CN104513258B - Substituted urea derivative and its application in medicine - Google Patents
Substituted urea derivative and its application in medicine Download PDFInfo
- Publication number
- CN104513258B CN104513258B CN201410498181.5A CN201410498181A CN104513258B CN 104513258 B CN104513258 B CN 104513258B CN 201410498181 A CN201410498181 A CN 201410498181A CN 104513258 B CN104513258 B CN 104513258B
- Authority
- CN
- China
- Prior art keywords
- compound
- disease
- alkyl
- cancer
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CC(C)(C)c1cc(NC(Nc(cc2)ccc2-c(nc2*3)c[n]2-c2c3cc3OCCOCCOCCOc3c2)=N)n[o]1 Chemical compound CC(C)(C)c1cc(NC(Nc(cc2)ccc2-c(nc2*3)c[n]2-c2c3cc3OCCOCCOCCOc3c2)=N)n[o]1 0.000 description 1
- HXMUXPWXTJYZEG-UHFFFAOYSA-N CC(C)(C)c1cc(NC(Nc(cc2)ccc2-c2c[n](c(c([s]3)c4)nc(OCCC5)c4OCCCS5(=O)=O)c3n2)=O)n[o]1 Chemical compound CC(C)(C)c1cc(NC(Nc(cc2)ccc2-c2c[n](c(c([s]3)c4)nc(OCCC5)c4OCCCS5(=O)=O)c3n2)=O)n[o]1 HXMUXPWXTJYZEG-UHFFFAOYSA-N 0.000 description 1
- OBYVIBDTOCAXSN-YUMQZZPRSA-N CC[C@H](C)N[C@@H](C)CC Chemical compound CC[C@H](C)N[C@@H](C)CC OBYVIBDTOCAXSN-YUMQZZPRSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the substituted carbamide derivative as shown in formula (I) 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
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 Cell1 (2002):421-432；Weisberg etc., Cancer Cell1 (2002) 433-443；
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 are multiple
Kinase inhibitor is (referring to the .Blood such as Heidel, F. (2006) 107:293–300.).There are some researches show FLT3-ITD inhibitor
The role that plays a part of hindering inducing Incidence mechanism and in patient AML effective therapeutic purpose (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.
The content of the 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, a kind of substituted carbamide derivative provided by the invention, it is the chemical combination with the structure as shown in formula (I)
Thing, or the stereoisomer of the compound shown in formula (I), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvent
Compound, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
K rings are the heteroaryl groups of 5-6 members；
Q and W is each independently CH or N；
Each L independently is amino, nitro, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, hydroxyl
Base, fluorine, chlorine, bromine, iodine, alkyl-C (=O)-NH-, alkoxy, hydroxy alkyl or cyano 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；
E rings are bicyclic heteroaryl group or tricyclic heteroaryl group；In wherein described heteroaryl groups at least 2 it is miscellaneous
Atom, each hetero atom independently are O, S, NR4Or N；
Each R4It independently is hydrogen, haloalkyl, alkyl-C (=O)-, alkoxyalkyl, hydroxy alkyl, benzyl, cycloalkyl,
Heterocyclic radical or alkyl；
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each e independently is 0,1,2,3 or 4；
Each d independently is 1,2,3 or 4；
Each a independently is 0,1,2,3 or 4；
B is 2；
Wherein, described bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl groups ,-(O- (CH2)n)e- O- ,-
(CH2)n- C (=O)-, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, alkyl-C (=O)-NH-, alkane
Epoxide, hydroxy alkyl, alkyl-C (=O)-, alkoxyalkyl, benzyl, alkyl-S (=O)t- and described B rings, can be independent
Ground is by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyanogen
Base, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl are single
Substitution is identical or different polysubstituted.
In some embodiments, wherein, described E rings are 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, each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or
Hydroxyl C1-4Alkyl；
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Wherein, each subformula representated by described B rings and E rings, can be independently by hydrogen, aminoalkyl, aminoacyl
Base, 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)-, benzyl, cyclopropyl or phenyl monosubstituted or identical or different to take more
Generation.
In other embodiments, E rings of the present invention be following subformula formed heteroaryl groups it
One：
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Wherein, each subformula representated by described B rings and E rings, can be independently by hydrogen, aminoalkyl, aminoacyl
Base, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methyl
Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=
O)-, propyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the heteroaryl groups that the subformula that K rings of the present invention are as follows is formed
One of：
Each L independently is the tert-butyl group.
In some embodiments, wherein substituted carbamide derivative of the present invention, has the change as shown in formula (II)
Compound, or the stereoisomer shown in formula (II), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate,
Metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
Q and W are each independently CH；
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；
E rings are 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；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl
C1-4Alkyl；
R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Wherein, described each B rings and E rings, 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-, C1-4Alkyl-C
(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted；
D is 1；
L is the tert-butyl group.
In other embodiments, E rings of the present invention be following subformula formed heteroaryl groups it
One：
Each G independently is-O-；
Wherein, described each E rings can be independently by hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkane
Base amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or benzene
Base, monosubstituted or identical or different is polysubstituted.
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 pharmaceutically acceptable comprising its
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, this
A little additional therapeutic agents are chemotherapeutic 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 described additional therapeutic agent is benzene
Butyric acid mustargen (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), different ring phosphinylidyne
Amine (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea
Assistant rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin),
Dacarbazine (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 present invention relates to described compound or pharmaceutical composition prepare be used to preventing, handle, mitigate or
Purposes in the medicine for the treatment of patient's proliferative diseases, autoimmune disease or inflammatory disease.
In some embodiments, purposes of the present invention, wherein the proliferative diseases are acute myeloid leukaemias, slowly
Property myelogenous leukemia, gastrointestinal stromal tumors, 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 gland
Cancer, carcinoma of urinary bladder, kidney, brain tumor, CNS (central nervous system) cancer, glioblastoma, myeloproliferative disease, Atherosclerosis
Change, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, it is papular glutinous
Proteinose, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease,
Malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia are primary
Property macroglobulinemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, it is non-suddenly
Strange golden lymthoma, Sezary syndromes, infectious mononucleosis, acute histocytic increase disease, Hodgkin lymphoma,
Hairy cell leukemia, colon cancer, the carcinoma of the rectum, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell swell
Knurl, islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha,
Malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus or myeloma.
In some embodiments, purposes of the present invention, wherein the autoimmune disease is rheumatic arthritis, wolf
Sore, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein described inflammatory disease refers to diverticulitis, colitis,
Pancreatitis, hepatitis, chronic hepatitis, hepatic sclerosis, cholecystitis or chronic inflammation.
In some embodiments, purposes of the present invention, cause wherein the disease is FLT3 mediations or FLT3-ITD
Disease.
On the other hand, the present invention relates to described compound or pharmaceutical composition come prepare be used for prevent, handle, treat or
Mitigate the method for patient's proliferative diseases, autoimmune disease or inflammatory disease, its method includes and given the infection or disease
Patient's compound as described in the present invention or pharmaceutical composition of the present invention effective therapeutic dose.
In some embodiments, method of the present invention, wherein the disease is that FLT3 is kinase mediated or FLT3-ITD
Disease caused by kinases.
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) or formula (II) compound or its pharmacy
Application of the upper acceptable salt in the disease agent for preparing regulation FLT3 mediations, particularly comprising the institute for giving therapeutically effective amount
State formula (I) or formula (II) compound 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.
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.
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.
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- can be had by an alkyl-substituted situation, wherein alkyl
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 that acyl group (- C (=O) -) can be by an alkyl-substituted situation, 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 " 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 " 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 ", " heteroaryl groups " are used interchangeably here, can be used alone or as " heteroaryl alkane
A part for base " or " heteroarylalkoxy ", all referring to monocyclic, bicyclic, three rings or tetracyclic ring system, wherein, bicyclic heteroaryl
Group, tricyclic heteroaryl group or four heteroaryl group systems are cyclic in the form of condensing.Wherein, heteroaryl groups system
It is armaticity, one or more atoms are substituted that (hetero atom is selected from N, O, P, S, in this S by hetero atom individually optionally on ring
Or P optionally substitutes to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group).Heteroaryl system can be any
It is connected on hetero atom or carbon atom in main structure so as to form stable compound.Heteroaryl system group can be 3-7
Original is molecular monocyclic, or 7-10 former molecular bicyclic, or 10-15 former molecular three ring.With 7-10 atom
It is bicyclic 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 heteroaryl groups can be 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, alkylamino, alkylthio group, haloalkoxy
Base, 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, heteroaryl can be monovalent radical
Group or divalent group (that is, inferior heteroaryl).
Other embodiment is that heteroaryl system (including heteroaryl, heteroaryl groups) includes example below, but and unlimited
In these examples：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls,
4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals,
2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazine
Base (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazoles
Base and 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, decahydro indyl, decahydro isoindolyl,
Oxazolidinedione base, oxazolidine base, oxazole and pyridine radicals, oxazolyl, Oxyranyle, embedding two pyridyl of tea, phenanthridinyl, it is luxuriant and rich with fragrance around
Quinoline base, phenarsazine base, phenazinyl, phenothiazinyl , phenoxazine groups, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoline
Evil quinoline bases, thio-phenyl, triazine radical, 2H- pyrrolo-es [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2,3] oxazole is 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] pyrrole
Piperidinyl, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridine radicals, pyrazolo [2 ', 1 ':2,3] thiazole simultaneously [4,5-b] pyrazine
Base, 1H- benzos [4,5] thieno [2,3-d] imidazole radicals, 1- methyl isophthalic acid H- benzos [4,5] thieno [2,3-d] imidazole radicals, miaow
Azoles simultaneously [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 heteroaryl group ", " tricyclic heteroaryl group " system are cyclic in the form of condensing.Wherein, heteroaryl
Group system is armaticity, on ring one or more atoms substituted individually optionally by hetero atom (hetero atom is selected from N, O,
P, S, optionally substituted to obtain picture SO, SO by one or more oxygen atoms in this S or P2, PO, PO2Group).Heteroaryl system
It can be connected on any hetero atom or carbon atom in main structure so as to form stable compound.Heteroaryl system group can
To be 7-10 former molecular bicyclic, or 10-15 molecular three ring of original.Can be two with 7-10 the bicyclic of atom
Ring [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 heteroaryl groups can be substituted or non-substituted, and wherein substituent can be with
It is, but is 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 is miscellaneous
Aryl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base, alkyl-(C=O)-, benzyl, cyclopropyl, benzene
Base, methyl-(C=O) NH- or alkoxyalkyl etc..Depending on structure, " bicyclic heteroaryl group ", " tricyclic heteroaryl group "
Can be monoradical or divalent group (that is, " sub- bicyclic heteroaryl ", " sub- tricyclic heteroaryl ").
Other embodiment is that heteroaryl system includes example below, but is not limited to these examples：Benzo [d] thiazole-
2- bases, imidazo [1,5-a] pyridine -6- bases, benzimidazolyl, benzoxazolyl, 1,8- phthalazinyl, benzothienyl,
Indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinoline), tetralyl, benzo pyrrole
Oxazolyl, acridinyl, benzimidazolyl, benzindole base, Ben Bing Yi oxazinyls, benzo [4,6] imidazo [1,2-a] pyridine radicals,
Benzo [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, aphthofurans base, diazosulfide base, benzo thio-phenyl, benzo
Triazolyl, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, B-carboline base, carbazyl, adjacent phenodiazine
Miscellaneous naphthyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizine base, indyl, different benzo thiophene
Uh base, iso-dihydro-indole-group, isoquinolyl, naphthyridines base, decahydro indyl, decahydro isoindolyl , oxazoles and pyridine radicals , oxazoles
Base, embedding two pyridyl of tea, phenanthridinyl, phenanthroline base, 2H- pyrrolo-es [3,4-c] pyridine radicals, pyrazolo [2 ', 1 ':2,3] oxazole
And [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole is simultaneously
[4,5-b] pyridine radicals, imidazo [2 ', 1 ':2,3] thiazole 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] miaow
Oxazolyl, imidazo [2', 1':2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzos [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] sulphur azepine
Zhuo Ji 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..
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, 1,2,3,4- tetrahydro isoquinolyls, 1,2,6- thiadiazine alkane 1,1- dioxy -2- bases, hexahydro -2H-
[1,4] dioxin [2,3-c] pyrrole radicals, 1,1- titanium dioxide thio-morpholinyls, 2,3,3a, 7a- tetrahydrochysene -1H- isoindolyls, different Yin
Diindyl quinoline base, 1,2,3,4- tetrahydric quinoline groups, N- pyridine radicals urea, dioxolanyl, dihydro pyrazine base, dihydropyridine base, dihydro
Pyrazolyl, dihydro-pyrimidin base, pyrrolin base, 1,4- dithiane base, morpholinyl, decahydro indyl, decahydro isoindolyl, piperazine
Base, piperidyl, pteridyl, purine radicals and pyrazinyl.And the heterocyclic radical can be substituted or non-substituted, wherein 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..Such as 1- picolines -2 (1H) -one, hexamethylene -2,4- dienone
Base, 2,6- dimethyl-purine base 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, and benzyl (benzyl) is right
Methylphenylethyl, 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, formamido (CH3C (=O)
NH-), acetamido (C2H5C (=O) NH-) 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 y 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
L and structural formula m each G between the two specific option is unaffected from each other, meanwhile, in same structure formula, such as formula l, multiple G
Specific option it is unaffected between each other；Multiple n specific option is unaffected between each other；Multiple n specific option phase
It is unaffected between mutually；Or as formula m, multiple G specific option are unaffected from each other；Multiple n specific option mutually it
Between it is unaffected.
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 or formula (II) compound can form internal hydrolyzable ester.This
The ester of sample is the pharmaceutically acceptable ester that hydrolysis produces parent alcohol for example in human or animal's body.Formula (I) containing hydroxyl or
The group of hydrolyzable ester includes, but not limited to phosphate, acetoxymethoxy, 2,2- diformazans in formula (II) compound body
Base propionyloxy methoxyl group, alkanoyl, benzoyl, the acyl group of benzene first and second, alkoxy carbonyl, dialkyl 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) or formula (II) compound bag may be present in compound
Include all such forms.To avoid feeling uncertain, when compound with one of several geometric isomers or dynamic isomer exist and only
When specifically describing or showing a kind of, it is clear that all other form is included in formula (I) or formula (II).
Term " prodrug " used in the present invention, represent a compound and be converted into vivo shown in formula (I) or formula (II)
Compound.Such conversion is hydrolyzed or is precursor structure through enzymatic conversion in blood or tissue in blood by pro-drug
Influence.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester as pro-drug in existing invention
Class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as the present invention
In a compound include hydroxyl, you can be acylated to obtain the compound of prodrug form.Other pro-drugs
Form includes phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug
Complete discuss 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
The quaternary ammonium salt that the compound for the group for intending contemplating any included N is formed.Water-soluble or oil-soluble or dispersion product can be with
Obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt
Further comprise appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide,
Carboxylate, 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, the reduction of N- methyl
Aminoglucose, procaine, N- benzyl-1-phenylethylamines, the p- chlorobenzyl -2- pyrrolidines -1 ' of 1--ylmethyl-benzimidazole, diethylamine and
Other alkylamines, 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
The description of group in general 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 (referring to Biochem.1972,11：942-944).
The compounds of this invention is described in detail
On the one hand, a kind of substituted carbamide derivative provided by the invention, it is the chemical combination with the structure as shown in formula (I)
Thing, or the stereoisomer of the compound shown in formula (I), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvent
Compound, metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
K rings are the heteroaryl groups of 5-6 members；
Q and W is each independently CH or N；
Each L independently is amino, nitro, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, hydroxyl
Base, fluorine, chlorine, bromine, iodine, alkyl-C (=O)-NH-, alkoxy, hydroxy alkyl or cyano 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；
E rings are bicyclic heteroaryl group or tricyclic heteroaryl group；In wherein described heteroaryl groups at least 2 it is miscellaneous
Atom, each hetero atom independently are O, S, NR4Or N；
Each R4It independently is hydrogen, haloalkyl, alkyl-C (=O)-, alkoxyalkyl, hydroxy alkyl, benzyl, cycloalkyl,
Heterocyclic radical or alkyl；
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Each n independently is 1,2,3 or 4；
Each t independently is 0,1 or 2；
Each e independently is 0,1,2,3 or 4；
Each d independently is 1,2,3 or 4；
Each a independently is 0,1,2,3 or 4；
B is 2；
Wherein, described bicyclic heteroaryl group, tricyclic heteroaryl group, heteroaryl groups ,-(O- (CH2)n)e- O- ,-
(CH2)n- C (=O)-, alkylthio group, alkyl, cycloalkyl, heterocyclic radical, haloalkyl, alkyl amino, alkyl-C (=O)-NH-, alkane
Epoxide, hydroxy alkyl, alkyl-C (=O)-, alkoxyalkyl, benzyl, alkyl-S (=O)t- and described B rings, can be independent
Ground is by hydrogen, aminoalkyl, aminoacyl, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkyl amino, hydroxyl, cyanogen
Base, nitro, amino, methyl-C (=O)-NH-, oxo (=O), C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or phenyl are single
Substitution is identical or different polysubstituted.
In some embodiments, wherein, described E rings are 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, each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or
Hydroxyl C1-4Alkyl；
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Wherein, each subformula representated by described B rings and E rings, can be independently by hydrogen, aminoalkyl, aminoacyl
Base, 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)-, benzyl, cyclopropyl or phenyl monosubstituted or identical or different to take more
Generation.
In other embodiments, E rings of the present invention be following subformula formed heteroaryl groups it
One：
The J on two adjacent carbon atoms on E rings can be coupled carbon atom form B rings, described B rings and E together
Ring can form following subformula：
Wherein, R2For a key ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Wherein, each subformula representated by described B rings and E rings, can be independently by hydrogen, aminoalkyl, aminoacyl
Base, fluorine, chlorine, bromine, iodine, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl group, isopropyl, dimethylamino, methyl
Amino, diethylamino, ethylamino, hydroxyl, cyano group, nitro, oxo (=O), methyl-C (=O)-, ethyl group-C (=
O)-, propyl-C (=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted.
In some embodiments, the heteroaryl groups that the subformula that K rings of the present invention are as follows is formed
One of：
Each L independently is the tert-butyl group.
In some embodiments, wherein substituted carbamide derivative of the present invention, has the change as shown in formula (II)
Compound, or the stereoisomer shown in formula (II), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate,
Metabolite, ester, pharmaceutically acceptable salt or its prodrug,
Wherein：
Q and W are each independently CH；
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；
E rings are 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；
Each R4It independently is H, C1-4Alkyl, C3-10Cycloalkyl, C2-10Heterocyclylalkyl, C1-6Alkoxy C1-6Alkyl or hydroxyl
C1-4Alkyl；
R2For a key ,-NR3- ,-O- ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- ,-S- ,-S (=O)t- ,-C (=O)-or-(CH2)n- C (=O)-；
Each R3It independently is hydrogen or C1-4Alkyl；
Wherein, described each B rings and E rings, 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-, C1-4Alkyl-C
(=O)-, benzyl, cyclopropyl or phenyl, monosubstituted or identical or different is polysubstituted；
D is 1；
L is the tert-butyl group.
In other embodiments, E rings of the present invention be following subformula formed heteroaryl groups it
One：
Each G independently is-O-；
Wherein, described each E rings can be independently by hydrogen, fluorine, chlorine, bromine, iodine, C1-4Haloalkyl, C1-4Alkyl, C1-4Alkane
Base amino, hydroxyl, cyano group, nitro, amino, methyl-C (=O)-NH-, C1-4Alkyl-C (=O)-, benzyl, cyclopropyl or benzene
Base, monosubstituted or identical or different is polysubstituted.
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 pharmaceutically acceptable comprising its
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, this
A little additional therapeutic agents are chemotherapeutic 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 described additional therapeutic agent is benzene
Butyric acid mustargen (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), different ring phosphinylidyne
Amine (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea
Assistant rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin),
Dacarbazine (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 present invention relates to described compound or pharmaceutical composition prepare be used to preventing, handle, mitigate or
Purposes in the medicine for the treatment of patient's proliferative diseases, autoimmune disease or inflammatory disease.
In some embodiments, purposes of the present invention, wherein the proliferative diseases are acute myeloid leukaemias, slowly
Property myelogenous leukemia, gastrointestinal stromal tumors, 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 gland
Cancer, carcinoma of urinary bladder, kidney, brain tumor, CNS (central nervous system) cancer, glioblastoma, myeloproliferative disease, Atherosclerosis
Change, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic disease, cryoglobulinemia, non-lymphoreticular system tumour, it is papular glutinous
Proteinose, familial splenic anemia, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease,
Malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia are primary
Property macroglobulinemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, it is non-suddenly
Strange golden lymthoma, Sezary syndromes, infectious mononucleosis, acute histocytic increase disease, Hodgkin lymphoma,
Hairy cell leukemia, colon cancer, the carcinoma of the rectum, polyposis intestinalis, ED-SCLC, neuroblastoma, neuroendocrine cell swell
Knurl, islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, oophoroma, G. cephalantha,
Malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus or myeloma.
In some embodiments, purposes of the present invention, wherein the autoimmune disease is rheumatic arthritis, wolf
Sore, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease, Crohn's disease or systemic lupus.
In some embodiments, purposes of the present invention, wherein described inflammatory disease refers to diverticulitis, colitis,
Pancreatitis, hepatitis, chronic hepatitis, hepatic sclerosis, cholecystitis or chronic inflammation.
In some embodiments, purposes of the present invention, cause wherein the disease is FLT3 mediations or FLT3-ITD
Disease.
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 be used for prepare or purify formula (I) or formula (II) compound intermediate formula (I) or formula (II) compound separation
Enantiomter salt, but be 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) or formula (II) is changed
Receptible salt or its pro-drug in compound, hydrate, solvate, isomers or physiology/pharmacy, the present invention listed by
Compound, or embodiment 1-14 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.The combination of the present invention
Thing can be used for the application for preparing the medicine for preventing, handle, treating or alleviating protein kinase mediated disease.The medicine group of the present invention
Application of the compound as FLT3 kinases or FLT3-ITD kinase inhibitors in medicament is prepared.
The pharmaceutical composition of the present invention, it includes formula (I) or formula (II) compound and its pharmaceutically acceptable carrier.Its
In, formula (I) or formula (II) compound can also be combined into pharmacy composite with the compound of second of therapeutic activity.The system used
Drug carrier 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：Syrup, peanut oil, olive oil, water
Deng.The example of gaseous carrier includes：Carbon dioxide and/or nitrogen.Equally, carrier or diluent can include disclosed in document
Time delay material, such as glycerin monostearate or distearin, individually or with wax use 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
The formula (I) or formula (II) compound of the present invention or its pharmaceutical composition can be used for treatment that there is unsuitable FLT3 to live
The situation of property such as Proliferative Disorders feature.Improperly the increase of FLT3 activity includes but is not limited to：In cell FLT3 expression increase or again
New constitutive activation caused by producing 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 formula (I) or formula (II) compound or its pharmaceutical composition of the present invention can be also used for as preparing following illness
Medicine, the medicine include but is not limited to this：By give patient's effective dose of the present invention formula (I) or formula (II) compound or
Person includes the pharmaceutical composition of formula (I) or formula (II) compound, preventing/treating patient proliferative diseases, situation or disorder.Institute
Stating illness includes：Cancer, especially hematopoietic system cancer, metastatic tumo(u)r, atherosclerosis 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.The formula (I) or formula (II) compound of the present invention, when in use including its pharmaceutically acceptable derivates.
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 the oral or parenteral formula (I) or formula (II) compound for giving the present invention.Here make
Term " parenteral " includes：Intravenous injection, intramuscular injection or Intraperitoneal medication.Parenteral is generally preferably subcutaneous and flesh
Inner injecting and administering form.The present invention can also by hypodermic injection, collunarium, in rectum, percutaneous or intravaginal give the present invention's
Formula (I) or formula (II) compound.
The formula (I) or formula (II) compound of the present invention or its pharmaceutical composition can also be administered by " suction "." suction "
Refer to nasal cavity and oral inhalation administration.The dosage forms of this administration such as aerosol or metered dose inhaler can be by general technology systems
.
The preparation and administration of the compounds of this invention and pharmaceutical composition
Multi-medicament formulation can be made in the formula (I) or formula (II) compound of the present invention or its pharmaceutical composition.If make
With oral solid formulation, can be prepared into：The forms such as tablet, hard shell capsules, lozenge, lozenge, drops, lotion.The amount of solid carrier can
It is very different, but typically from 0.025mg or so to about 1g.If oral administration is liquid dosage form, formulation is typically prepared
Such as：Syrup, emulsion, soft capsule, suspension or solution form.When using intravenous dosage forms, medicine can be solid or liquid shape
Formula, and can be made into direct administration or be administered after being adapted to restructuring.In Topical dosage forms are also included within, the example of Topical dosage forms
Such as：Solid, liquid and semisolid.Solid includes gumming agent, application etc..Liquid includes solution, suspension and emulsion.Semisolid bag
Include emulsifiable paste, ointment and gel etc..
The certain chemical combination selected by of formula (I) or formula (II) compound or the amount of its pharmaceutical composition local application of the present invention
Thing, character and the order of severity change and change, can also be weighed according to the tailoring of doctor different and different.The formula (I) of the present invention
It is excellent or formula (II) compound local application amount is representational from the paramount about 2.0g of low about 0.01mg, is administered one to four time within one day
Administration one in one day is selected to twice.Active component for being locally administered can include from about 0.001% or so 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 DEG C 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%), benzene
Prick oronain (0.01%) and chlorhexidine (0.01%).Suitable solvent for preparing oil solution includes：Glycerine, Diluted Alcohol and the third two
Alcohol.
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 shown in the definition of substituent such as formula (I) or formula (II).Following reaction scheme and embodiment are used to further lift
Example explanation present disclosure.
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 Aldrich Chemical 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)
Agilent6120 series LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detector applications
In analysis, 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
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatogram (HPLC), 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：
MeCN,CH3CN acetonitriles
CHCl3Chloroform
CDC13Deuterochloroform
DMF N,N-dimethylformamides
d6- DMSO deuterated dimethyl sulfoxides
EtOAc ethyl acetate
CH3COOH acetic acid
KSCN potassium rhodanates
Br2Bromine
MeOH,CH3OH methanol
MeI iodomethane
CH2Cl2, DCM dichloromethane
NMP 1-METHYLPYRROLIDONEs
ML, ml milliliter
N2Nitrogen
Pd/C palladiums/carbon
PE petroleum ethers (60-90 DEG C)
RT rt room temperatures
Rt retention times
H2O water
Reaction scheme 1
Compound 9, it can be prepared by the method for reaction scheme 1, wherein a, R1, R2, E, G and n have such as the present invention
Described implication.In the basic conditions, cyclization obtains compound 3 for compound 1 and compound 2.Compound 3 is subjected to reduction reaction
Product 4 is obtained, subsequent compound 4 obtains compound 5 with rhodanate cyclization, after compound 5 is reacted with compound 6, by also
Original reaction, obtains compound 7, further obtains product 9 with the reaction of compound 8.
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- (12- crown ethers [2', 3':4,5] benzo [1,2-d] imidazo [2,
1-b] thiazol-2-yl) phenyl) urea
Step 1) 12- nitro benzo -12- crown ethers -4
Sequentially added in reaction bulb 4- Nitrocatechols (2.5g, 16.12mmol), potassium carbonate (8.91g,
64.56mmol) with DMF (300mL), after being heated to 80 DEG C, two p-methyl benzenesulfonic acid triglycol esters are slowly added into reaction bulb
DMF (50mL) solution of (8.45g, 18.62mmol), continue to keep 80 DEG C overnight.Reaction is finished, and the reaction solution of cooling is poured into
In the separatory funnel for filling 1M hydrochloric acid (200mL), DCM (200mL) extractions, liquid separation, organic layer anhydrous sodium sulfate drying are added
Afterwards, it is concentrated under reduced pressure, crosses post purifying (V (petroleum ether)/V (ethyl acetate)=3/1), obtain yellow solid 1.93g, yield is
44%.
LC-MS：270.1[M+1]+。
Step 2) 12- amino benzo -12- crown ethers -4
Sequentially added in reaction bulb 12- nitro benzo -12- crown ethers -4 (1.93g, 7.17mmol), ethanol (20mL) and
Pd/C (0.2g, 10%), mixture under hydrogen, is stirred overnight at room temperature.After detecting raw material reaction completely by MS, it is filtered to remove
After solid, be concentrated under reduced pressure filtrate, directly carries out in next step, obtaining dark brown liquid 1.84g, yield is>100%.
LC-MS：240.1[M+1]+。
Step 3) [1,2-d] thiazole -2- amino-phendioxin 2- crown ethers -4
Potassium rhodanide (2.73g, 28.09mmol), glacial acetic acid (30mL) and 12- aminobenzenes are sequentially added in reaction bulb
And glacial acetic acid (30mL) solution of -12- crown ethers -4 (1.6g, 6.69mmol), after stirring 15 minutes, bromine is then added dropwise under agitation
Glacial acetic acid (30mL) solution of plain (1.39g, 8.70mmol), then continue to stir 3.5h at room temperature.Solid is filtered to remove, is depressurized
Remove acetic acid, ammoniacal liquor is added in mixed liquor and adjusts pH value be 9 after, add ethyl acetate (200mL x3) extraction, anhydrous sodium sulfate is done
After dry, it is concentrated under reduced pressure, crosses silicagel column purifying (V (dichloromethane)/V (methanol)=20/1), obtain brown solid 1.37g, yield
For 69%.
LC-MS：297.0[M+1]+。
Step 4) 2- (4- nitrobenzophenones) -12- crown ethers [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazole
Sequentially added in reaction bulb [1,2-d] thiazole -2- amino-phendioxin 2- crown ethers -4 (1.37g, 4.62mmol),
The bromo- 4'- nitro-acetophenones (1.13g, 4.63mmol) of 2- and ethanol (20mL), mixture heated overnight at reflux.Mixed liquor cools down
To room temperature, then filter, a small amount of ethanol rinse of filter cake, be dried under reduced pressure, obtain yellow solid 0.61g, yield 30%.
LC-MS：442.0[M+1]+。
Step 5) 2- (4- aminophenyls) -12- crown ethers [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazole amine
2- (4- nitrobenzophenones) -12- crown ethers [2', 3' are sequentially added in reaction bulb:4,5] benzo [1,2-d] imidazo
[2,1-b] thiazole (0.61g, 1.39mmol), zinc powder (0.91g, 13.92mmol), ammonium chloride (0.30g, 5.55mmol) and second
Alcohol/water (30/7,37mL), heating reflux reaction 3 hours.Solid is filtered to remove, filtrate decompression adds unsaturated carbonate hydrogen after being evaporated
Sodium solution (50mL) and dichloromethane (100mL), dichloromethane (100mL x2) extract and separate, anhydrous sodium sulfate drying are organic
Phase, light yellow solid 0.18g, yield 32% are obtained after concentration.
LC-MS：412.2[M+1]-。
Step 6) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (12- crown ethers [2', 3':4,5] benzo [1,2-d] imidazoles
And [2,1-b] thiazol-2-yl) phenyl) urea
2- (4- aminophenyls) -12- crown ethers [2', 3' are sequentially added in reaction bulb:4,5] benzo [1,2-d] imidazo
[2,1-b] thiazole amine (0.18g, 0.44mmol), dry methylene chloride (5mL), phenyl (5- (tert-butyl group) isoxazole -3- bases) amino
Formic acid esters (0.13g, 0.49mmol) and DMAP (3mg, 0.02mmol), the dichloromethane of triethylamine (0.01mL) is added dropwise after stirring
(0.1mL) solution, heat 40 DEG C of backflows overnight.After removal of solvent under reduced pressure, post purifying (V (dichloromethane)/V (methanol)=20/ is crossed
1) light yellow solid 100mg, yield 39%, are obtained.
1H NMR(400MHz,d6-DMSO):δ9.54(s,1H),8.88(s,1H),8.55(s,1H),7.74-7.79(m,
4H), 7.51-7.53 (d, J=8.4Hz, 2H), 6.53 (s, 1H), 4.23 (s, 2H), 4.17 (s, 2H), 3.79 (s, 2H), 3.72
(s,2H),3.64(s,4H),1.30(s,9H)ppm.
LC-MS：578.3[M+1]+。
Embodiment 2：
1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (2,3- dihydros-[1,4]-dioxine simultaneously [2', 3':
4,5] benzene [1,2-d] imidazo [2,1-b] thiazole -8- bases) phenyl) urea
Step 1) 6,7- dihydros-[1,4] dioxine simultaneously [2', 3':4,5] benzo [1,2-d] thiazole -2- amine
2,3- dihydrobenzos [b] [1,4] dioxin -6- amine (300mg, 1.98mmol) is dissolved in CH3COOH (70mL), then
After adding KSCN (385mg, 3.96mmol), Br is added dropwise under condition of ice bath2(1mL), it is stirred overnight at room temperature, subtracts after being added dropwise to complete
Pressure concentration, residue addition buck is adjusted to PH=8, extracted with DCM, organic phase is washed with saturated sodium-chloride water solution (100mL)
Wash, anhydrous sodium sulfate drying, be concentrated under reduced pressure, rapid column chromatography separation (V (DCM)/V (MeOH)=40/1), obtain product
210mg, yield 50.8%.
MS-ESI:(ESI,pos.ion)m/z：209.0[M+1]+.
1H NMR(400MHz,d6-DMSO)δ:7.22 (s, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 4.20 (d, J=
1.1Hz,4H)ppm.
Bromo- 6- chlorine imidazo [1,2-b] pyridazine 8- (4- nitrobenzophenones) -2,3- dihydros-[1,4] dioxanes of step 2) 8-
Hexene simultaneously [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazole
By 6,7- dihydros-[1,4] dioxine simultaneously [2', 3':4,5] benzo [1,2-d] thiazole -2- amine (700mg,
3.36mmol) it is dissolved in CH3CN (30mL), 2- bromoacetophenones (1.64g, 6.72mmol) are added, heat 85 DEG C of back flow reaction 8h.
Reaction separates out a large amount of solids after terminating and directly filtered, CH3CN (20mL) is washed three times, rapid column chromatography separation (V (DCM)/V
(MeOH) white solid 820mg, yield 69.0%=10/1), are obtained.
MS-ESI:(ESI,pos.ion)m/z：353.9[M+1]+
Step 3) 4- (2,3- dihydros-[1,4] dioxine simultaneously [2', 3':4,5] benzo [1,2-d] imidazo [2,
1-b] thiazole -8- bases) aniline
By bromo- 6- chlorine imidazo [1,2-b] pyridazine 8- (4- nitrobenzophenones) -2,3- dihydros-[1,4] dioxines of 8-
And [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazole (700mg, 1.98mmol) is dissolved in methanol (90mL), adds
Water (30mL), after ammonium chloride (1.06g, 31.29mmol), and iron powder (0.876g, 15.65mmol), mixture is warming up to 80 DEG C
Back flow reaction 3h.After reaction terminates, decompression removes solvent, adds saturated nacl aqueous solution (50mL) that reaction, ethyl acetate is quenched
(500mL) is extracted, and organic phase washing (50mL), saturated nacl aqueous solution (50mL) is washed, anhydrous sodium sulfate drying, is concentrated under reduced pressure,
Residue column chromatography for separation (V (ethyl acetate)/V (petroleum ether)=1/5), obtains grease 450mg, yield 70.2%.
MS-ESI:(ESI,pos.ion)m/z：324.2[M+1]+
Step 4) 1- (5- (tert-butyl group) isoxazoles -3- (4- (2,3- dihydro-dioxine-[1,4] dioxa hexamethylenes
Alkene simultaneously [2', 3', 4,5] benzo [1,2-d] imidazo [2,1-b] thiazole -8- bases)-phenyl) urea
By 4- (2,3- dihydros-[1,4] dioxine simultaneously [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b]
Thiazole -8- bases) aniline (450mg, 1.39mmol) is dissolved in acetonitrile (120mL), it is anti-to be warming up to 85 DEG C of stirring reaction 8h, TLC monitorings
Should be complete, stop reaction, reaction solution is concentrated under reduced pressure, residue column chromatography for separation (V (DCM)/V (MeOH)=50/1), obtained white
Color solid 0.48g, yield 70.0%.
MS-ESI:(ESI,pos.ion)m/z：489.9[M+1]+
1H NMR(400MHz,d6- DMSO) δ 9.53 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.75 (d, J=
8.6Hz, 2H), 7.56 (d, J=1.6Hz, 2H), 7.51 (d, J=8.6Hz, 2H), 6.52 (s, 1H), 4.33 (dd, J=10.7,
4.7Hz,4H),1.30(s,9H).
Embodiment 3：
((8,9- dihydros -7H- [1,4] dislikes heptan because of simultaneously [2 ', 3 ' to 4- to 1- (5- (tert-butyl group) isoxazole -3- bases) -3-:4,5]
Benzo [1,2-d] imidazo [2,1-b] thiazol-2-yl) phenyl) urea
Step 1) 3,4- dihydro -2H- benzos [b] [1,4] benzodioxepin -7- amine
By 7- nitro -3,4- dihydro -2H- benzos [b] [Isosorbide-5-Nitrae] benzodioxepin (2.00g, 10.25mmol), iron powder
(2.87g, 51.26mmol) and ammonium chloride (5.54g, 102.50mmol) are placed in 500mL bottle with two necks, add 40mL water and
120mL ethanol, 85 degree of reaction 4h under mechanical agitation.Sand core funnel filters, concentrated solvent, ethyl acetate (200mL) extraction,
Anhydrous sodium sulfate drying, filtering, filtrate concentration, column chromatography for separation (V (petroleum ether)/V (ethyl acetate)=1/10), obtain canescence
Solid 1.26g, yield 74.4%.
MS-ESI:(ESI,pos.ion)m/z：166.15[M+1]+
Step 2) 7,8- dihydros -6H- [1,4] dislikes heptan because of simultaneously [2 ', 3 ':4,5] benzo [1,2-d] thiazole -2- amine
By 3,4- dihydro -2H- benzos [b] [1,4] benzodioxepin -7- amine (1.00g, 4.44mmol) and potassium rhodanide
(1.29g, 13.33mmol) is dissolved in 200mL acetic acid, and under condition of ice bath, the acetic acid of bromine (0.23mL, 4.44mmol) is added dropwise
(200mL) solution, is added dropwise, and room temperature reaction is overnight.After concentrated solvent, 1mol/L sodium hydroxide solutions regulation solution is added dropwise
PH=9, ethyl acetate (500mL) extraction, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, column chromatography for separation (V
(MeOH)/V (DCM)=1/50), obtain faint yellow solid 650mg, yield 65.87%.
MS-ESI:(ESI,pos.ion)m/z：223.20[M+1]+
1H NMR(400MHz,d6-DMSO)：δ7.33(s,2H),7.28(s,1H),6.93(s,1H),4.11–4.01(m,
4H),2.11–2.00(m,2H).
The heptan of step 3) 2- (4- nitrobenzophenones) -8,9- dihydros -7H- [1,4] two is because of simultaneously [2 ', 3 ':4,5] benzo [2,1-d]
Imidazo [2,1-b] thiazole
7,8- dihydros -6H- [1,4] is disliked into heptan because of simultaneously [2 ', 3 ':4,5] benzo [1,2-d] thiazole -2- amine (350mg,
1.58mmol) it is dissolved in acetonitrile (50mL), 85 degree of reaction 5h, has big with 4 '-nitro-acetophenone of 2- bromines (769mg, 3.15mmol)
Measure yellow solid to separate out, filtering, filter cake is beaten with methanol (15mL), is filtered again, filter cake vacuum drying, obtains yellow solid
260mg, yield 44.94%.
MS-ESI:(ESI,pos.ion)m/z：368.20[M+1]+
(8,9- dihydros -7H- [1,4] dislikes heptan because of simultaneously [2 ', 3 ' to step 4) 4-:4,5] benzo [2,1-d] imidazo [2,1-b]
Thiazol-2-yl) aniline
By the heptan of 2- (4- nitrobenzophenones) -8,9- dihydros -7H- [1,4] two because of simultaneously [2 ', 3 ':4,5] benzo [2,1-d] imidazoles
And [2,1-b] thiazole (260mg, 0.71mmol), iron powder (0.20g, 3.54mmol) and ammonium chloride (0.38g, 7.08mmol) are put
In 100mL single port bottles, 10mL water and 30mL ethanol are added, solution reacts 4h, filtering, filtrate decompression concentration, acetic acid in 85 degree
Ethyl ester (300mL) extracts, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, column chromatography for separation (V (MeOH)/V (DCM)=
1/50) yellow solid 176mg, yield 73.71%, are obtained.
MS-ESI:(ESI,pos.ion)m/z：338.20[M+1]+
1H NMR(400MHz,d6- DMSO) δ 8.33 (s, 1H), 7.65 (d, J=7.9Hz, 2H), 7.49 (d, J=8.4Hz,
2H), 6.60 (d, J=8.4Hz, 2H), 5.18 (s, 2H), 4.19 (dt, J=17.5,5.2Hz, 4H), 2.20-2.12 (m, 2H)
Step 5) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (8,9- dihydros -7H- [1,4] dislike heptan because simultaneously [2 ',
3’:4,5] benzo [1,2-d] imidazo [2,1-b] thiazol-2-yl) phenyl) urea
By 4-, (8,9- dihydros -7H- [1,4] dislikes heptan because of simultaneously [2 ', 3 ':4,5] benzo [2,1-d] imidazo [2,1-b] thiophene
Azoles -2- bases) aniline (170mg, 0.50mmol), phenyl (5- (tert-butyl group) isoxazole -3- bases) t-butyl carbamate (262mg,
1.01mmol) it is dissolved in 10mL acetonitriles, triethylamine (0.21mL, 1.51mmol) is added dropwise under stirring condition, solution is in 85 degree of reactions
Overnight, there is pale solid precipitation after cooling, filter, the mashing of filter cake methanol, filter again, obtain pale solid 93mg, yield
37.83%.
MS-ESI:(ESI,pos.ion)m/z：504.05[M+1]+
1H NMR(400MHz,d6- DMSO) δ 9.53 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 7.76 (d, J=
8.4Hz, 2H), 7.68 (s, 2H), 7.52 (d, J=8.5Hz, 2H), 6.52 (s, 1H), 4.20 (dt, J=17.4,4.7Hz,
4H),2.20–2.13(m,2H),1.30(s,9H).
Embodiment 4
((7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa cyclonoene is simultaneously by 4- by 1- (5- (tert-butyl group) isoxazole -3- bases) -3-
[2',3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazol-2-yl) phenyl) urea
Step 1) 9- nitro -2,3,5,6- tetrahydro benzos [b] [1,4,7] trioxa cyclonoene
4- Nitrocatechols (3.1g, 20mmol), potassium carbonate (8.30g, 60mmol) and DMF are sequentially added in reaction bulb
(300mL), after being heated to 80 DEG C, it is double (4- toluene sulfonic acides) that oxygen double (ethane -2,1- diyls) is slowly added into reaction bulb
DMF (50mL) solution of (8.3g, 20mmol), continue to keep 80 DEG C of stirring reactions to stay overnight.It is concentrated under reduced pressure, adds ethyl acetate
(300mL) dilutes, filtering, filtrate decompression concentration, direct column chromatography for separation (V (petroleum ether)/V (ethyl acetate)=3/1), obtains
Yellow solid 2.03g, yield 45%.
MS-ESI:(ESI,pos.ion)m/z：226.1[M+1]+
Step 2) 2,3,5,6- tetrahydro benzos [b] [1,4,7] trioxa cyclonoene -9- amine
9- nitro -2,3,5,6- tetrahydro benzos [b] [1,4,7] trioxa cyclonoene (2.03g, 9.0mmol) is dissolved in first
Alcohol (50mL), 10%Pd/C catalyst (0.2g) is added, solution pumping is taken a breath three times, the stirring reaction 6h under hydrogen ball pressure.
Filtering, filtrate decompression are concentrated to give product 1.67g, yield 95%, are directly used in and react in next step.
MS-ESI:(ESI,pos.ion)m/z：196.1[M+1]+
Step 3) 6,7,9,10- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3':4,5] benzo [1,2-d] thiazole-
2- amine
Potassium rhodanide (2.92g, 30mmol), glacial acetic acid (30mL) and 2,3,5,6- tetrahydrochysene benzene are sequentially added in reaction bulb
And glacial acetic acid (30mL) solution of [b] [Isosorbide-5-Nitrae, 7] trioxa cyclonoene -9- amine (1.67g, 8.55mmol), after stirring 15 minutes,
Then glacial acetic acid (30mL) solution of bromine (1.39g, 8.70mmol) is added dropwise under agitation, then continues to stir at room temperature
3.5h.Be filtered to remove solid, be removed under reduced pressure acetic acid, ammoniacal liquor is added in mixed liquor and adjusts pH value be 9 after, add ethyl acetate (200mL
X3) extract, after anhydrous sodium sulfate drying, be concentrated under reduced pressure, cross silicagel column purifying (V (dichloromethane)/V (methanol)=20/1), obtain
To brown solid 1.51g, yield 70%.
MS-ESI:(ESI,pos.ion)m/z：253.1[M+1]+
Step 4) 2- (4- nitrobenzophenones) -7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3':4,5]
Benzo [1,2-d] imidazo [2,1-b] thiazole
By 6,7,9,10- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3':4,5] benzo [1,2-d] thiazole -2- amine
(1.51g, 6.0mmol) is dissolved in ethanol (40mL), adds the bromo- 4'- nitro-acetophenones (1.50g, 6.0mmol) of 2-, solution heating
It is stirred at reflux reaction overnight.Solid is separated out after cooling, is filtered, a small amount of ethanol rinse of filter cake, is obtained yellow after vacuum drying and consolidate
Body 0.95g, yield 40%.
MS-ESI:(ESI,pos.ion)m/z：398.1[M+1]+
Step 5) 4- (7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3':4,5] benzo [1,2-d] miaow
Azoles simultaneously [2,1-b] thiazol-2-yl) aniline
By 2- (4- nitrobenzophenones) -7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3'：4,5] benzo
[1,2-d] imidazo [2,1-b] thiazole (0.95g, 2.39mmol) is dissolved in the in the mixed solvent of ethanol (30mL) and water (7mL),
Sequentially add zinc powder (0.39g, 6.0mmol) and ammonium chloride (0.53g, 10mmol), solution heating reflux reaction 3h.It is filtered to remove
Solid, saturated sodium bicarbonate solution (50mL), dichloromethane (100mL x2) extraction, anhydrous slufuric acid are added after filtrate decompression concentration
Sodium dries organic phase, and light yellow solid 0.61g, yield 70% are obtained after being concentrated under reduced pressure.
MS-ESI:(ESI,pos.ion)m/z：368.1[M+1]+
Step 6) 1- (5- (tert-butyl group) isoxazole -3- bases) -3- (4- (7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa ring
Nonene simultaneously [2', 3':4,5] benzo [1,2-d] imidazo [2,1-b] thiazol-2-yl) phenyl) urea
By 4- (7,8,10,11- tetrahydrochysenes-[1,4,7] trioxa cyclonoene simultaneously [2', 3':4,5] benzo [1,2-d] imidazo
[2,1-b] thiazol-2-yl) aniline (0.61g, 1.66mmol) is dissolved in acetonitrile (30mL), sequentially adding phenyl, (5- (tert-butyl group) is different
Azoles -3- bases) carbamate (1.30g, 5.0mmol) and triethylamine (2mL), solution heating reflux reaction 10h.It is concentrated under reduced pressure,
Direct column chromatography for separation (V (methanol)/V (dichloromethane)=1/20), obtains light yellow solid 0.44g, yield 50%.
MS-ESI:(ESI,pos.ion)m/z：534.2[M+1]+
1H NMR(400MHz,d6- DMSO) δ 9.53 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 7.76 (d, J=
8.4Hz, 2H), 7.68 (s, 2H), 7.52 (d, J=8.5Hz, 2H), 6.52 (s, 1H), 4.20 (dt, J=17.4,4.7Hz,
4H),2.25–2.06(m,4H),1.31(s,9H).
Embodiment 5-14
From suitable initiation material, embodiment 5-14 can be prepared according to embodiment 1-4 synthetic method.
Embodiment 15FLT3 kinase inhibiting activities
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) 1x is free of MnCl2Kinase buffer liquid (50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2,
2mM DTT)；
(2) test buffer (100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating are 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 L100%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 L1x kinase buffer liquids, 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) 2.5x enzyme solutions are prepared：Enzyme is added in 1x kinase buffer liquids.
(2) 2.5x peptide solutions are prepared：FAM-labeled peptide and ATP are added in 1x kinase buffer liquids.
(3) 10 μ L2.5x enzyme solutions are added to the 384 holes reality containing the compound solution that 5 μ L DMSO contents are 10%
Test in plate, be incubated at room temperature 10 minutes.
(4) 10 μ L2.5x peptide solutions are added in 384 hole brassboards.
(5) kinase reaction and termination：28 DEG C 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：
The FLT3 kinase inhibiting activities of the compounds of this invention of table 2
| Embodiment is numbered | FLT3(IC50,nM) |
| 1 | 49 |
| 4 | 9.9 |
Experiment conclusion：
As a result show, the compounds of this invention has preferably external zymetology inhibitory activity.
The proliferation inhibition activity of experimental example 16MV-4-11 cells
Experimental method：
Cytoactive detection
Cell experiment condition：
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.
The preparation and addition of compound:
1) 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 conducts
Positive control drug.
2) 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. it is incubated 72 hours in 37 DEG C of incubators.
Detection and analysis
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.
| Embodiment is numbered | MV4-11(IC50,nM) |
| 1 | 0.5 |
| 2 | 2.7 |
| 3 | 4.9 |
| 4 | 1.7 |
Experiment conclusion
As a result show, compound of the invention has preferable inhibitory activity to MV4-11 cells propagation.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (12)
1. a kind of compound as shown in formula (II), or the pharmaceutically acceptable salt shown in formula (II),
Wherein：
Q and W are each independently CH；
R1For hydrogen；
E rings are
Wherein, X, Y, Z, Z1, Z2And Z3It is each independently N or CH；
T is-O- or-S-；
Wherein, the X, Y, Z, T, Z on the E rings1, Z2And Z3It is hetero atom at least while to have two；
R2For key ,-S (=O)t- or-(O- (CH2)n)e-O-；
Each G independently is-O- or-(CH2)n- C (=O)-；
Each e is independently 0,1,2,3 or 4；
D is 1；
A is 1；
Each n is independently 1,2,3 or 4；L is the tert-butyl group.
2. compound according to claim 1, wherein
E rings are one of heteroaryl groups that following subformula is formed：
Each G independently is-O-.
3. compound according to claim 1, there is the structure of one of：
Or its pharmaceutically acceptable salt.
4. a kind of pharmaceutical composition, it includes the compound as described in claim 1-3 is any.
5. pharmaceutical composition according to claim 4, further dilute comprising its pharmaceutically acceptable carrier, excipient
Release agent, at least one of assistant agent and medium.
6. pharmaceutical composition according to claim 4, wherein further including additional therapeutic agent, these additional treatments
Agent is chemotherapeutic agent, antiproliferative, anti-inflammatory preparation, immunodepressant, immunostimulant, for treating Atherosclerosis
The medicine of change, for treating the medicine or combinations thereof of pulmonary fibrosis.
7. pharmaceutical composition according to claim 6, wherein described additional therapeutic agent is Chlorambucil, melphalan,
Endoxan, ifosfamide, busulfan, BCNU, lomustine, Streptozotocin, cis-platinum, carboplatin, oxaliplatin, reach
Carbazine Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, fluorine, which reaches, to be drawn
Shore, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, TPT, Irinotecan, Etoposide, bent shellfish
For fixed, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, Yi Sha
It is grand, TAM, Flutamide, megestrol acetate, prednisone, dexamethasone, methylprednisolone, Thalidomide, interferon-' alpha ', folinic acid
Calcium, sirolimus, everolimus, Afatinib, alisertib, amuvatinib, Ah pa replace Buddhist nun, and Axitinib, boron is for assistant
Rice, SKI-606, brivanib, cabozantinib, AZD2171, crenolanib, gram Zhuo replace Buddhist nun, dabrafenib,
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.
8. any described compounds of claim 1-3 or any described pharmaceutical compositions of claim 4-7 are preparing use
In prevention, treatment or mitigate purposes in the medicines of autologous patient immunological diseases, inflammatory disease or proliferative diseases.
9. purposes according to claim 8, wherein the proliferative diseases are acute myeloid leukaemia, the white blood of chronic Myelogenous
Disease, gastrointestinal stromal tumors, the chronic myelogenous leukemia (CML) of mutation, ALL (ALL), stomach cancer, mammary gland
Cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, CNS (central nervous system) cancer, evil
Property glioma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, rheumatic disease, cryoglobulinemia, non-lymphatic reticulation
It is system tumor, papular mucinosis, familial splenic anemia, amyloidosis, solitary plasmacytoma, heavy chain disease, light
Chain disease, chronic lymphocytic leukemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia, Secondary cases are benign
Monoclonal gamma globulin disease, osteolytic lesion, lymphoblastoma, NHL, Sezary syndromes, infectiousness
Monocytosis,mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, polyposis intestinalis, cellule lung
Cancer, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, melanoma, retinoblastoma, uterine cancer,
Oophoroma, G. cephalantha, malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma or orchioncus.
10. purposes according to claim 8, wherein the autoimmune disease is rheumatic arthritis, lupus is multiple
Hardening, thyroiditis, type i diabetes, sarcoidosis, inflammatory bowel disease or Crohn's disease.
11. purposes according to claim 8, wherein described inflammatory disease refers to diverticulitis, colitis, pancreatitis, liver
Scorching or cholecystitis.
12. purposes according to claim 8, wherein the disease be that FLT3 is kinase mediated or FLT3-ITD kinases caused by disease
Disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410498181.5A CN104513258B (en) | 2013-09-26 | 2014-09-25 | Substituted urea derivative and its application in medicine |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013104454352 | 2013-09-26 | ||
| CN201310445435 | 2013-09-26 | ||
| CN201410108087 | 2014-03-22 | ||
| CN2014101080874 | 2014-03-22 | ||
| CN201410498181.5A CN104513258B (en) | 2013-09-26 | 2014-09-25 | Substituted urea derivative and its application in medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104513258A CN104513258A (en) | 2015-04-15 |
| CN104513258B true CN104513258B (en) | 2018-04-03 |
Family
ID=52789157
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410498232.4A Active CN104513257B (en) | 2013-09-26 | 2014-09-25 | Substituted urea derivatives and application thereof in drugs |
| CN201410498181.5A Active CN104513258B (en) | 2013-09-26 | 2014-09-25 | Substituted urea derivative and its application in medicine |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410498232.4A Active CN104513257B (en) | 2013-09-26 | 2014-09-25 | Substituted urea derivatives and application thereof in drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN104513257B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008530B (en) * | 2016-07-24 | 2018-06-26 | 石家庄久正生物科技有限公司 | A kind of preparation method of ovarian cancer resistance medicament Rucaparib key intermediates |
| CN106831793B (en) * | 2017-01-25 | 2019-01-22 | 青岛大学附属医院 | A kind of synthesis technology for treating ovarian cancer Rucaparib intermediate |
| CN106831792B (en) * | 2017-01-25 | 2019-02-12 | 李绵利 | A kind of preparation method of PARP inhibitor Rucaparib intermediate |
| CN106749282B (en) * | 2017-01-25 | 2019-01-04 | 青岛市妇女儿童医院 | A kind of preparation method for treating ovarian cancer Rucaparib intermediate |
| CN110833554B (en) * | 2018-08-15 | 2022-03-08 | 广西梧州制药（集团）股份有限公司 | Use of pyrazolopyrimidine derivatives for the treatment of autoimmune thyroid disorders |
| WO2020142729A1 (en) * | 2019-01-04 | 2020-07-09 | BellBrook Labs | Inhibitors of cgas activity as therapeutic agents |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101448843A (en) * | 2006-03-17 | 2009-06-03 | 埃姆比特生物科学公司 | Imidazolothiazole compounds for the treatment of disease |
| CN101868465A (en) * | 2007-09-19 | 2010-10-20 | 埃姆比特生物科学公司 | Solid forms comprising n-(5-tert-butyl-isoxazol-3-yl)-n'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith |
| CN103172648A (en) * | 2011-12-20 | 2013-06-26 | 上海迪诺医药科技有限公司 | Tri-heterocyclic derivative, preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5686736B2 (en) * | 2008-11-06 | 2015-03-18 | アムビト ビオスシエンセス コルポラチオン | Imidazolothiazole compounds as protein kinase modulators |
| WO2011056764A1 (en) * | 2009-11-05 | 2011-05-12 | Ambit Biosciences Corp. | Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles |
-
2014
- 2014-09-25 CN CN201410498232.4A patent/CN104513257B/en active Active
- 2014-09-25 CN CN201410498181.5A patent/CN104513258B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101448843A (en) * | 2006-03-17 | 2009-06-03 | 埃姆比特生物科学公司 | Imidazolothiazole compounds for the treatment of disease |
| CN101868465A (en) * | 2007-09-19 | 2010-10-20 | 埃姆比特生物科学公司 | Solid forms comprising n-(5-tert-butyl-isoxazol-3-yl)-n'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith |
| CN103172648A (en) * | 2011-12-20 | 2013-06-26 | 上海迪诺医药科技有限公司 | Tri-heterocyclic derivative, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104513257B (en) | 2017-02-15 |
| CN104513258A (en) | 2015-04-15 |
| CN104513257A (en) | 2015-04-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105272930B (en) | Substituted urea derivative and its application in drug | |
| CN104513259B (en) | Substituted urea derivative and its application in medicine | |
| US11760753B2 (en) | Benzoxazepin oxazolidinone compounds and methods of use | |
| CN105294683B (en) | Compound of CDK type small molecular inhibitors and application thereof | |
| CN105294681B (en) | Compound of CDK type small molecular inhibitors and application thereof | |
| EP2364302B1 (en) | Triazine analogs and their use as therapeutic agents and diagnostic probes | |
| CN104513258B (en) | Substituted urea derivative and its application in medicine | |
| EP2958564B1 (en) | Heteroaromatic compounds as pi3 kinase modulators | |
| CN103304552B (en) | Substituted pyridine compounds and using method thereof and purposes | |
| CN104447701B (en) | Pyrazole derivatives and application thereof | |
| CN109729716B (en) | PI3K inhibitor combination | |
| CN103319468B (en) | The spiral shell dicyclic compound replaced and using method and purposes | |
| WO2013177092A1 (en) | Substituted alkynyl pyridine compounds and methods of use | |
| TWI684591B (en) | Substituted urea derivatives and pharmaceutical uses thereof | |
| CN105461709A (en) | Substituted carbamide derivative and applications thereof in drugs | |
| CN103387535B (en) | The alkynes yl pyridines compound replaced and using method and purposes | |
| BR112017023121B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, PROCESS FOR PREPARING A PHARMACEUTICAL COMPOSITION, KIT FOR THE THERAPEUTIC TREATMENT OF CANCER, AND USE OF A COMPOUND |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Substituted urea derivatives and application thereof in drugs Effective date of registration: 20200611 Granted publication date: 20180403 Pledgee: Zhuhai Huarun bank Limited by Share Ltd. Pledgor: SUNSHINE LAKE PHARMA Co.,Ltd. Registration number: Y2020980002961 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220930 Granted publication date: 20180403 Pledgee: Zhuhai Huarun bank Limited by Share Ltd. Pledgor: SUNSHINE LAKE PHARMA Co.,Ltd. Registration number: Y2020980002961 |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |