti-micro- Pipe agent (for example, Vinca alkaloids such as vincristine, vinblastine, taxane such as taxol, polyenoid taxol), alkylation examination Agent (such as endoxan, melphalan, carmustine, nitroso ureas such as double chlorethylnitrosoureas and hydroxycarbamide), platinum reagent (such as Cis-platinum, Kapo Platinum, Oxalipratin, JM-216, Cl-973), anthracyclines (such as doxrubicin, daunomycins), Antitumor antibiotics (such as mitomycin, jaundice element, adriamycin, daunomycins), topoisomerase inhibitors (such as sufficient leaf second Glucoside, camptothecine), anti-angiogenic agent (such as and Bevacizumab) or any cytotoxic agent (estramustine phosphate, sprinkle Buddhist nun Mustargen), hormone or hormone activator, antagonist, partial agonist agent or topical antagonist, kinase inhibitor and radiation control Treat.
As described in the present invention, the member ring systems that substituent R is formed by a key connection to the ring at center represent substituent R Any on ring it can may replace or any rational position is substituted.For example, formula a represents any possible quilt on A rings or B rings Substituted position can be substituted by R, such as formula b, formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, substituent (R)nThe member ring systems formed by a key connection to the ring at center represent n Substituent R can be substituted any commutable position on ring.For example, formula i is represented and any on A rings or B rings may taken The position in generation can be substituted by n R.
As described in the invention, there are two tie points to be connected with molecule remainder on ring C, for example, such as formula j institutes Show, expression can be E ends or be that E ' ends are connected with the remainder of molecule, i.e., the connected mode at both ends can exchange.
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder.Example Such as, formula k represent any position that may be connected on A rings or B rings can be as the point of connection.
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder, together When the both ends that connect can exchange.For example, formula m represent any position that may be connected on ring can be as the point of connection, together When tie point both ends can exchange.
In addition, it is necessary to explanation, unless otherwise explicitly pointing out, the describing mode used in the whole text herein " each ... and ... independently be ", " ... and ... be each independently " and " ... and ... separately for " can exchange, and should do extensively Reason and good sense solution, it can both refer in different groups, not influenceed mutually between expressed specific option between same-sign, It can represent in identical group, not influenceed mutually between expressed specific option between same-sign.For example, structural formula Q and structural formula s each Z between the two1Specific option it is unaffected from each other, meanwhile, it is multiple such as formula q in same structure formula G specific option is unaffected between each other；Or such as formula s, multiple R9Specific option it is unaffected from each other.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：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, the compound of 1994. present invention can include asymmetric center or chiral centre, therefore Different stereoisomers be present.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture, constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use To name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50:50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause do not have stereoselectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.
Term " dynamic isomer " or " tautomeric form " represent that the isomer of different-energy can be by relatively low The mutual inversion of phases of energy barrier.Such example includes, but is not limited to, and proton tautomer (i.e. prototropic change isomers) includes The change migrated by proton, such as the isomerization of keto-enol and imine-enamine.Valence dynamic isomer bag Include the restructuring change of some bonding electrons.
" hydrate " of the present invention refers to compound or its salt provided by the present invention, and it also includes chemical quantity or non-chemical The water that equivalent is combined by non-covalent intermolecular forces, can also say it is that solvent molecule is the associated matter that water is formed.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.
" ester " of the present invention refers to that the formula (I) containing hydroxyl, formula (II) or formula (III) compound can form internal hydrolyzable Ester.Such ester is the pharmaceutically acceptable ester that hydrolysis produces parent alcohol for example in human or animal's body.Contain hydroxyl The group of hydrolyzable ester includes, but not limited to phosphate, acetoxyl group in formula (I), formula (II) or formula (III) compound body Methoxyl group, 2,2- dimethylpropionyloxymethoxies, alkanoyl, benzoyl, the acyl group of benzene first and second, alkoxy carbonyl, dialkyl group Carbamoyl and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyls etc..
" nitrogen oxides " of the present invention refers to that when compound contains several amine functional groups nitrogen that can be by 1 or more than 1 is former Son oxidation forms N- oxides.The particular example of N- oxides is the N- oxidations of the N- oxides or nitrogen heterocyclic ring nitrogen-atoms of tertiary amine Thing.The corresponding amine formation N- oxides of available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) processing (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxides can be prepared (Syn.Comm.1977,7,509-514) with L.W.Deady method, wherein for example molten in inertia In agent such as dichloromethane, amines is set to be reacted with m- chloroperoxybenzoic acid (MCPBA).
A variety of different geometric isomers and dynamic isomer, the formula (I), formula (II) or formula (III) may be present in compound Compound includes all such forms.To avoid feeling uncertain, when compound is deposited with one of several geometric isomers or dynamic isomer And when only specifically describing or showing a kind of, it is clear that all other form is included in formula (I), formula (II) or formula (III).
Term " prodrug " used in the present invention, represent a compound and be converted into formula (I), formula (II) or formula in vivo (III) compound shown in.Such conversion is hydrolyzed or is through enzymatic conversion in blood or tissue in blood by pro-drug The influence of precursor structure.Pro-drug compounds of the present invention can be ester, and ester can be used as precursor medicine in existing invention Thing has phenyl ester class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters. Such as a compound in the present invention includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other Prodrug form include phosphate, if these phosphate compounds are being obtained through the di on parent.Close Completely discussed in pro-drug and may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche, ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.
The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that i.e. they are substantially nontoxic and needed for providing for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, it is more practical in nature, for choosing Select also critically important, these are：The costs of raw material, the easy of crystallization, yield, stability, the stream of hygroscopicity and result bulk drug Dynamic property.Simply, pharmaceutical composition can be prepared by active ingredient and pharmaceutically acceptable carrier.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: It is 1-19,1977. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, 2 hydroxy propanoic acid Salt, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor Hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, anti-fourth Enedioic acid salt, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- Hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, first sulphur Hydrochlorate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenyl Propionate, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valeric acid Salt etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to Contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble or dispersion product can lead to Quaternization is crossed to obtain.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium etc..Pharmaceutically acceptable salt enters One step includes appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylic Compound, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as, but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocanine, choline, ammonia, diethanol amine and other hydroxyalkyl amines, ethylenediamine, N- methyl reduction Portugal Osamine, procaine, N- benzyl-1-phenylethylamines, the p- chlorobenzyl -2- pyrrolidines -1 ' of 1--ylmethyl-benzimidazole, diethylamine and its Its alkylamine, piperazine and three (methylol) aminomethanes；Alkali salt, such as, but not limited to barium, calcium and magnesium；Transition metal Salt, such as, but not limited to zinc.
When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl etc..For protection group Group's in general description refers to document：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
In this manual, if any difference between chemical name and chemical constitution be present, structure is dominant.
The abbreviation of any blocking group used in the present invention, amino acid and other compounds, unless otherwise indicated, all with Their usually used, generally acknowledged abbreviations are defined, or with reference to IUPAC-IUBCommission on Biochemical Nomenclature is (referring to Biochem.1972,11:942-944).
The description of the compounds of this invention
The invention provides the substituted carbamide derivative for drug therapy and its pharmaceutical composition and for adjusting Flt3 Kinase activity and for suppress FLT3-ITD a series of substitute urea compounds and for treat flt3 mediation or flt3-ITD The purposes of caused disease.
On the one hand, the present invention provides a kind of compound, its shown substitute urea compound or formula (I) institute for formula (I) Show the stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
Q and W is each independently CH or N；
G is-O- ,-S (=O)t- ,-S- ,-C (=O)-or five yuan of inferior heteroaryls；
R is-NR3R2, alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkyl-S (=O)t-, alkoxyalkyl, hydroxyl Alkyl, hydroxy alkoxy base, aminoalkoxy, halogenated alkoxy, alkylamino halogenated alkoxy, alkylaminoalkoxy, alkoxy alkane Epoxide, cycloalkyl, cycloalkyl-alkyl, cycloalkyl oxy, cycloalkyl amino, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, Heterocyclylalkoxy, heterocyclic radical epoxide alkoxy, heterocyclic radical epoxide, carbocylic radical epoxide alkoxy, carbocyclylalkoxy, carbocylic radical Alkylamino, aryl, aryl alkyl, aryloxy group alkyl epoxide, aryloxy group, alkoxy aryl, aryl alkane amino, heteroaryl alkyl are miscellaneous Aryl, heteroarylalkoxy, heteroarylalkylamino, heteroaryl epoxide, heteroaryl epoxide alkoxy, condensed-bicyclic base epoxide are thick Bicyclic group alkyl is closed, miscellaneous bicyclic group alkyl is condensed, condenses miscellaneous bicyclic group epoxide, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group Alkoxy, miscellaneous bicyclic group alkylamino is condensed, condense miscellaneous bicyclic group epoxide alkoxy, condense miscellaneous bicyclic group epoxide alkylamino, spiral shell is miscellaneous Bicyclic group alkyl, the miscellaneous bicyclic group alkoxy of spiral shell, the miscellaneous bicyclic group alkyl of bridge, the miscellaneous bicyclic group epoxide of bridge, the miscellaneous bicyclic group alkoxy of bridge, bridge Miscellaneous bicyclic group alkylamino, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell or the miscellaneous bicyclic group of fusion；
K is the heteroaryl groups of 5-6 members；At least 2 hetero atoms, each hetero atom are only in wherein described heteroaryl groups It is on the spot O, S, NR4Or N；
Each L independently is amino, nitro, C1-4Alkylthio group, C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-4Alkyl halide Base, C1-4Alkyl amino, hydroxyl, fluorine, chlorine, bromine, iodine, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkyl or cyanogen Base；
E is bicyclic heteroaryl group；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
Each R3And R2It independently is hydrogen, C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-6Alkoxy C1-6Alkyl or hydroxyl Base C1-4Alkyl；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each d independently is 1,2,3 or 4；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each a independently is 0,1,2,3 or 4；
Wherein, described aryl, bicyclic heteroaryl group, heteroaryl groups ,-(CH2)n- C (=O)-, alkoxy, alkyl- S (=O)t- ,-G- (CH2)n- R, alkoxyalkyl, hydroxy alkyl, aryl alkyl, heteroaryl alkyl, heteroaryl, heterocyclic radical, bridge Miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell, condense miscellaneous bicyclic group, alkyl, haloalkyl, alkyl amino, hydroxy alkoxy base, Aminoalkoxy Base, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, alkoxyalkyl, hydroxy alkyl, alkylamino halo Alkoxy, alkylaminoalkoxy, alkyloxy-alkoxy, cycloalkyl oxy, alkoxy aryl, aryl alkane amino, heteroarylalkoxy Base, heteroarylalkylamino, heterocyclic radical alkylamino, cycloalkyl oxy, cycloalkyl amino, heterocyclylalkoxy, carbocyclylalkoxy, Carbocylic radical alkylamino, aryloxy group alkyl epoxide, aryloxy group, heteroaryl epoxide, heteroaryl epoxide alkoxy, heterocyclic radical epoxide alcoxyl Base, carbocylic radical epoxide alkoxy, heterocyclic radical epoxide, condensed-bicyclic base epoxide, condensed-bicyclic base alkyl, condense miscellaneous bicyclic group alkane Base, miscellaneous bicyclic group epoxide is condensed, condense miscellaneous bicyclic group amino, condense miscellaneous bicyclic group alkoxy, condense miscellaneous bicyclic group alkylamino, it is thick Miscellaneous bicyclic group epoxide alkoxy is closed, condenses miscellaneous bicyclic group epoxide alkylamino, the miscellaneous bicyclic group alkyl of spiral shell, the miscellaneous bicyclic group alkoxy of spiral shell, The miscellaneous bicyclic group alkyl of bridge, the miscellaneous bicyclic group epoxide of bridge, the miscellaneous bicyclic group alkoxy of bridge, the miscellaneous bicyclic group alkylamino of bridge, alkyl-C (=O)- NH-, alkylthio group, and cycloalkyl, can be independently by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, wherein, described E is one of heteroaryl groups that following subformula is formed：
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
T and T1It is each independently-O- ,-S- ,-NR4- or-CH2-；
Wherein, the X, Y, Z, T, T on the E rings1, Z1, Z2, Z3And Z4It is hetero atom at least while to have two；
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl C1-4Alkyl, C2-10Heterocyclic radical C1-4Alkane Base, C1-6Alkyl-S (=O)t-, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, Halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C3-10Cycloalkyl oxy, C6-10Aryl C1-4Alkoxy, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl C1-4Alkoxy, C1-9Heteroaryl Base C1-4Alkylamino, C2-10Heterocyclic radical C1-4Alkylamino, C3-10Cycloalkyl oxy, C3-10Cycloalkyl amino, C2-10Heterocyclic radical C1-4Alkane Epoxide, C3-10Carbocylic radical C1-4Alkoxy, C3-10Carbocylic radical C1-4Alkylamino, C6-10Aryloxy group C1-4Alkoxy, C6-10Aryloxy group, C1-9Heteroaryl epoxide, C1-9Heteroaryl epoxide C1-4Alkoxy, C2-10Heterocyclic radical epoxide C1-4Alkoxy, C3-10Carbocylic radical epoxide C1-4 Alkoxy, C2-10Heterocyclic radical epoxide, C1-4Alkoxy, C1-4Alkyl, C1-4Haloalkyl, C6-10Aryl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C1-9Heteroaryl, or R are following subformula：
Wherein, each X8, X9And X10It independently is N or CH；
Each X1, X2, X3, X4, X5, X6And X7It independently is-CH2- ,-O- ,-NR4a- ,-S (=O)t- or-S-；
Each q, m, p, r and s independently are 0,1,2,3 or 4；
Each R3And R2It independently is C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)- NH-, oxo (=O), C1-4Alkyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In other embodiments, wherein described E is one of heteroaryl groups that following subformula is formed：
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl halide Base, C1-9Heteroaryl C1-6Alkyl or R are following subformula：
Each R3And R2It independently is methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, n-pentyl, isopentyl, cyclopropyl, ring Amyl group, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methyl Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl-C (=O)-, N-propyl-C (=O)-, isopropyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In some embodiments, wherein described G is-O- or furylidene.
In some embodiments, wherein one of heteroaryl groups that the subformula that described K is as follows is formed：
Each L independently is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, C3-6Heterocyclylalkyl, amino, cyano group, nitro, fluorine, Chlorine, bromine, iodine, C1-4Haloalkyl, methyl, ethyl, butyl, n-propyl, isopropyl, the tert-butyl group, C1-4Alkyl amino, hydroxyl, cyanogen Base, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkyl or C1-4Alkylthio group.
In some embodiments, the present invention provides a kind of substituted carbamide derivative, and it is the compound shown in formula (II) Or the stereoisomer of compound shown in formula (II), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvation Thing, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
Q and W is each independently CH or N；
Each R1It independently is hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-6Alkane Epoxide C1-6Alkyl, C1-4Alkyl amino, hydroxyl, cyano group, nitro, C1-4Alkyl-C (=O)-NH-, C1-4Alkoxy, hydroxyl C1-4Alkane Base or C1-4Alkylthio group；
Each L independently is the tert-butyl group；
D is 1；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each a independently is 0,1,2,3 or 4；
E is one of heteroaryl groups that following subformula is formed：
R is-NR3R2, C2-4Alkenyl, C2-4Alkynyl, C2-10Heterocyclic radical C1-4Alkyl, C1-6Alkyl-S (=O)t-, C1-4Alkoxy C1-4Alkyl, hydroxyl C1-4Alkyl, hydroxyl C1-4Alkoxy, amino C1-4Alkoxy, halo C1-4Alkoxy, C1-4Alkylamino halo C1-4Alkoxy, C1-4Alkylamino C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, C1-4Alkoxy, C1-4Alkyl, C1-4Alkyl halide Base, C1-9Heteroaryl C1-6Alkyl, or R are following subformula：
Each R3And R2It independently is methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, n-pentyl, isopentyl, cyclopropyl, ring Amyl group, cyclohexyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl C1-4Alkyl；
Wherein, each subformula representated by described E and each R, can be independently by hydrogen, aminoalkyl, aminoacyl, Fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, dimethylamino, methyl Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl-C (=O)-, N-propyl-C (=O)-, isopropyl-C (=O)-, C2-10Heterocyclic radical, benzyl or phenyl, it is monosubstituted or identical or different to take more Generation.
In some embodiments, the present invention provides a kind of substituted carbamide derivative, and it is the compound shown in formula (III) The stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvation as shown in formula (III) Thing, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein, X, Y, Z, Z1, Z2, Z3And Z4It is each independently N or CH；
Wherein, described X, Y, Z, Z1, Z2, Z3And Z4It is hetero atom at least while to have two.
In some embodiments, substituted carbamide derivative of the present invention, or its stereoisomer, geometrical isomerism Body, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or it before Medicine, there is the structure of one of：
On the other hand, present invention also offers a kind of pharmaceutical composition, the pharmaceutical composition to include of the present inventionization Compound.
In some embodiments, pharmaceutical composition of the present invention, it is further comprising pharmaceutically acceptable Carrier, excipient, diluent, at least one of assistant agent and medium.
In some embodiments, pharmaceutical composition of the present invention, it further includes additional therapeutic agent, institute It is chemotherapeutic agent to state additional therapeutic agent, antiproliferative, anti-inflammatory reagent, immunodepressant, immunostimulant, for treating The medicine of atherosclerosis, for treating the medicine or combinations thereof of pulmonary fibrosis.
In other embodiments, pharmaceutical composition of the present invention, wherein the additional therapeutic agent is benzene fourth Sour mustargen (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea assistant Rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), reach Carbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), TPT (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), TAM (tamoxifen), Flutamide (flutamide), Gonadorelin analog (gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib angstrom gram are replaced Buddhist nun (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), come that For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relax Buddhist nun replaces Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or combinations thereof.
On the other hand, the purposes the present invention relates to described compound or pharmaceutical composition in medicine is prepared, wherein institute Medicine is stated to be used to preventing, handle, mitigate or treating patient's proliferative diseases, autoimmune disease or inflammatory disease.
In some embodiments, the proliferative diseases are acute myeloid leukaemias, chronic myelogenous leukemia, and gastrointestinal stromal swells Knurl, acute myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, ALL (ALL), Colorectal cancer, stomach cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, CNS (in Pivot nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, Rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic are white Blood disease, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, Secondary cases Benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, NHL, Sezary syndromes, pass Metachromia monocytosis,mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, rectum Cancer, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, medullary thyroid sample Cancer, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha, malignant tumor of digestive tract, non-small cell lung Cancer, cervical carcinoma, orchioncus, carcinoma of urinary bladder or myeloma.
In some embodiments, the autoimmune disease is rheumatic arthritis, lupus, multiple sclerosis, thyroiditis, Type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, described inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, liver Hardening, cholecystitis, or chronic inflammation.
In some embodiments, the disease is disease caused by FLT3 mediations or FLT3-ITD.
On the other hand, the present invention relates to described compound or pharmaceutical composition to be used to preventing, handle, treat or mitigating trouble The method of person's proliferative diseases, autoimmune disease or inflammatory disease, its method include and give the infection or with disease Effective therapeutic dose of patient's compound as described in the present invention or pharmaceutical composition of the present invention.
In some embodiments, the disease be that FLT3 is kinase mediated or FLT3-ITD kinases caused by disease.
On the other hand, the present invention relates to described compound or pharmaceutical composition to be used to preventing, handle, treat or mitigating trouble Person's proliferative diseases, autoimmune disease or inflammatory disease.
Another aspect of the present invention is related to prevention, processing, treatment or mitigates patient's proliferative diseases, autoimmune disease or inflammation Property disease method, methods described include using the present invention compound pharmaceutically acceptable effective dose patient is carried out to Medicine.
Another aspect of the present invention is related to prevention, processing, treatment or mitigates patient's proliferative diseases, autoimmune disease or inflammation Property disease method, methods described includes to be had using the pharmaceutically acceptable of pharmaceutical composition of compound containing the present invention Effect dosage is administered to patient.
Another aspect of the present invention is directed to use with a kind of compound of the invention and is used to preventing, handle or treating patient to produce Proliferative diseases, autoimmune disease or inflammatory disease, and mitigate the purposes of the medicine of its order of severity.
The purpose of another aspect of the present invention is that providing one kind includes the formula (I), formula (II) or formula (III) compound Or application of its pharmaceutically acceptable salt in the disease agent for preparing regulation FLT3 mediations, particularly have comprising giving treatment The formula (I), formula (II) or formula (III) compound of effect amount or its pharmaceutically acceptable salt, its isomers, solvate, Hydrate or pro-drug.
On the other hand, compound provided by the invention and composition can effectively adjust the work of Ab1 protein-tyrosines family Property.
In some embodiments, compound provided by the invention and composition can effectively adjust class fms EGFR-TKs 3 The activity of receptor kinase (FLT-3 kinases).
In some embodiments, compound provided by the invention and composition can effectively suppress class fms EGFR-TKs 3 The activity of receptor kinase mutation (FLT-3-ITD kinases).
In some embodiments, compound provided by the invention and composition can effectively adjust the activity of Src subfamilies, It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
In some embodiments, compound provided by the invention and composition can effectively adjust one or more kinases Activity, the kinases are selected from：(calmodulin adjusts kinases and phase to sterile20, sterile11, sterile, camk subfamily Close kinases), AGC subfamilies (protein kinase A, protein kinase G and protein kinase C), CMGC subfamilies (cdk, map kinases, glycogen Synthase kinase and clk), sterile20 subfamilies, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack (and its respective subfamily).
In other embodiments, the invention provides the disclosed compound of use and composition, or it is pharmaceutically Acceptable salt, solvate, hydrate or its prodrug are used to locally or systemically treat or prevent living by kinases for people and beast Property the regulation or method of disease, illness and discomfort that otherwise influences.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the model of the present invention Enclose.Specifically, salt is pharmaceutically acceptable salt." pharmaceutically acceptable " material or composition of including of term must be suitable Combination or toxicologically, with forming the other components of preparation and relevant for the mammal for the treatment of.The compound of the present invention Salt also include being used to preparing or purifying intermediate or formula (I), the formula (II) or formula of formula (I), formula (II) or formula (III) compound (III) salt of the enantiomter of compound separation, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.
If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R14)4Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R14)4Salt, such as R14It is H, C1-4Alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. Also appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylation are included Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The composition of the compound of the present invention
According on the other hand, the characteristics of pharmaceutical composition of the invention including formula of the present invention (I), formula (II) or formula (III) receptible salt or its pro-drug in compound, hydrate, solvate, isomers or physiology/pharmacy, the present invention Listed compound, or embodiment 1-34 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.The present invention Composition can be used for prepare prevent, handle, treat or alleviate protein kinase mediated disease medicine application.The present invention's Application of the pharmaceutical composition as FLT3 kinases or FLT3-ITD kinase inhibitors in medicament is prepared.
The pharmaceutical composition of the present invention, it includes formula (I), formula (II) or formula (III) compound and its pharmaceutically acceptable Carrier.Wherein, formula (I), formula (II) or formula (III) compound can also be combined into system with the compound of second of therapeutic activity Drug composition.The pharmaceutical carrier used can be：Solid, liquid or gas.The example of solid carrier includes：Lactose, land plaster, Sucrose, talcum powder, gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid etc..The example of liquid-carrier includes：Sugar Slurry, peanut oil, olive oil, water etc..The example of gaseous carrier includes：Carbon dioxide and/or nitrogen.Equally, carrier or diluent The time delay material disclosed in document can be included, such as glycerin monostearate or glycerol stearate, individually or with wax used together.
On the other hand, can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger；Aluminium；Oxygen Change aluminium；Aluminum stearate；Lecithin；Haemocyanin such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Sorb Sour potassium；The partial glyceride mixtures of saturated vegetable fatty acid；Water；Electrolyte such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid Hydrogen potassium；Salt such as sodium chloride, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxy Propylene-blocking condensate；Lanolin；Sugar such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose With its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder； Auxiliary material such as cocoa butter and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil； Glycol compound, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer is such as Magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol；Phosphate buffer solution；With Other nontoxic suitable lubricant such as Sodium Laurylsulfates and magnesium stearate, colouring agent, releasing agent, coating agents, sweetener, adjust Taste agent and spices, preservative and antioxidant.For convenience, local anesthetic, preservative, buffer etc. can be directly dissolved in load In body.
The compound of the present invention and the purposes of composition
It is inappropriate that formula (I), formula (II) or formula (III) compound or its pharmaceutical composition of the present invention can be used for treatment to have FLT3 activity as Proliferative Disorders feature situation.FLT3 activity increases include but is not limited to：In cell FLT3 expression increase or Constitutive activation caused by regenerating FLT3 expression, increased FLT3 expression or activity and FLT3 mutation.It is improper or abnormal FLT3 aglucons and FLT3 level or activity can use well-known method in document to determine.For example, FLT3 horizontal abnormalities are high, Commercially available ELISA kit can be used to determine.The horizontal usable flow cytometric analysises of FLT3, immunohistochemical analysis Determined with hybridization in situ technique.
One unsuitable FLT3 activation, can pass through the work after rear generation of one or more after FLT3 is attached to acceptor Property increase determines：(1) FLT3 phosphorylation or autophosphorylation；The phosphorylation of (2) FLT3 substrates, substrate such as Stat5, Ras；(3) related complex such as PI3K activation；(4) activation of acceptor molecule；(5) cell is bred.These activities are easy to use Well-known literature method detection.
The present invention formula (I), formula (II) or formula (III) compound or its pharmaceutical composition can be also used for as prepare with The medicine of lower illness, the medicine include but is not limited to this：By formula (I), the formula (II) of giving patient's effective dose of the present invention Or formula (III) compound or the pharmaceutical composition for including formula (I), formula (II) or formula (III) compound, preventing/treating are suffered from Person's proliferative diseases, situation or disorder.The illness includes：Cancer, especially hematopoietic system cancer, metastatic tumo(u)r, artery Atherosclerotic disease, pulmonary fibrosis disease.
The compound or its pharmaceutical composition of the present invention can be additionally used in the medicine for preparing the formation for the treatment of knurl, and the knurl includes Cancer and metastatic cancer, include but is not limited to：Carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including cellule Lung cancer), cancer of the esophagus, gallbladder cancer, oophoroma, cancer of pancreas, stomach cancer, cervix cancer, thyroid cancer, prostate cancer, cutaneum carcinoma (including Squamous cell carcinoma)；Lymphatic cells tumour (including leukaemia, ALL, the white blood of acute lymphoblast Disease, B cell lymphoma, T- cell lymphomas, Hodgkin lymphoma, NHL, hairy cell lymphoma and Bai Kete Lymthoma)；Marrow sample hematopoietic system cancer (including acute and chronic myelocytic leukemia, myelodysplastic syndrome and preceding Myelocytic leukemia)；Tumour (including fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as soft tissue of mesenchyma origin And bone)；Maincenter and peripheral nervous system neoplasms (including astrocytoma, neuroblastoma, glioma and neurolemma Knurl) and other tumours (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, Keratoctanthoma thyroid follcular carcinomas and Kaposi's sarcoma).
The compound or its pharmaceutical composition of the present invention can also be used for preparing or treat FLT3 mediations, FLT3-ITD mediations And/or the disease medicament of CSF-1R mediations, the disease include：It is autoimmune disease, kidney trouble, tissue transplantation rejection, red Yabbi sore, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, arthritis, asthma etc..
The compound or its pharmaceutical composition of the present invention can also be used to prepare or treat diabetic keratopathy situation such as diabetic keratopathy Retinopathy and microangiopathy medicine, it is highly useful.
The compound or its pharmaceutical composition of the present invention reduces also useful for CBF in tumour.
Reduction of the compound or its pharmaceutical composition of the present invention for metastases is also useful.
The compound or its pharmaceutical composition of the present invention is beneficial except the treatment for the mankind, it can also be used to the treatment of animal doctor Such as pet, rare animal and farm-animals, including mammal, rodent etc..Other say that animal includes more specificly Horse, dog and cat.Formula (I), formula (II) or formula (III) compound of the present invention, pharmaceutically acceptable spread out including its when in use Biology.
The compound or its pharmaceutical composition of the present invention, which can also be used to prepare, suppresses VEGF expression R or c-Met cell growth Medicine, the medicine include connection cell with the present invention compound or composition.On the repressed example bag of cell growth Include：Breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphocytic cancer cell, knot Colon-cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, osteosarcoma cell, kidney Cell, liver cancer cells, transitional cell bladder carcinoma cell line, stomach cancer cell, G. cephalantha cell, melanoma cells or leukaemia.
The compound or its pharmaceutical composition of the present invention, which can also be used to prepare, suppresses VEGFR and/or c-Met kinase activities Medicine, the medicine include connection Biosample and compound disclosed by the invention or composition.Term " biology examination used herein Sample ", refer to the organism sample of the work of an outside, including but not limited to cell culture or its extract；Taken from mammal The biopsy material or its extract obtained；Blood, saliva, urine, excrement, seminal fluid, tears or other body fluid or its extract.Kinases The suppression of activity, particularly VEGFR or c-Met kinase activities, the use disclosed in various kinds of document to be used in the form of Biosample On the way.The example of this purpose includes but is not limited to：Blood transfusion, organ transplant, biological specimen storage and bioassay.
The administration of the compounds of this invention and composition
Compound, salt etc. or its pharmaceutical composition of the present invention simultaneously a variety of can be given, can also be with single chemical combination Thing, salt etc. are given.
Treatment of the present invention includes：The compound or composition of the study subject present invention is given, is further comprised： A kind of additional therapeutic agent of study subject (therapeutic alliance) is given, is selected from：Chemotherapy or antiproliferative or a kind of antiinflammatory, wherein, it is attached The therapeutic agent added is relatively adapted to for the disease treatment treated, additional therapeutic agent and compound disclosed by the invention or Composition is given together, can as single dosage form or with separated one as multiple dose form of compound and composition Point.Additives can from compound disclosed by the invention simultaneously give or asynchronously give.In the latter case, administration can To stagger, such as：6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
Typically therapeutically effective amount should produce about 0.1ng/ml to about 50-100 micrograms/ml active component serum it is dense Degree.Described pharmaceutical composition should be typically provided from about 0.001mg to about 2000mg compound/daily/kg body weight Dosage.Pharmaceutical quantities unit form can be prepared to provide every dosage unit form about 1mg to about 1000mg, in some embodiments In, required active component from about 10mg to about 500mg, from about 20mg to about 250mg or from about 25mg to about 100mg or must Want the combination of composition.In certain embodiments, the pharmaceutical dosage unit forms can be prepared with provide about 1mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg required active component.In certain embodiments, make The standby pharmaceutical dosage unit forms are to provide about 50mg necessary active component.
The active component of reactive compound can be with once daily in pharmaceutical composition, or is divided into some smaller doses with one Interval fix time to be administered.It should be appreciated that accurate dosage and treatment duration are the functions of the disease to be treated, it can Rule of thumb determined using known experimental method, or obtained by inner or in vitro experimental data to extrapolate.It should note Meaning concentration and dose value can also change with the seriousness degree of the symptom to be alleviated.It is to be further understood that for appointing What specific object, should be adjusted according to the professional judgement of individual demand and the people for being administered or supervising composition administration with the time Whole specific dosage regimen, the concentration range proposed here have only been example effects, are not intended to limit claimed composition Scope or implementation.
" effective dose " or " effective dose " of the present invention refer to：It is one or more foregoing for treating or mitigating Disorderly effective amount.According to compound disclosed by the invention or composition, any effective quantity can be used and any had The method of administration treatment treatment of effect either mitigates disorderly or disease seriousness.Required exact amount is by according to different themes And it is different, according to the ordinary circumstance of species, age and theme, the order of severity of infection, special preparation, administering mode etc..Chemical combination Thing or composition can also be given together with one or more other drugs, as described above.
The compound or its pharmaceutical composition of the present invention can also be used for wrapping up Implantable Medical Device, such as artificial limb, artificial valve Film, artificial blood vessel, support and conduit.Intravascular stent such as has been used for overcoming ISR (reducing again for vessel wall after injury).So And patient will risk the risk of blood clot formation or platelet activation using support or other implanted devices.These harmful effects, can With by equipment pre-coating include a kind of compound of the invention its pharmaceutically acceptable composition, to prevent or subtract Gently.
When for treating cancer patient, dosage can according to cancer species, patient age, ordinary circumstance, give Special compound, toxicity presence or level, once bad kickback of using medicine and other factors were changed.One Suitable dosage ranges Representative example is from as little as about 0.01mg/kg is paramount of about 100mg/kg.However, dosage is typically freely cut out by doctor Amount.
Treatment method preferably passes through oral or parenteral formula (I), formula (II) or formula (III) chemical combination for giving the present invention Thing.Term " parenteral " used herein includes：Intravenous injection, intramuscular injection or Intraperitoneal medication.Parenteral is typically excellent Select subcutaneous and intramuscular drug administration by injection form.The present invention can also by hypodermic injection, collunarium, in rectum, percutaneous or intravaginal gives Give formula (I), formula (II) or formula (III) compound of the present invention.
Formula (I), formula (II) or formula (III) compound or its pharmaceutical composition of the present invention can also be given by " suction " Medicine." suction " refers to nasal cavity and oral inhalation administration.The dosage forms of this administration such as aerosol or metered dose inhaler can pass through General technology is made.
The preparation and administration of the compounds of this invention and pharmaceutical composition
Multi-medicament agent can be made in formula (I), formula (II) or formula (III) compound or its pharmaceutical composition of the present invention Type.If using oral solid formulation, can be prepared into：The forms such as tablet, hard shell capsules, lozenge, lozenge, drops, lotion.Solid carries The amount of body can be very different, but typically from 0.025mg or so to about 1g.If oral administration is liquid dosage form, typically Prepare formulation such as：Syrup, emulsion, soft capsule, suspension or solution form.When using intravenous dosage forms, medicine can be solid Or liquid form, and can be made into direct administration or be administered after being adapted to restructuring.It is local to give medicament in Topical dosage forms are also included within The example of type is such as：Solid, liquid and semisolid.Solid includes gumming agent, application etc..Liquid includes solution, suspension and emulsion. Semisolid includes emulsifiable paste, ointment and gel etc..
Formula (I), formula (II) or formula (III) compound of the present invention or the certain basis of amount of its pharmaceutical composition local application Selected compounds, character and the order of severity change and change, can also be weighed according to the tailoring of doctor different and different.The present invention Formula (I), formula (II) or formula (III) compound local application amount it is representational from the paramount about 2.0g of low about 0.01mg, one day Administration one to four time, administration one is to twice within preferably one day.Active component for being locally administered can include left from about 0.001% It is right to about 10%W/W.
When for drops when, it may include sterile or non-sterile water or oil solution or suspension, can be by the way that active component be dissolved It is prepared in the appropriate aqueous solution, is optionally included with sterilization and/or fungicide and/or any other is suitable anti- Rotten agent, and can selectively include surfactant.Final solution can make its clarification by filtration, be transferred to suitable container In, then seal, by autoclaving or maintain 98-100 degrees Celsius of half an hour sterilizing.In addition, the solution may filter that Sterilizing, and it is transferred to sterile chamber.The sterilization and fungicide example included in drops be：Phenylmercuric nitrate or acetic acid (0.002%), benzalkonium chloride (0.01%) and chlorhexidine (0.01%).Suitable solvent for preparing oil solution includes：Glycerine, Diluted Alcohol and propane diols.
When for lotion when, in addition to those are suitably applied the lotion of skin or eyes.Eye lotions may include a kind of nothing Bacterium aqueous solution, optionally contains bactericide, can be prepared by preparing the similar approach of drops.Suitable for skin Lotion or liniment, a kind of reagent is may also include, it can accelerate drying, cool down skin such as alcohol or acetone and/or humidizer such as Glycerine or oil, oil such as castor oil or peanut oil.
It is application semisolid preparation outside active component according to emulsifiable paste of the present invention, ointment or patch.They can pass through Mixed active composition and grease sample or non-grease sample matrix obtain, active component with divided mode or Micronised form, individually Or in the solution or it is suspended in water or on-aqueous liquid.Matrix may include hydrocarbon, such as：Firmly, soft or atoleine, it is sweet Oil, beeswax；Metallic soap；A kind of cement；A kind of natural oil-producing class such as almond, coenzyme M, peanut, castor-oil plant or olive oil；Wool fat Or derivatives thereof, or aliphatic acid such as stearic acid or oleic acid be together with ethanol, ethanol such as propane diols or macrogel.Preparation can mix Any suitable surfactant, such as anion, cation or nonionic surfactant, such as sorbitol ester or its polyoxyethylene Derivative.Suspending agent such as natural gum, cellulose derivative or inorganic material such as silicate, may also include other compositions such as wool Fat.
The compound or its pharmaceutical composition of the present invention can also be administered in the form of coating, and suitable coating is implanted into equipment For known to those skilled in the art.The coating be representative biocompatible polymeric material such as：Aquogel polymer, Poly- tetramethyldisiloxane, PCL, polyethylene glycol, PLA, vinyl acetate and their mixture.Coating is alternative Ground is further covered by a suitable film, such as：Fluorosilicon oil, polysaccharase, polyethylene glycol, phosphatide or its mixture, make medicine Composition has control release characteristic.The compound of the present invention can be also applied on Implantable Medical Device, such as beads or with gathering Compound or other molecules are prepared jointly, there is provided and a kind of " drug storage institute ", so that medicine discharges in the long period, rather than It is administered in the form of pharmaceutical aqueous solution.
General synthetic method
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein the definition of substituent is as shown in formula (I), formula (II) or formula (III) compound.Following reaction scheme and implementation Example is used to present disclosure be further illustrated.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention Or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13,d6-DMSO,CD3OD or d6- acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represented with hertz (Hz).
By being equipped with G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, ESI sources are applied to LC-MS spectrometers.
Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent 6120 serial LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detectors should For analyzing, ESI sources are applied to LC-MS spectrometers.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；HPLC peak value is by 210nm and 254nm UV-Vis wavelength records reading.The formic acid acetonitrile solution (phase A) and 0.1% formic acid that mobile phase is 0.1% are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1：
Table 1
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by the series of high efficiency liquid chromatograies (HPLC) of Agilent 1100, wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.
The use of brief word below is through the present invention：
BOC, Boc tert-butoxycarbonyl
CHCl3Chloroform
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DMAP DMAPs
DMSO dimethyl sulfoxide (DMSO)s
EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
EtOAc ethyl acetate
HCl hydrochloric acid
H2Hydrogen
H2O2Hydrogen peroxide
Fe iron
MeOH,CH3OH methanol
CH2Cl2, DCM dichloromethane
ML, ml milliliter
N2Nitrogen
Pd/C palladiums/carbon
PE petroleum ethers (60-90 DEG C)
RT rt room temperatures
Rt retention times
MsCl mesyl chlorides
NaHCO3Sodium acid carbonate
Na2SO4Sodium sulphate
THF tetrahydrofurans
Et3N, TEA triethylamine
TFA trifluoroacetic acids
NBS N-bromo-succinimides
H2O water
The synthesis of intermediate
The synthesis of intermediate 2
Compound 2, can be prepared by following two methods, wherein R, and n have contain as described in the present invention Justice.Method one：Compound 1A and compound 2A in the basic conditions, obtain compound 3A；Compound 3A chlorinations generate compound 2.Method two：Compound 1A and compound 4A in the basic conditions, generate compound 2.
Intermediate 8A synthesis
Compound 8A, it can be prepared by the following method to obtain.Compound 5A and compound 6A in the basic conditions, are obtained Compound 7A；Compound 7A deprotection generation compounds 8A.
The synthetic schemes of compound
Reaction scheme 1
Compound 6, it can be prepared by the method for reaction scheme 1, wherein R1, a, R, E, G and n have such as the present invention Described implication.Compound 1 and compound 2 in the basic conditions, obtain compound 3.Compound 3 is carried out into reduction reaction to obtain Product 4, then obtain product 6 with the reaction of compound 5.
Reaction scheme 2
Compound 6, it can be prepared by the method for reaction scheme 2, wherein R1, a, R, E, G and n have such as the present invention Described implication.Compound 4 and the reaction of compound 7 are obtained into product 6.
Reaction scheme 3
Compound 6, it can be prepared by the method for reaction scheme 3, wherein R1, a, R, E, G and n have such as the present invention Described implication.Compound 1 and compound 2a in the basic conditions, obtain compound 3a.Compound 3a hydroxyl is protected Shield obtains compound 8, then carries out reduction reaction and obtain product 4, then obtains product 6 with the reaction of compound 5.
The following examples can be so that the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright scope.
Embodiment
Embodiment 1
1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-b] pyridazine - 2- yls) phenyl) urea
Step 1) 6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazine
3- amino -6- methoxyl groups pyridazines (250mg, 2.0mmol) are dissolved in acetonitrile (50mL), add the bromo- 4 '-nitros of 2- Acetophenone (970mg, 3.99mmol).Solution heating reflux reaction 5h, after reaction terminates, directly filter, after filter cake vacuum drying, Obtain product (408mg, 75.7%).
ESI-MS:(ESI,pos.ion)m/z：271.2[M+1]+.
Step 2) 2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazine -6- alcohol
By 6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazines (540mg, 2.0mmol) and pyridine hydrochloride (1.15g, 10.0mmol) is mixed, and is heated to 150 degrees Celsius of melting stirring reaction 5h.Residue is added into water (100mL), extracted with dichloromethane (400mL), organic phase is washed with saturated sodium-chloride water solution (100mL), anhydrous sodium sulfate Dry, be concentrated under reduced pressure, rapid column chromatography separation (V (petroleum ether)/V (ethyl acetate)=5/1), obtain white solid (260mg, 50.7%).
ESI-MS:(ESI,pos.ion)m/z：257.1[M+1]+.
Step 3) 4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazine -6- bases) epoxide) propyl group) morpholine
2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazine -6- alcohol (256mg, 1.0mmol) is dissolved in acetonitrile (30mL), Sequentially add 1- (3- chloropropyls)-morpholine (187mg, 1.14mmol) and potassium carbonate (430mg, 3.12mmol).Solution heats back Stream reaction 10h, is concentrated under reduced pressure, and residue is added into water (50mL), extracted with dichloromethane (300mL), organic phase saturation chlorine Change sodium water solution (50mL) washing, anhydrous sodium sulfate drying, be concentrated under reduced pressure, rapid column chromatography separation (V (DCM)/V (MeOH)= 10/1) white solid (276mg, 72%), is obtained.
ESI-MS:(ESI,pos.ion)m/z：384.2[M+1]+.
Step 4) 4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-b] pyridazine -2- bases) aniline
By 4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-b] pyridazine -6- bases) epoxide) propyl group) morpholine (766mg, 2.0mmol) it is dissolved in mixed solvent (V (MeOH)/V (H2O)=3/1,160mL), add ammonium chloride (830mg, 15.65mmol) and Reduced iron powder (438mg, 7.83mmol), it is warming up to 80 degrees Celsius and is stirred at reflux reaction 3h, TLC, which is monitored, reacts complete, adds Reaction, ethyl acetate (300mL) extract and separate is quenched in saturated sodium bicarbonate solution (100mL), and organic phase is washed with water (100mL), Saturated nacl aqueous solution (50mL) is washed, and anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography for separation (V (MeOH)/V (DCM)=1/ 10) grease (550mg, 78.3%), is obtained.
ESI-MS:(ESI,pos.ion)m/z：354.3[M+1]+.
Step 5) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- morpholinoes propoxyl group) imidazos [1,2-b] Pyridazine -2- bases) phenyl) urea
4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-b] pyridazine -2- bases) aniline (172mg, 0.5mmol) is dissolved in Acetonitrile (30mL), sequentially add triethylamine (0.3mL, 2.2mmol) and phenyl N- (5- tert-butyl group isoxazole -3- bases) carbamic acid Ester (0.29g, 1.1mmol), heating stirring back flow reaction are stayed overnight, and after reaction terminates, are concentrated under reduced pressure, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtain white solid (50mg, 19.2%).
ESI-MS:(ESI,pos.ion)m/z：520.5[M+1]+.
1H NMR(400MHz,d6- DMSO) δ 9.89 (s, 2H), 8.53 (s, 1H), 7.98 (d, J=9.6Hz, 1H), 7.90 (d, J=8.4Hz, 2H), 7.53 (d, J=8.5Hz, 2H), 6.85 (d, J=9.6Hz, 1H), 6.54 (s, 1H), 4.34 (t, J= 6.5Hz, 2H), 3.58-3.56 (m, 4H), 3.43 (t, J=6.3Hz, 2H), 2.48-2.39 (m, 4H), 1.57 (dd, J= 13.1,6.6Hz,2H),1.30(s,9H).
Embodiment 2
1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (7- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine - 2- yls) phenyl) urea
Step 1) 7- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine
The bromo- 4'- nitrobenzene of 2- amino-4-methoxyls pyridine (6.21g, 50.02mmol), 2- is sequentially added in reaction bulb Ethyl ketone (6.3g, 75mmol), sodium acid carbonate (6.3g, 75mmol) and ethanol (125mL), it is heated to reflux backflow 1 hour.Mixed liquor 0 DEG C is cooled to, is then filtered, filter cake crosses post purifying (V (petroleum ether)/V (ethyl acetate)=3/2) with after a small amount of ethanol rinse, Obtain yellow solid (1.84g, 14%).
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1]+。
Step 2) 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -7- alcohol
Sequentially added in reaction bulb 7- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine (1.84g, It is extensive after Boron tribromide (1.0mL) is added dropwise under ice bath and stirs 0.5 hour at such a temperature 6.83mmol) with DCM (300mL) It is stirred overnight at room temperature again.After detecting raw material reaction completely by MS, saturated sodium bicarbonate solution is added into reaction solution to without gas Body produces, and after continuing stirring 0.5 hour, solid is collected by filtration and is dried under reduced pressure, obtains brown solid (1.48g, 85%).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1]+。
Step 3) 4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridin-7-yl) epoxide) propyl group) morpholine
Sequentially added in reaction bulb 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -7- alcohol (1.48g, 5.80mmol), potassium carbonate (2.4g, 17.39mmol), tetrabutyl iodate amine (0.43g, 1.16mmol), 4- (3- chloropropyls) Quinoline (2.37g, 14.48mmol) and DMF (30mL), heating reflux reaction 6 hours.Reaction finishes, and is cooled to room temperature, and mixed liquor pours into In water (200mL), after being stirred at room temperature 1 hour, filtering, filter cake is dried under reduced pressure, and obtains brown solid (1.69g, 76%).
ESI-MS:(ESI,pos.ion)m/z：383.1[M+1]+。
Step 4) 4- (7- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine -2- bases) aniline
4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridin-7-yl) epoxide) third are sequentially added in reaction bulb Base) morpholine (1.69g, 4.42mmol), zinc powder (2.89g, 44.46mmol), ammonium chloride (0.95g, 17.68mmol) and ethanol/ Water (15/4,38mL), heating reflux reaction 4 hours.Solid is filtered to remove, after filtrate decompression is evaporated, dichloro is added in residue Methane (100mL) and saturated sodium bicarbonate solution (100mL), extract and separate, anhydrous sodium sulfate drying organic phase, are obtained after concentration Brown solid (1.48g, 95%).
ESI-MS:(ESI,pos.ion)m/z：353.1[M+1]+。
Step 5) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (7- (3- morpholinoes propoxyl group) imidazos [1,2-a] Pyridine -2- bases) phenyl) urea
4- (7- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine -2- bases) aniline is sequentially added in reaction bulb (0.6g, 1.70mmol) and dry methylene chloride (8mL), phenyl (5- (tert-butyl group) isoxazole -3- bases) is sequentially added at room temperature Carbamate (0.49g, 1.88mmol) and DMAP (12mg, 0.1mmol), the two of triethylamine (0.035mL) is added dropwise after stirring Chloromethanes (0.1mL) solution, heated overnight at reflux.Solid is collected by filtration, is eluted with a small amount of dichloromethane (10mL), obtains white Solid (208mg, 24%).
1H NMR(400MHz,d6-DMSO):δ 9.55 (s, 1H), 8.90 (s, 1H), 8.33 (d, J=7.2Hz, 1H), 8.10 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 6.92 (d, J=2.0Hz, 1H), 6.56-6.58 (dd, J=2.4,7.2Hz, 1H), 6.53 (s, 1H), 4.08-4.05 (t, J=6.0Hz, 2H), 3.58-3.56 (t, J= 4.4Hz, 4H), 2.44-2.40 (t, J=6.8Hz, 2H), 2.36 (s, 4H), 1.91-1.88 (t, J=6.8Hz, 2H), 1.30 (s,9H).
ESI-MS:(ESI,pos.ion)m/z：519.4[M+1]+。
Embodiment 3
1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine - 2- yls) phenyl) urea
Step 1) 6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine
The bromo- 4'- nitrobenzene of 2- amino -5- methoxypyridines (6.21g, 50.02mmol), 2- is sequentially added in reaction bulb Ethyl ketone (6.3g, 75mmol), sodium acid carbonate (6.3g, 75mmol) and ethanol (125mL), it is heated to reflux backflow 1 hour.Mixed liquor 0 degree Celsius is cooled to, is then filtered, filter cake is with after a small amount of ethanol rinse, column chromatography for separation (V (petroleum ether)/V (ethyl acetate) =3/2) yellow solid (1.84g, 14%), is obtained.
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1]+。
Step 2) 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- alcohol
Sequentially added in reaction bulb 6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine (1.84g, 6.83mmol) with dichloromethane (300mL), Boron tribromide (1.0mL) is added dropwise under ice bath and stirs 0.5 hour at such a temperature Afterwards, recover to be stirred overnight at room temperature.After detecting raw material reaction completely by LC-MS, it is molten that saturated sodium bicarbonate is added into reaction solution Liquid to without gas produce, continue stirring 0.5 hour after, solid is collected by filtration and is dried under reduced pressure, obtain brown solid (1.48g, 85%).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1]+。
Step 3) 4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) propyl group) morpholine
Sequentially added in reaction bulb 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- alcohol (0.51g, 1.99mmol), potassium carbonate (0.83g, 6.01mmol), tetrabutylammonium iodide (0.15g, 0.41mmol), 4- (3- chloropropyls) Quinoline hydrochloride (0.8g, 4mmol) and DMF (20mL), heating reflux reaction 6 hours.Reaction finishes, and is cooled to room temperature, and mixed liquor falls Enter in water (200mL), after being stirred at room temperature 1 hour, filtering, filter cake is dried under reduced pressure, and obtains brown solid (0.61g, 80%).
ESI-MS:(ESI,pos.ion)m/z：383.2[M+1]+
Step 4) 4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine -2- bases) aniline
4- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) third are sequentially added in reaction bulb Base) morpholine (0.61g, 1.60mmol), zinc powder (1.31g, 20mmol), ammonium chloride (0.5g) and ethanol/water (15/4,40mL), Heating reflux reaction 4 hours.Solid is filtered to remove, dichloromethane (300mL) is added after filtrate decompression is evaporated, in residue and is satisfied With sodium bicarbonate solution (100mL), extract and separate, anhydrous sodium sulfate drying organic phase, brown solid is obtained after being concentrated under reduced pressure (0.4g, 70%).
ESI-MS:(ESI,pos.ion)m/z：353.2[M+1]+.
Step 5) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- morpholinoes) imidazo [1,2-a] pyridine - 2- yls) phenyl) urea
4- (6- (3- morpholinoes propoxyl group) imidazo [1,2-a] pyridine -2- bases) aniline is sequentially added in reaction bulb (0.4g, 1.13mmol) and dry methylene chloride (20mL), phenyl (5- (tert-butyl group) isoxazole -3- bases) is sequentially added at room temperature Carbamate (1.04g, 4.0mmol) and DMAP (20mg), triethylamine (0.3mL), heating reflux reaction mistake are added dropwise after stirring Night.Solid is collected by filtration, is eluted with a small amount of dichloromethane (10mL), obtains white solid (176mg, 30%).
ESI-MS:(ESI,pos.ion)m/z：519.3[M+1]+。
1H NMR(400MHz,d6-DMSO)δ9.57(s,1H),8.93(s,1H),8.21–8.04(m,2H),7.88(d,J =8.6Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.45 (d, J=9.7Hz, 1H), 6.98 (dd, J=9.7,2.2Hz, 1H), 6.55 (s, 1H), 3.91 (t, J=6.2Hz, 2H), 3.54 (m, 8H), 2.36 (m, 6H), 1.94-1.70 (m, 2H), 1.28 (s, 9H).
Embodiment 4
1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- ((4aR, 7aS)-tetrahydrochysene -2H- [1,4] dioxins [2,3-c] pyrroles -6 (3H)-yl) propoxyl group) imidazo [1,2-a] pyridine -2- bases) phenyl) urea
Step 1) 6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine
The bromo- 4'- nitro-acetophenones (6.3g, 75mmol) of 2- amino -5- methoxypyridines (6.21g, 50.02mmol), 2- With sodium acid carbonate (6.3g, 75mmol) according to the synthetic method of the step 1 of embodiment 2 be prepared yellow solid (1.84g, 14%).
ESI-MS:(ESI,pos.ion)m/z：270.2[M+1]+。
Step 2) 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- alcohol
6- methoxyl groups -2- (4- nitrobenzophenones) imidazo [1,2-a] pyridines (1.84g, 6.83mmol) and Boron tribromide Brown solid (1.48g, 85%) is prepared into method according to the step of embodiment 2 is 2-in-1 in (1.0mL).
ESI-MS:(ESI,pos.ion)m/z：256.0[M+1]+。
Step 3) (4aR, 7aS) -6- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) third Base) hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles
2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- alcohol (0.51g, 1.99mmol), potassium carbonate (0.83g, 6.01mmol), tetrabutylammonium iodide (0.15g, 0.41mmol), (4aR, 7aS) -6- (3- chloropropyls) hexahydro -2H- [1,4] two Oxygen glutinous rehmannia [2,3-c] pyrroles (0.82g, 3.99mmol) and DMF (10mL) obtain brown according to step 3 synthetic method of embodiment 2 and consolidated Body (0.7g, 83%).
ESI-MS:(ESI,pos.ion)m/z：425.1[M+1]+。
Step 4) 4- (6- (3- ((4aR, 7aS)-tetrahydrochysene -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) third oxygen Base) imidazo [1,2-a] pyridine -2- bases) aniline
(4aR, 7aS) -6- (3- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) propyl group) hexahydro - 2H- [1,4] dioxin [2,3-c] pyrroles (0.7g, 1.65mmol), zinc powder (1.31g, 20.15mmol) and ammonium chloride (0.43g, Brown solid (0.32g, 41%) 8.04mmol) is obtained according to step 4 synthetic method of embodiment 2.
ESI-MS:(ESI,pos.ion)m/z：395.2[M+1]+。
Step 5) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (6- (3- ((4aR, 7aS)-tetrahydrochysene -2H- [1,4] two Oxygen glutinous rehmannia [2,3-c] pyrroles -6 (3H)-yl) propoxyl group) imidazo [1,2-a] pyridine -2- bases) phenyl) urea
4- (6- (3- ((4aR, 7aS)-tetrahydrochysene -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) propoxyl group) miaows Azoles simultaneously [1,2-a] pyridine -2- bases) aniline (0.32g, 0.81mmol), phenyl (5- (tert-butyl group) isoxazole -3- bases) carbamate (0.23g, 0.88mmol), DMAP (6mg, 0.05mmol) and triethylamine (0.1mL) obtain according to step 5 synthetic method of embodiment 2 To white solid (52mg, 11%).
1H NMR(400MHz,d6-DMSO):δ 9.53 (s, 1H), 8.90 (s, 1H), 8.21-8.22 (d, J=2.0Hz, 1H), 8.19 (s, 1H), 7.85 (d, J=8.4Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.46 (d, J=9.6Hz, 1H), 7.01 (dd, J=2.4,10.0Hz, 1H), 6.52 (s, 1H), 4.02-3.99 (t, J=6.4Hz, 4H), 3.72-3.68 (m, 2H), 3.47-3.44 (m, 2H), 2.87-2.83 (m, 2H) 2.70-2.67 (m, 2H), 2.65-2.61 (t, J=7.2Hz, 2H), 1.90-1.85(m,2H),1.31(s,9H).
ESI-MS:(ESI,pos.ion)m/z：561.3[M+1]+。
Embodiment 5
1- (5- tert-butyl group isoxazole -3- bases) -3- { 4- [6- (2- morpholines ethyoxyl) imidazo [1,2-b] pyridazine -3- bases] Phenyl } urea
The bromo- 6- of step 1) 3- [2- (morpholine -4- bases) ethyoxyl]-imidazo [1,2-b] pyridazine
N- hydroxyethyl morpholines (1.15g, 8.4mmol) are dissolved in 50mL THF, are cooled to -10 degrees Celsius, add t- BuOK (1.45g, 12.6mmol), then heats to and 30min is stirred at room temperature, then is cooled to -10 degrees Celsius, and the bromo- 6- chlorine of 3- is added dropwise THF (30mL) solution of imidazoles [1,2-b] pyridazine (1.5g, 6.5mmol), is finished, stirring reaction is stayed overnight at room temperature.Add a small amount of Reaction is quenched in water (10mL), is concentrated under reduced pressure, and residue is dissolved in 200mL dichloromethane, organic layer saturated sodium-chloride water solution (50mL) is washed, and anhydrous sodium sulfate drying, is concentrated under reduced pressure, and column chromatography for separation (V (DCM)/V (MeOH)=15/1), is obtained yellow and is consolidated Body (1.86g, 88%).
ESI-MS:(ESI,pos.ion)m/z：327.1[M+1]+。
Step 2) 4- [6- (2- morpholines ethyoxyl) imidazo [1,2-b] pyridazine -3- bases] Phenyl-carbamic acid tert-butyl ester
3- bromo- 6- [2- (morpholine -4- bases) ethyoxyl]-imidazo [1,2-b] pyridazine is added in 250ml single port bottles (700mg, 2.14mmol) and potassium acetate (460mg, 4.64mmol), 100mL DMF and 25mL water is then added, is followed by stirring for down Sequentially add PdCl2(dppf) (180mg, 0.24mmol) and [4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentanes -2- Base) phenyl] t-butyl carbamate (770mg, 2.41mmol), finish, pumping ventilation three times, is warming up to 80 under nitrogen protection Degree Celsius stirring reaction is stayed overnight.Room temperature is cooled to, reaction solution is concentrated, residue is dissolved in 300mL dichloromethane, with saturation chlorine Change sodium water solution (50mL) to wash once, anhydrous sodium sulfate drying, be concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=15/ 1) yellow oil (350mg, 37.22%), is obtained.
ESI-MS:(ESI,pos.ion)m/z：440.3[M+1]+。
Step 3) 4- [6- (2- morpholines ethyoxyl) imidazo [1,2-b] pyridazine -3- bases] aniline
By 4- [6- (2- morpholines ethyoxyl) imidazo [1,2-b] pyridazine -3- bases] the Phenyl-carbamic acid tert-butyl ester (350mg, 0.796mmol) is dissolved in 20mL dichloromethane, is cooled to 0 degree Celsius, and 5mL trifluoroacetic acids are added dropwise, slowly return to room Warm stirring reaction 3h.It is concentrated under reduced pressure, residue adds saturated sodium bicarbonate aqueous solution (50mL) to be quenched, ethyl acetate (400mL) extraction Take, separate organic layer, anhydrous sodium sulfate drying, be concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain Huang Color grease (232mg, 85.5%).
ESI-MS:(ESI,pos.ion)m/z：340.2[M+1]+。
Step 4) 1- (5- tert-butyl group isoxazole -3- bases) -3- { [rattle away 4- by 6- (2- morpholines ethyoxyl) imidazo [1,2-b] Piperazine -3- bases] phenyl } urea
4- [6- (2- morpholines ethyoxyl) imidazo [1,2-b] pyridazine -3- bases] aniline (232mg, 0.684mmol) is dissolved in In 30mL dichloromethane, 5- (tert-butyl group) isoxazole -3- bases are sequentially added under stirring) phenyl carbamate (0.78g, 3.0mmol) with DMAP (45mg, 0.37mmol), triethylamine (0.3mL) is then added dropwise, finishes, temperature rising reflux reaction is overnight.TLC Monitoring reaction is complete, is cooled to room temperature, organic phase washed with water (10mL) and saturated sodium-chloride water solution (10mL) are washed, nothing Aqueous sodium persulfate dry, be concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain faint yellow solid (180mg, 54%).
ESI-MS:(ESI,pos.ion)m/z：506.3[M+1]+。
1H-NMR(400MHz,CDCl3)δ:8.04 (d, J=8.7Hz, 2H), 7.90 (s, 1H), 7.87 (d, J=9.6Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 6.76 (d, J=9.6Hz, 1H), 5.95 (s, 1H), 4.52 (t, J=5.5Hz, 2H), 3.77 (m, 4H), 2.88 (t, J=5.5Hz, 2H), 2.61 (s, 4H), 1.38 (s, 9H)
Embodiment 6
1- (5- tert-butyl group isoxazole -3- bases) -3- { 4- [6- (3- morpholines propoxyl group) imidazo [1,2-b] pyridazine -3- bases] Phenyl } urea
The bromo- 6- of step 1) 3- [3- (morpholine -4- bases) propoxyl group]-imidazo [1,2-b] pyridazine
N- hydroxypropyls morpholine (1.39g, 9.50mmol) is dissolved in 35mL THF, is cooled to 0 degree Celsius, adds t-BuOK (1.65g, 14.4mmol), then heat to and 30min is stirred at room temperature, then be cooled to 0 degree Celsius, stir the lower addition bromo- 6- chlorine of 3- THF (25mL) solution of imidazoles [1,2-b] pyridazine (1.5g, 6.5mmol), is finished, stirring reaction is stayed overnight at room temperature.Add a small amount of Reaction is quenched in water (10mL), is concentrated under reduced pressure, and residue is dissolved in 200mL dichloromethane, organic phase saturated sodium-chloride water solution (50mL) is washed, and anhydrous sodium sulfate drying, is concentrated under reduced pressure, and column chromatography for separation (V (DCM)/V (MeOH)=20/1), is obtained yellow and is consolidated Body (1.65g, 75%).
ESI-MS:(ESI,pos.ion)m/z：341.1[M+1]+
Step 2) 4- [6- (3- morpholines propoxyl group) imidazo [1,2-b] pyridazine -3- bases] Phenyl-carbamic acid tert-butyl ester
3- bromo- 6- [3- (morpholine -4- bases) propoxyl group]-imidazo [1,2-b] pyridazine is added in 250ml single port bottles (900mg, 2.64mmol) and potassium acetate (520mg, 5.31mmol), 80mL DMF and 20mL water is then added, is followed by stirring for down Sequentially add PdCl2(dppf) (200mg, 0.27mmol) and [4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentanes -2- Base) phenyl] t-butyl carbamate (960mg, 3.00mmol), finish, pumping ventilation three times, is warming up to 80 under nitrogen protection Degree Celsius stirring reaction is stayed overnight.TLC monitoring reactions are complete, are cooled to room temperature, reaction solution is concentrated, residue is dissolved in 300mL dichloromethane, then washed once, anhydrous sodium sulfate drying, be concentrated under reduced pressure with saturated sodium-chloride water solution (50mL), post layer Analysis separation (V (DCM)/V (MeOH)=10/1), obtains yellow oil (357mg, 29.8%).
ESI-MS:(ESI,pos.ion)m/z：454.3[M+1]+
Step 3) 4- [6- (3- morpholines propoxyl group) imidazo [1,2-b] pyridazine -3- bases] aniline
By 4- [6- (3- morpholines propoxyl group) imidazo [1,2-b] pyridazine -3- bases] the Phenyl-carbamic acid tert-butyl ester (320mg, 0.70mmol) is dissolved in 20mL dichloromethane, is cooled to 0 degree Celsius, and 5mL trifluoroacetic acids are added dropwise, slowly return to room temperature Stirring reaction 4h.It is concentrated under reduced pressure, residue adds saturated sodium bicarbonate aqueous solution (50mL) to be quenched, ethyl acetate (400mL) extraction, Organic layer is separated, anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains yellow Grease (205mg, 82.2%).
ESI-MS:(ESI,pos.ion)m/z：354.2[M+1]+
Step 4) 1- (5- tert-butyl group isoxazole -3- bases) -3- { [rattle away 4- by 6- (3- morpholines propoxyl group) imidazo [1,2-b] Piperazine -3- bases] phenyl } urea
4- [6- (3- morpholines propoxyl group) imidazo [1,2-b] pyridazine -3- bases] aniline (205mg, 0.58mmol) is dissolved in In 30mL dichloromethane, 5- (tert-butyl group) isoxazole -3- bases are sequentially added under stirring) phenyl carbamate (0.34g, 1.16mmol) with DMAP (40mg, 0.33mmol), triethylamine (0.3mL) is then added dropwise, finishes, temperature rising reflux reaction is overnight. TLC monitoring reactions are complete, are cooled to room temperature, organic phase washed with water (10mL) and saturated sodium-chloride water solution (10mL) Wash, anhydrous sodium sulfate drying, be concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtain faint yellow solid (120mg, 39.8%).
ESI-MS:(ESI,pos.ion)m/z：520.4[M+1]+
1H NMR(600MHz,CDCl3) δ 8.06 (d, J=8.7Hz, 2H), 7.89 (dd, J=36.9,19.9Hz, 2H), 7.68 (d, J=8.7Hz, 2H), 6.72 (d, J=9.6Hz, 1H), 5.93 (s, 1H), 4.43 (t, J=6.2Hz, 2H), 3.75 (t, J=4.5Hz, 4H), 2.58-2.51 (m, 6H), 2.18-1.90 (m, 2H), 1.39 (s, 9H)
Embodiment 7
1- [5- (tert-butyl group) isoxazole -3- bases] -3- 4- [7- (2- morpholinoes ethyoxyl) pyrazolo [1,5-a] pyrimidine - 3- yls] phenyl } urea
The iodo- pyrazolos of the chloro- 3- of step 1) 7- [1,5-a] pyrimidine
7- chlorine pyrazolo [1,5-a] pyrimidine (3.0g, 19.5mmol) is dissolved in 30mL DMF, add NIS (5.3g, 23mmol), reaction 12h is stirred at room temperature.25mL water is added into system, there are a large amount of solids to separate out, continues to stir 15min, filters, Filter cake is dried in vacuo, obtains off-white powder (4.8g, 88%).
ESI-MS:(ESI,pos.ion)m/z：280.0[M+1]+
Step 2) 4- { 2- [(3- iodine pyrazolo (1,5-a) pyrimidin-7-yl) epoxide] ethyl } morpholine
Potassium tert-butoxide (0.60g, 5.0mmol) is dissolved in THF (50mL), is cooled to 0 degree Celsius, then N- hydroxyls are slowly added dropwise Ethyl morpholine (0.71g, 5.4mmol), the stirring reaction 30min under zero degrees celsius.It is slow added into the iodo- pyrazolos of the chloro- 5- of 7- [1,5-a] pyrimidine (1.0g, 3.6mmol), keeping temperature are no more than 10 degrees Celsius, finished, and keep 0 degree Celsius of reaction 2h.Add water Reaction is quenched in (30mL), is concentrated under reduced pressure, and residue is extracted with dichloromethane (300mL), (50mL), saturation is washed with water in organic phase Salt washes (50mL), anhydrous sodium sulfate drying, is concentrated under reduced pressure to give faint yellow solid (0.98g, 73%).It is not required to further pure Change, directly cast single step reaction.
ESI-MS:(ESI,pos.ion)m/z：375.1[M+1]+
Step 3) { 4- [7- (2- morpholinoes ethyoxyl) pyrazoles [1,5-a] pyrimidin-3-yl] phenyl } t-butyl carbamate
4- { 2- [(3- iodine pyrazolo (1,5-a) pyrimidin-7-yl) epoxide] ethyl } morpholine is added in 250ml single port bottles (800mg, 2.14mmol) and potassium acetate (460mg, 4.64mmol), 100mL DMF and 25mL water is then added, is sequentially added PdCl2(dppf) (180mg, 0.24mmol) and [4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- bases) phenyl] ammonia Base t-butyl formate (770mg, 2.41mmol), is finished, and solution pumping ventilation three times, is warming up to 80 degrees Celsius under nitrogen protection Stirring reaction is stayed overnight.TLC monitoring reactions are complete, are cooled to room temperature, reaction solution is concentrated, residue is dissolved in 200mL dichloros Methane, respectively washed once, anhydrous sodium sulfate drying, filtered, filtrate with water (50mL) and saturated sodium-chloride water solution (50mL) successively It is concentrated under reduced pressure, column chromatography for separation (V (MeOH)/V (DCM)=1/15), obtains yellow oil (250mg, 27.12%).
ESI-MS:(ESI,pos.ion)m/z 440.3[M+1]+
Step 4) 4- [7- (2- morpholinoes ethyoxyl) pyrazoles [1,5-a] pyrimidin-3-yl] aniline
By { 4- [7- (2- morpholinoes ethyoxyl) pyrazoles [1,5-a] pyrimidin-3-yl] phenyl } t-butyl carbamate (250mg, 0.57mmol) is dissolved in 20mL dichloromethane, is cooled to 0 degree Celsius, and 5mL trifluoroacetic acids are added dropwise, slowly return to room temperature Stirring reaction 4h.It is concentrated under reduced pressure, residue adds saturated sodium bicarbonate aqueous solution (50mL) to be quenched, ethyl acetate (400mL) extraction, Organic layer is separated, anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains yellow Grease (150mg, 78.1%).
ESI-MS:(ESI,pos.ion)m/z：340.2[M+1]+
Step 5) 1- [5- (tert-butyl group) isoxazole -3- bases] -3- { 4- [7- (2- morpholinoes ethyoxyl) pyrazolos [1,5-a] Pyrimidin-3-yl] phenyl } urea
4- [7- (2- morpholinoes ethyoxyl) pyrazoles [1,5-a] pyrimidin-3-yl] aniline (75mg, 0.23mmol) is dissolved in In 40mL dichloromethane, sequentially add 5- (tert-butyl group) isoxazole -3- bases) phenyl carbamate (117mg, 0.45mmol) and DMAP (45mg, 0.37mmol), triethylamine (0.3mL) is then added dropwise, finishes, the reaction of solution temperature rising reflux is overnight.TLC monitorings are anti- Should completely, solution is cooled to room temperature, and organic phase washed with water (10mL) and saturated nacl aqueous solution are washed (10mL), anhydrous sulphur Sour sodium is dried, filtering, filtrate decompression concentration, column chromatography for separation (V (DCM)/V (MeOH)=10/1), obtains faint yellow solid (18mg, 16%).
ESI-MS:(ESI,pos.ion)m/z 506.2[M+1]+
1H NMR(400MHz,CDCl3) δ 9.25 (s, 1H), 8.44 (d, J=12.0Hz, 1H), 8.29 (s, 1H), 7.97 (d, J=8.5Hz, 2H), 7.59 (d, J=8.5Hz, 2H), 6.40 (d, J=7.5Hz, 1H), 5.95 (s, 1H), 5.37 (s, 1H), 4.63 (t, J=5.7Hz, 2H), 3.79-3.72 (m, 4H), 2.88 (t, J=5.7Hz, 2H), 2.65-2.57 (m, 4H), 1.38(s,9H).
Embodiment 81- (4- (6- (2- (2- oxa- -6- azepine spiroheptane -6- bases) ethyoxyl) imidazos [1,2-a] Pyridine -2- bases) phenyl) -3- (5 (tert-butyl group) isoxazole -3- bases) urea
Step 1) 2-((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine-6- bases) epoxide) ethanol
2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- alcohol (2.0g, 7.84mmol) is dissolved in DMF (30mL), according to Secondary addition potassium carbonate (14g, 101.30mmol) and ethylene bromohyrin (3.0mL, 42.33mmol), it is anti-that solution is heated to 80 degree of stirrings 6h is answered, is concentrated under reduced pressure, ethyl acetate (3X100mL) extraction, organic phase is washed with water (100mL), anhydrous sodium sulfate drying, and decompression is dense Contracting, rapid column chromatography separation, column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtains brown solid (1.5g, 64%).
MS-ESI:(ESI,pos.ion)m/z：300.1[M+1]+
Step 2) 2- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) ethyl methane sulfonate ester
2- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) ethanol (1.0g, 3.34mmol) is molten In THF (50mL), 0 degree is cooled to, triethylamine (2.5mL, 18mmol) and MsCl (0.52mL, 6.7mmol) are added dropwise successively, slowly Returning to and reaction 2h is stirred at room temperature, add saturated sodium bicarbonate aqueous solution (50mL) that reaction is quenched, ethyl acetate (300mL) extracts, Anhydrous sodium sulfate drying, it is concentrated under reduced pressure and is directly used in after fully drying and reacted in next step.
MS-ESI:(ESI,pos.ion)m/z：378.1[M+1]+。
Step 3) 6- (2- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) ethyl) -2- oxa-s - 6- azepine spiroheptanes
By 2- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) ethyl methane sulfonate ester (100mg, Acetonitrile (20mL) 0.265mmol) is dissolved in, sequentially adds 2- oxa- -6- azepines spiroheptanes (80mg, 0.4233mmol), carbon Sour potassium (0.21g, 1.5mmol) and KI (25mg, 0.15mmol), solution heating reflux reaction 7h, filtering, filtrate decompression are dense Contracting, direct column chromatography for separation (V (MeOH)/V (DCM)=1/10), obtains brown solid (70mg, 70%).
MS-ESI:(ESI,pos.ion)m/z：381.2[M+1]+
Step 4) 4- (6- (2- (2- oxa- -6- azepine spiroheptane -6- bases) ethyoxyl)-imidazo [1,2-a] pyrroles Pyridine -2- bases) aniline
6- (2- ((2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine -6- bases) epoxide) are added in 100mL single port bottles Ethyl) -2- oxa- -6- azepines spiroheptanes (80mg, 0.21mmol) are dissolved in methanol/water solution (V/V, 3/1,40mL), according to Secondary addition ammonium chloride (170mg, 3.21mmol) and reduced iron powder (100mg, 1.79mmol), solution heating reflux reaction 4h, subtract Pressure concentration, ethyl acetate (200mL) extraction, anhydrous sodium sulfate drying, is concentrated under reduced pressure, direct column chromatography for separation (V (MeOH)/V (DCM) brown solid (40mg, 55%)=1/10), is obtained.
MS-ESI:(ESI,pos.ion)m/z：351.2[M+1]+
Step 5) 1- (4- (6- (2- (2- oxa- -6- azepine spiroheptane -6- bases) ethyoxyl) imidazos [1,2-a] Pyridine -2- bases) phenyl) -3- (5 (tert-butyl group) isoxazole -3- bases) urea
By 4- (6- (2- (2- oxa- -6- azepine spiroheptane -6- bases) ethyoxyl)-imidazo [1,2-a] pyridine -2- Base) aniline (140mg, 0.40mmol) is dissolved in DCM (20mL), sequentially add triethylamine (0.6mL, 4mmol) and phenyl (5- (uncles Butyl) isoxazole -3- bases) carbamate (0.21g, 0.81mmol), solution heating reflux reaction 4h, it is concentrated under reduced pressure, direct post Chromatography (V (MeOH)/V (DCM)=1/10), obtains brown solid (80mg, 39%).
MS-ESI:(ESI,pos.ion)m/z：517.3[M+1]+
1H NMR(600MHz,CD3OD) δ 8.12 (d, J=2.0Hz, 1H), 8.09 (s, 1H), 7.90-7.83 (m, 2H), 7.57 (d, J=8.7Hz, 2H), 7.47 (d, J=9.7Hz, 2H), 7.38 (t, J=8.4Hz, 1H), 7.14 (dd, J=9.7, 2.3Hz, 1H), 6.43 (s, 1H), 4.57 (s, 4H), 4.06 (t, J=5.1Hz, 2H), 3.69 (s, 4H), 3.00 (dd, J= 11.0,6.0Hz,2H),1.38(s,9H).
Embodiment 9-23
Using suitable initiation material, embodiment 9-23 obtains according to embodiment 1-7 synthetic method：
Embodiment 24-34
Using suitable initiation material, embodiment 24-34 obtains according to the synthetic method of embodiment 8：
Embodiment 35FLT3 kinase inhibition assays
Experimental method：
Representative implication of being abridged in following experiments is as follows：
HEPES：Hydroxyethyl piperazine second thiosulfonic acid；Brij-35：Brij-35；DTT：Dithiothreitol (DTT)； EDTA：Ethylenediamine tetra-acetic acid；EGFR：Human epidermal growth factor acceptor；HER2：Human epidermal growth factor receptor 2；EGFR T790M：Human epidermal growth factor acceptor T790M mutant；Peptide FAM-P22：FAM-labeled peptide 22；ATP：Triphosphoric acid Adenosine monophosphate；DMSO：Dimethyl sulfoxide (DMSO)；Staurosporine：Staurosporine；Coating Reagent#3：#3 fruit glaze agents
1.1 × kinase buffer liquid and termination test buffer are prepared：
(1) 1 × be free of MnCl2Kinase buffer liquid (50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl2,2mM DTT)；
(2) test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating is terminated Reagent#3,50mM EDTA)。
2. the compound of test kinase prepares：Compound serial dilution
(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration.By the compound of the 100 μ L concentration Solution is transferred to a hole of 96 orifice plates.
(2) ratio diluted in 20 μ L original solutions with 60 μ L DMSO 10 concentration of diluted compounds successively.
(3) 100 μ L 100%DMSO solution are added in two emptying apertures, compareed as without compound control and without enzyme.
(4) prepare an intermediate plate, each concentration compounds of 10 μ L are transferred to intermediate plate from raw sheet respectively, and add 90 μ 1 × kinase buffer liquids of L, vibration mix 10 minutes.
(5) preparing experiment plate：Corresponding aperture transferase 45 μ L compound solutions are to corresponding 384 hole from the intermediate plate of 96 orifice plates In plate.
3. kinase reaction
(1) 2.5 × enzyme solutions are prepared：Enzyme is added in 1 × kinase buffer liquid.
(2) 2.5 × peptide solution is prepared：FAM-labeled peptide and ATP are added in 1 × kinase buffer liquid.
(3) 10 μ 2.5 × enzyme solutions of L are added to 384 holes containing the compound solution that 5 μ L DMSO contents are 10% In brassboard, it is incubated at room temperature 10 minutes.
(4) 10 2.5 × peptide solutions of μ L are added in 384 hole brassboards.
(5) kinase reaction and termination：28 degrees Celsius are incubated the corresponding time, add 25 μ L stop buffer terminating reactions.
4. DATA REASONING
Read data and collect.
5. curve matching
(1) data of copy and converted measurement
(2) inhibiting rate is converted to
Inhibiting rate=(maximum-sample value)/(maximum-minimum value) × 100；
" maximum " is DMSO control values；" minimum value " is without kinase control hole count value.
(3) enter data into corresponding analysis software Xlfit and draw IC50Value.
Experimental result is as follows：
IC50 value of the compounds of this invention of table 2 to flt3 kinase inhibitory activities
Embodiment is numbered FLT3(IC50,nM)
2 107
3 50
4 <3
Experiment conclusion：
As a result show, majority of compounds of the present invention has preferably external zymetology inhibitory activity, has very to flt3 kinases Good inhibitory action.
Experimental example 36MV4-11 cell inhibitory effects are tested
Experimental method：
Cell experiment condition：
1) plating cells：
Cell count is carried out with Vi-Cell XR cell counters.With corresponding culture medium adjust cell density to 1.5 × 105Individual/milliliter, 100 μ L cell suspensions are entered per hole kind to 96 white orifice plates of bottom transmural, the ultimate density of cell for 15000/ 100 μ L/ holes.At 37 DEG C, 5%CO2Cell pellet overnight is cultivated with the cell culture incubator of 95% humidity.
2) preparation and addition of compound:
I) preparation (10 concentration are diluted in DMSO) of compound plate：
Compound is configured to 10mM storing liquid with DMSO, the used time is diluted to 4mM, then is diluted to 0.4mM with DMSO, with 0.4mM is maximum concentration, with DMSO progressively 3 times of dilutions, obtains the compound of 10 concentration gradients.Staurosporine is as positive right According to medicine.
Ii) the addition of compound:
A. 0.5 μ L are pipetted from corresponding compound plate to add in the Tissue Culture Plate being incubated overnight.
B. at 37 degrees Celsius.It is incubated 72 hours in incubator.
2) detect and analyze
A. after compound is handled 72 hours, cellular morphology is observed under inverted microscope, the cell life in DMSO control wells Long status is normal, there are no contamination phenomenon.
B. Tissue Culture Plate holding chamber middle benefit gas is balanced 30 minutes.
C. the proliferation inhibition activity using CellTiter-Glo detection methods measure compound to MV-4-11 cells.
D. the experimental result obtained by record analysis.
The inhibitory activity that 3 representation compound of the present invention of table is bred to MV4-11 cells
Experiment conclusion
The result of table 3 shows that compound of the invention is respectively provided with preferable inhibitory activity to MV4-11 cells propagation.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the feature for combining the embodiment or example description It is contained at least one embodiment or example of the present invention.In this manual, need not to the schematic representation of above-mentioned term Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be any Combined in an appropriate manner in individual or multiple embodiments or example.In addition, in the case of not conflicting, the technology of this area Different embodiments or example and the feature of different embodiments or example described in this specification can be combined by personnel And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (22)

  1. A kind of 1. compound, wherein being the pharmaceutically acceptable of compound shown in the compound shown in formula (II) or formula (II) Salt,
    Wherein：
    Q and W are each independently CH；
    Each R1For hydrogen；
    L is the tert-butyl group；
    D is 1；
    N is 2 or 3；
    A is 4；
    E is one of heteroaryl groups that following subformula is formed：
    R is following subformula：
    Wherein,Represent that attachment point can be connected any attachable position on ring with molecule remainder；
    Wherein, each subformula representated by described E, can be independently monosubstituted by hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl It is or identical or different polysubstituted.
  2. 2. a kind of compound, there is the structure of one of：
    Or its pharmaceutically acceptable salt.
  3. 3. a kind of pharmaceutical composition, it includes the compound as described in claim any one of 1-2.
  4. 4. pharmaceutical composition according to claim 3, further comprising pharmaceutically acceptable carrier, excipient, dilution Agent, at least one of assistant agent and medium.
  5. 5. pharmaceutical composition according to claim 3, wherein further including additional therapeutic agent, the additional treatment Agent is chemotherapeutic agent, antiproliferative, anti-inflammatory reagent, immunodepressant, immunostimulant, for treating Atherosclerosis The medicine of change, for treating the medicine or combinations thereof of pulmonary fibrosis.
  6. 6. pharmaceutical composition according to claim 5, wherein the additional therapeutic agent is Chlorambucil, melphalan, ring Phosphamide, ifosfamide, busulfan, BCNU, lomustine, Streptozotocin, cis-platinum, carboplatin, oxaliplatin, Dacca Bar piperazine Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, fludarabine, Vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, TPT, Irinotecan, Etoposide, bent shellfish are replaced It is fixed, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, Ipsapirone, TAM, Flutamide, megestrol acetate, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon-' alpha ', Calciumlevofolinate, Sirolimus, everolimus, Afatinib, alisertib, amuvatinib, Ah pa replace Buddhist nun, Axitinib, bortezomib, ripple Relaxing and replace Buddhist nun, brivanib, cabozantinib, AZD2171, crenolanib, gram Zhuo replaces Buddhist nun, Da Lafeini, Dacomitinib, danusertib, Dasatinib, dovitinib, Tarceva, foretinib, ganetespib, Ji Fei For Buddhist nun, ibrutinib, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, Linsitinib, Masitinib, momelotinib, not for husky Buddhist nun, HKI-272, nilotinib, niraparib, Oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, Rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, Tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474, Veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab Vedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, Buddhist nun's trastuzumab, method wood difficult to understand Monoclonal antibody, Victibix, Rituximab, tositumomab, Herceptin or combinations thereof.
  7. 7. prepared by the pharmaceutical composition described in compound or claim any one of 3-6 described in claim any one of 1-2 Purposes in medicine, the medicine are used to preventing, handle, mitigate or treating proliferative diseases, autoimmune disease or inflammatory disease Disease.
  8. 8. purposes according to claim 7, wherein the proliferative diseases are breast cancer, lung cancer, liver cancer, prostate cancer, Cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, the cancer of central nervous system, atherosclerosis, pulmonary fibrosis, leukaemia, Lymph cancer, rheumatic disease, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, amyloid Become, solitary plasmacytoma, heavy chain disease, light chain disease, half molecule disease, Secondary cases benign monoclonal gammopathy, osteolytic Lesion, Sezary syndromes, infectious mononucleosis, acute histocytic increase disease, polyposis intestinalis, neuroendocrine Cell tumour, islet-cell tumour, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha, alimentary canal are disliked Property tumour, cervical carcinoma or orchioncus.
  9. 9. purposes according to claim 8, wherein described malignant tumor of digestive tract is gastrointestinal stromal tumors.
  10. 10. purposes according to claim 9, the gastrointestinal stromal tumors are colorectal cancer or stomach cancer.
  11. 11. purposes according to claim 10, the colorectal cancer is colon cancer or the carcinoma of the rectum.
  12. 12. purposes according to claim 8, wherein described lymph cancer is malignant lymphoma.
  13. 13. purposes according to claim 8, wherein the cancer of described central nervous system is brain tumor, glioblastoma, Myeloproliferative disease or neuroblastoma.
  14. 14. purposes according to claim 13, wherein described myeloproliferative disease refers to myeloma.
  15. 15. purposes according to claim 14, wherein described myeloma refers to Huppert's disease.
  16. 16. purposes according to claim 7, wherein the autoimmune disease is rheumatic arthritis, lupus is multiple Hardening, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease or Crohn's disease.
  17. 17. purposes according to claim 7, wherein the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, Hepatic sclerosis, cholecystitis or chronic inflammation.
  18. 18. purposes according to claim 8, wherein the leukaemia refers to acute myeloid leukaemia, the white blood of chronic Myelogenous Disease, the chronic myelogenous leukemia of mutation, ALL, cryoglobulinemia, chronic lymphocytic leukemia are former Hair property macroglobulinemia, monocytic leukemia or hairy cell leukemia；Wherein described lung cancer refers to ED-SCLC or non- ED-SCLC；Wherein described thyroid cancer refers to medullary carcinoma of thyroid gland；Wherein described lymph cancer refers to lymphoblastoma, non- Hodgkin lymphoma or Hodgkin lymphoma.
  19. 19. purposes according to claim 18, wherein the acute myeloid leukaemia refers to acute myelocytic leukemia； Wherein described primary macroglobulinaemia refers to primary macroglobulinaemia purpura.
  20. 20. purposes according to claim 16, wherein the lupus refers to systemic lupus.
  21. 21. purposes according to claim 17, wherein the hepatitis refers to chronic hepatitis.
  22. 22. according to the purposes described in claim any one of 7-21, cause wherein the disease is FLT3 mediations or FLT3-ITD Disease.
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